Can probiotics and prebiotics go viral?

Prof. Glenn Gibson, Food Microbial Sciences Unit, Department of Food and Nutritional Sciences, The University of Reading, UK

I usually think that psychics are pretty funny and are to be avoided, but what about this from Sylvia Browne published in 2008? “In around 2020 a severe pneumonia-like illness will spread throughout the globe, attacking the lungs and the bronchial tubes and resisting all known treatments.”

Let’s hope the latter few words of this prophesy are badly wrong but, eerily, we are now living through this prediction made 12 years ago. The coronavirus (COVID-19) pandemic has dramatically changed the world in a few weeks, how we are currently behaving and how we will behave in future. I am typing this in my office at the university and have seen just one other person all morning. Who thought you could self-isolate by coming to work? It is a bit like living in a science fiction film, but this is real and very serious. Everyone is worried about themselves, family, friends, food, way of life, travel, entertainment, jobs, finance, property, ability to exercise, the more vulnerable members of society and other major challenges (not to mention toilet rolls, hand gels, soap). If we think humans run the world – then microbes may well have their own valid claim on that!

What can we do? Wait for a vaccine — science is progressing remarkably quickly on that front and it is brilliant to see. But what for now? How may we help flatten the infection curve?

I’ve always thought that the way you deal with harmful microorganisms is to attack them with other microbes, the simplest form of germ warfare (either their direct antagonism, non-specific immune effects or metabolic products). I’ve also thought that the below work from Kiel in Germany is among the most impressive studies I have seen on probiotics:

Effect of Lactobacillus gasseri PA 16/8, Bifidobacterium longum SP 07/3, B. bifidum MF 20/5 on Common Cold Episodes: A Double Blind, Randomized, Controlled Trial (2005)

Other similar research then followed. In 2015, the Cochrane group looked at the totality of such evidence available for all probiotics (Probiotics for preventing acute upper respiratory tract infections). They concluded “Probiotics were found to be better than placebo in reducing the number of participants experiencing episodes of acute URTI by about 47% and the duration of an episode of acute URTI by about 1.89 days.”

These studies convinced me that gut bacteria could mediate activities outside of their normal habitat – amazing! The German study showing a quantifiably speedier recovery from flu (almost 2 days quicker on average) and fewer symptoms (ca. 20% less), in a placebo-controlled trial involving a large number of volunteers, opened up new views for me on what probiotics could do. I must admit that I have been recommending the product to everyone I know since the COVID-19 outbreak started. By the way, if the manufacturers see this blog and you have experienced sales increasing in the Reading area or North East England (where I am from) then I am unashamedly taking the credit!! I have also been recommending a prebiotic for improved gut health, but this is no surprise since it is a product my research group first developed in 2000 and worked upon in human intervention studies until 2017.

The plot thickened yesterday, when I was made aware of this article published a few weeks ago:

2019 Novel coronavirus infection and gastrointestinal tract

For the last couple of years, I have been lucky to have worked with one of the world’s leading campaigners Alan Barnard (more later). His summary on the above paper has been sent to the UK Government, other MPs and Lords and is as follows:

In the article, the authors say:

  • They have found, “the presence of viral nucleic acids in the faecal samples and anal swabs of patients with COVID-19.”
  • And states, “Numerous studies have shown that modulating gut microbiota can reduce enteritis and ventilator-associated pneumonia, and it can reverse certain side effects of antibiotics to avoid early influenza virus replication in lung epithelia.”
  • It suggests that, “Therefore, we speculate that COVID-19 may, to some extent, be related to the gut microbiota.” This is a similar activity to the SARS virus.
  • And says, “The Chinese government and first-line medical staffs accept the importance of the role of gut microbiota in COVID-19 infection.”
  • And concludes, “We speculate that probiotics may modulate the gut microbiota to alter the gastrointestinal symptoms favourably and may also protect the respiratory system.”

A representative of the Government has acknowledged that they are now aware of the research. I feel this is great news in having this at least on their radar screen and that the UK may consider it as part of the mixture of responses.

As we would expect, Gregor Reid is right on the case and published an excellent opinion piece yesterday: Can bacteria help humans fight COVID-19?

Gregor says, “there is a scientific basis for probiotics helping the respiratory tract against colds and flu, and right now we’re short on therapies for COVID-19. We’re only asking for people to consider this and maybe someone to instigate a quick study. If they can get a vaccine into testing by now in the US, someone should test a probiotic versus placebo.”

Then, there is this today: Coronavirus: Australian scientists map how immune system fights virus summarising research published in Nature Medicine, that showed people are recovering from the new virus like they would from the flu. “This is important because it is the first time where we are really understanding how our immune system fights novel coronavirus,” said co-author Prof Katherine Kedzierska. She also said, “It is really key now to understand what is lacking or different in patients who have died or who have really severe disease – so we can understand how to protect them.” Well, we know that indigenous gut bifidobacteria (strains of which are used as probiotics) do decrease with age and this possibly contributes to so-called “immunosenescence” with concomitant higher risk of acquiring, and dealing with, infections. Hence, great interest in probiotic and prebiotic use for the older adults in our societies, ever since the Crownalife EU funded research which ended in 2004 (by the way, my views on the effect of Brexit to UK science and society generally are not publishable…). But guess what? – two probiotic strains used in the German cold and flu trials cited above were bifidobacteria.

I know some cleverer people than I will rubbish all of this but, in my humbly subjective view, there are too many jigsaw pieces to ignore here and I will keep on recommending the probiotic and prebiotic products.

Back to Alan, here is his new effective and striking message on COVID-19, now rolled out all over the UK:

ISAPP is delighted to work with Alan, and he attended our Antwerp conference in 2019. Together we helped set up an All Party Parliamentary Group (APPG) on the microbiome chaired by the esteemed Julie Elliot MP (whom we approached because of her boundless energy but also because she is a Sunderland AFC fan – the unequivocal professional and personal seal of approval). As part of the APPG activities, we were very pleased to welcome Lords Taylor (of Holbeach) and Haworth (of Fisherfield) to our gut model laboratories in Reading 2 weeks ago. Both their Lordships were very positive about probiotics and prebiotics, promising to help propel the messages.

A further peer, Lord Stone of Blackheath, even went as far as mentioning ISAPP in a House of Lords debate on wellbeing held on March 12th. At the end of his speech, Lord Stone said:

 

“Finally, we are what we eat. Trillions of bacteria live in our guts. We know that these can be altered by diet to promote well-being. Again, there are thousands of published research studies showing how prebiotic and probiotic interventions can have positive effects on our well-being. They address coughs and colds, eczema, inflammatory bowel disease, bowel cancer, obesity and even mental illness. The International Scientific Association for Probiotics and Prebiotics brings together leading scientists in gut microbial research to enhance understanding in this area. As such, there are many useful resources available on its website. That would be another route to national well-being that the Minister might have the department examine, thereby increasing well-being and saving money and resources in the long term.”

Do these views apply to the COVID-19 outbreak, the world’s most serious and unprecedented issue of modern times? Obviously, there is no evidence that probiotics or prebiotics directly influence COVID-19 and we may never know if they will, but a quick benefit-to-risk thought makes recommendation of some a “no brainer” for me.

The science on gut microbiota and intestinal gas: Everything you wanted to know but didn’t want to ask

By Kristina Campbell, science and medical writer

Even on the days when you don’t eat a large meal of Boston baked beans, the inside of your intestines is a gas-generating factory. This serves a valuable purpose for the body when everything is working as it should, with gases being produced and eliminated through a complex set of physiological processes. But sometimes gas becomes a problem—and this is when it’s valuable to know not only what contributes to intestinal gas symptoms, but also how dietary adjustments can alleviate some of the problems.

Dr. Fernando Azpiroz, Chief of Gastrointestinal Research at the Vall d’Hebron Research Institute and Professor of Medicine, Autonomous University of Barcelona (Spain), is an expert in both the pathophysiology of the gas produced in the digestive tract and the clinical problems related to intestinal gas. Dr. Azpiroz is the author of a chapter on intestinal gas in the well-known textbook, Sleisenger and Fordtran’s Gastrointestinal and Liver Disease, which is now in its 10th edition. And for more than 20 years he has been conducting research on digestive tract function, intestinal gas, and the contributions of the gut microbiota.

ISAPP caught up with Dr. Azpiroz to ask him about everything you wanted to know—where intestinal gas comes from, when it becomes a problem, and the latest research on the dietary changes that can reduce symptoms of intestinal gas while keeping the gut microbiota intact.

In different parts of the digestive tract, where does intestinal gas come from?

For the most part, the gas in the digestive system comes from metabolic activities of the colonic microbiota.

In addition, some air enters the stomach during swallowing. Most of this air is eliminated by eructation (i.e. burping), so there is a homeostasis. There is a small air chamber in the stomach of about 20 mLs, and this is pure atmospheric air, or CO2 after recent consumption of carbonated drinks.

In the small intestine, the neutralization of acids and alkali can theoretically produce large amounts of CO2. However, it’s more in theory than measured in experimental conditions.

Other gases originate from the metabolism of the gut microbiota. The residues of the diet that are not absorbed in the small bowel pass into the colon. These are the parts of the diets that we, as humans, cannot use. These pass into the colon, and in the colon serve as substrates for colonic microbiota. Gas is produced during this process of colonic fermentation.

What types of gases are produced in the digestive tract?

The composition of intestinal gas depends on where in the gut it is produced.

In the stomach, the gas is virtually all atmospheric air or CO2.

In the small bowel, theoretically it should be CO2, although the hard data are very scarce.

And in the colon, the largest component is likely hydrogen and CO2. But the data on that are very limited, and it is not known for sure that these theories are really true. The measurements of gas composition, in the colon or even in the gas eliminated per anus are still uncertain but so far the main concept is that most of the gas is hydrogen and CO2, and methane in subjects that have a methanogenic microbiota.

How does this gas normally get eliminated?

Throughout the GI tract, particularly the colon, about 80% of the gases produced are absorbed through the mucosa, pass into the blood, and are eliminated by breath. So only about 20-25% of the volume of gases produced, particularly in the colon, are eliminated per anus.

What influences the amount of gas produced?

The amount of gas produced in different subjects depends on two factors: one is the diet—the amount of residues (i.e. fiber) in the diet—and the second is the type of microbiota, which is very individual. It varies a lot from one subject to another.

How much intestinal gas is ‘too much’?

From the point of view of patients, of symptoms, what might be relevant is the volume of gases produced, and possibly the type of gases. One evolving idea is that some gases, which are produced in very small quantities, might serve as neurotransmitters, might play a role, but so far the information we have about the role of these gases is very limited so we cannot extrapolate that to clinical use.

Very recent data indicate that symptoms occur when the GI tract has a poor tolerance to its contents, and particularly to gas.

So what is the factor that makes gas produce symptoms? Well there are two factors. One is the amount of gas, and the other one is the tolerance of the subject.

In healthy subjects, it will typically take a large amount of gas to develop symptoms, if at all.

But even small amounts of gas in patients that have a hypersensitivity of the gut and poor tolerance to contents might contribute to their symptoms. This can be seen because, if we reduce the amount of flatulogenic substances in their diet, the symptoms reduce.

This is if we just take into consideration the volume of gas produced, but there is also another factor.

If we give a high flatulogenic diet or a high-residue diet, we know, because we have measured, that we increase the volume of gas produced into the colon. However, we also increase the amount of the fecal content in the colon. So it could be that these diets produce symptoms because they increase the amount of gas, but also because other non-gaseous components, the fecal content of the colon, also are poorly tolerated.

How can someone manipulate their diet to change the amount of intestinal gas that’s produced?

A ‘challenge’ diet, or a high flatulogenic diet in healthy subjects, makes them sick. They go from being symptom-free to having some symptoms, particularly flatulence and bloating.

In patients, the effect of the diet is more accentuated. If patients consume a diet with high residues they get very symptomatic, and if these patients will reduce residues in the diet, they see quite an improvement.

What are the options for dietary change when someone has IBS or wants to reduce gas symptoms?

One thing that has been shown recently is that the effect of a low-residue diet is similar regardless of the type of diet. In the past ten years or so there’s been a major trend with the use of low-FODMAP fermentable oligo-, di-, mono-saccharides and polyols diets.

However, the effect of these complex diets is not better than the effect of any sensible and simple low-residue diet. So if you reduce legumes, veggies from the diet, and fruits, you get a similar improvement.

The problem with low-residue diets, in particular the low-FODMAP diet, is that they introduce a restriction of the substrates for the feeding of the microbiota, and this is deleterious to the microbiota. The microbiota is impoverished.

The other limitation of low-residue diet is that the moment that the patient returns to a normal diet, the symptoms come back.

There is an alternative that has been shown in the past few years, which is to use some type of prebiotics that initially—because they are fermented—produce symptoms, but after a few days they induce an adaptation of the microbiota towards a microbiota that produces less gas with normal fermentation. And down the road, these prebiotics have a positive effect on symptoms in patients. As a matter of fact, the effect on symptoms is similar to a restrictive diet. The advantage of the prebiotics is that, after interruption, …the effect is sustained at least over a few weeks. And this is because it has been shown that prebiotics serve as substrates for microbiota and induce a proliferation of beneficial organisms.

There is also some preliminary evidence that some probiotics reduce the volume of gas production and reduce digestive symptoms in patients.

Is it a good idea to test your gut microbiota when you have IBS or gas symptoms?

There are different companies that claim that by analyzing microbiota they can diagnose some functional conditions, for instance IBS. The practical application of this technology has not been demonstrated. Usually they are expensive techniques and of no value.

It’s important to understand the real value of these methodologies and take the myth out of ‘wonder’ techniques that make a diagnosis from the microbiota and claim it explains everything.

Hopefully, this might be true in the future, but not right now. And actually many of the technologies that are used for this type of analysis are suboptimal.

 A previous blog post by Dr. Bob Hutkins on diet, gut microbiota, and intestinal gas is ISAPP’s most-read blog post of all time. Read it here.

A Miracle Treatment! Or Not?

By Daniel J. Merenstein, MD, Professor, Department of Family Medicine and Director of Research Programs, Georgetown University Medical Center, Washington DC

Here’s a scenario for a physician: A drug rep walks into your office. She has a new product she wants to talk to you about. You are super excited to talk to her as you have heard all about this product from many other sources. The data that are being reported are amazing. There are hundreds if not many more case reports of it working. People were dying and then totally recovered after being given this product. It has been witnessed and published! The efficacy is well over 90%. You are not sure there is any intervention you have ever heard of that has such amazing efficacy.  She tells you that in some of the cases, the patients were very sick and despite numerous courses of antibiotics they did not improve until this new product was given. You ask for more information as you are starting to think this must be like when doctors first heard of penicillin.

The product can be taken orally but that is not the way it is generally given. She tells you that although there are 2-3 ways to administer, most hospitals are doing it the most expensive way now. (You later learn that the typical– and most expensive – approach to administering the product may not even be the best approach.) But you withhold judgement as this sounds exciting. And remember, you have been hearing all about this from so many different sources.

But as you listen, it gets a little confusing. She tells you that the makeup of the product is different in nearly every application. This makes it exciting to use, as one really never knows what is in it. It is also relatively cheap to obtain, as the patient can have a friend just bring it in for them.

Since you are trained in evidence-based medicine, you ask a few questions. It is exciting there are all sorts of case reports but what about the randomized controlled trials, and what does the FDA say about it? You ask if you can look at the trials—there is no way you can review hundreds of studies now but if she leaves them for you, you will look at them this weekend. But before she leaves you ask a few quick questions. How many of these studies are randomized? She says 10. How many use a placebo? She says 6. You tell her what you really want to do is review all the randomized placebo-controlled blinded studies, if she can just leave those.

Later in the week you go pick up the folder she left and right away are a little surprised at how light it is. It looks like there are only 3 randomized placebo-controlled blinded studies, only two of which are peer-reviewed and published. One was a positive study; overall, 91% of patients in the new drug group achieved clinical cure compared with 63% in the control group. But you realize this is not exactly a placebo-controlled trial. What they did is compare two types of the new application. Furthermore, this study was conducted at two sites and at one of the sites both the new application and the control had nearly identical rates of improvement, both over 90%. Okay so this was not a perfect study, only 46 total participants, but still pretty exciting with over 90% improvement.

The second study had three groups of 83 people. Group A (2 doses of new drug), B (2 doses of placebo) and C (1 dose of new drug and 1 placebo dose). The efficacy for these three groups was 61%, 45%, and 67%, respectively. The primary endpoint was not met (P = .152). Interestingly, Group C, which included one dose of placebo, was superior to all placebo (group B) but Group A, in which the drug was given two times, was not superior to placebo.

The third study, a Phase II trial, appears to not be peer-reviewed or published, but just reported online. However, it does appear this was far from a positive study, with 44% of subjects (26 of 59) who received the new application improving versus 53% of subjects (16 of 30) who received placebo. I have been told that this study will be published soon and that a Phase III study of this intervention was also undertaken.

Well now you are getting a little more confused. You have heard from fellow docs, the lay press, medical literature and the drug rep that this new application was over 90% effective. But it appears in the three reasonably well controlled studies, the ones from which we can really draw conclusions, only one was positive and in that study the control was not a real placebo.

Besides efficacy, you remember that one has to always consider the cost and adverse events. Maybe this new application is like recommending the Mediterranean Diet, where the efficacy from studies is limited but the adverse events are nearly non-existent. But when you do a quick PubMed search you learn that this is far from the case with this product. This application has been reported to cause very serious adverse events, including extended-spectrum beta-lactamase (ESBL)–producing Escherichia coli bacteremia resulting in one death. You look online expecting that the FDA must have some serious warnings about this new drug. You don’t find any such warnings.

You may have guessed that the product is in fact a Fecal Microbiota Transplant (FMT). Besides having a professional interest in this much-discussed treatment, I have a personal interest. Last year my son was in a Johns Hopkins Hospital with a central line and two broad-spectrum antibiotics for a bone infection. I asked them to provide him with probiotics since the number needed to treat to prevent pediatric antibiotic associated diarrhea is 9, per a 2019 Cochrane review. This review included 20 randomized, placebo-controlled studies of a single strain. However, I was told no Hopkins hospital will administer probiotics, and further, that we could not even bring in our own because of concerns for the safety of others. But no worries – if my son got recurrent C. diff infection, Hopkins would allow this great new procedure, FMT.

In medicine I cannot truly imagine a probiotic with the same evidence base as FMT receiving such widespread acceptance and escaping regulatory scrutiny. And currently used probiotics have an excellent safety record. Just imagine, if this were a new drug being sold there would be widespread condemnation of the attempt to get approval mainly based on anecdotal case reports.  Shockingly, based on the level of evidence I have described many experts now think a randomized placebo-controlled trial is not even ethical for the placebo group, as of course they know FMT works.

It is a quandary. I am not opposed to FMT; I find it fascinating. But why has it been so widely accepted and why has the FDA, which in general has been very careful with probiotic applications in medicine, allowed this to proceed for recurrent C diff infection with only enforcement discretion? Both treatments administer live microorganisms, one with 31 placebo controlled randomized trials, including 8672 subjects [of C. diff prevention (number needed to prevent=42), not treatment like FMT], the other with pretty limited data.  I have my thoughts, but better for you to ponder it.

 

 

The past decade of probiotics and prebiotics research: ISAPP board members share their perspectives.

By ISAPP board members, compiled by Kristina Campbell

Scientific progress in the field of probiotics and prebiotics, as in any other field, often seems to occur one tiny step at a time. Yet over the course of several years, these tiny steps can add up to significant progress.

Current members of the ISAPP board of directors hold academic positions across North America, and Europe, representing some of the experts at the forefront of scientific innovation in probiotics and prebiotics. Their collective experience encompasses functional foods, fermentations, microbial ecology, microbial genetics, immunology, and clinical medicine, including pediatrics, family medicine and gastroenterology. As we enter into 2020 and a new decade, these board members have taken a moment to reflect on how far they and their colleagues have come over the past ten years, by answering the question: What changes have occurred in the domains of research, applications, and awareness about probiotics and prebiotics?

ISAPP board members, 2019 annual meeting

Available scientific methods and tools

The change that stood out the most to the ISAPP board members over the past decade was the rapid expansion of available scientific methods and tools – from gene sequencing technology to CRISPR-Cas to bioinformatic approaches. These exciting developments have enabled scientists to obtain more information, and to do it both quickly and economically. In the words of the board members:

“Advances in sequencing technology [have] revolutionized our ability to understand the gene repertoire of each individual probiotic strain (whole genome sequencing) and the interplay with the microbiome (metagenomics). This has been really energizing to the field, but has also meant that competence in bioinformatics has become an essential tool for probiotic and prebiotic scientists.”

“A decade ago, human studies on prebiotics would look at changes in the gut microbiota using fairly laborious procedures. Nowadays, the analysis is much more extensive and straightforward to do, and probably more accurate… The biggest change has been the capability to assess not only composition of the microbiota but also its functionality. So, today, the trials include metabonomics as well as assessments of health effects (through changes in particular symptoms and /or biomarkers such as blood lipids, microbial products, immune and inflammatory status). That way, we get a far better picture of what prebiotics can do.”

“In 2010 we only had DGGE to characterize the genome and were trying to figure out how to implement 16S amplicon sequencing. Now we are implementing shotgun & shallow shotgun sequencing for similar prices. In 2010, we did only work on 3-4 probiotic lactobacilli for molecular research, now we work on 400-500 lactobacilli. We do comparative genomics and functional analyses at much larger scale. And in 2010, we paid almost 10000 euro just to sequence one genome of lactobacilli, with limited analysis, now a few hundred euro for sequencing.”

Probiotics and prebiotics for microbiome modulation

Because of the rapid advancements in scientific tools and techniques during the past decade, as mentioned above, many more research groups are endeavoring to study the microbial communities that relate to probiotics and prebiotics. Gut microbiota are of great interest—not least because, among the strategies for microbiome modulation, probiotics and prebiotics are two of the leading candidates. Moreover, microbiome data can help researchers understand the context of probiotics and prebiotics in the gut and in different environments. In particular, many clinical trials of probiotics and prebiotics now include a microbiota-related measure. Novel species and strains for food use may be identified from gut microbiota studies, although safety and efficacy assessment will form challenges for regulatory bodies. Board members said:

“My collaborators and I initiated our first human clinical trials with prebiotics in 2008 and published several papers in 2010 and 2011. These early papers were among the first in which high throughput 16S DNA sequencing was used to assess how the human gut microbiota was affected by the prebiotic, GOS. Although this is now a routine method in the field, in 2008, having a Roche 454 pyrosequencer in the lab was very special, and we were astounded to be able to identify and measure abundances of the main members of the gut microbiota. Having these large data sets also led us to realize the importance of what was at the time the “new” field of bioinformatics that was critical in analyzing and reporting the data. This research showed that GOS was bifidogenic (with high specificity) in healthy adults, but was also subject-dependent. Thus, the results clearly showed there were prebiotic responders and non-responders. This remains an important area of research for my group.”

“The decade started with general excitement that ‘dysbiosis’ of the gut microbiota is involved in just about every human health problem, and has turned into re-remembering that correlation is not causation and microbiota patterns are often driven more by random factors or factors unrelated to disease than by microbiology.”

“It’s worth noting that in 2020, the well-controlled probiotic studies showing health benefits in humans are still more convincing and valuable than the studies showing any ‘beneficial’ effects on the human microbiota.”

“Over the past decade we have witnessed a tremendous explosion in our understanding of the microbiome and its interactions with us, its host. Progress in translating this knowledge into new treatments has been slower but glimmers of encouragement have appeared and we look forward to the next decade when interventions that modulate the microbiome to benefit our health will be based on a true understanding of how they act and will be selected to the maximal benefit of each individual.”

Probiotic mechanisms of action

Probiotic mechanisms of action are a perennial hot topic within the scientific community—and many had hoped that the new suite of scientific tools at scientists’ disposal would significantly advance this area of research during the past decade. But according to one ISAPP board member:

“In 2010 I would have confidently predicted that by 2020 we would have much more of a mechanistic understanding of probiotic mechanisms [and] the importance of strain effects… But this simply has not happened.  The field has become more biologically and computationally complex and many millions have been spent on research, but I still don’t think we can answer the fundamental question we faced in 2010, and in 2000, and in 1990 – what makes one a strain a probiotic, while another is not?”

But in the views of other board members:

“Through genomic and metabolomic studies we are identifying differences between strains that function at different sites and what properties are important for their probiotic function.”

“Identify[ing] the key effector molecules turned out to be more complex [than] we thought 10 years ago. It has become clear to me that probiotic mechanisms of action are per definition complex and multifactorial, because they are living microbes having thousands of molecules that all play a role. Yet, there is clearly an hierarchy of effector molecules.”

Probiotic and prebiotic applications

In general, microbiome studies of the past decade have led to a better appreciation of the ubiquity and complexity of microbial communities—not just those associated with different human body sites, but also those occupying every possible niche on Earth. ISAPP board members reflect:

“In 2010, I was mainly studying probiotics for the gut and vagina, now we have explored probiotics for the skin, respiratory tract, animals, plants, isolates from fermented vegetables that can boost vegan probiotic formulations etc., and other areas.”

“Two areas of research I am doing I’d never have imagined in 2010 are in honey bees and Chinook salmon and against environmental chemicals, administering probiotics.”

Public awareness of probiotics and prebiotics

Numerous studies and surveys show the general public has more awareness than ever of probiotics – and increasingly, of prebiotics too. Individuals receive their information through many different channels, both digital (e.g. blogs, websites) and non-digital (e.g. magazines, product packaging). The past decade also saw the creation of valuable evidence-based resources, such as the Clinical Guides available in the US and Canada, and resources from World Gastroenterology Organisation and from ESPGHAN (probiotics for pediatric acute gastroenteritispediatric nosocomial diarrheapreterm infants, and pediatric AAD). These resources have been enabled by a critical mass of studies that have examined the efficacy of various probiotic strains for certain indications. One board member says:

“From a clinical perspective, the biggest change for us has been that the general public knows so much about probiotics; now we are doing a lot less educating of docs and patients about the concepts behind our probiotic studies.”

But there’s still work to be done:

“The term probiotic is now widely known, but still too often people are misinterpreting what it means, or generalizing the whole field instead of recognizing strain and product differences. We need to continue to educate and clarify to keep the messaging on track.”

“There is still lack of knowledge that not all probiotics are equal. The clinical effects and safety of any single probiotic or combination of probiotics should not be extrapolated to other probiotics. The same applies to prebiotics.”

“Choosing a probiotic continues to be a major hurdle for the consumer – for every probiotic strain that is well characterized, studied in detail in appropriate disease models, and shown to be effective in clinical trials there are hundreds that would fail to pass even the most basic tests of quality control. We must help the consumer to make informed choices.”

 

It seems that, while the past decade has been a fruitful time for probiotics and prebiotics research and public awareness, scientists still have a lot of work to do. In the 2020s they will use the tools available to them, and continue to develop new ones, to gain more detailed and multi-faceted information about probiotic strains and prebiotic compounds—and about the context in which they operate (for instance, the gut microbiome), to ultimately confer benefits on human health.

The FDA’s view on the term “probiotics”

By James Heimbach, Ph.D., F.A.C.N., JHEIMBACH LLC, Port Royal, VA

James Heimbach, food and nutrition regulatory consultant

Over the past 20 years as a food and nutrition regulatory consultant, I have filed about 40 GRAS notices with the United States Food and Drug Administration (FDA), including 15 strains of probiotic bacteria and 5 prebiotics. This fall I submitted notices dealing with 4 strains of bacteria and on January 16 received a telephone call from FDA that surprised me and initially infuriated me, but which I have come to understand.

The essence of the call was that FDA was declining to file my probiotic notices because the notices had identified the subject bacteria as “probiotics” or “probiotic bacteria.” FDA suggested that I resubmit without calling the subject microorganisms “probiotics.”

 

 

As I said, I was surprised and frustrated, and I still would prefer that when FDA makes a policy swerve they would do it in a way that does not make extra work for me and delay my clients’ ability to get to market in a timely manner.

What I have had to do here is remove my advocate’s hat and put on my regulator’s hat. (I worked for FDA for a decade . . . long ago [1978 to 1988], but I still remember how to think like a regulator.) And here is the issue. Recall that GRAS is concerned with safety, not efficacy (generally recognized as safe, or GRAS), and the information provided in a GRAS notice is focused on safety (although benefits may be more-or-less incidentally covered). The reviewers at FDA are charged with assessing whether the notice provides an adequate basis to conclude that there is a reasonable certainty that no harm will result from the intended use. They are not charged, and they are not equipped, to evaluate what benefits ingestion of the substance or microorganism might provide. So they are not in a position to say whether the subject microorganism will “confer a health benefit on the host,” which is to say, they are not in a position to say whether or not it may be regarded as a probiotic. Remember, probiotics are defined as live microorganisms that, when administered in adequate amounts, confer a health benefit on the host (Hill et al. 2014).

Given that the FDA reviewers cannot say whether the notified microorganism is rightly called a probiotic, they are reluctant to sign off that they have no questions about a notice that calls it one. Regulatory agencies have to be careful; things sometimes come back to haunt them. Those who have been following FDA’s GRAS-notice response letters for a couple of decades will be aware that the agency is putting more and more disclaimers into the letters—about standards of identity, about potential labeling issues, about benefits shown in clinical trials, and about Section 201(II) of the FD&C Act.

One concern that FDA likely has is that if some issue comes up in the future regarding a claim made for benefits from use of a product containing the subject bacterium, someone may make the argument that FDA had accepted that the strain is indeed a probiotic and so it presumably confers probiotic benefits. In the case of probiotics, there are also some internal FDA politics. As ISAPP meeting attendees may already be aware, FDA’s Center for Biologics Evaluation and Research (CBER) would like to claim jurisdiction over all administration of live microorganisms, and the Center for Food Safety and Applied Nutrition (CFSAN) does not seem willing to have a confrontation.

I suspect that a similar situation obtains with the term “prebiotic.” Although I have filed a number of GRAS notices for prebiotics, they haven’t been called that; they have been called fructooligosaccharides, or tamarind seed polysaccharide, or polydextrose, or 2’-O-fucosyllactose. I don’t know how FDA would respond if a GRAS determination were filed with the substance labeled as a prebiotic.

So, I’ve decided that my sympathies lie with FDA. Until and unless a microorganism has been confirmed by competent authority to have probiotic properties when used as intended in a GRAS notice, FDA is probably correct in rejecting its right to be labeled a probiotic. If it’s any consolation, this new position by the FDA has its origin in their acknowledgment of the official scientific definition of the word “probiotic”.

When Mary Ellen Sanders (ISAPP’s Executive Science Officer) reviewed my first draft of this note, she asked what I had in mind by “competent authority,” to which I don’t have a good answer at the present time except to insist that it is not FDA’s Division of GRAS Notice Review. Thirty years ago, when I was at FDA, I was in the Office of Food Science and Nutrition, and that office was charged with making determinations of that type (although I don’t recall anything about probiotics coming before us). But FDA no longer has such an office. Until it does, or until it agrees on another source of authority on designation of microorganisms as non-CBER-domain probiotics, I suspect that CFSAN will continue to be very cautious in this area.

Probiotics, Prebiotics and Globobiotics!

By Prof. Colin Hill, PhD, APC Microbiome Ireland, University College Cork, Ireland

Growing up I could not imagine what the world would look like in 2020, but I was convinced it would be amazing. The future was exciting, new planets and solar systems would be explored, diseases would be cured, and everyone would have sufficient food and shelter.  I sometimes think my generation may have been born at the most perfect time in human history (for someone brought up in a first world country at any rate).  We avoided the major world wars which our parents and grandparents endured, we had the benefits of cheap airfares so we could travel the world as tourists, not as armies. Oil was cheap and plentiful. Access to education was widely available. We benefited from antibiotics while they were still effective.  Gender inequalities and racism began to be addressed, even though there is still a long way to go. Computers became commonplace and the internet provided access to almost unlimited sources of information.

But here we are in 2020, and now things do not look so promising. Perhaps cynicism is a natural by-product of getting older, but now the future seems to be presented in apocalyptic terms. Climate change, antibiotic resistance, ageing populations, the paradoxes of increasing obesity and increasing hunger, exploding populations, depletion of natural resources and pollution of our oceans. Watching nature programmes hosted by the incomparable David Attenborough has changed from generating a sense of awe at the wonders of the natural world to a sense of despair as to what we are doing to it. Australia is literally on fire as I write this!  Can our planet survive the onslaught of the projected 10 billion humans by 2050 – each one hungry for a share of finite resources?  Is this really going to be the legacy from my generation to the next – a dystopian future without hope and optimism?

But it’s a New Year and a new decade, and I really want to be hopeful. I am encouraged by the fact that we are gradually beginning to come to grips with this new reality. The UN Sustainable Development Goals provide a roadmap guiding societies and individuals as to how to make a contribution. Attitudes are changing.  Too slowly for sure, but we do seem to be at a tipping point.

But what has this tirade have to do with prebiotics and probiotics, you may ask? Well, everything of course. One of the things that really gives me hope is our growing understanding of how humans are simply occupying space in a microbial world. If we squander our opportunity and destroy our planet in terms of human habitation, microbes will carry on for billions of years to come. We should remember that we can only live on Earth because all of the oxygen we breathe is the result of billions of years of microbial metabolism, that most of the carbon cycling on earth is due to microbes, and that every natural system on Earth depends on microbes. Of course we are also inhabited by a vast ecosystem of microbes (our microbiomes) that are required for our health and wellbeing, and we live in environments shaped by microbes. Understanding this will help us to live in harmony with our microbial world, rather than constantly forcing our poor planet to deliver our short term needs.

How can microbes help us to achieve sustainability and restore a healthy ecosystem? I believe that there are many opportunities. By 2050 I predict that we will be using microbes to restore productivity to land damaged by excessive use and pollution.  We will be using microbes to clean our oceans of plastic waste. We will improve food production without using chemicals, and we will have certainly reduced food waste (it is estimated that one third of all the food we produce on earth is lost to spoilage, much of it caused by microbes). We will have reduced methane emissions by manipulating the rumen microbiome in domesticated ruminants. We can look forward to a world where we can work with microbes to restore and replenish our atmosphere by unlocking the enormous potential of microbes to scavenge and store carbon. We will have reduced our reliance on antibiotics and will have found microbiome-friendly solutions to prevent and treat infection. We will have developed probiotics and prebiotics that will help us to address metabolic diseases, we will be using bacteriophage to sculpt microbiomes, while psychobiotics will be helping to prevent age related loss of brain function.

Given that the world is a microbial ecosystem, I propose that in the same way we can treat our human ecosystems with prebiotics and probiotics to improve or restore health, we can think in terms of developing microbial solutions to improve or restore planetary health. Because we haven’t had one in at least a month, I propose yet another new term; globobiotics. Globobiotics would be defined as “live microorganisms, microbial products or substrates selectively utilized by microorganisms, that are used in a manner that contributes to the sustainability of our planet”.

We’ve had the Stone Age, the Iron Age, the Oil Age, the Atomic Age and the Information Age, welcome to the Microbial Age!

ISAPP discussion group leads to new review paper providing a global perspective on the science of fermented foods and beverages

By Kristina Campbell, MSc, Science & Medical Writer

Despite the huge variety of fermented foods that have originated in countries all over the world, there are relatively few published studies describing the microbiological similarities and differences between these very diverse foods and beverages. But in recent years, thanks to the availability of high throughput sequencing and other molecular technologies combined with new computational tools, analyses of the microbes that transform fresh substrates into fermented foods are becoming more frequent.

A group of researchers from North America, Europe, and Asia gathered at the International Scientific Association for Probiotics and Prebiotics (ISAPP) 2018 conference in Singapore to discuss the science of fermented foods. Their goal was to provide a global perspective on fermented foods to account for the many  cultural, technological, and microbiological differences between east and west. This expert panel discussion culminated in a new review paper, published in Comprehensive Reviews in Food Science and Food Safety, entitled Fermented foods in a global age: East meets West.

Prof. Robert Hutkins, the paper’s lead author, says the diversity of panelists in the discussion group was an important aspect of this work. “Although we were all connected by our shared interests in fermented foods, each panelist brought a particular expertise along with different cultural backgrounds to our discussions,” he says. “Thus, one of the important outcomes, as noted in the published review paper, was how greatly historical and cultural factors, apart from microbiology, influence the types of fermented foods and beverages consumed around the world.”

The review captures the current state of knowledge on the variety of microbes that create fermented foods: whether these are starter cultures or microbes already present in the surrounding environment (i.e. the ‘authochthonous’ or ‘indigenous’ microbiota). The paper identifies general region-specific differences in the preparation of fermented foods, and the contrast between traditional and modern production of fermented foods—including the trade-offs between local and larger-scale manufacturing.

The authors of the article also took on the painstaking work of cataloging dozens of fermented foods from all over the world, including fermented milk products, fermented cereal foods, fermented vegetable products, fermented legume foods, fermented root crop foods, fermented meat foods, fermented fish products, and alcoholic beverages.

The expert panel discussions held every year at the ISAPP annual meeting provide a much-anticipated opportunity for globally leading scientists to come together to discuss issues relevant to scientific innovation and the direction of the field. This paper is an example of a concrete outcome of one of these discussion groups.

For more on fermented foods, see this ISAPP infographic or this educational video.

Maintaining a family tradition: Bulgarian whole fermented cabbage

By Mariya Petrova, PhD, Microbiome insights and Probiotics Consultancy, Karlovo, Bulgaria

Dr. Mariya Petrova with her father

November and December mark a wonderful time of the year when the cold weather makes you want to stay at home and enjoy homemade foods and drinks. However, the heavy food during the holidays makes all of us think about healthier alternatives and how to keep our gut microbiomes in check. That’s why it can be great idea to supplement your festive menu with fermented foods.

Cabbage ready to be fermented

Partly to have healthier food options at home and partly to engage in longstanding traditions, at this time of the year, millions of people in Eastern Europe roll up their sleeves, get out their knives, salt and large containers, and make fermented vegetables at home. While Western cultures are seeing fermented foods as a trendy health food option, Eastern Europeans have never forgotten how to preserve food by using natural fermentation. In my country of Bulgaria, fermented foods are simply a part of our life. Our most popular fermented foods include whole sour cabbage, pickles and pickled vegetables, yogurt, boza (a special fermented beverage), and fermented apple cider vinegar. We do not take shortcuts by pickling our vegetables with vinegar. Ours is a traditional fermentation process – add salt and then let the natural lactic acid bacteria perform their magic.

Although all of these products are interesting and delicious, the winter season brings to my mind my father’s whole cabbage fermentation. My father is busy with it every year from the beginning of November until mid-December. Whole sour cabbage is a fermented food popular not only in Bulgaria but in many of our neighboring countries such as Serbia, Macedonia, and Romania. Although similar to sauerkraut, Bulgarian whole fermented cabbage ferments the entire cabbage head, not separate cut or shredded leaves. Using whole cabbage requires both an extended period of fermentation time (around 30 to 40 days) and extra care in handling.

Preparing for fermentation

I have pictures etched in my mind of a busy local Saturday vegetable market where people would buy between 30-50 kilograms (sometimes even more) of cabbages for fermentation – depending on the size of their families. These come to life every time I hear “fermented foods” at a conference!

Cabbage and brine

But how do you ferment such a spectacular amount of cabbage? Well, first you need some rather large barrels, of course. Then you remove the outer leaves from the cabbage, core the cabbage heads, and stick them in the barrel. This is not unlike putting together a jigsaw puzzle. The cabbage heads have to be very dense without leaving to much space between them or the fermentation will not work well. The cabbage is then covered with a brine of around 2-4% salt. Finally, something heavy is placed on top of the cabbage. Many people place a heavy rock (clean of course), to keep the cabbage heads under the salty water and to allow them to ferment properly. Packing the cabbage densely and pressing it down is done to reduce oxygen to a minimum, creating an anaerobic environment for the fermentation. For better taste some people optionally add apple, quince, horseradish, and/or beetroot (which also makes the salty water more pink).

Finished fermented cabbage

Every day the salty water has to be inverted which is achieved by flushing it from the bottom of the barrel by using connected vessels and then adding it onto the top. Day-to-day shuffling of the salty water ensures a uniform distribution of microorganisms in the barrel so that all cabbage heads ferment. The best quality fermented cabbage is produced at 12-18°C temperature for around 30 days. This is why the fermentation

is done only in November – to maintain these low temperatures. Temperature from 7.5 to 18°C favors the growth and metabolism of Leuconostoc mesenteroides, while temperatures higher than 20°C favor the growth of Lactobacillus species. At higher temperatures the fermentation process takes shorter time (around 10 days), but the quality of the fermented cabbage is lower. Leuconostoc mesenteroides is essential to start the first fermentation that produces lactic acid, acetic acid, ethyl alcohol, carbon dioxide, and mannitol. All these acids, in combination with aromatic ester alcohol, contribute to the characteristic taste of high-quality sour cabbage.

Following Leuconostoc mesenteroides fermentation, Lactobacillus plantarum takes over lactic acid production, which gives a sour taste to the fermented cabbage. At the end of this Lactobacillus fermentation the cabbage is ready to enjoy as part of traditional Bulgarian cuisine. Like a special gift left by St. Nick, many people use the salted water in which the cabbage was fermenting as a drink, rich in lactic acid bacteria, and said to help digestive health.

Acknowledgment: I thank my father for showing me how to make the fermented cabbage and taking some pictures of the process this year!

Fermented foods on the holiday dinner table

Highlighting the importance of lactic acid bacteria: An interview with Prof. Seppo Salminen

By Kristina Campbell, M.Sc., science & medical writer

 

In a 2009 book called What on Earth Evolved?, British author Christopher Lloyd takes on the task of ranking the top 100 species that have influenced the planet throughout its evolutionary history.

What comes in at number 5, just slightly more influential than Homo sapiens? Lactobacilli, a diverse group of lactic-acid-producing bacteria.

The influential status of these bacteria on a global scale comes as no surprise to Prof. Seppo Salminen, ISAPP president and Professor at University of Turku (Finland), who has spent most of his career studying these microbes. He is the co-editor of the best-selling textbook Lactic Acid Bacteria: Microbiological and Functional Aspects, the fifth edition of which was released earlier this year. Salminen says the scientific community has come a long way in its understanding of lactic acid bacteria (LAB)—and in particular, lactobacilli.

Seppo Salminen at ISAPP annual meeting 2019

“If you think about the history of humankind, earlier on, more than 60% of the food supply was fermented,” explains Salminen. “On a daily basis, humans would have consumed many, many lactic acid bacteria.”

Yet 30 years ago when Salminen and his colleagues published the first edition of the textbook on lactic acid bacteria, they were working against perceptions that bacteria were universally harmful. The science on using live microorganisms to achieve health benefits was still emerging.

“Most people in food technology, they had learned how to kill bacteria but not how to keep them alive,” he explains. “They didn’t yet know how to add them to different formulations in foods and what sort of carrier they need. At that time, the safety and efficacy of probiotics was not well understood.”

Around ten years later, scientists came together to develop a definition of probiotics on behalf of the Food and Agriculture Organization of the United Nations and the WHO (FAO/WHO)—in a report that formed the basis of ISAPP Consensus meeting and today’s international consensus definition: “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host”.

With probiotics having been more precisely defined, the following years were a time of rapid scientific progress in the field. Lactobacilli became the stars of the show, as research emerged on the benefits of various strains and combinations of strains in food science and medicine.

Fast forward to today, when rapidly expanding gut microbiome research adds another dimension to what we know about these bacteria. While lactic acid bacteria are still primarily of interest for the health benefits they impart, scientists can now also study their interactions with other microorganisms in the intestinal microbiome. In some cases, this kind of research may help uncover new mechanisms of action.

After everything Salminen and his textbook co-editors (Vinderola, Ouwehand, and von Wright) have learned about lactic acid bacteria over the past few decades, Salminen says there are two main reasons for the perennial importance of the bugs. “One is their importance in food fermentation, extending the shelf life of foods, making a kind of food processing or ‘agricultural processing’ possible. To make sauerkraut shelf-stable for weeks, or to make yogurt or cheese.”

The second reason, he says, relates to their benefits for the host. “Lactic acid bacteria, especially lactobacilli, reinforce intestinal integrity. So they protect us against pathogens; and sometimes against toxins and heavy metals by binding them away.”

He continues, “The more we know, the more we understand that LAB are needed. There are very specific strains that are helpful in different conditions for animal feeds or for clinical nutrition for infants, for example.” He says the knowledge is expanding at such a rapid pace that it may only be a few more years before the textbook he co-edited will need another edition.

Salminen is currently one of the world’s most cited probiotic researchers, and has diverse ongoing research projects related to digestive health, eczema, early life, and nutrition economics—but lactic acid bacteria are the thread that weaves everything together.

“I’m proud to be working on the fifth most important factor in human evolution,” he says.

Misleading press about probiotics: ISAPP responses

By Mary Ellen Sanders, PhD, Executive Science Officer, ISAPP

It seems over the last couple of years, open season on “probiotics” has been declared. Responding in a scientifically accurate fashion to misleading coverage, whether it is in reputable scientific journals or in the lay media, takes time and care.

I want to be clear: well-conducted clinical trials, regardless of the outcomes, are welcome contributions to the body of evidence. No one expects that every probiotic will work for every indication. Null trials document this – they tell researchers to look elsewhere for solutions. Further, we must acknowledge the limitations and weaknesses of available evidence; unfortunately, not all trials are well-conducted. We also need to be just as diligent in criticizing press that is overly positive about probiotic benefits, which are not backed by evidence.

However, articles with misleading information are all-too-frequently published. Below are ISAPP responses to some of these stories.

  1. A paper on rhamnosus GG bacteremia in ICU patients led to headlines about ‘deadly infections’ and probiotic administration ‘backfiring’, even though no patients died and clinical outcomes were not collected. ISAPP responded to clarify appropriate context for understanding the safety issues raised from this paper. See Lactobacillus bacteremia in critically ill patients does not raise questions about safety for general consumers.
  2. The Wall Street Journal published an article condemning probiotics for reducing fecal microbial diversity. ISAPP responded with a blog Those probiotics may actually be helping, not hurting, pointing out the errors in the author’s thinking (equating diversity with gut health).
  3. A pair of well-conducted clinical trials that did not show impact of probiotics on pediatric acute diarrhea led to some ignoring all previous evidence and concluding that no probiotics were useful for acute pediatric diarrhea. ISAPP responded about the importance of putting new evidence in the context of the totality of evidence: L. rhamnosus GG for treatment of acute pediatric diarrhea: the totality of current evidence. Also, Dr. Eamonn Quigley, an ISAPP board member, published an independent response.
  4. Pieter Cohen concluded that evidence for probiotic safety is insufficient in an article in JAMA Internal Medicine. ISAPP’s response was published in a letter to the editor, along with Cohen’s response to our letter.
  5. Responding to two papers in Cell (here and here), and accompanying media coverage that called into question probiotic safety and efficacy, ISAPP published a detailed post Clinical evidence and not microbiota outcomes drive value of probiotics objecting to conclusions, and released a public statement.
  6. Jennifer Abbasi wrote a critical article about probiotics with the inflammatory title “Are Probiotics Money Down the Toilet? Or Worse?” ISAPP responded with the following blog post: Probiotics: Money Well-Spent For Some Indications.
  7. When Rao, et al incriminated probiotics as a cause of D-lactic acidosis, ISAPP posted a blog and published a letter to the editor of Clin Transl Gastroenterol objecting to this conclusion.
  8. ISAPP responded to a paper claiming that probiotics were unsafe in children: Probiotics and D-lactic acid acidosis in children and Brain Fogginess and D-Lactic Acidosis: Probiotics Are Not the Cause.

Board member and Professor Colin Hill wrote a blog post called Another day, another negative headline about probiotics? His post provides some useful questions to consider when reacting to a publication:

  • Is the article describing an original piece of research and was it published in a reputable, peer-reviewed journal?
  • What evidence is there that the strain or strain mix in question is actually a probiotic? Does it fit the very clear probiotic definition?
  • Was the study a registered human trial? How many subjects were involved? Was it blinded and conducted to a high standard?
  • What evidence was presented of the dose administered and was the strain still viable at the time of administration?
  • Were the end points of the study clear and measurable? Are they biologically or clinically significant to the subjects?
  • Did the authors actually use the words contained in the headline? “Useless”, or “waste of money”, etc?

 

Lactobacillus bacteremia in critically ill patients does not raise questions about safety for general consumers

By Dan Merenstein MD, Professor of Family Medicine, Georgetown University Medical Center, Washington DC, USA; Eamonn Quigley MD, Professor of Medicine, Houston Methodist Hospital and Weill Cornell Medical College, Texas USA; Gregory Gloor PhD, Professor of Biochemistry, Schulich School of Medicine and Dentistry, The University of Western Ontario, Canada; Hania Szajewska MD, Professor of Paediatrics, The Medical University of Warsaw, Poland;  and Mary Ellen Sanders PhD, Executive Science Officer, ISAPP, Colorado, USA.

A recent Nature Medicine paper reported blood cultures positive for L. rhamnosus GG in six critically ill patients at Children’s Hospital in Boston.

About this study

Patients (aged 1, 2, 4, 12, 19 and 19 years) with L. rhamnosus-associated bacteremia suffered from different chronic conditions (mitochondrial disorder, cerebral palsy, congenital heart disease, cystic fibrosis) and were located either in the ICU (cardiac or medical/surgical ICU) or ICP (intermediate care program) at the hospital at the time of bacteremia. The bacteremia was discovered during routine blood culture screens. Clinical presentations were not described in detail; however, none had endocarditis or died from the bacteremia, although one did get a central line infection. Two of the six cases of bacteremia in probiotic-consuming patients were determined by attending physicians to be transient or due to contaminants, and were not treated. The other four cases were treated with antibiotics. A further 516 patients dosed with the same probiotic did not develop bacteremia.

The researchers examined the blood isolates and using whole genome sequencing were able to confirm that the Lactobacillus isolated from the blood of these patients was genetically identical – with the exception of a few SNPs – to L. rhamnosus GG present in the probiotic product. This is the preferred approach to confirming the source of blood culture isolates.

Important questions arising from critical review of this paper

  1. Was the study appropriately controlled?

The authors report a seemingly high rate (1.1%) of Lactobacillus bacteremia among the 522 L. rhamnosus-consuming patients compared with 0.009%, the rate of Lactobacillus bacteremia among 21,652 patients who did not receive probiotics.  However, the paper does not justify the legitimacy of comparing these two groups to each other. Indeed, other underlying factors could contribute to the different rates of bacteremia, as these were not matched cohorts. It is important to recognize the limitations of the retrospective design used here, which limits the ability to match controls, and to control for cofounders such as underlying illness, severity of clinical illness and co-therapies (including antibiotics).

  1. What is the mechanism of transmission of the probiotic to the patients’ blood?

Most of the patients had a central line venous catheter. The paper reported that probiotics were mostly administered via tube feeding. If a probiotic is able to readily translocate the gut barrier in such patients, this would be a safety concern. But if the observed bacteremia was due to contamination of a central line, this may say more about hospital procedures than safety of the probiotic. Indeed, 16 years ago, central line contamination leading to fungemia was reported. In a 2005 paper, 92% of cases of fungemia associated with Saccharomyces cerevisiae var boulardii administration had an IV catheter. Based on such reports, handling dried probiotics in a hospital environment with critically ill patients should be done with caution. However, with proper administration procedures, certain probiotics are medically recommended in this setting.

  1. What was the clinical impact of administration of L. rhamnosus GG?

Important clinical parameters such as all-cause mortality (the outcome of greatest importance), length of hospital stay, abscesses, required medications, and others were not reported (although central line infection was reported) for the patients studied. The clinical context of this study would be more easily understood if information on the indications driving probiotic administration was provided. The authors question the risk/benefit of probiotic administration to ICU patients in a children’s hospital yet focus solely on risk and do not measure benefit. This suggests an underlying assumption by the authors that when it comes to probiotics, any risk is too much. Did the patients given L. rhamnosus GG suffer negative clinical outcomes more often than age and condition-matched controls? If so, then giving this probiotic to these patients cannot be recommended. But if not, then even though risk of bacteremia may be higher, if the patients given the probiotic fared better than matched patients, then the probiotic should be considered a reasonable option.

Lastly, the finding of a rate of Lactobacillus bacteremia of 1.1% needs to be viewed in the context of a 20% rate of nosocomial infections in the ICU (here and here).

Lessons regarding probiotic safety

Two main issues are raised by this study. The first is whether the evidence suggests opportunistic pathogenic properties of L. rhamnosus GG or rather that procedures used to administer probiotics in the ICU environment resulted in contamination, which caused bacteremia. No conclusions can be made from this study regarding this. The second is the importance of placing the results of this study into a clinical framework. The study implies risk from probiotic administration, even though the study was not powered for clinical outcomes and could not place any perceived increased risk into the context of any achieved benefit. Further, reporting rates of Lactobacillus bacteremia between cohorts unmatched for important characteristics except for probiotic use does not inform on relative risk.

Importantly for the broader situation of probiotic use, the ICU population is not reflective of the general population, so this study does not allow us to draw conclusions about safety of L. rhamnosus GG use in non-ICU patients.

We recognize the value of careful tracking of potential probiotic-associated infections and appreciate the application of bacterial genomic sequencing to identify the probiotic in the blood. Used more widely, this approach could resolve many purported claims of probiotic bacteremia.

This paper serves as an important reminder that use of probiotics in critically ill patients must be carefully considered and practice must align with learnings from the past, including the risk of central line contamination with probiotics. In addition, this paper highlights the importance of knowing the exact strain (including its antibiotic resistance profile and preferentially also its genome sequence), so that in the rare case of bacteremia, appropriate antibiotics can be administered.

See related article: Hill, C. Balancing the risks and rewards of live biotherapeuticsNat Rev Gastroenterol Hepatol (2019)

See here for an additional related open-access publication: Probiotic use in at-risk populations. Sanders et al. 2014.

 

 

 

 

Reflections on a career in probiotic science, from ISAPP founding board member Prof. Gregor Reid

Past President and founding board member Prof. Gregor Reid is stepping down from the ISAPP Board in Banff in June 2020, as he retires from Western University and his Endowed Chair position at Lawson Health Research Institute the following month. In this blog post, he shares thoughts on his career and the opportunities for his replacement and for others to continue probiotic research. See here for information on the position of Research Chair in Human Microbiome and Probiotics at the Lawson Health Research Institute.

By Gregor Reid BSc (Hons), PhD, MBA, ARM CCM, Dr HS, FCAHS, FRSC

A mere blue dot. A pinhead, if that. But it’s us, all we have been and all we will be – for a while at least. The planet Earth.

Its magnificence is there for all to see.

Creative Commons Earth Illustration, Pixabay

Creative Commons Earth Illustration, by Pixabay

I’ve been fortunate to have visited over 60 of the countries on this majestic globe. One of the perks of being a scientist. And for those who know me well, I’ve taken my camera and my music with me on the journey. In this blog post, I’ll share some pieces of both and how they form part of who we are and what we study.

Across the vast surface of our planet, and within it, there are countless microbes. As life emerges from the surface, we shouldn’t be surprised that microbes climb on board. Whether plants, honey bees, fish, birds, lions, humans, microbes accompany each.

Photo by Andrew Pitek. Used with permission.

Just being human is a guest house1.

Understandably, since some of these microbes can be deadly to humans, our ancestors had to find ways to stop them. Whether plague, diphtheria, smallpox, influenza, wound infections, or other fatal diseases. And so, the marvels of vaccination and antibiotics were born.

Arguably, these miraculous interventions also brought complacency as a societal side-effect, despite the warnings of people like Alexander Fleming. The greatest possibility of evil in self-medication is the use of too small doses so that instead of clearing up infection the microbes are educated to resist penicillin2.

We all but ignored the collateral damage, pacified by label warnings of diarrhea and nausea until Clostridium difficile woke us from our slumber. When the antibiotics stopped working, we went out into left field and started using human poop! Too ridiculous to work, until it worked. Really well.

We’re running through the dark, and that’s how it starts. Don’t know what you’re doing to me. And it might be getting better3.

Prior to that radical step, an awakening had occurred through people like Metchnikoff but more recently Savage, Tannock, McKay, Costerton, Bruce, and others who led us to the microbes that have been helping us all along. In the case of Andrew Bruce, he wondered if replenishment of lactobacilli into the urogenital tract of women might help prevent recurrence of infection. But in the late seventies and early eighties, the collective ‘we’ wasn’t ready to listen.

You came like a comet, blazing your trail. Too high, too far, too soon, you saw the whole of the moon4.

In 2001 in the city of Cordoba, Argentina, a group of experts were assembled and asked to come up with a definition for probiotics5. This helped set a path that we remain on today.

But a definition is nothing without application and acceptance and stewardship. It requires passage to voices across the world. That is why the International Scientific Association for Probiotics and Prebiotics (ISAPP) has been a mountain overseeing the field. Led so wonderfully by Mary Ellen Sanders, Glenn Gibson and other outstanding scientists, it is symbolic of the climb many have had to make.

If you understand or if you don’t. If you believe, or if you doubt. There’s a universal justice, and the eyes of truth are always watching you6.

There’s always gonna be another mountain. I’m always gonna wanna make it move. Always gonna be an uphill battle. Sometimes I’m gonna have to lose. Ain’t about how fast I get there, ain’t about what’s waiting on the other side. It’s the climb7.

It has certainly been a climb. For each of us. Cynicism too often outweighing optimism. Hype outweighing truth. Profit ahead of science. Ignorance over understanding. But together, we have reiterated the message, the importance of studies and data. Not in experimental mice or test tubes, but in the ultimate host where benefits are sought.

The road has taught me to fight our corner, but also that there is a magnificence and mystery in this planet we share. From the birth of a baby to the honey bee that pollinates our crops, to the salmon that crosses from salt to fresh water and back. All from the Mother we share8.

I’ve been fortunate that my career has allowed me to pursue my dream, although it’s never quite as it seems9. One song sums it up for me: While I’m alive I’ll make tiny changes to earth10.

I hope that I have made some tiny changes, especially in the poorest regions of Africa where the probiotic fermented foods of Western Heads East and Yoba-for-life are impacting lives of the young and old. Such inspiring people!

I think if each person is able to make tiny changes, we can leave this life better than whence we came.

As retirement looms, it’s funny how the same question is asked repeatedly. “So, what will you do now?” My answer is I’m moving to America. It’s an empty threat11. Actually, I think back to second year of my honours’ degree at Glasgow University and second year of my PhD at Massey University when my answer was “I don’t know for sure, but I’ll do my best.” I think we need to follow the voice inside us and hope that tomorrow brings wellness and satisfaction.

I won’t fill my walls with framed degrees or awards. Those are for photo albums of a blessed past. They were made possible because of hard work, an incredible family, and a set of friends and talented colleagues too numerous to name.

I’m proud of my publications and students, and hope they inspire others. But I only have two hands12, and we need the Big Ideas for you and me13. So, the laboratory, supplies, offices, and amazing staff and students at the St. Joseph’s Hospital site in London, Ontario await a new direction and someone to carry the fire14. For whoever is my successor, I will wish that tomorrow brings another day, another ray of hope15 and that he or she remembers you only get what you give16, and you only get one shot, do not miss your chance17.

Scientific endeavour, an open mind, supportive colleagues, and taking chances all make for an exciting career. I followed a path barely walked. It ostracized me from many in mainstream microbiology. When grant panel reviewers don’t believe your work has value or is needed, life gets challenging. So, you follow your heart, you lean on those who agree with you, and publish on peripheral topics to stay noticed. Then you smile when your critics actually start studying beneficial microbes and probiotics, and understand what you’ve been saying all along.

Probiotics are more than science. They encompass a philosophy, an anthropological perspective, a bridge between past and future. They are a mountain range of possibilities. As researchers we are still people. We should never shut out the disciplines and sounds and voices that surround us. We need to awaken them like adding medium to a dried Lactobacillus and watching it grow.

The possibilities are just as endless as when I started. But they need younger hands with the latest and future technical skill-sets to pursue the big ideas and to be a steward in defending probiotic science and excellence. These are indeed exciting times.

In closing, I hope you enjoy the music selection — and the irony of some of the album names.

As for me heading into the sunset of this journey: Let the music play. I just wanna dance the night away18.

References (unlike any you’ve seen before)

  1. Coldplay. 2017. Kaleidoscope, from A Head Full of Dreams.
  2. Alexander Fleming. 1945. In, The New York Times.
  3. British Sea Power. 2017. What You’re Doing, from Let the Dancers Inherit the Party.
  4. The Waterboys. 1985. The Whole Of The Moon, from This is the Sea.
  5. Food and Agriculture Organization of the United Nations and World Health Organization. 2001. Probiotics in Food. http://www.fao.org/3/a-a0512e.pdf
  6. Enigma. 1993. The Cross Of Changes from album of the same name.
  7. Miley Cyrus. 2009. The Climb, from Hannah Montana: The Movie.
  8. Chvrches. 2013. The Mother We Share, from The Bones of What You Believe.
  9. The Cranberries. 1992. Dreams, from Everybody Else is Doing It.
  10. Frightened Rabbit. 2008. Head Rolls Off, from Midnight Organ Fight.
  11. Kathleen Edwards. 2012. Empty Threat, from Voyageur.
  12. Avicii. 2013. Wake Me Up, from True.
  13. The Boxer Rebellion. 2016. Big Ideas, from Ocean by Ocean.
  14. Editors. 2010. No Sound But The Wind, from the Twilight Saga: New Moon.
  15. Bill Nelson. 1983. Another Day, Another Ray of Hope, from Chimera.
  16. New Radicals. 1998. You Get What You Give, from Maybe You’ve Been Brainwashed Too.
  17. Eminem. 2002. Lose Yourself, from the movie 8 Mile.
  18. Barry White. 1975. Let The Music Play, from the album of the same name.

See here for information on the position of Director of Human Microbiome and Probiotics at the Lawson Health Research Institute.

Those probiotics may actually be helping, not hurting

By Mary Ellen Sanders PhD, Executive Science Officer, ISAPP, and Gregory B. Gloor PhD, Department of Biochemistry, Schulich School of Medicine and Dentistry, The University of Western Ontario, London

 

A recent Wall Street Journal essay posits that probiotics are harmful, but does so by misrepresenting probiotic and microbiome science in some important ways.

The focus of this essay was an anecdotal report showing that consuming probiotic products (the composition of which was not disclosed), as well as making other dietary modifications, was associated with lower fecal microbiota diversity. This equates, in the author’s mind, to an “unhealthier gut” and leads to the sensational article title “Those Probiotics May Actually Be Hurting Your ‘Gut Health’”.

How important is fecal microbiota diversity to gut health? There is no evidence in humans that increased gut microbiota diversity is causally linked to any better health outcome. In hunter-gatherer populations, the diversity of the gut microbiome cycles seasonally with diet, yet both the low and high diversity microbiomes are presumably equally ‘healthy’. Many different gut diseases are associated with microbiota compositions that differ from those from healthy subjects. But importantly, we don’t know if the different microbiota is the cause of or the result of the disease. So contrary to the author’s assertion, to speak of gut health is not to speak “really…about the gut microbiome”. Scientists don’t even know what a “healthy microbiome” looks like (see review here).

Perhaps more importantly, it is not at all surprising that consuming high numbers of a few probiotics would result in lower fecal microbial diversity. Probiotics typically survive intestinal transit and are observed in fecal samples when the microbiota is measured. A quirk of measuring the microbiome is that it is typically measured as relative abundance, and the thing about relative abundance is that as the number of one microbe goes up, others appear to decline. They don’t decline in absolute number, but their percentage of the total measured is reduced and hence our ability to detect them is also reduced. So, when you add probiotic microbes to your gut microbiota, and then measure the species present, the probiotic organisms appear at the expense of others. As illustrated in the figure, the probiotic species will appear to displace many rare species because the probiotic species comprise a high percentage of the total population. Although the other resident bacteria are all still there, they are more difficult to detect because they are now below the detection limit after probiotics were added to the community.

 

We are not aware of any evidence that probiotics will increase the diversity of fecal microbiota. In fact, based on the rationale above, we expect that probiotics may appear to decrease fecal microbiota diversity. Does that mean probiotics are harmful? No.

The author glosses over another weakness in his anecdotal report. He treats his fecal microbiota as if it is equivalent to his gut microbiota. Fecal samples represent a terminal microbial community with diminishing nutrients and many dead, but measurable, bacteria. This community is much different from what occurs farther upstream in the colon, and likely has little in common with small intestinal microbial communities. Granted, this is a weakness of much research on the gut microbiome, but discerning scientific reporting should call this what it is: fecal microbiota, not gut microbiome.

Are probiotics actually good for us? To answer this question, consult the literature that evaluates specific probiotics for the health outcome that interests you. Some good evidence exists for several clinical endpoints including antibiotic-associated diarrhea, reduced risk of C. difficile, treatment of colic in infants, reduced incidence in upper respiratory tract infections, and others (see review here).

We agree with one conclusion of the essay, that eating a diverse, whole-food, high-fiber diet likely promotes gut health. But there is nothing new about this recommendation and it seems hardly worth column space in the Wall Street Journal.

 

 

Researchers submit recommendations for revised Lactobacillus taxonomy

By Mary Ellen Sanders PhD, Executive Science Officer, ISAPP

A team of researchers has submitted their recommendations for new classification for the heterogeneous group of species currently considered to belong to the genus Lactobacillus. The paper is under review by the International Journal of Systematic and Evolutionary Microbiology, the premier journal for bacterial taxonomy.

Three research teams that were independently working on comparative genomics and taxonomic inconsistencies among lactobacilli (see here, here, here, here, here, and here) came together to openly collaborate on this publication. These teams included scientists from Italy, Canada, Belgium, Germany, China, Ireland, and Japan.

Several species important from a commercial perspective will be impacted, including Lactobacillus casei, Lactobacillus plantarum, Lactobacillus sakei, Lactobacillus salivarius, Lactobacillus reuteri and Lactobacillus brevis. New genus names are expected for these. Lactobacillus delbrueckii, Lactobacillus acidophilus, Lactobacillus gasseri, Lactobacillus johnsonii, Lactobacillus helveticus and Pediococcus are not expected to undergo name changes. Since L. delbrueckii (which includes the subspecies L. delbrueckii subspecies bulgaricus, the yogurt starter culture) was the first Lactobacillus named, convention in naming bacterial genera requires that species from this taxonomic clade will keep the Lactobacillus name.

Driving this effort is the pressing need to apply modern phylogenetic methods to establishing relationships among the many species of Lactobacillus (see previous post). The genus Lactobacillus currently comprises more than 240 species, and has been growing rapidly for decades. In 1980, 36 Lactobacillus species were recognized. By 2012, there were 152. Scientists recognized the need to reorganize the phylogenetic assignments of this genus; they are proposing splitting the Lactobacillus genus into more than 20 genera.

Once the paper is published, the task of disseminating the message about new genus names for commercially important species will begin.

See here for a detailed article on this topic.

The small intestinal ‘mysteriome’: A potentially important but uncharted microbiome

By Eamonn MM Quigley MD FRCP FACP MACG FRCPI, Lynda K and David M Underwood, Center for Digestive Disorders, Division of Gastroenterology and Hepatology, Houston Methodist Hospital, Houston, Texas, USA

 

Over recent years, countless publications have documented the status of the microbiota of the gastrointestinal tract by examining fecal samples. While this approach does provide a “snapshot” or representation of what is going on in the gut, and especially in the colon, it is a crude measure of the complex interactions between micro-organisms in the gut, as well as between these same microorganisms and us (their hosts). Fecal samples comprise a terminal microbial ecosystem, characterized by depletion of readily fermentable substrates, with a concomitant change in microbial composition, even compared to those farther upstream in the colon. It is unlikely, for example, that studies using fecal samples provide a full picture of what happens when bacteria (or other microorganisms) “talk” to the lining of the gut (the mucosa) or interact with the immune system of the intestine. Even less likely is that they provide any insights into bacterial populations in the small intestine, where most of the digestion of food and absorption of nutrients takes place. The small intestine also possesses the most abundant immune tissue of the entire gastrointestinal tract.

Yet, details of which bacteria actually inhabit this long and important organ, the small intestine, are sketchy. This lack of knowledge has apparently not restricted much theorizing and speculation about the role of an overgrowth of colonic-type bacteria (referred to as small intestinal bacterial overgrowth – SIBO) in the small intestine in many symptoms, disorders, and diseases. According to one especially popular theory – the “leaky gut” hypothesis – the list of conditions is nearly endless. The “leaky gut” hypothesizes that dysbiosis in the small intestine (in other words SIBO) and a disruption of the gut barrier leads to “leakage” of bacteria and bacterial products into the circulation causing inflammation, allergy, and autoimmunity.

There are several leaps of faith involved in “leaky gut” including, of course, the definition and diagnosis of SIBO. Traditional methods of diagnosing SIBO (obtaining fluid samples directly from the upper small intestine or a variety of breath tests) are fraught with problems and, in essence, have precluded a universally accepted definition of SIBO.

Fundamental to this dilemma is the definition of the normal small intestinal microbiome – how can we diagnose abnormal when we do not know the limits of normality? I would contend that, while there are situations where it is undoubted (based on the clinical context and various laboratory and other findings) that SIBO is an issue, there are countless more instances where SIBO is over-diagnosed and incorrectly implicated as the cause of an individual’s symptoms. This is an important issue as it can lead to the inappropriate use of antibiotics – something we all wish to avoid.

There is some good news – clever techniques exist for obtaining uncontaminated fluid samples from the small intestine, a capsule technology that permits live sampling of intestinal gases (generated by bacteria) as it traverses the intestine and the application, at last, of high-throughput sequencing, metagenomics, metabolomics, and metatranscriptomics to small intestinal microbiota suggest that the accurate definition of the normal small intestinal microbiome is not far off. At that time, we can all agree on an accurate and clinically meaningful definition of SIBO.

 

Is probiotic colonization essential?

By Prof. Maria Marco, PhD, Department of Food Science & Technology, University of California, Davis

It is increasingly appreciated by consumers, physicians, and researchers alike that the human digestive tract is colonized by trillions of bacteria and many of those bacterial colonists have important roles in promoting human health. Because of this association between the gut microbiota and health, it seems appropriate to suggest that probiotics consumed in foods, beverages, or dietary supplements should also colonize the human digestive tract. But do probiotics really colonize? What is meant by the term “colonization” in the first place? If probiotics don’t colonize, does that mean that they are ineffective? In that case, should we be searching for new probiotic strains that have colonization potential?

My answer to the first question is no – probiotics generally do not colonize the digestive tract or other sites on the human body. Before leaping to conclusions on what this means for probiotic efficacy, “colonization” as defined here means the permanent, or at least long-term (weeks, months, or years) establishment at a specific body site. Colonization can also result in engraftment with consequential changes to the gut microbiota composition and function. For colonization to occur, the probiotic should multiply and form a stably replicating population. This outcome is distinct from a more transient, short-term (a few days to a week or so) persistence of a probiotic. For transient probiotics, it has been shown in numerous ways that they are metabolically active in the intestine and might even grow and divide. However, they are not expected to replicate to high numbers or displace members of the native gut microbiota.

Although some studies have shown that digestive tracts of infants can be colonized by probiotics (weeks to months), the intestinal persistence times of probiotic strains in children and adults is generally much shorter, lasting only few days. This difference is likely due to the resident gut microbiota that develops during infancy and tends to remain relatively stable throughout adulthood. Even with perturbations caused by antibiotics or foodborne illness, the gut microbiome tends to be resilient to the long-term establishment of exogenous bacterial strains. In instances where probiotic colonization or long-term persistence was found, colonization potential has been attributed more permissive gut microbiomes specific to certain individuals. In either case, for colonization to occur, any introduced probiotic has to overcome the significant ecological constraints inherent to existing, stable ecosystems.

Photo by http://benvandenbroecke.be/ Copyright, ISAPP 2019.

This leads to the next question: Can probiotics confer health benefits even if they do not colonize? My answer is definitely yes! Human studies on probiotics with positive outcomes have not relied on intestinal colonization by those microbes to cause an effect. Instead of colonizing, probiotics can alter the digestive tract in other ways such as by producing metabolites that modulate the activity of the gut microbiota or stimulate the intestinal epithelium directly. These effects could happen even on short-time scales, ranging from minutes to hours.

Should we be searching for new probiotic strains that have greater colonization potential? By extension of what we know about the resident human gut microbiota, it is increasingly attractive to identify bacteria that colonize the human digestive tract in the same way. In some situations, colonization might be preferred or even essential to impacting health, such as by engrafting a microbe that performs critical metabolic functions in the gut (e.g. break down complex carbohydrates). However, colonization also comes with risks of unintended consequences and the loss of ability to control the dose, frequency, and duration of exposure to that particular microbe.

Just as most pharmaceutical drugs have a transient impact on the human body, why should we expect more from probiotics? Many medications need to be taken life-long in order manage chronic conditions. Single or even repeated doses of any medication are similarly not expected to cure disease. Therefore, we should not assume a priori that any observed variations in probiotic efficacy are due to a lack of colonization. To the contrary, the consumption of probiotics could be sufficient for a ripple effect in the intestine, subtly altering the responses of the gut microbiome and intestinal epithelium in ways that are amplified throughout the body. Instead of aiming for engraftment directly or hand-wringing due to a lack of colonization, understanding the precise molecular interactions and cause/effect consequences of probiotic introduction will lead to a path that ultimately determines whether colonization is needed or just a distraction.

Prebiotics do better than low FODMAPs diet

By Francisco Guarner MD PhD, Consultant of Gastroenterology, Digestive System Research Unit, University Hospital Vall d’Hebron, Barcelona, Spain

Bloating and visible abdominal distention after meals is a frequent complaint of people suffering from irritable bowel syndrome, but even generally healthy people sometimes have these complaints. These symptoms are thought to be due to fermentation of food that escapes our digestive processes. Some sugars and oligosaccharides end up at the far end of our small bowel and cecum, where they become food for our resident microbes.

To manage this problem, medical organizations recommend antibiotics to suppress the microbial growth in our small intestine (known as small intestinal bacterial overgrowth or SIBO) or avoidance of foods that contain fermentable oligosaccharides, disaccharides, monosaccharides and polyols, called a low “FODMAP” diet. These approaches are generally successful in reducing symptoms, but do not provide permanent relief: symptoms typically return after the strategies are stopped.

Even worse, both approaches are known to disrupt the entire gut microbial ecosystem (not only at small bowel and cecum). Whereas a healthy microbial gut ecosystem has many different types of bacteria, antibiotics deplete them.  The low FODMAP diet deprives beneficial bacteria (such as Faecalibacterium, Roseburia, Bifidobacterium, Akkermansia, Lactobacillus and others) of the food they like to eat, and these species wane (see here).

Prof. Glenn Gibson, a founding father of prebiotic and synbiotic science, suggested that increasing ingestion of certain prebiotics could increase levels of bifidobacteria. These bifidobacteria in turn could prevent excessive gas production since they are not able to produce gas when fermenting sugars.  (Instead, bifidobacteria product short chain fatty acids, mainly lactate, which are subsequently converted to butyrate by other healthy types of bacteria, such as Faecalibacterium and Roseburia.)

Prof. Gibson’s hypothesis was tested in pilot studies where volunteers ingested a prebiotic known as galacto-oligosaccharide (Brand name: Bimuno). Healthy subjects were given 2.8 g/day of Bimuno for 3 weeks. At first, they had more gas: significantly higher number of daily anal gas evacuations than they had before taking the prebiotic (see here). The volume of gas evacuated after a test meal was also higher. However, after 3 weeks of taking the prebiotic, daily evacuations and volume of gas evacuated after the test meal returned to baseline. The microbe populations also started to recover. The relative abundance of healthy butyrate producers in fecal samples increased and correlated inversely with the volume of gas evacuated. This suggested that the prebiotic induced an adaptation of microbial metabolism, resulting in less gas.

Then researchers launched a second study, also in healthy volunteers, to look at how the metabolic activity of the microbiota changed after taking this prebiotic. They showed that adaptation to this prebiotic involves a shift in microbiota metabolism toward low-gas producing pathways (see here).

A third controlled study (randomized, parallel, double-blind), this time in patients with functional gastrointestinal disorders with flatulence, compared the effects of the prebiotic supplement (2.8 g/d Bimuno) plus a placebo diet (mediterranean-type diet) to a placebo supplement plus a diet low in FODMAPs. The study subjects were divided between these 2 diets, which they consumed for 4 weeks (see here). Both groups had statistically significant reductions in symptom scores during the 4-week intervention. Once subjects stopped taking the prebiotic, they still showed improved symptoms for 2 additional weeks (at this point, the study was completed). However, for subjects on the low-FODMAP diet, once the diet was stopped, symptoms reappeared. Very interestingly, these 2 diets had opposite effects on fecal microbiota composition. Bifidobacterium increased in the prebiotic group and decreased in the low-FODMAP group, whereas Bilophila wadsworthia (a sulfide producing species) decreased in the prebiotic group and increased in the low-FODMAP group.

The bottom line conclusion is that a diet including intermittent prebiotic administration might be an alternative to the low FODMAP diets that are currently recommended for people with functional gut symptoms, such as bloating and abdominal distention. Since low FOD MAP diets are low in fiber, the prebiotic option may provide a healthier dietary option.

 

  1. Halmos EP, Christophersen CT, Bird AR, Shepherd SJ, Gibson PR, Muir JG. Diets that differ in their FODMAP content alter the colonic luminal microenvironment. Gut. 2015;64(1):93–100.
  2. Mego M, Manichanh C, Accarino A, Campos D, Pozuelo M, Varela E, et al. Metabolic adaptation of colonic microbiota to galactooligosaccharides: a proof-of-concept-study. Aliment Pharmacol Ther. 2017;45(5):670–80.
  3. Mego M, Accarino A, Tzortzis G, Vulevic J, Gibson G, Guarner F, et al. Colonic gas homeostasis: Mechanisms of adaptation following HOST-G904 galactooligosaccharide use in humans. Neurogastroenterol Motil. 2017;29(9):e13080.
  4. Huaman J-W, Mego M, Manichanh C, Cañellas N, Cañueto D, Segurola H, et al. Effects of Prebiotics vs a Diet Low in FODMAPs in Patients With Functional Gut Disorders. Gastroenterology. 2018;155(4):1004-7.

 

Additional reading:

Halmos EP, Christophersen CT, Bird AR, Shepherd SJ, Gibson PR, Muir JG. Diets that differ in their FODMAP content alter the colonic luminal microenvironment. Gut. 2015;64(1):93–100.

Mego M, Manichanh C, Accarino A, Campos D, Pozuelo M, Varela E, et al. Metabolic adaptation of colonic microbiota to galactooligosaccharides: a proof-of-concept-study. Aliment Pharmacol Ther. 2017;45(5):670–80.

Mego M, Accarino A, Tzortzis G, Vulevic J, Gibson G, Guarner F, et al. Colonic gas homeostasis: Mechanisms of adaptation following HOST-G904 galactooligosaccharide use in humans. Neurogastroenterol Motil. 2017;29(9):e13080.

Huaman J-W, Mego M, Manichanh C, Cañellas N, Cañueto D, Segurola H, et al. Effects of Prebiotics vs a Diet Low in FODMAPs in Patients With Functional Gut Disorders. Gastroenterology. 2018;155(4):1004-7.

Halmos EP, Gibson PR. Controversies and reality of the FODMAP diet for patients with irritable bowel syndrome. J Gastroenterol Hepatol. 2019 Jul;34(7):1134-1142. doi: 10.1111/jgh.14650. Epub 2019 Apr 4.

 

 

The threat of disease – Ignore science at your peril

By Dr. Karen Scott, University of Aberdeen

We live in an age when life expectancy has increased and many diseases that used to be fatal are curable. Much of this is the result of years of efforts by dedicated scientists, painstakingly working out the causes of diseases, and then the best way to treat or prevent them. Yet the high profile of social media can boost the profile of results from poorly conducted studies, sometimes even beyond the publicity received by the original seminal results. Responsible scientists are partly to blame for this. We are a cagey bunch, frequently suffixing stories about our wonderful successes with caveats, maybes and the recurring refrain “more research is needed”. Those spreading sensationalist publicity have no such qualms.

Take vaccination for diseases caused by viruses. In 1796, Dr Edward Jenner realised that milk parlour girls did not seem to get small pox and theorised that they were protected from the devastating disease due to their continual exposure to the less dangerous cow pox virus. He proceeded to prove his theory by inoculating many people with cow pox, and then exposing them to the small pox virus. Although the experiment would nowadays perhaps be considered unethical, it worked and people infected with cow pox did not get small pox. This heralded the start of vaccination, a huge medical advance that has since protected millions of people from contracting polio, measles, mumps, rabies, tuberculosis and many more devastating diseases. In the 19th Century, Louis Pasteur advanced the method, using inactivated viruses as the inoculation. Vaccination has been so successful that small pox was ‘officially’ eradicated globally in 1979, and the polio vaccine, which was developed in 1955, has led to the virtual world-wide elimination of polio.

But more and more people people are declining to vaccinate their children. The very success of the vaccination scheme may be why it is now in danger. People have forgotten the devastating consequences and lasting effects of these diseases. In the western world it is now unusual to see people crippled by the effects of childhood polio. What about measles? Prior to vaccination, measles was a highly contagious disease, spreading through water droplets in air when an infected person sneezed. Forty percent of those with measles develop complications including pneumonia (which is often the case of measles-related deaths), deafness, blindness and encephalitis (brain swelling), which can even cause brain damage. If the patient survives, the effects of such complications can last for life. Yes – measles, a disease fully preventable by vaccination, kills. I was struck by a recent story about Roald Dahl, whose daughter sadly died after contracting measles when she was seven (see here). In 1986 Roald Dahl wrote an open letter describing his experience, encouraging people to vaccinate their children. The post was illustrated with a picture of a ward full of children suffering from polio, all confined in iron lungs as their breathing had been so badly affected due to paralysis of their chest muscles. No one can want to return to that.

Another contributor to reduced vaccination rates are reports that vaccinations cause more harm than good. Such reports are sustained in part by non-science-based social media claims. Even when original scientific reports are discredited, many parents continue to decide not to vaccinate their children.

How will these “anti-vaccination” parents/carers feel, sitting at the bedside of their critically ill child trying to make sense of the doctor’s explanation that even if their child pulls through, they will never be able to see again? Or explaining to their grown up child that he will never be able to father children due to an almost forgotten childhood disease? All because Mum and/or Dad paid more attention to a campaign on social media with no scientific basis, than to medical advice supported by decades of evidence? Yes, there are instances of people becoming ill with the diseases themselves, or suffering rare side effects of vaccination, but these are rare and pale in comparison to the morbidity and mortality prevented by vaccinations. After all, these same people do not stop driving their car to work when they hear that someone else had an accident doing so. The huge decline in epidemics of viral diseases following the introduction of vaccination programmes speaks to their effectiveness. The vaccine for measles was introduced in 1968 and is estimated to have prevented 20 million cases of measles and 4,500 deaths. In fact the vaccination programme was so successful that it led to the UK being declared ‘measles free’ in 2017.

 

 

 

 

 

 

 

Source – Public Health England; University of Oxford Vaccine Knowledge Project

Yet countries that we travel to on holiday still have measles outbreaks so it is still crucial to get children vaccinated. Even in the US and UK, the large increase in non-vaccinated children means that measles outbreaks (starting with people catching the disease abroad) are becoming more common – evidenced by the second graph above. An alarming statistic is that there are more cases of measles in 2018 than there were in 1998.

Increased numbers of unvaccinated people pose a threat to society at large. Herd immunity can protect a small number of unvaccinated individuals. Indeed, some individuals cannot be effectively vaccinated, including very young infants or when there is a problem with their immune system. But when the number of unvaccinated people rises, these viruses can ‘find’ susceptible hosts and take root once again in the population. This puts our most vulnerable society members at risk. The decision to not immunize is not a victimless decision. We need to maintain vaccination programmes on a global scale, to maintain ‘herd immunity’ and halt the current increase in the numbers of cases occurring.

Bottom line – vaccination works and prevents needless suffering from preventable diseases.

L. rhamnosus GG for treatment of acute pediatric diarrhea: the totality of current evidence

By Mary Ellen Sanders PhD, Executive Science Officer, ISAPP

For the past several years, studies have been adding to the evidence base on the efficacy of Lactobacillus rhamnosus GG for the treatment of pediatric diarrhea. A new systematic review and meta-analysis led by Prof. Hania Szajewska concluded that Lactobacillus rhamnosus GG is effective for treating acute diarrhea in hospitalized children, even when a 2018 null trial (Schnadower et al. 2018) was included.

“Despite a recent large RCT demonstrating no effect of L rhamnosus GG, current evidence shows that, overall, L rhamnosus GG reduced both the duration of diarrhoea (with a higher impact in European countries) and hospitalisation in inpatients.”

The authors acknowledge that the quality of evidence for this conclusion is low: 13 of 18 included studies suffered from problems with randomization, allocation concealment, blinding, and/or follow‐up. However, the rigorous process used to assess the current state of evidence provides confidence in the paper’s conclusions.

In an editorial in Alimentary Pharmacology & Therapeutics, Prof. Eamonn Quigley suggests that reports dismissing L. rhamnosus GG as ineffective (for example, see The Washington University School of Medicine opinion, “Probiotics no help to young kids with stomach virus“) were premature.

As Prof. Quigley points out, it is necessary to put the findings of the null study into context. He states several reasons why the Schnadower et al. 2018 study may not have shown an effect of L rhamnosus GG, even though previous studies had. Notably, the rotavirus vaccination status of the subjects – with two-thirds of the study population having been vaccinated – seemed important. Subgroup analysis showed that the probiotic was more effective among children who had not been vaccinated for rotavirus.

In addition, as discussed in a previous ISAPP blog, the timing of initiating probiotic therapy is likely an important factor. In the null trial, the average time of diarrhea prior to treatment was 53 hours, and subjects were enrolled up to 72 hours after onset of diarrhea – likely too late to have a possibility of positive impact by the probiotic.

For now the ESPGHAN recommendation to initiate L. rhamnosus GG treatment in conjunction with rehydration therapy early after the onset of diarrhea in children can still be supported by the totality of evidence.

Both Prof. Hania Szajewska and Prof. Eamonn Quigley serve on the ISAPP board of directors.

Defining emerging ‘biotics’

By Mary Ellen Sanders PhD

From its inception, ISAPP has been committed to clarity in both the definitions and the contextual use of terms in the fields of probiotics and prebiotics fields. This is reflected in the FAO/WHO probiotic guidelines working group conducted immediately prior to the first ISAPP meeting in 2002, as well as our more recent consensus panels convened on probiotics (2013), and prebiotics (2016). We also have additional panels in progress on synbiotics (convened in May 2019 in Antwerp), fermented foods (scheduled for September) and postbiotics (scheduled for December).

A recently published paper, Emerging Health Concepts in the Probiotics Field: Streamlining the Definitions, addresses definitions of many newer terms in the ‘biotics’ arena, including probiotics, prebiotics, synbiotic, pharmabiotics, postbiotics, probioceuticals, paraprobiotics, oncobiotics, psychobiotics, and live biotherapeutic products. In my opinion, although this paper provides useful discussion of issues surrounding the proliferation of terms in the ‘biotics’ area, it falls short of providing clear direction for the field and indeed may well add to confusion by introducing unnecessary, new and poorly defined terms.

For example, the term ‘symbiotics’ is perpetuated, presumably as a synonym to synbiotic. It was a missed opportunity to clarify that the term ‘synbiotic’ is derived from the Greek root ‘syn’ meaning ‘with’ or ‘together.’ The term ‘symbiotic’ is simply incorrect, adds nothing and should be eliminated altogether.

This paper fails to advance the ISAPP consensus definition of prebiotic, published in 2017, by lead author Glenn Gibson, co-inventor of the terms ‘prebiotic’ and ‘synbiotic’. It is not clear whether the authors disagree with the ISAPP consensus definition, and if so, on what basis. They state that the ISAPP consensus definition is “the most actual definition”, the meaning of which is not clear to me, but then use an outdated definition in their summary box.

Further is the failure to acknowledge the broad scope of the definition of probiotics. Live biotherapeutic products (LBPs), which the paper states is a term that was “recently” introduced by the FDA, has been in use for over at least 15 years by the FDA’s Center for Biologics Evaluation and Research. The authors equate LBPs (which are defined as drugs) with next generation probiotics, yet these do not have to fall under the drug category any more than traditional probiotics are necessarily foods. Next generation probiotics, traditional probiotics or just probiotics can fall under numerous regulatory categories including foods, infant formulas, drugs, supplements, animal feeds, medical foods, foods for special dietary uses, and perhaps even cosmetics or medical devices. Thus, regulatory category is not stipulated by the definition, which is appropriate.

One of the difficulties with sorting through these terms is the lack of any consistent basis for defining them. Some terms, such as pharmabiotics and LBPs, are linked to specific regulatory categories. Others are defined by the nature of how they are comprised: live cells, cell components, or fermentation endproducts. Others are defined by their physiological benefit: psychobiotic, oncobiotic, immunobiotic. Even still, others are defined by their state of innovation: traditional vs. next generation probiotics. This state of affairs makes is impossible to develop a logical framework for categorizing them. Instead, we are left with a long list of substances that might be related, but have little real value. Where does it all stop? Next we will have to sift through thera/metabo/gen/retro/plas/func-biotics or any other pointless terms that can be arbitrarily slapped in front of ‘biotic.’

Certainly, there is nothing to prevent any person from coining a new term for a niche development. The many stakeholders in the broader ‘biotics’ field will, I suppose, determine any given term’s utility. I believe it would have been worthwhile for this paper to make an appeal to scientists to refrain from muddying the water by proposing new terms, and instead use existing terms with appropriate modifiers. For example, use ‘immune-active probiotic’ instead of ‘immunobiotic’, or ‘probiotic drug’ instead of ‘live biotherapeutic product.’ This approach is clearer to regulators and international organizations such as Codex Alimentarius, the US Food and Drug Administration and European Food Safety Authority. To the extent that the definitions of terms need to be clarified, I believe that the ISAPP approach, using groups of 10 or more well-known academic experts in the field reaching a consensus after extensive background search, is preferred over unilateral proclamations as delivered by this paper.

Effects of the food matrix on probiotic’s efficacy: how much should we care?

By Gabriel Vinderola PhD, Researcher at the Dairy Products Institute (National Scientific and Technical Research Council – CONICET) and Associate Professor at the Food Technology and Biotechnology Department, Faculty of Chemical Engineering, National University of Litoral, Santa Fe, Argentina.

The issue of to what extent food components may affect probiotic efficacy when compared to the strain delivered as supplement has lately been the subject of debate. This is especially so in the context of the Codex Alimentarius guidelines on probiotics, presently under development.

When considering the importance of the food formulation delivering the probiotic, it’s worthwhile to keep in mind that people may get their daily probiotic together with an enormous variety of foods. For instance, one person may get the probiotic at breakfast along with a yoghurt or with cereal, whereas another person may choose to consumer a fruit juice, while a third may get the probiotic dose before a meal consisting of pasta, meat and vegetables. In those cases, the same strain can undergo gastrointestinal passage in the context of very different food exposures. Does this suggest that perhaps the specific food format is not so critical? What does research tell us?

An interesting, however in vitro, study was conducted by Grześkowiak et al. (2011). In this work, Lactobacillus rhamnosus GG was recovered from more than 12 foods and supplements and its ability to inhibit food pathogens was assessed in vitro. Authors showed that even when the inhibitory capacity was quantitatively different among isolates, the qualitative probiotic capacity of inhibiting pathogens was present in all of them. That is to say, the probiotic capacity had been retained to a somewhat greater or lesser degree, regardless the matrix.

Few human studies have measured to what extent a health endpoint changes when a probiotic is delivered in different food matrixes. For instance, Saxelin et al. (2010) showed that the administration matrix (capsules, yogurt or cheese) did not influence the faecal quantity of lactobacilli, but affected faecal counts of propionibacteria and bifidobacteria. However no health endpoint was considered in this study. Several studies demonstrate that dairy products are able to confer enhanced protection during gastrointestinal transit in in vitro settings (Vinderola et al., 2000; Sagheddu et al., 2018; da Cruz Rodrigues et al., 2019), suggesting that dairy products may be better at delivering an efficacious dose of probiotic. But again, no clinical endpoint was measured in these studies.

The first comparative study on the probiotic capacity of a strain delivered in food or supplement was reported by Isolauri et al. (1991). Authors demonstrated that Lactobacillus GG either in fermented milk or freeze-dried powder was effective in shortening the course of acute diarrhea. Later on, Meng et al. (2016) found similar patterns of immune stimulation when studying the impact of Bifidobacterium animalis subsp. lactis BB12 administration in yoghurt or capsules on the upper respiratory tract of healthy adults.

As these kinds of studies are scarce, we can look to meta-analysis where the same strain is compared for the same clinical endpoint, but in studies conducted by different groups in different matrixes. For instance, Szajewska et al. (2013) concluded that Lactobacillus GG delivered in capsules or fermented milk significantly reduced the duration of diarrhea and Urbańska et al. (2016) reported that L. reuteri DSM 17938 delivered in either capsules or infant formula reduced the duration of diarrhoea and increased the chance of cure.

In vitro studies find that survival of the probiotic delivered in different food matrices through a (simulated) gastrointestinal transit may quantitatively differ, but no matrix completely eliminates probiotic capacity. Human clinical trials comparing different matrices with a clear health endpoint are scarce, but a general conclusion seems to emerge: regardless of the food matrix, the probiotic effect is achieved.  When the data are assessed through meta-analysis, the top of the “levels of evidence” in the pyramid of evidence-based studies, the probiotic capacity exists for the same strain among different studies, conducted by different research groups, using different food matrices.

In many countries regulators require that the probiotic effect be demonstrated in the same food or supplement that will be offered to consumers. This is a conservative approach in the lack of other evidence, but it may be challenging at the same time for probiotic food development, as any new food, even similar to one already existing, may require new human clinical studies to demonstrate efficacy. This approach may raise economic and ethical concerns too, and be discouraging for the future of probiotics.

Surely additional clinical trials directly comparing effects among different delivery matrices would provide clarity on the importance of this factor to probiotic functionality. Until that time, regulators should enable probiotic food manufacturers to offer a sound scientific rationale that bio-equivalency of different matrices could be expected, and thereby circumvent the requirement need to re-conduct human clinical trials on probiotics delivered in new matrices.

 

References

da Cruz Rodrigues VC, Salvino da Silva LG, Moreira Simabuco, F, Venema K, Costa Antunes AE. Survival, metabolic status and cellular morphology of probiotics in dairy products and dietary supplement after simulated digestion. J Funct. Foods, 2019, 55, 126-134.

Grześkowiak Ł, Isolauri E, Salminen S, Gueimonde M. Manufacturing process influences properties of probiotic bacteria. Br J Nutr. 2011, 105(6):887-94.

Isolauri E, Juntunen M, Rautanen T, Sillanaukee P, Koivula T. A human Lactobacillus strain (Lactobacillus casei sp strain GG) promotes recovery from acute diarrhea in children.

Meng H, Lee Y, Ba Z, Peng J, Lin J, Boyer AS, Fleming JA, Furumoto EJ, Roberts RF, Kris-Etherton PM, Rogers CJ. Consumption of Bifidobacterium animalis subsp. lactis BB-12 impacts upper respiratory tract infection and the function of NK and T cells in healthy adults. Mol Nutr Food Res. 2016, 60(5):1161-71.

Pediatrics. 1991 , 88(1):90-7.

Sagheddu V, Elli M, Biolchi C, Lucido J, Morelli L. Impact of mode of assumption and food matrix on probiotic viability. J Food Microbiol. 2018, 2.

Saxelin M, Lassig A, Karjalainen H, Tynkkynen S, Surakka A, Vapaatalo H, Järvenpää S, Korpela R, Mutanen M, Hatakka K. Persistence of probiotic strains in the gastrointestinal tract when administered as capsules, yoghurt, or cheese. Int J Food Microbiol. 2010, 144(2): 293-300.

Szajewska H, Skórka A, Ruszczyński M, Gieruszczak-Białek D. Meta-analysis: Lactobacillus GG for treating acute gastroenteritis in children-updated analysis of randomised controlled trials. Aliment Pharmacol Ther. 2013 Sep;38(5):467-76.

Urbańska M, Gieruszczak-Białek D, Szajewska H. Systematic review with meta-analysis: Lactobacillus reuteri DSM 17938 for diarrhoeal diseases in children. Aliment Pharmacol Ther. 2016, 43(10):1025-34.

Vinderola G, Prosello W, Ghiberto D, Reinheimer J. Viability of  probiotic- (Bifidobacterium, Lactobacillus acidophilus and Lactobacillus casei) and non probiotic microflora in Argentinian Fresco Cheese (2000). J Dairy Sci. 2000, 83 (9), 1905-1911.

Another day, another negative headline about probiotics?

By Prof. Colin Hill, PhD, APC Microbiome Ireland, University College Cork, Ireland

Scientists have a particular job. We try to discover what is unknown and we want to help to create a better understanding of the underlying forces, both physical and biological, that underpin our amazing universe. It is usually a slow and meticulous process. Gathering data usually takes weeks, or months, or years of work and so there is plenty of time to consider the numerous possible interpretations and the limitations and gaps in our understanding. Everything has to be repeated and subjected to statistical analysis. Finally, we publish our findings and our interpretation of that carefully accumulated data. Even this process takes weeks or months (or years) because of discussions with fellow authors and colleagues, numerous drafts of the manuscript, peer review and editorial comment. We are very aware that whatever we have published will almost certainly be repeated, or built upon, and if we are wrong (in either our data or our interpretation) that it will not withstand the test of time. Thus, we are slow and cautious and often qualify our findings with “this suggests” or “this strongly suggests” and we often finish with the unavoidable conclusion that “more research needs to be done”.

Journalists have a particular job. Journalists have to react quickly, perhaps in minutes or hours, to a breaking story or a commission from their editors, on topics with which they may not be familiar, and write short articles or present short pieces to camera that will appeal to the public and have a clear message. Nuance and complexity must often be left for long-form journalism or that as-yet unwritten novel. Being slow and complete and debating all of the possible interpretations is simply not an option. Finishing up with a cautious, equivocal “on the one hand, but also on the other hand” is also not really an option. Very few journalistic pieces end with “more journalism needs to be done”. It may also be difficult to construct a story along the lines of “some good science was well performed and led to careful and understated conclusions, which should really be repeated before we get too excited”.

It is not surprising then that scientists and journalists can sometimes find themselves at loggerheads. “Do probiotics work?” is a very reasonable question that a journalist can ask a scientist. “Well,” responds the scientist, “that depends on what you mean by ‘work’, and which probiotic you are asking about, and for what condition, and quite often strains are called probiotics but they do not fit the definition, and of course, there was that paper published last year which showed ……”. Cue frustration on both sides. Why can’t the scientist just answer the question? And why can’t the journalist understand that just because a question can be simply stated does not mean that it has a simple answer? Ask a doctor “do pills work?” and you might very well get a similarly convoluted answer, but no one would think it evasive. No wonder the scientist sometimes ends up reading the resultant article in frustration – how did the journalist come to that conclusion, where did all my careful explanations go? Of course, most scientists are imagining his or her scientific colleagues reading the article and wondering at the ‘incomplete’ or ‘trivial’ response. While the journalist may well wonder what planet the scientist lives on if he or she thinks that the editor is going to publish a long essay capturing all of the subtlety of the research.

This almost certainly comes across as me implying that scientists are impeccable purveyors of truth and that journalists are willing to sacrifice truth for simplicity, but I truly am not suggesting that. In almost every instance there is no bad faith involved from either party, it is simply the consequence of the different demands placed on two very different and very valuable roles in society.

So, these things will happen. We will see newspaper articles and online pieces (or editorial comments in journals) that do not contain all the nuance and complexity of the complex paper which it is based. We will see press articles that draw simple and reader-friendly conclusions. “Probiotics quite useless”, “Are probiotics money down the toilet? Or worse?”, etc. So, how should we respond? Do we write erudite articles pointing out the limitations of the commentator, coming across perhaps as arrogant or supercilious? [And yes, of course I use the words erudite and supercilious because it makes me feel better than you.] Do we send angry missives complaining about the article, and perhaps risk drawing further attention to it?

If you are asked by a journalist to comment on a paper, or if your local/national paper or favourite website has published an article that you think is unfair, perhaps the way to respond is to have a few simple questions of your own which can be put to journalists and/or readers. Perhaps we can use a checklist such as the following:

  • Is the article describing an original piece of research and was it published in a reputable, peer-reviewed journal?
  • What evidence is there that the strain or strain mix in question is actually a probiotic? Does it fit the very clear probiotic definition?
  • Was the study a registered human trial? How many subjects were involved? Was it blinded and conducted to a high standard?
  • What evidence was presented of the dose administered and was the strain still viable at the time of administration.
  • Were the end points of the study clear and measurable? Are they biologically or clinically significant to the subjects?
  • Did the authors actually use the words contained in the headline? “Useless”, or “waste of money”, etc?

Once these relatively simple questions are answered, then we can move on to the details and the complexities, but that is not where we should start. Of course, if a study is well performed and reaches a negative conclusion we should absolutely acknowledge that. But we can still point out that one strain or strain mix not working under one set of conditions is only evidence of the fact that one particular strain or strain mix does not work under one particular set of conditions. It does not warrant a blanket condemnation or criticism of all probiotics. Maybe ask the journalist to think about the obvious flaws in the headline ‘Headache pill does not cure cancer, all pills obviously a waste of money!”, and ask why the same standards should not be applied to probiotics?

Scientists and journalists have different roles in society, that is clear, but we can assume a priori that both have clear motives and do not want to mislead readers. Let’s start from there and make it easier for both sides to work together to make the public aware of the very real potential, and very real limitations, of probiotics and prebiotics in preserving health in a society in dire need of practical solutions.

“A healthy woman, a healthy baby, a healthy generation” lessons learned from the 4th Annual Women and their Microbes Conference

By Dr. Mariya Petrova, Microbiome insights and Probiotics Consultancy, Bulgaria

The 4th annual Women and their Microbes conference took place at the beginning of March celebrating the International Women’s day. The first-ever conference outside Europe in Hamilton, Canada brought together top scientists to discuss the importance of women’s health through the prism of women’s specific microbiomes. The theme of the conference was Microbiome Management in Pregnancy with a uniquely designed high-quality program translating the latest research into the clinical setting. I was honored to serve on the organizing committee for this meeting, and I provide highlights below.

Our health starts long before birth. The developing fetus receives information from the mother in the form of hormones and nutrients and uses these to predict the external environment. The fetus then uses this information to adapt its development to better its chances of survival after birth. However, the developing fetus can be “misinformed.” This happens through the maternal factors such as her use of drugs, stress, and diseases such as obesity and asthma. For example, both absolute maternal weight and weight gain during pregnancy affect microbiota development in infants (Carmen Collado et al., 2010). Maternal microbiota can also shape the immune system of the newborns. Therefore, keeping women on the right course before pregnancy and healthy during pregnancy must be a priority. This will later be translated into a healthier life for the infant through adulthood. Many of us associate healthy pregnancy with women taking the right nutrients and minerals such as folic acid, B12 vitamins, and iron and we are not wrong. But microbes also play an essential role in health. Microbes are a crucial factor providing nutrients, immune protection and regulating host physiology. Particular strains of Lactobacillus sp. and Bifidobacteria sp. can produce vitamin B12 and folic acid in the gut (Magnusdottir et al., 2015), which may be very beneficial during pregnancy. Of interest, this production increases when paired with prebiotics. Not only that, but microbes are increasingly recognized as important in reproduction, pregnancy, and development. Fertilization doesn’t happen in a sterile environment. Distinct bacterial communities are present in the female reproductive tract, but semen health and male fertility are also important (Weng et al., 2014). So don’t forget the “Y” in the equation – fathers also play a role in the health of their offspring. Gestational tissue microbes can also play an important role in development. More research is needed to better understand these microbiomes and the extent to which they can be influenced by maternal diet and health state.

What if the things go wrong – adverse pregnancy outcomes. Preterm birth is an ongoing challenge with rates steadily growing and with limited approaches for prevention. It results in 75% of neonatal morbidity and mortality. High numbers (55-80 %) of preterm births are associated with dysbiosis and a shift of the vaginal microbiota towards a more diverse state (Freitas et al., 2018). It seems likely that the vaginal microbiome can protect against adverse pregnancy outcomes. However, it appears that both antibiotics and probiotic therapy used to date are not effective at preventing preterm birth. “How to prevent adverse pregnancy outcomes?” is a million dollar question. We need a highly discriminatory diagnostic test that defines versions of ‘abnormal’ vaginal microbiomes. This test needs to be significantly associated with adverse health outcomes. The type of abnormal profile that results in preterm birth needs to be distinguishable from other possible ‘abnormal’ profiles. Such a diagnostic tool needs to be simple enough for a clinical environment and cost-effective. We need to have a safe intervention that can ‘treat’ or normalize a microbiome ideally preconception or early pregnancy.

Where do probiotics fit? Probiotics and prebiotics can enhance the nutrient status of the mother via increasing micronutrient and mineral absorption. During pregnancy, about 3.6% of North American women, 14% of The Netherlands women and 23% of Australian women consume probiotics. A lot of studies focus on the role of probiotics for preventing Group B Streptococcus infections, maternal obesities, postpartum depression, and mastitis. Although results are promising, more studies are needed to make clear conclusions and select the best strains for each condition. Importantly, currently used probiotics do not appear to pose safety concerns for pregnant and lactating women. Nevertheless, consumers’ knowledge regarding probiotics is not very precise. This confusion often may stem from a probiotic market with many different manufacturers, some of which are not legitimate, selling products that are not well defined, with very little clinical evidence. A major effort in educating clinicians, pharmacists and the consumers has been made by creating probiotic guidelines. Dragana Skokovic Sunjic has been working in the last ten years in publishing and updating the “probiotic chart.” The probiotic chart summarizes commercially available probiotic supplements or foods sold in Canada or the USA that have published clinical evidence for the particular strain(s) present in each product. Of note, for products containing multiple strains, evidence must be provided for the specified combination and not extrapolated from the evidence for the separate probiotic strains. At present these guidelines are used by primary care providers, specialists (pediatrics, GI), academic teaching hospitals, universities and others.

With the increasing number of microbiome studies, we are witnessing a paradigm shift in the scientific literature with more people focusing on the importance of microbes in human health. Women’s health is a cornerstone for successful reproduction, with important implications for the health of the next generation. Initiatives such as Women and their Microbes are crucial to link the science and medicine together to bring awareness within the healthcare and academic community.

Reading, writing, and making an impact

Bob Hutkins, University of Nebraska-Lincoln, Department of Food Science and Technology and Leslie Delserone, University of Nebraska-Lincoln, University Libraries

For scientists who study probiotics and prebiotics, these are exciting times.  Every day, there are new discoveries and new opportunities.  There certainly are many challenges – obtaining grants, recruiting and mentoring students and postdocs, editorial duties, and maintaining competitive research programs.

But perhaps the most challenging activity is keeping up with the literature. Back in our respective graduate school days, there were only a handful of journals that required regular reading (and most arrived via regular mail in print).  One of us even remembers waiting for mail delivery to learn about the latest science.

There are now dozens of journals that publish high-quality papers on probiotics, prebiotics, fermented foods, gut health, and other relevant topics.  No longer does one have to wait for the latest scientific report – most of us are bombarded with emailed journal highlights, tables of contents, and latest science alerts.

The figure below illustrates this situation.  In 2001 (when ISAPP was formed), there was about 1 probiotic-oriented paper published per day. Now, with prebiotics included, there are more than ten new papers in the literature every single day!

Indeed, just since 2015, there have been more than 12,000 papers on probiotics and prebiotics listed in PubMed. Add in fermented foods, gut health, and methods papers, and those numbers will easily double or triple.

For researchers, clinicians, and other scientists, there are simply too many papers to read and digest.  Thus, for better or worse, many scientists perform a literature triage of sorts, reading papers mainly from so-called high-impact journals.

As a result, probiotic and prebiotic papers published in the top journals inevitably get the most attention, whether deserved or not.  An unfortunate consequence is that papers in other journals sometimes are over-looked.  Perhaps that’s one reason why, based on searches of several citation indexes, about a fourth of all papers published in our field never get cited at all!

So which papers in our field attracted the most attention or had the greatest impact?  Until recently, the only metrics used to assess impact were the journal’s impact factor and an article’s citation score – how many times a particular paper had been cited by other papers. This is no longer the case, as noted below.  But assuming citation numbers actually reflect impact, we’ve compiled a short list of the most important papers in our field.

To do this, we used two multidisciplinary online indexes, Web of Science Core Collection (WoS) and Scopus. The WoS indexes more than 20,000 journals, while Scopus covers more than 30,000 peer-reviewed journals; we limited the WoS search to its Science Citation Index Expanded.  We separately searched the terms probioti* and prebioti* in the article title, looking for papers and reviews published since 1990, and sorting the results for “times cited” or “cited by” from highest to lowest.

For probiotics, there were more than 10,000 (WoS) and 13,600 (Scopus) articles and reviews. As expected, several of the most cited papers were reviews.  Surprisingly, two were reviews on use of probiotics in aquaculture. Indeed, Verschuere et al. (2000) was the second and third most cited study in WoS and Scopus, respectively.  The 2014 ISAPP consensus paper (Hill et al., 2014) was the 2nd and 3rd most cited paper (Scopus and WoS respectively, with 920 and 1,034 citations as of late March 2019).

And the top probiotic paper in our field since 1990?  That would be a Lancet report that described results of an RCT in which Lactobacillus GG was administered to pregnant women and newborns with atopic eczema as the clinical end-point (Kalliomäki et al., 2001). This paper garnered more than 1,500 citations within the WoS, and 1,953 as tracked by Scopus. Among the authors of this study is current ISAPP president, Seppo Salminen. Incidentally, the 4-year follow-up to that same study (Kalliomaki et al., 2003) was the 4th most cited paper in both indexes!

For prebiotics, there were more 3,000 papers listed.  Leading the list of most cited papers is the seminal Gibson and Roberfroid (1995) paper in the Journal of Nutrition that “introduced the concept”.  Papers by Glenn Gibson and his colleagues dominate the list of most cited prebiotic papers.  But the most cited primary research paper on prebiotics was another clinical study from Finland (Kukkonen et al., 2007).

As noted above, citations are no longer the only way to measure impact.  After all, clinicians, industry scientists, and government regulators and policy makers also read and apply published information.  If a paper leads to a new treatment or technology, could there be a greater impact for the social good?

Consider the science paper with perhaps the greatest overall societal impact in the past 20 years. That would be Brin and Page’s 1998 paper published in what at the time was a relatively obscure journal, Computer Networks and ISDN Systems. The article began, in case you haven’t read it, with these six simple words, “In this paper, we present Google”.

Until recently, paper impacts were difficult to measure. But now we have Altmetrics, Twitter, and other ways to assess impact. Given that it usually takes at least a year before a published paper receives a citation in the WoS and Scopus environments, social media provide a way to gauge impact in real-time.  Indeed, a recent editorial in Nature Cell Biology (2018) suggests that plenty of scientists embrace social media. Evidently, many use it to sort through information as quickly as their fingers can tap.

 

Anonymous. 2018. Social media for scientists. Nature Cell Biology 20(12): 1329. doi: 10.1038/s41556-018-0253-6

Brin, S., and L. Page. 1998. The anatomy of a large-scale hypertextual Web search engine. Computer Networks and ISDN Systems 30(1-7):107-117. doi: 10.1016/S0169-7552(98)00110-X

Gibson, G.R., and M.B. Roberfroid. 1995. Dietary modulation of the human colonic microbiota: Introducing the concept of prebiotics. Journal of Nutrition 125(6):1401-1412. doi: 10.1093/jn/125.6.1401

Hill, C., F. Guarner, G. Reid, G.R. Gibson, D.J. Merenstein, B. Pot, L. Morelli, R.B. Canani, H.J. Flint, S. Salminen, P.C. Calder, and M.E. Sanders. 2014. Expert consensus document: The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the scope and appropriate use of the term probiotic. Nature Reviews Gastroenterology and Hepatology 11(8):506-514. doi: 10.1038/nrgastro.2014.66

Hutkins, R.W. 2019. Microbiology and Technology of Fermented Foods, 2nd ed.; Hoboken, N.J., Ed.; Wiley-Blackwell: Hoboken, NJ, USA

Kalliomäki, M., S. Salminen, H. Arvilommi, P. Kero, P. Koskinen, and E. Isolauri. 2001. Probiotics in primary prevention of atopic disease: A randomised placebo-controlled trial. Lancet 357(9262):1076-1079. doi: 10.1016/S0140-6736(00)04259-8

Kalliomaki, M., S. Salminen, T. Poussa, H. Arvilommi, and E. Isolauri. 2003. Probiotics and prevention of atopic disease: 4-year follow-up of a randomised placebo-controlled trial. Lancet 361(9372): 1869-1871. doi: 10.1016/S0140-6736(03)13490-3

Kukkonen, K., E. Savilahti, T. Haahtela, K. Juntunen-Backman, R. Korpela, T. Poussa, T. Tuure, and M. Kuitunen. 2007. Probiotics and prebiotic galacto-oligosaccharides in the prevention of allergic diseases: A randomized, double-blind, placebo-controlled trial. Journal of Allergy and Clinical Immunology 119(1):192-198. doi: 10.1016/j.jaci.2006.09.009

Verschuere, L., G. Rombaut, P. Soorgeloos, and W. Verstraete.  2000. Probiotic bacteria as biological control agents in aquaculture.  Microbiology and Molecular Biology Reviews 64(4):655-671. doi: 10.1128/MMBR.64.4.655-671.200

Probiotics: Money Well-Spent For Some Indications

Eamonn M M Quigley MD, Houston Methodist Hospital and Weill Cornell Medical College, Houston, Texas, USA; Hania Szajewska MD, The Medical Univesrity of Warsaw, Department of Paediatrics, Poland; Dan Merenstein MD, Department of Family Medicine, Georgetown University

We read with interest and some concern the Medical News and Perspectives article by Jennifer Abbasi titled “Are Probiotics Money Down the Toilet? Or Worse?” (Abbasi 2019).  As researchers committed to the study of fecal microbiota transplant, prebiotics and probiotics, we find the title overly sensationalist for an article that ultimately provides a more nuanced view. It is unfortunate that the author focused on studies which either did not report on any clinical outcome and hence provide limited insight on the effectiveness of probiotics, or, whose null results likely reflect the late timing of the intervention while failing to refer to many high-quality studies that illustrate the subtlety of commensal and probiotic bacterial actions or clinical efficacy. Tanoue and colleagues provide a reminder that commensal engagement with the immune system is selective and precise (Tanoue et al. 2019). As Dr Knight points out, it would be surprising to witness the same response to any intervention in all individuals (Abbasi 2019). Efforts to individualize medical interventions, including probiotics, are worthwhile, but not yet realized. Until then, available evidence must be critically considered, but not ignored.  We wholeheartedly agree with the call for high quality clinical studies of probiotics but assert that it is also important to stress the challenges of performing clinical studies that seek to demonstrate clinical benefits in healthy human subjects; they require large study populations and are consequently very expensive. That clinical studies have been performed and demonstrated robust and clinically meaningful outcomes was illustrated by the study of Panigrahi where they demonstrated that an intervention comprising a probiotic plus prebiotic reduced sepsis among high-risk infants in rural India (Panigrahi et al. 2017). In the meantime, meta-analyses of smaller studies can provide insights into clinical benefit or harm. For example, systematic reviews and meta-analyses have consistently supported a role for probiotics in the prevention of Clostridium difficile–related illness, leading a JAMA review to state: “moderate-quality evidence suggests that probiotics are associated with a lower risk of C. difficile infection” (Goldenberg et al. 2018). Balanced with the low number needed to harm, probiotic interventions are attractive clinical options. We also question Abbasi’s focus on colonization as there is little, if any, evidence that this is necessary for probiotic activity.

We stress the obligation to provide a balanced view of the field which provides equal emphasis on successes as well as failures. No two probiotics (or probiotic cocktails) are alike; we should not expect they all have the same clinical impact.

 

References

  1. Abbasi J. Are probiotics money down the toilet? Or worse. JAMA 321(7):633-635. doi:10.1001/jama.2018.20798
  2. Tanoue T, Morita S, Plichta DR, et al. A defined commensal consortium elicits CD8 T cells and anti-cancer immunity. Nature. 2019;565:600-605.
  3. Panigrahi P, Parida S, Nanda NC, et al. A randomized synbiotic trial to prevent sepsis among infants in rural India. Nature. 2017;548:407-412.
  4. Goldenberg JZ, Mertz D, Johnston BC. Probiotics to prevent Clostridium difficile infection in patients receiving antibiotics. JAMA 2018;320:499-450. 

 

Acknowledgements:

Conflicts of interest:

All three authors are members of the Board of Directors of ISAPP

Eamonn M M Quigley holds equity in Alimentary Health and has served as a consultant to Alimentary Health, Allergan, Axon Pharma, Biocodex, Glycyx, Menarini, Pharmasierra, Salix and Vibrant.

Hania Szajewska reports no conflicts

Dan Merenstein has served as a consultant to Bayer, Debevoise & Plimpton, Pharmavite and Reckitt Benckiser