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.

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.

For information on the position of Director of Human Microbiome and Probiotics at the Lawson Health Research Institute, contact Dr. David Hill: David.hill@nulllawsonresearch.com

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

Challenges ahead in the probiotic field – insights from Probiota2019

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

Recently, I attended the Probiota Conference, which brings together representatives from industry and academia on the topic of probiotics and related fields. The goal of many of the speakers at the conference was to provide insight about how to translate scientific discoveries for, and share commercial insights with, end consumers. I would like to share a few points that caught my attention.

Do good science. End-consumers rely on news coverage of science, which unfortunately is too often more sensationalist than accurate. Prof. Gregor Reid’s talk, “Disentangling facts from fake news,” noted that news article titles such as “Probiotics labeled ‘quite useless’” and “Probiotics ‘not as beneficial for gut health as previously thought’” – after research was published last year in Cell (here and here) – were misleading to end-users and of great concern to people in the field of probiotics who are familiar with the totality of the data. Researchers have a responsibility to situate their results in the context of existing evidence. However, Prof. Reid also observed that “too many products are called probiotics with strains not tested in humans”; “too many products are making un-verified claims”; “too many journalist don’t have expertise in science”; “too many rodent studies making association with human health”; “researchers making up their own terms without defining them”. So how do we solve this? Do good science and communicate results clearly, accurately and without bias – to journalists, to peers and to end-users. (See related ISAPP blogs here and here).

Understand the probiotic mode of action. Understanding probiotic modes of action may be the most challenging issues ahead of us. Currently, we have too little understanding of mechanisms by which probiotics provide health benefits. Probiotic strains are living microorganisms, which most likely work through multiple mechanisms and molecules, but we indeed need more in-depth research. When I reflect on my own experience and the struggles to do molecular studies, I can appreciate how difficult this research is. Although others may be focused on screening the microbiome and developing bioinformatics tools, I applaud the researchers trying to develop deeper understandings of how probiotics function, which will enable more rational approaches to probiotic selection and use. (See related ISAPP blog here.)

New names, new glory. The forthcoming reclassification of the Lactobacillus genus was discussed. We are faced with the largest taxonomic upheaval of this genus in history, including many economically important species. The current Lactobacillus genus will be split into at least ten genera. The species and strain names will not change, but many species will have different genus names. Researchers are expected to propose that all new genera names will begin with the letter “L.” The reclassification can help us better understand the mode of action of industrially important probiotics and help tailor probiotic applications. The changes will be communicated with regulatory bodies such as EFSA and FDA. Name changes could also have consequences for medical stakeholders and may lead to potential issues with intellectual properties. Consumers of probiotic products will likely be less affected by this change, but an educational website targeted to consumers could be beneficial. (See related ISAPP blog here.)

EFSA claims as expected. EFSA claims and regulations were also discussed. To date, approximately 400 health claims applications have been submitted to EFSA without any approved. Experts advised to keep the claims simple and easy. EFSA’s strict approach to claims may have the advantage of compelling industry to conduct studies that better support health claims. Responsible companies are adapting to regulatory requirements and are developing good products, and they will probably succeed in meeting claim standards. Nevertheless, it seems that although health claims are deemed important to companies and medical representatives, end-users of probiotics obtain information from other sources. Obtaining health claims is only one piece of the puzzle. Also important is providing science-based information to end-users, especially those keen on keeping their good health through nutrition.

Be transparent. Don’t forget to disclose the strains you use on product labels. Strains designation is one key way to distinguish your product and it is an important way to communicate to your consumer exactly what is in your product. Surprisingly still, some scientific papers fail to report the strains they used to perform their clinical trials. The field is moving towards more transparency with high-quality clinical trials, the best-selected strains for certain condition and clear designation of the probiotic strain on the label. (See related ISAPP infographics here, here and here)

Educate, educate and again educate. Often discussed at the conference was the subject of educating the end consumers. Companies should take a proactive approach to engage consumers and promote understanding of the available evidence where probiotics can promote health. It is difficult for consumers to differentiate science-based evidence from journalistic sensationalism or researcher self-aggrandizement. A major obstacle is also the ready availability in the marketplace of unproven products containing strains that have been tested only in animal models or not proven experimentally at all. Taking the need for reliable communications on probiotics and probiotics to end-users very seriously, ISAPP has developed a range of science-based videos and infographics. The infographics include topics such as how to read the labels of the probiotics products (USA and EU versions) and a probiotic checklist. Thanks to the enthusiastic work of many volunteers, some ISAPP infographics can now be found in 10 different languages.

Despite having great discussions, one thing keeps troubling my mind: Where is the field of probiotics going and how will it look like in 10 or 20 years? The fight for probiotics is not over, despite the progress we have made so far.

Limitations of microbiome measurement: Prof. Gloor shares insights with ISAPP

February 20, 2019

The number of papers published on the human microbiome is growing exponentially – but not all of the studies are equally well designed or reported. Evaluating the latest research requires a basic understanding of the latest approaches to microbiome methods and data analysis.

To help equip scientists not conducting microbiome research with the tools to understand microbiome-focused publications, ISAPP hosted a webinar titled Understanding microbiome experiments: a critical assessment of methods and data analysis. The webinar featured Gregory Gloor, PhD., Professor, Department of Biochemistry, Schulich School of Medicine and Dentistry, The University of Western Ontario, Canada.

A recording of the webinar is available here, and Prof. Gloor’s slides are available here.

Prof. Gloor opened his talk with a sobering perspective: the current body of microbiome publications is fraught with problems. There is a fundamental lack of reproducibility in the microbiome field (Sinha et al. 2017). This is largely due to the large number of tools available and a lack of an a priori established research plan for microbiome analysis, which should be consistently followed throughout a project. At every step of the way, many decisions must be made regarding wet lab methods, bioinformatics toolsets and statistics to use. Different choices lead to different results. Once the biological specimens are assayed, choices for bioinformatics and statistical analyses can greatly influence the conclusions. In short, it’s possible to view the data through so many different lenses that eventually a researcher can find a story worth telling. How close that story comes to the truth is a principle that sometimes is sacrificed for the sake of an interesting story.

Another important challenge to the field is representative sampling. Too few samples are typically taken, often because of cost limitations, so that the samples do not reasonably approximate the truth about the environment being sampled. Conclusions from such studies result in both many false positives and many false negatives.

Prof. Gloor also warned about outsourcing microbiome analysis. Commercial entities often use every metric, hoping the customer will get some outcome they hoped for. Further, their tools are often outdated or proprietary. So caution must be used – there is no substitute for expertise.

Some suggestions for improving outcomes were offered:

  • Each project should stipulate a research approach and outcome a priori, which is consistently followed throughout the project.
  • Methodological consistency is important within a lab, but analytical methods do not necessarily need to be standardized across all labs. If all labs use the same methods, consistent, but incorrect, outcomes may result. So use of different metrics is good, but methods should be consistent within a project. The value of different research groups using different methods to ask particular research questions is that if the same result emerges from different approaches, it increases confidence that the results are true.
  • Gloor cautioned that microbiome datasets are compositional, and compositional data approaches must be used (Gloor et al 2017).
  • Functional readouts have less methodological variation than taxonomic readouts. Therefore, functional analysis of shotgun metagenomics or shotgun metatranscriptomics is typically a more reproducible, and also more informative, readout.
  • Recent advances have significantly decreased the cost of performing shotgun metagenomics for both taxonomic and functional readouts (Hillmann et al 2018).
  • There are now near-complete microbial genomic datasets available for European, North American and Asian populations (Almeida et al 2019) that will make it easier to functionally map datasets.

Prof. Gloor mentioned an interesting aside: prior clinical trial registration, ~60% of large clinical trials showed benefit of the intervention being tested. After the registration process required declaration of primary research outcomes, that number dropped to closer to 10% (Kaplan and Irvin 2015). This suggests that primary outcomes and analysis methods need to be in place to restrict researcher bias. Right now such mechanisms are insufficient in the microbiome field.

Prof. Gloor’s paper, Microbiome Datasets Are Compositional: And This Is Not Optional, provides great background reading for this webinar.

This webinar was developed by ISAPP Industry Advisory Committee representatives as an extension of the annual IAC Learning Forum.

Dr. Gloor is a professor of biochemistry with broad experience in molecular biology, genetics and genomics. His research is focused on the development of tools to examine 16S rRNA gene composition, gene expression of mixed population samples and metabolomic analysis of clinical samples. He is currently working on developing and adapting principled methods to characterize correlation and differential abundance in sparse, high throughput sequencing data as generated in 16S rRNA gene sequencing surveys, meta-genomics and meta-transcriptomics. One of his primary contributions has been the ALDEx2 tool in Bioconductor for the analysis of high-throughput experiments that generate counts per sequence tag: 16S rRNA gene sequencing, metagenomics, transcriptomics and selex-type experiments.

The Children of Masiphumelele Township

Gregor Reid PhD MBA FCAHS FRSC, Professor, Western University and Scientist, Lawson Health Research Institute, London, Canada

Just off the main road from Cape Town, South Africa to Simon’s Town, sits Masiphumelele township where challenges of poverty, malnutrition, HIV and the risk of violence face people every day.

It is also the location for the Desmond Tutu HIV Foundation Youth Centre, a safe haven that provides adolescent-friendly sexual and reproductive health services alongside educational and recreational activities for youth living in Masiphumelele and surrounding areas.

To understand some of the dangers that children face, in 2017, about 270,000 people in South Africa were newly infected with HIV, adding to one of the highest HIV prevalence rates in the world. The Tutu Youth Centre aims at helping educate youth to reduce their risk of becoming another HIV statistic.

I was invited there by University of Cape Town Professor Jo-Ann Passmore, a woman not only recognized for her research but whose passion for helping others is reflected in her warm smile (4th from left in group photo). She asked if I would be interested in holding a workshop to illustrate to the youth how using sachets of probiotic bacteria could empower them. I jumped at the chance. On an afternoon break from the Keystone Symposium, thirty researchers joined me along with Jo-Ann and my wife Debbie, a teacher of children with learning disabilities.

After a tour of the areas where children learn on computers, play games in safety, or have personal discussions about sexual health, everyone filled the room with a stunning backdrop of the Nobel Laureate’s image. Having been privileged to meet the Archbishop when he was hosted by St. Joseph’s Healthcare Foundation in 2008, it was a nerve-tingling experience for me.

Giving a lecture on beneficial microbes is hard enough to peers sitting in the back of the room, but to do so with young South Africans was more somewhat daunting. However, it proved to be a lot of fun especially when we had to identify kids who were good leaders (the boys all pointed to a girl), who liked to make stuff and sell it to others (two boys stood out). By the end, we had picked the ‘staff’ of a new company.

The next step was for four groups to decide on the company’s name, what products they’d make from the probiotic sachets (the options were many including yoghurt, cereals, fruit juices, maize), what marketing tools they would use and who they would target to obtain a respectable income.

Interestingly, several of the conference participants seemed less engaged, as if they had never considered how microbiology research could affect real lives. In front of them were children facing huge challenges on a day-to-day basis. In one group, the kids were quiet until my wife brought out pens and paper, then they went to town designing products, names and labels. A lesson for me on how different people need different stimuli to become engaged. The faculty left early to beat the traffic back to Cape Town, so unfortunately, they did not hear the outcome of the children’s work.

When we re-assembled to present the results, I was impressed with what could be created in such a short time. My favourite was the Amazing Maize, a bottle shaped like a corn cob with the idea it would contain fermented maize. It emphasized the importance of marketing and for products to taste and look good to be purchased.

It has been over ten years since Archbishop Tutu applauded us for the Western Heads East project and thanked us for empowering women and youth and contributing to nutrition in Africa. Since then, thanks to the huge efforts of Western staff and students, and more recently IDRC funding and partnerships especially with Yoba-for-life, Heifer International and Jomo Kenyatta University of Agriculture and Technology, over 260,000 people in east Africa are now consuming probiotic yoghurt every week. The children of the South African townships were maybe too young to join in this new wave of microenterprises, but at least now they have heard about it and the importance of fermented food and beneficial bacteria.

In the background of the workshop several wonderful women committed to start up a new production unit using the Yoba/Fiti sachets developed by Yoba-for-life. I left them some sachets for them to try out the process.

But it was me who left with the biggest lesson on how precious each life is, and how those of us with the knowledge, need to provide the means for others to use their own talents to fulfill the purposes of their lives.

No better way than to start with the children.

Humpty Dumpty and the Microbiome

Prof. Colin Hill, Microbiology Department and Alimentary Pharmabiotic Centre, University College Cork, Ireland (@colinhillucc)

When I use a word,” Humpty Dumpty said, in rather a scornful tone, “it means just what I choose it to mean—neither more nor less.”

Microbiome science is an evolving discipline, and new terminology is an important part of any developing field.  But precise language is important, especially in a multidisciplinary field with researchers from many diverse scientific backgrounds.  Language provides us a means of communicating with brevity and accuracy, but this is effective only if the reader is deriving the correct (intended) information from the author.

For example, is there a difference between ‘microbiome’, ‘microbiota’ and ‘microflora’?  Are the terms interchangeable, or would it be useful to have them mean related but distinctly different concepts?  I have heard people state that ‘microbiota’ refers to the microbial content of an environment, whereas ‘microbiome’ refers to the microbes AND their environment (the biome).  I have heard others suggest that ‘microbiome’ actually refers to the genetic content of a particular microbiota, in the same way that the genome is the genetic content of an organism.  Some definitions assert that the microbiome/microbiota/microflora only describes the microbial cells (bacteria, archaea and fungi) in a particular niche, while others include non-cellular microbes such as viruses and bacteriophage in their definition.  It has also been pointed out that ‘microflora’ is a misnomer, since technically the term ‘flora’ is reserved for the kingdom Plantae.

A few other examples.  Do we all know what is meant when someone uses the term ‘metagenomics’?  Also, people often refer to analysing the microbiome by 16S – but they are really only analysing the bacterial fraction of the microbiome, the ‘bacteriome’.  Of course ‘16S’ itself is not a valid term – it is 16S rRNA genes that are being analysed.  Would a clear distinction between microbiome, bacteriome, phageome, mycome, virome, archaeome and all the other ‘omes’ help or hinder our understanding of the subject under discussion?  Should most studies actually use the term ‘faecal bacteriome’ rather than ‘gut microbiome’, since it is almost always faeces that is under investigation, and usually only the bacterial component?

I am not going to call out any individuals for abuse of language, since I am pretty sure I could look at my own output and find lots of examples of poorly expressed concepts.  But does any of this matter or am I simply being pedantic? I think it does matter, since if terms are poorly defined it may lead to confusion on the part of the reader (or listener), whereas the authors (or speakers) may know exactly what they mean – neither more or less, as suggested by Humpty Dumpty.

ISAPP has convened consensus panels on the meaning of some very commonly used terms such as probiotic1 and prebiotic2, but there is a limit to this activity, and consensus panels cannot be convened for every new term.  Even with these consensus papers, we still have a plethora of additional terms surrounding beneficial microbes, including paraprobiotics (killed microbes), psychobiotics (originally defined as probiotics with a mental health benefit, but the definition has recently been expanded to any exogenous influence whose effect on the brain is bacterially-mediated3), synbiotics (probiotics and prebiotics administered simultaneously – a term for which ISAPP is convening another Consensus Panel in 2019), live biotherapeutics, etc, etc.  One site I saw referred to bacteriophage as a prebiotic, using the argument that they can influence a microbiome in a selective manner to achieve a beneficial outcome.  This is surely a good example of where the ISAPP definition could provide clarity since prebiotics have to be utilised in order to qualify for the term. Other terms we often use without an agreed consensus as to their meaning are ‘dysbiotic’ (when we could use disturbed, or different, or disrupted), ‘unculturable’ (when we usually mean ‘not yet cultured as far as I know but I haven’t really tried’), ‘hypothetical genes’ (when we actually mean ‘function unknown’), ‘stability’, ‘resilience’, etc.  It may be useful to have some kind of standardised microbiome dictionary, or an accepted glossary of terms.  This is not a new idea (so few of mine ever are), and Julian Marchesi and Jacques Ravel published a lovely short paper to this effect in 20154.  The World Microbiome Day website also has a very short Glossary5.

Obviously, words must be the servants of the author and should not restrict expression or limit our ideas, and in many instances context can make it abundantly clear what meaning is intended by the author.  But in general, a strict definition is not the enemy of understanding, but makes it easier for author and reader to share common ground.

Who should create and curate such a Microbiome Glossary?  Ideally it would be interactive, perhaps along the line of a wiki page, where people could provide their newly coined terms along with a strict definition and arrive at a consensus for commonly used terms.  Reviewers of journal papers and reviews could help, by challenging authors on what terms they use, and whether or not they are the appropriate ones.

Meanwhile, I have to go back to the lab to do some comprehensive metagenomics on the gut microbiome – by which I mean that a competent scientist who works with me is going to go into the lab and conduct a particular form of 16s rRNA gene analysis to profile the more abundant members of the bacteriome of a portion of a faecal sample which has been collected, stored and extracted according to our in-house protocols.  Obviously!

 

  1. Hill et al., 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.  Nat. Rev. Gastroenterol. Hepatol. 11, 506.
  2. Gibson et al., 2017. Expert consensus document: The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics.  Nat. Rev. Gastroenterol. Hepatol. 14, 491.
  3. Sarkar et al., 2016. Psychobiotics and the Manipulation of Bacteria–Gut–Brain Signals.  Trends in Neurosciences 39, 763
  4. Marchesi JR and J. Ravel. 2015. The vocabulary of microbiome research: a proposal.  Microbiome 3, 31
  5. http://worldmicrobiomeday.com/glossary-of-microbiome-terms/
hospital_room

Late initiation of probiotic therapy for acute pediatric gastroenteritis may account for null results

Francisco Guarner, MD, PhD, University Hospital Vall d’Hebron, Barcelona, Spain; Michael Cabana, MD, MPH, University of California, San Francisco, CA, USA; and Mary Ellen Sanders, PhD, International Scientific Association for Probiotics and Prebiotics, Centennial, CO, USA. 

Schnadower et al (1) and Freedman et al (2) conclude that probiotics given to children who presented to emergency departments with gastroenteritis are not effective; however, these new well-conducted trials used probiotics in children who were symptomatic much longer than when current recommendations suggest initiating therapy.  Both studies recruited children that were symptomatic for up to 72 hours or more at time of randomization. Half the cohort of Freedman (2) had diarrhea for 43 hours at randomization. In the study by Schnadower, (1) children were symptomatic at randomization for a median of 53 hours. It is not surprising that probiotic intervention at this late stage was not successful, since most children were close to spontaneous remission. Acute gastroenteritis in high-income countries is usually benign and after 48 hours typically remits spontaneously. These new studies should not change current recommendations (3,4,5) to use probiotics early after onset of pediatric gastroenteritis in conjunction with oral rehydration, consistent with previous beneficial trials.

 

  1. Schnadower D, Tarr PI, Casper TC, et al. Lactobacillus rhamnosus GG versus placebo for acute gastroenteritis in children. N Engl J Med. 2018; 379(21):2002-2014.
  2. Freedman SB, Williamson-Urquhart S, Farion KJ, et al. Multicenter trial of a combination probiotic for children with gastroenteritis. N Engl J Med. 2018;379(21):2015-2026.
  3. Allen SJ, Martinez EG, Gregorio GV, Dans LF. Probiotics for treating acute infectious diarrhoea. Cochrane Database Syst Rev. 2010 Nov 10;(11):CD003048.
  4. Szajewska H, Guarino A, Hojsak I, et al. Use of probiotics for management of acute gastroenteritis: a position paper by the ESPGHAN Working Group for Probiotics and Prebiotics. J Pediatr Gastroenterol Nutr. 2014;58(4):531-9.
  5. Lo Vecchio A, Dias JA, Berkley JA, et al. Comparison of recommendations in clinical practice guidelines for acute gastroenteritis in children. J Pediatr Gastroenterol Nutr. 2016;63(2):226-35.