By Kristina Campbell, science and medical writer
Even on the days when you don’t eat a large meal of Boston baked beans, the inside of your intestines is a gas-generating factory. This serves a valuable purpose for the body when everything is working as it should, with gases being produced and eliminated through a complex set of physiological processes. But sometimes gas becomes a problem—and this is when it’s valuable to know not only what contributes to intestinal gas symptoms, but also how dietary adjustments can alleviate some of the problems.
Dr. Fernando Azpiroz, Chief of Gastrointestinal Research at the Vall d’Hebron Research Institute and Professor of Medicine, Autonomous University of Barcelona (Spain), is an expert in both the pathophysiology of the gas produced in the digestive tract and the clinical problems related to intestinal gas. Dr. Azpiroz is the author of a chapter on intestinal gas in the well-known textbook, Sleisenger and Fordtran’s Gastrointestinal and Liver Disease, which is now in its 10th edition. And for more than 20 years he has been conducting research on digestive tract function, intestinal gas, and the contributions of the gut microbiota.
ISAPP caught up with Dr. Azpiroz to ask him about everything you wanted to know—where intestinal gas comes from, when it becomes a problem, and the latest research on the dietary changes that can reduce symptoms of intestinal gas while keeping the gut microbiota intact.
In different parts of the digestive tract, where does intestinal gas come from?
For the most part, the gas in the digestive system comes from metabolic activities of the colonic microbiota.
In addition, some air enters the stomach during swallowing. Most of this air is eliminated by eructation (i.e. burping), so there is a homeostasis. There is a small air chamber in the stomach of about 20 mLs, and this is pure atmospheric air, or CO2 after recent consumption of carbonated drinks.
In the small intestine, the neutralization of acids and alkali can theoretically produce large amounts of CO2. However, it’s more in theory than measured in experimental conditions.
Other gases originate from the metabolism of the gut microbiota. The residues of the diet that are not absorbed in the small bowel pass into the colon. These are the parts of the diets that we, as humans, cannot use. These pass into the colon, and in the colon serve as substrates for colonic microbiota. Gas is produced during this process of colonic fermentation.
What types of gases are produced in the digestive tract?
The composition of intestinal gas depends on where in the gut it is produced.
In the stomach, the gas is virtually all atmospheric air or CO2.
In the small bowel, theoretically it should be CO2, although the hard data are very scarce.
And in the colon, the largest component is likely hydrogen and CO2. But the data on that are very limited, and it is not known for sure that these theories are really true. The measurements of gas composition, in the colon or even in the gas eliminated per anus are still uncertain but so far the main concept is that most of the gas is hydrogen and CO2, and methane in subjects that have a methanogenic microbiota.
How does this gas normally get eliminated?
Throughout the GI tract, particularly the colon, about 80% of the gases produced are absorbed through the mucosa, pass into the blood, and are eliminated by breath. So only about 20-25% of the volume of gases produced, particularly in the colon, are eliminated per anus.
What influences the amount of gas produced?
The amount of gas produced in different subjects depends on two factors: one is the diet—the amount of residues (i.e. fiber) in the diet—and the second is the type of microbiota, which is very individual. It varies a lot from one subject to another.
How much intestinal gas is ‘too much’?
From the point of view of patients, of symptoms, what might be relevant is the volume of gases produced, and possibly the type of gases. One evolving idea is that some gases, which are produced in very small quantities, might serve as neurotransmitters, might play a role, but so far the information we have about the role of these gases is very limited so we cannot extrapolate that to clinical use.
Very recent data indicate that symptoms occur when the GI tract has a poor tolerance to its contents, and particularly to gas.
So what is the factor that makes gas produce symptoms? Well there are two factors. One is the amount of gas, and the other one is the tolerance of the subject.
In healthy subjects, it will typically take a large amount of gas to develop symptoms, if at all.
But even small amounts of gas in patients that have a hypersensitivity of the gut and poor tolerance to contents might contribute to their symptoms. This can be seen because, if we reduce the amount of flatulogenic substances in their diet, the symptoms reduce.
This is if we just take into consideration the volume of gas produced, but there is also another factor.
If we give a high flatulogenic diet or a high-residue diet, we know, because we have measured, that we increase the volume of gas produced into the colon. However, we also increase the amount of the fecal content in the colon. So it could be that these diets produce symptoms because they increase the amount of gas, but also because other non-gaseous components, the fecal content of the colon, also are poorly tolerated.
How can someone manipulate their diet to change the amount of intestinal gas that’s produced?
A ‘challenge’ diet, or a high flatulogenic diet in healthy subjects, makes them sick. They go from being symptom-free to having some symptoms, particularly flatulence and bloating.
In patients, the effect of the diet is more accentuated. If patients consume a diet with high residues they get very symptomatic, and if these patients will reduce residues in the diet, they see quite an improvement.
What are the options for dietary change when someone has IBS or wants to reduce gas symptoms?
One thing that has been shown recently is that the effect of a low-residue diet is similar regardless of the type of diet. In the past ten years or so there’s been a major trend with the use of low-FODMAP fermentable oligo-, di-, mono-saccharides and polyols diets.
However, the effect of these complex diets is not better than the effect of any sensible and simple low-residue diet. So if you reduce legumes, veggies from the diet, and fruits, you get a similar improvement.
The problem with low-residue diets, in particular the low-FODMAP diet, is that they introduce a restriction of the substrates for the feeding of the microbiota, and this is deleterious to the microbiota. The microbiota is impoverished.
The other limitation of low-residue diet is that the moment that the patient returns to a normal diet, the symptoms come back.
There is an alternative that has been shown in the past few years, which is to use some type of prebiotics that initially—because they are fermented—produce symptoms, but after a few days they induce an adaptation of the microbiota towards a microbiota that produces less gas with normal fermentation. And down the road, these prebiotics have a positive effect on symptoms in patients. As a matter of fact, the effect on symptoms is similar to a restrictive diet. The advantage of the prebiotics is that, after interruption, …the effect is sustained at least over a few weeks. And this is because it has been shown that prebiotics serve as substrates for microbiota and induce a proliferation of beneficial organisms.
There is also some preliminary evidence that some probiotics reduce the volume of gas production and reduce digestive symptoms in patients.
Is it a good idea to test your gut microbiota when you have IBS or gas symptoms?
There are different companies that claim that by analyzing microbiota they can diagnose some functional conditions, for instance IBS. The practical application of this technology has not been demonstrated. Usually they are expensive techniques and of no value.
It’s important to understand the real value of these methodologies and take the myth out of ‘wonder’ techniques that make a diagnosis from the microbiota and claim it explains everything.
Hopefully, this might be true in the future, but not right now. And actually many of the technologies that are used for this type of analysis are suboptimal.
A previous blog post by Dr. Bob Hutkins on diet, gut microbiota, and intestinal gas is ISAPP’s most-read blog post of all time. Read it here.
New publication gives a rundown on probiotics for primary care physicians
/in News, ISAPP Science Blog /by KCWith an increasing number of patients becoming aware of the human microbiome and its role in health, primary care physicians are faced with questions about probiotics as a possible strategy for maintaining health. Patients may see conflicting messages in the news and on product labels – so how can they know which probiotic benefits are scientifically proven?
A new publication in the Journal of Family Practice provides a quick update on evidence for the use of probiotics in different indications, so primary care physicians can equip themselves to provide evidence-based recommendations and to answer patients’ most commonly asked questions about probiotics.
Written by ISAPP board members Daniel J. Merenstein, MD and Mary Ellen Sanders, PhD, along with Daniel J. Tancredi, PhD, the article provides practical advice in the form of practice recommendations, along with comments about safety data from numerous clinical trials.
As Dr. Merenstein stated, “We wrote this article for working clinicians. They are interested in the science but are busy and want a straightforward evidence-based resource. We are hopeful this will be a go-to resource during the busy clinic day.”
Verbatim from the article are the following practice recommendations:
The full text can be accessed by logging into Medscape.
How some probiotic scientists are working to address COVID-19
/in ISAPP Science Blog, News /by KCBy ISAPP board of directors
With the global spread of COVID-19, the scientific community has experienced an unusual interruption. Across every field, many laboratories are temporarily shuttered and research programs of all sizes are on hiatus. Principal investigators around the world are doing their part to keep their students and local communities safe, and many are donating lab safety equipment to medical first responders who urgently need it.
In this global circumstance of research being put on hold, it is enlightening to consider what some scientists in the fields of probiotics, prebiotics, and fermented foods are working on—or proposing—in the context of understanding ways to combat viral threats. These individuals are rising to the scientific challenge of finding effective ways to prevent or treat viral infections, which may directly or indirectly contribute to progress against SARS-CoV-2.
Here, ISAPP shares words from some of these scientists—and how they have connected the dots from probiotics to coronavirus-related work with potential medical relevance.
Prof. Sarah Lebeer, University of Antwerp, Belgium: Relevance of the airway microbiome profile to COVID-19 respiratory infection and using certain lactobacilli to enhance delivery or efficacy of vaccines
Could the microbes in our upper and lower airways play a role in how we respond to the virus? Significant individual differences exist in the microbes that are prevalent and dominant in our airways. Lactobacilli are found in the respiratory tract, especially in the nasopharynx. They might originate there from the oral cavity via the oronasopharynx, but we have found some strains that seem to be more adapted to the respiratory environment, for example by expressing catalase enzymes to withstand oxidative stress. Currently we have a Cell Reports paper in press that shows certain lactobacilli are more prevalent in the upper respiratory tract of healthy people compared to those with chronic rhinosinusitis. Further investigation of one strain found in healthy people showed it inhibited growth and virulence of several upper respiratory tract pathogens. Our work on other viruses shows that certain lactobacilli can even block the attachment of viral particles to human cells. This raises the possibility that lactobacilli could be supplemented through a local spray to help improve defenses against the inhaled virus. Based on these data, we are initiating an exploratory study with clinicians and virologists on whether specific strains of lactobacilli in the nasopharynx and oropharynx could have potential to reduce viral activity via a multifactorial mode of action, including barrier-enhancing and anti-inflammatory effects, and reduce the risk of secondary bacterial infections in COVID-19.
Another line of exploratory research from our lab pertains to the delivery or efficacy of SARS-CoV-2 vaccines. Currently, many groups are rapidly developing vaccines, which predominantly use the viral spike S protein or its receptor-binding domain as antigen to induce protective immunity. We are exploring the potential of specific strains of lactobacilli with immunostimulatory effects as adjuvants for intranasal SARS-CoV-2 vaccination, or the potential of a genetically engineered antigen-producing organism for vaccine delivery.
At this year’s virtual ISAPP annual meeting, Dr. Karen Scott and I will also be leading an ISAPP discussion group called “How your gut microbiota can help protect against viral infections”. We will discuss previous work that has shown bacteria can have anti-viral effects. For many years, our colleagues, Profs. Hania Szajewska and Seppo Salminen, have studied a different virus, namely rotavirus, that causes acute diarrhea in children, and have found that Lactobacillus rhamnosus GG (new taxonomy Lacticaseibacillus rhamnosus GG) binds rotavirus and disables it, thereby blocking viral infection/multiplication. This may explain why this probiotic reduces the incidence and duration of acute diarrhea in children. Similar findings have been reported for specific probiotics and prebiotics and prevention of upper respiratory tract infections.
Prof. Rodolphe Barrangou, North Carolina State University, USA: Engineering probiotic lactobacilli for vaccine development
Between NC State University and Colorado State University (CSU) there is a historical collaborative effort aiming at engineering probiotics to develop novel vaccines. The intersection of probiotics and antivirals is the focus here with expressing antigens on the cell surface of probiotics to develop oral vaccines. The CSU infectious diseases center is very much fully operational and focused on COVID-19 now, and we recently received a research exception to open our lab for two individuals assigned to this NIH-funded project, and pivot our rotavirus efforts here to coronavirus. We are actively engineering Lactobacillus acidophilus probiotics expressing COVID-19 proteins to be tested as potential vaccines at CSU in the near future, as progress dictates.
Prof. Colin Hill, University College Cork, Ireland: The microbiome as a predictor of COVID-19 outcomes
We have recently proposed a project to examine oral and faecal microbiomes to identify correlations/associations between COVID-19 disease severity and individual microbiome profiles. If funded, we propose to analyse bacterial and viral components of the microbiome from three body sites (nasopharyngeal swabs, saliva, and faeces) in 200 donors and mine the data for biomarkers of disease risk and clinical severity. We will use machine learning to identify microbiome signatures in patients who contract the virus and remain asymptomatic, those who develop a mild infection, or those who have an acute infection requiring admission to an intensive care unit and intubation. This will enable microbiome-based risk stratification of subjects testing positive, and appropriate clinical management and early intervention, and prioritization of subjects for receiving an eventual vaccine.
Dr. Dinesh Saralaya, Bradford Institute for Health Research, UK: A live biotherapeutic product for targeted immunomodulation in COVID-19 infection
The COVID-19 pandemic presents an unprecedented challenge to our healthcare systems and we desperately require the rapid development of new therapies to ease the burden on our intensive care units. As well as its appropriate mechanism of action (targeted immunomodulation rather than broad immunosuppression), the highly favourable safety profile of MRx-4DP0004 makes it a particularly attractive candidate for COVID-19 patients, and may potentially allow us to prevent or delay their progression to requiring ventilation and intensive care.
The trial is a Phase II randomised, double-blind, placebo-controlled trial to evaluate the efficacy and safety of oral Live Biotherapeutic MRx-4DP0004 in addition to standard supportive care for hospitalised COVID-19 patients. Up to 90 subjects will be randomised 2:1 to receive either MRx-4DP0004 or placebo (two capsules, twice daily) for 14 days. The primary endpoint is change in mean clinical status score as measured by the WHO’s 9-point Ordinal Scale for Clinical Improvement, while secondary endpoints include a suite of additional measures of clinical efficacy such as need for and duration of ventilation, time to discharge, mortality, as well as safety and tolerability. The size and design of the trial are intended to generate a meaningful signal of clinical benefit as rapidly as possible.
Drs. Paul Wischmeyer and Anthony Sung, Duke University School of Medicine, USA: Probiotics for prevention or treatment of COVID-19 infection
We are planning several randomized clinical trials of probiotics in COVID-19 prevention and treatment. These trials are based on multiple randomized clinical trials and meta-analyses that have shown that prophylaxis with probiotics may reduce upper and lower respiratory tract infections, sepsis, and ventilator associated pneumonia by 30-50%. These benefits may be mediated by the beneficial effects of probiotics on the immune system. The Wischmeyer laboratory and others have shown that probiotics, such as Lactobacillus rhamnosus GG, can improve intestinal/lung barrier and homeostasis, increase regulatory T cells, improve anti-viral defense, and decrease pro-inflammatory cytokines in respiratory and systemic infections. These clinical and immunomodulatory benefits are especially relevant to individuals who have developed, or are at risk of developing, COVID-19. COVID-19 has been characterized by severe lower respiratory tract illness, and patients may manifest an excessive inflammatory response similar to cytokine release syndrome, which has been associated with increased complications and mortality. We hypothesize that probiotics will directly reduce COVID-19 infection risk and severity of disease/symptoms. Thus, we are proposing a range of trials, the first of which will be:
A Randomized, Double-Blind, Placebo-Controlled Trial of the PRObiotics To Eliminate COVID-19 Transmission in Exposed Household Contacts (PROTECT-EHC). Objective: Prevent infection and progression of illness in household contacts/caregivers of known COVID-19 patients exposed to COVID-19 (who have a >20-fold increased risk of infection). We will conduct a multicenter, randomized, double blind, phase 2 trial of the probiotic Lactobacillus rhamnosus GG vs. placebo to decrease infections and improve outcomes. This trial will include weekly collection of microbiome samples from multiple locations (i.e. fecal, oral). This trial will utilize a commercial probiotic, delivering 20 billion CFU of Lactobacillus rhamnosus GG, and placebo.
We are currently developing protocols to study prevention and treatment of COVID-19 in a range of other at-risk populations including: 1) Healthcare providers; 2) Hospitalized patients; 3) Nursing home and skilled nursing facilities workers. We are seeking additional funding and potential collaborators/trial sites for this work, and encourage interested funders and collaborators to reach out for further information or to join the effort at: Paul.Wischmeyer@nullduke.edu and also encourage you to follow our progress and our other probiotic/microbiome work on Twitter: @paul_wischmeyer
Prof. Gregor Reid, University of Western Ontario, Canada: Documenting anti-viral mechanisms of certain probiotic strains
While our institute is now studying the cytokine storm in COVID-19 patients, the closure of my lab has meant I have turned to surveying the literature: Prof. Glenn Gibson and I have a paper published in Frontiers in Public Health stating a case for probiotics and prebiotics to help ‘flatten the curve’ and keep patients from progressing to severe illness. There is good evidence that certain orally administered probiotic strains can reduce the incidence and severity of viral respiratory tract infections. Mechanistically this appears to be, in part, through modulation of inflammatory responses similar to those causing severe illness in COVID-2 patients, and antiviral activity — which has not been shown against SARS-Co-V2 but has been documented against common respiratory viruses, including influenza, rhinovirus and respiratory syncytial virus. Improving gut barrier integrity and affecting the gut-lung axis may also be part of these probiotics’ mechanism of action. At a time when drugs are being tried with little or no anti-COVID-19 data, probiotic strains documented for anti-viral, immunomodulatory and respiratory activities should be considered for clinical trials to be part of the armamentarium to reduce the burden and severity of this pandemic.
Rapid, collaborative effort
As the world waits in ‘lockdown’ mode, continued scientific progress for coronavirus prevention or treatment is critically important. ISAPP salutes all probiotic and prebiotic scientists who are stepping up to pursue unique solutions. Addressing the important research questions described above will require a rapid collaborative effort, from obtaining ethical approval and involving medical staff to collecting the samples, to recruiting participants as well as experts to process and analyze samples. All of this has to be done in record time – but from our experience of this scientific community, it’s definitely up to the challenge.
ISAPP provides guidance on use of probiotics and prebiotics in time of COVID-19
/in ISAPP Science Blog, News /by KCBy ISAPP board of directors
Summary: No probiotics or prebiotics have been shown to prevent or treat COVID-19 or inhibit the growth of SARSCoV-2. We recommend placebo-controlled trials be conducted, which have been undertaken by some research groups. If being used in clinical practice in advance of such evidence, we recommend a registry be organized to collect data on interventions and outcomes.
Many people active in the probiotic and prebiotic fields have been approached regarding their recommendations for using these interventions in an attempt to prevent or treat COVID-19. Here, the ISAPP board of directors provides some basic facts on this topic.
What is known. Some human trials have shown that specific probiotics can reduce the incidence and duration of common upper respiratory tract infections, especially in children (Hao et al. 2015; Luoto et al. 2014), but also with some evidence for adults (King et al. 2014) and nursing home residents (Van Puyenbroeck et al. 2012; Wang et al. 2018). However, not all evidence is of high quality and more trials are needed to confirm these findings, as well as determine the optimal strain(s), dosing regimens, time and duration of intervention. Further, we do not know how relevant these studies are for COVID-19, as the outcomes are for probiotic impact on upper respiratory tract infections, whereas COVID-19 is also a lower respiratory tract infection and inflammatory disease.
There is less information on the use of prebiotics for addressing respiratory issues than there is for probiotics, as they are used mainly to improve gut health. However, there is evidence supporting the use of galactans and fructans in infant formulae to reduce upper respiratory infections (Shahramian et al. 2018; Arslanoglu et al. 2008). A meta-analysis of synbiotics also showed promise in repressing respiratory infections (Chan et al. 2020).
Mechanistic underpinnings. Is there scientific evidence to suggest that probiotics or prebiotics could impact SARS-CoV-2? Data are very limited. Some laboratory studies have suggested that certain probiotics have anti-viral effects including against other forms of coronavirus (Chai et al. 2013). Other studies indicate the potential to interfere with the main host receptor of the SARS-CoV-2 virus, the angiotensin converting enzyme 2 (ACE2). For example, during milk fermentation, some lactobacilli have been shown to release peptides with high affinity for ACE (Li et al. 2019). Recently, Paenibacillus bacteria were shown to naturally produce carboxypeptidases homologous to ACE2 in structure and function (Minato et al. 2020). In mice, intranasal inoculation of Limosilactobacillus reuteri (formerly Lactobacillus reuteri) F275 (ATCC 23272) has been shown to have protective effects against lethal infection from a pneumonia virus of mice (PVM) (Garcia-Crespo et al. 2013). These data point towards immunomodulatory effects involving rapid, transient neutrophil recruitment in association with proinflammatory mediators but not Th1 cytokines. A recent study demonstrated that TLR4 signaling was crucial for the effects of preventive intranasal treatment with probiotic Lacticaseibacillus rhamnosus (formerly Lactobacillus rhamnosus) GG in a neonatal mouse model of influenza infection (Kumova et al., 2019). Whether these or other immunomodulatory effects, following local or oral administration, could be relevant to SARS-CoV-2 infections in humans is at present not known.
Our immune systems have evolved to respond to continual exposure to live microbes. Belkaid and Hand (2016) state: “The microbiota plays a fundamental role on the induction, training, and function of the host immune system. In return, the immune system has largely evolved as a means to maintain the symbiotic relationship of the host with these highly diverse and evolving microbes.” This suggests a mechanism whereby exposure to dietary microbes, including probiotics, could positively impact immune function (Sugimura et al. 2015; Jespersen et al. 2015).
The role of the gut in COVID-19. Many COVID-19 patients present with gastrointestinal symptoms and also suffer from sepsis that may originate in the gut. This could be an important element in the development and outcome of the disease. Though results from studies vary, it is evident that gastrointestinal symptoms, loss of taste, and diarrhea, in particular, can be features of the infection and may occur in the absence of overt respiratory symptoms. There is a suggestion that gastrointestinal symptoms are associated with a more severe disease course. Angiotensin converting enzyme 2 and virus nucleocapsid protein have been detected in gastrointestinal epithelial cells, and infectious virus particles have been isolated from feces. In some patients, viral RNA may be detectable in feces when nasopharyngeal samples are negative. The significance of these findings in terms of disease transmission is unknown but, in theory, do provide an opportunity for microbiome-modulating interventions that may have anti-viral effects (Cheung et al. 2020; Tian et al. 2020; Han et al. 2020).
A preprint (not peer reviewed) has recently been released, titled ‘Gut microbiota may underlie the predisposition of healthy individuals to COVID-19’ (Gao et al. 2020) suggesting that this could be an interesting research direction and worthy of further discussion. A review of China National Health Commission and National Administration of Traditional Chinese Medicine guidelines also suggested probiotic use, although more work on specific strains is needed (Mak et al. 2020).
Are probiotics or prebiotics safe? Currently marketed probiotics and prebiotics are available primarily as foods and food/dietary supplements, not as drugs to treat or prevent disease. Assuming they are manufactured in a manner consistent with applicable regulations, they should be safe for the generally healthy population and can be consumed during this time.
Baud et al. (in press) presented a case for probiotics and prebiotics to be part of the management of COVID-19. Although not fully aligned with ISAPP’s official position, readers may find the points made and references cited of interest.
Conclusion. We reiterate, currently no probiotics or prebiotics have been shown to prevent or treat COVID-19 or inhibit the growth of SARSCoV-2.
Connecting with the ISAPP community: Continuing to advance the science of probiotics and prebiotics
/in ISAPP Science Blog, News /by KCBy Mary Ellen Sanders PhD, executive science officer, ISAPP
On behalf of the ISAPP board of directors, I am reaching out to the ISAPP community to say we hope you are doing well and taking all the necessary steps in your local communities to remain healthy. At present, the global ISAPP community is physically distant but digitally close, and it is important for us to remain connected and strong.
ISAPP’s activities are as important as ever during this time of increased attention to health, and ISAPP is continuing to uphold its commitment to (1) stewardship, (2) advancing the science, and (3) working with stakeholders. Although our annual meeting, which some of you may have initially planned to attend, has been cancelled, other ISAPP activities are continuing or expanding as follows:
See here for all published ISAPP papers.
ISAPP board members, 2019 annual meeting
Messages about probiotics and COVID-19
With many conflicting and confusing health messages circulating during this global pandemic, including some criticisms of our field as well as some unsupported claims made by certain individuals and companies, ISAPP will remain an important touchstone for scientifically accurate information. Focusing on health effects is key to demonstrating probiotic and prebiotic efficacy, and we acknowledge that human studies are the ultimate measure of efficacy, but also, elucidating mechanisms of action help us understand how these interventions interface with the immune system and other mediators of health. Currently, there is some evidence that certain probiotics/prebiotics can reduce the risk of viral infections (discussed in other blog posts here and here), but it is important to remember that they have not been studied specifically for COVID-19 prevention or treatment. This must be acknowledged when communicating with the wider community.
We greatly appreciate the continued support of our IAC members. The ISAPP Board, colleagues, and SFA will continue to chart a course forward in preparation for life after the pandemic. Our intent is to emerge from these experiences more connected and purposeful than ever. We welcome suggestions on how collectively we can endure and strengthen the science and communications that remain foundations of our field.
Safety and efficacy of probiotics: Perspectives on JAMA viewpoint
/in ISAPP Science Blog /by KCBy Mary Ellen Sanders PhD, executive science officer, ISAPP, and Daniel Merenstein MD, Department of Family Medicine, Georgetown University School of Medicine
The Journal of the American Medical Association (JAMA) recently published a short viewpoint that called into question the safety and efficacy of probiotics. After careful review, we concluded that some opinions expressed were not consistent with available data. We share our perspectives here.
Claim 1: The paucity of high-quality data supporting the value of probiotics.
The authors speak to the “paucity” and “lack” of data supporting probiotic use. They criticize probiotic meta-analyses in general, even though there are many well-done ones, which describe clear PICOS, assess the quality of studies included, and assess publication bias. Many conclude that there is evidence that certain probiotics may be beneficial for several clinical endpoints. In the case of treatment of colic, an individual participant data meta-analysis was conducted on a single strain, and concluded “L reuteri DSM17938 is effective and can be recommended for breastfed infants with colic” (Sung et al. 2018). For necrotizing enterocolitis (NEC), a change in practice is recommended by a Cochrane meta-analysis (AlFaleh et al. 2018), which is consistent with draft American Gastroenterological Association (AGA) recommendations posted last month. In some cases, conclusions are qualified as being based on low quality data, which is also the case with many standard-of-care medical interventions. Other benefits supported for certain probiotics by evidence are shown in Table 1 of Sanders et al. 2018. But an evidence-based review of available data would not support a general statement that “data are lacking.”
Instead, we think a discussion of what evidence is actionable is reasonable to have. For this discussion, different people or groups can reasonably set the bar at different levels for what constitutes actionable evidence. But several medical organizations, including the European Society for Paediatric Gastroenterology, Hepatology and Nutrition, World Gastroenterology Organisation, American College of Gastroenterology, AGA (proposed, for antibiotic-associated diarrhea, NEC and pouchitis), European Crohn’s and Colitis Organization, and European Society for Primary Care Gastroenterology have actionable recommendations for probiotic use for one or more indications. For those indications, any individual physician may judge that the available evidence as not convincing to him or her, but many qualified healthcare experts did find the evidence convincing and have made recommendations accordingly. We recognize that the JAMA viewpoint was limited in the number of words and references allowed, but to impugn an entire field, the authors are obliged to explain why their views differ so much from established organizations.
The authors also criticize the inclusion of small, single-center trials in probiotic meta-analyses. They state such studies have less oversight, are more susceptible to misconduct and are at greater risk of bias than larger, multicenter trials, and thereby skew conclusions of meta-analyses in favor of probiotics. They state, without evidence, that small trials are more likely to show large effects and are more likely to be published. They advocate for meta-analyses that only include multi-center trials, thereby ignoring much available evidence on the basis of unsubstantiated preferences. There are a number of reasons why some trials are multi-center, but improved quality or closer monitoring are not among them (see here, here and here). Multicenter trials may be necessary to study a rare medical endpoint, a condition with an expected small effect size but significant health implications, or to accelerate the time course for a study. In fact, an analysis of 81 meta-analyses of RCTs in 2012 concluded:
In our experience, the size of a study does not inevitably minimize risk of bias. We have directly witnessed private physicians enroll for large multi-site trials without such oversight or professionalism. As the great David Sackett said in his paper from 20 years ago, “The more detailed the entry form and eligibility criteria for ‘somebody else’s’ RCT, the greater the risk the criteria will be ignored, misunderstood or misapplied by distracted clinicians who regard them as further intrusions into an overfull call schedule.” Further, due to often being underpowered, taken alone smaller studies are less, not more, likely to generate positive findings than larger trials. But when they are included in a meta-analysis, these studies contribute to the total body of evidence. We have personally worked on many single-center randomized controlled trials on probiotics. These often have monitors from the U.S. Food and Drug Administration and/or the National Institutes of Health, they are all registered with both primary and secondary outcomes listed, they utilize a data safety monitoring board, they undergo true allocation concealment, and otherwise are conducted to minimize risk of bias. To criticize probiotic studies for being single-center vs multicenter seems unjustified and baseless.
It is quite true that many of the studies conducted on probiotics were done 15 or more years ago, and the quality standards do not meet what we expect today. We wholeheartedly agree but would ask the authors to review studies conducted on drugs 15 years ago, and they will see the same issues. So we agree that more trials using modern quality standards are needed in the field of probiotics, as is the case for any interventions with a long history of being studied.
Claim 2: Potentially biased reviews of probiotic efficacy
In trying to explain why physicians might recommend probiotics, the authors speculate that some professional societies and some journals may be insufficiently critical in reviewing probiotic studies due to financial conflicts of interest. We have no doubt that there is bias in the scientific realm, which is not just limited to financial conflicts of interest, but question if there is any evidence that this occurs any more or less frequently with probiotics compared to any other realm of science. To leverage this accusation at the probiotic field specifically implies it is especially egregious, but no data supporting this accusation were provided. Also there is no face validity for this accusation. There is much more money to be made by pharmaceuticals and medical interventions than probiotic supplements and yogurts.
Claim 3: Complex framework in which probiotics are regulated and sold
The regulatory framework for probiotics can be difficult to navigate and is not always in the best interest of stakeholders, but we don’t think it’s reasonable to criticize the probiotic field for this situation. In the USA, probiotic products are bound by law that was enacted by Congress and the rules/guidance developed by the FDA for allowable product claims, levels of required regulatory oversight, and lack of requirements for premarket approval. It is fair to criticize Congress and the FDA for these circumstances surrounding the category of dietary supplements, but doing this in the context of an article on probiotics unfairly maligns probiotics.
Drugs vs dietary supplements. Most probiotics are sold as foods or dietary supplements. Since probiotics were first described as fermenting microbes in soured milk, this makes historical sense. Companies and consumers do not view these products as drugs, and in most cases they are not used as drugs. Outside a regulatory mindset, it makes perfect sense for foods to be useful for promoting health and managing symptoms, and this is what has driven 30 years of research and marketing of probiotics. Forcing all probiotics into a drug rubric would deprive consumers of access, would greatly increase their cost, and would preclude responsible food/supplement manufacturers from producing them. Drugs are drugs primarily to protect the safety of the patient. All drugs are assessed with a risk/benefit balance, and in some cases, the risk is significant. In the case of probiotics, we agree with the authors that most probiotics are likely safe for the general population. We see no reasonable justification to advocate that these products must all be researched and sold as drugs.
Probiotic product quality.The authors seem to prefer the drug model for probiotics based on a perceived need for improved product quality and oversight. Yet all foods and dietary supplements in the USA are required by law to be manufactured under good manufacturing practices. This includes most every product bought at the grocery store and served for dinner as well as probiotic foods and supplements. Further, companies are required to label their products in a truthful and not misleading fashion, including representations of contents and claims. Companies that fail to meet these standards are in violation of the law. Yes, there are products – of all types – that fall short of these requirements. The many responsible probiotic manufacturers and probiotic scientists decry such occurrences. However, these cases do not define the probiotic field any more than medical errors define physicians. It is not fair to impugn the entire probiotic industry based on the ‘bad apples’ that participate in it. A 2017 ESPGHAN review cites surveys of probiotic products from different regions globally, most of which report examples of probiotic products falling short in some quality attribute. Such surveys highlight quality problems, but due to sampling and methodological approaches, their results do not provide a reliable estimate of the extent of problem among commercial probiotic products. Many probiotic products are produced responsibly and are subjected to third party quality audits. The absence of such third party documentation is not evidence of poor quality, but we agree that it serves to improve consumer and healthcare provider confidence (see Jackson et al. 2019), and if more fully adopted, would weed out irresponsible probiotic manufacturers.
Oversight of probiotic research. The authors state, “If a manufacturer claims that any product, including a probiotic, cures, mitigates, treats, or prevents disease, the product is classified as a drug, thereby triggering a costly Investigational New Drug (IND) application process.” However, they seem to conflate the regulatory approach to product claims and the regulatory oversight of biologic drug research. In the case of product claims, if a product claims to cure, treat, prevent or mitigate disease, it is by definition a drug. If it has not undergone appropriate drug approval process, it is an illegally marketed drug and is subject to FDA action, including recall. Probiotics not destined for sale as drugs should not have to be researched under a drug rubric. This does NOT mean that such studies will de facto be substandard studies. We all understand the importance of conducting and reporting trials according to well-established guidelines. Studies on foods and supplements can and should follow those same principles.
Claim 4: Possible concerns about probiotic safety
The authors further state that studies identifying adverse events from probiotics are the “tip of the iceberg” – creating an image of a huge number of unreported adverse incidents poised to be revealed. We have personally studied the most widely used Bifidobacterium strain, and in well over 30,000 pediatric patient days have not seen any serious adverse events and no more adverse events than placebo. The article cited by the authors states that our trials adequately reported harm. Obviously, no intervention is harmless, and no one claims as much for probiotics. It is true that older probiotic studies can rightly be criticized for not rigorously collecting and reporting data on adverse events (Hempel et al. 2011). However, a reasonable assessment of all available data, including data from well-conducted clinical trials, including trials in vulnerable populations, history of safe use, FDA notified assessments for GRAS use of certain probiotic strains, European Food Safety Authority QPS list, and others support that commonly used probiotics have a strong safety record for use in the general public.
Transferable antibiotic resistance. Regarding the risk that probiotics may transfer antibiotic resistance genes, this is a hypothetical concern – there is no documented case of this. Further, one pillar of probiotic safety assessments is that strains with antibiotic resistance genes flanked by mobile genetic elements are excluded from commercialization. As stated by Ouwehand et al. 2016, “Probiotics are specifically selected to not contribute to the spread of antibiotic resistance and not carry transferable antibiotic resistance.” The current approach to probiotic safety is that complete, well annotated genome sequences are available for commercial strains. This information is typically included in GRAS notices submitted to the FDA, and all the major probiotic suppliers require this level of safety assessment. This is the expected standard by the European Food Safety Authority as well, a standard that we enthusiastically and unreservedly endorse. Transferable antibiotic resistance is not a lurking threat of probiotics use, but is a well-considered issue adequately addressed by responsible probiotic manufacturers.
Conclusion
We believe that this JAMA viewpoint misrepresents the totality of data on probiotics and can potentially do harm by dissuading use of probiotics in an evidence-based manner. Important points have been raised by the authors, especially with regard to the use of probiotics in vulnerable populations, but this does not characterize most of probiotic use. We agree, as we expect the majority of scientists working on probiotics would, that additional, well controlled human studies are needed. That was why we were pleased to see the authors’ studies assessing the impact of L. rhamnosus R0011 and L. helveticus R0052 or L. rhamnosus GG on acute pediatric gastroenteritis, even though the results of both studies were null (see blog post regarding these studies here and here). But as we await additional trials, we have a responsibility to consider available evidence. The authors raise many good points that the entire medical field could learn from, but there are clear indications for probiotics and they should continue to be used for these indications, likely benefitting many while harming few.
Acknowledgements
MES and DM are grateful for the critical review of this perspective by probiotic safety expert Dr. James Heimbach, biostatistician Dr. Daniel Tancredi, and gastroenterologist and probiotic expert Dr. Eamonn Quigley.
New names for important probiotic Lactobacillus species
/in ISAPP Science Blog, News /by KCBy Mary Ellen Sanders, PhD, and Sarah Lebeer, PhD
The genus Lactobacillus was listed as the fifth most important category of living organism to have influenced the planet throughout its evolutionary history in a 2009 book, What on Earth Evolved?. From their central role in food fermentations around the globe to their ability to benefit health in their human and animal hosts, species of Lactobacillus have great importance in our lives.
But for the past several decades there’s been a problem brewing with this genus. Using the research tools available at the time, researchers through history who discovered new bacteria grouped many diverse species under the “umbrella” of the genus Lactobacillus. Since the naming of the first Lactobacillus species, Lactobacillus delbrueckii, in 1901, microbial taxonomists assigned over 250 species to this genus.
These species were a diverse group, and when DNA analysis tools became more sophisticated, many were found to be only loosely related. A consensus grew among scientific experts that, given the genetic makeup of these bacteria, the current Lactobacillus genus was too diverse and did not conform to nomenclature conventions. Moreover, it was important to split the genus into functionally relevant groups that shared certain physiological, metabolic properties and lifestyles in order to facilitate functional and ecological studies on bacteria from this genus.
To tackle this problem, 15 scientists (see below) from 12 different institutions and 7 different countries came together, applying whole genome analysis to analyze each Lactobacillus species. Their proposal, which was accepted for publication in the official journal of record for bacterial names, is that the species once contained within the Lactobacillus genus should now spread over 25 genera, including 23 novel genera (see paper link here).
Based on this polyphasic approach, the authors reclassified the genus Lactobacillus into 25 genera including the emended genus Lactobacillus, which includes host-adapted organisms that have been referred to as the L. delbrueckii group; Paralactobacillus; as well as 23 novel genera: Acetilactobacillus, Agrilactobacillus, Amylolactobacillus, Apilactobacillus, Bombilactobacillus, Companilactobacillus, Dellaglioa, Fructilactobacillus, Furfurilactobacillus, Holzapfelia, Lacticaseibacillus, Lactiplantibacillus, Lapidilactobacillus, Latilactobacillus, Lentilactobacillus, Levilactobacillus, Ligilactobacillus, Limosilactobacillus, Liquorilactobacillus, Loigolactobacilus, Paucilactobacillus, Schleiferilactobacillus, and Secundilactobacillus.
While genus names have changed in some cases, the parts of the names that indicate species were not changed. See the table below for some examples of how names of important probiotic lactobacilli have changed. Note that all new genera proposed for this group begin with the letter “L”. Thus, the ‘L.’ genus abbreviation may still be used.
Because of the importance of this genus and the implications of the name change for both science and industry, the researchers involved in this project have developed a web-based tool that makes it very easy to determine the new names of all Lactobacillus species.
Scientifically, one exciting outcome of these new taxonomic groupings is that species that are more closely related, and therefore are more likely to share physiological traits, are grouped into the same genus. This may facilitate our understanding of common mechanisms that may mediate health benefits, as described in an ISAPP consensus paper and a publication entitled “Shared mechanisms among probiotic taxa: implications for general probiotic claims”.
To date, bacteria in the group Bifidobacterium have not changed, but nomenclature changes are expected soon for this genus, too.
Names of important Lactobacillus probiotic species
The following chart lists the new names for some prominent Lactobacillus probiotic species. (Note: All new genera proposed for this group begin with the letter “L”, so abbreviated genus/species – such as L. rhamnosus – remain unchanged.)
(aka Lactobacillus bulgaricus)
Authors
See ISAPP’s press release on the Lactobacillus name changes here.
ISAPP Students and Fellows Association announce blog posting: A new way to share our work and perspectives
/in News, ISAPP Science Blog /by KCBy Anna-Ursula Happel, president ISAPP-SFA and postdoctoral fellow at the Faculty of Health Sciences at the University of Cape Town, South Africa
Our professors keep telling us to write, write, write. Reports, papers, reviews, presentations. You can’t blame them as that’s what most of them had to do, and in a competitive environment academic output is critical. But while professors urge students to produce academic outputs, there’s a whole world of research ‘impact’ in a digital world that is beginning to matter for career advancement. To further our reach along this axis, we as the ISAPP-Students and Fellows Association (SFA) are launching a blog platform, which will be regularly updated with perspectives from our members and ideas on recent developments in the field of probiotics and prebiotics.
Our very first blog post centered on an innovative project I never thought I would hear about. Through our SFA meeting, I had heard about the Reid lab from Western University in Canada trying to find a way to prevent the decline of honey bee populations. It was a shock, since their focus for years has been women’s health. My first question to one of Dr. Reid’s students, Brendan Daisley, was: How did this come about? It turns out, the interest in how environmental toxins affect humans led to wondering how it helped really important pollinators. Not such a tangential switch as I’d thought. But what’s this got to do with the field of probiotics and my career?
Well, it shows that probiotics, as the definition states, can be applied to many hosts. It also shows that the microbiome plays a role in the health of insects as well as humans. And many of the study tools are the same – microbiota analysis, bioinformatics, immune responses, etc., yet some are totally different – using Drosophila models, counting larvae, measuring honey volumes. Read more about it here. The lesson for me: think laterally, look at how you can apply your knowledge, think of ecosystem health, and learn lots of basic skills.
Then, I thought to myself, how can research provide me with opportunities for developing leadership, initiatives and skills that are valuable for my careers. How can I gain visibility as an early-career researcher, grow my networks, improve my writing and scientific communication skills and find a platform to highlight projects that matter to me? The new blog will be helpful for all of this.
As members of the SFA, we’re very fortunate to have our voices heard; to organize our own annual meeting (well, except for 2020 when the world shut down); to be exposed to amazing scientists and ground breaking ideas – and to communicate our work, ideas and perspectives to a broad audience through our new blog. Beyond formal networking at annual meetings, the SFA blog now offers a way to stay actively connected throughout the entire year on a more informal platform with our peers, may strengthen ties within the community and even lead to collaborations and career opportunities.
See here for the ISAPP-SFA blog — bookmark it or watch for new posts on social media!
Twitter: @ISAPPSFA
[IN SPANISH] Creciente interés en Argentina en microorganismos benéficos y alimentos fermentados
/in Consumer Blog, ISAPP Science Blog /by KCDr. Prof. Gabriel Vinderola, Investigador Principal CONICET, Instituto de Lactología Industrial (INLAIN, CONICET-UNL), Profesor Asociado, Cátedra de Microbiología, Facultad de Ingeniería Química, Universidad Nacional del Litoral, Santa Fe, Argentina.
El interés sobre las bacterias intestinales, los alimentos fermentados y los probióticos está en aumento en Argentina y la región. Nutricionistas e influencers, que en los últimos años han comenzado a promover un estilo de vida más saludable, están aprovechando sus redes sociales para publicar recetas sobre cómo hacer alimentos fermentados, consejos para promover una microbiota más saludable e información sobre el posible papel de los probióticos y prebióticos en la salud humana. Pero, ¿están estas recomendaciones basadas en la ciencia? No siempre! En particular, he tenido la oportunidad de contribuir a que la comunicación sobre la microbiota, los alimentos fermentados, los probióticos y los prebióticos se haga desde la ciencia, para una audiencia amplia y con un leguaje simple.
En Argentina, y desde hace 50 años, hay un programa de televisión con un formato particular: la anfitriona, la Sra. Mirtha Legrand, cada domingo invita a almorzar a 4-6 personas para hablar, durante 3 horas, de política, economía, cultura popular, arte e incluso ciencia. Según ella, se trata del programa de televisión que se ha transmitido, ininterrumpidamente, por más tiempo en el mundo. Cada domingo, miles de personas de Argentina, Uruguay y Paraguay lo sintonizan. En octubre de 2019, me invitaron a unirme a la mesa y hablar sobre el mundo invisible que existe dentro y alrededor de nosotros. Discutimos cómo podemos beneficiarnos de las bacterias a través de alimentos fermentados y los probióticos, y cómo alimentar nuestros microbios intestinales con prebióticos. De hecho, en 2019, di más de 40 charlas sobre este tema a audiencias muy variadas a través de conferencias para profesionales, cursos para estudiantes de doctorado, seminarios y talleres para gente sin formación científica. Estas acciones están dirigidas no sólo a científicos y estudiantes, sino también a niños en escuelas, adolescentes en clubes deportivos y gimnasios o personal que trabaja en hospitales. El interés por los “bichos amistosos” es amplio y variado, y se alimenta de la información que circula por programas de radio y televisión.
“Almorzando con Mirtha Legrand”, un talk show que ha estado al aire en televisión por más de 50 años en Argentina, donde la discusión sobre microorganismos benéficos fue llevada a la mesa por Gabriel Vinderola (último a la derecha). Mirtha Legrand, de 93 años, está en el centro de los invitados (03/10/2019).
El entusiasmo de la audiencia fue inmediato. Se recibieron numerosos mensajes por correo electrónico, WhatsApp, Facebook o Instagram. La gente demostró estar interesada en saber más, preguntando por fuentes confiables para leer material con base científica, pero “fácil de entender”, planteando preguntas específicas sobre cuestiones intestinales, de dónde obtener probióticos y prebióticos o cómo hacer alimentos fermentados de manera segura. Afortunadamente, las infografías de la ISAPP sobre probióticos y prebióticos ya estaban disponibles en español, traducidas por Miguel Gueimonde (España) y por mí, y fueron un recurso muy utilizado. Sin embargo, la gente solicitaba más información, y hacía más y más preguntas específicas.
Estimulado por el creciente interés, me puse en contacto con una chef local, Ana Milena Giacomini, quien dejó atrás su carrera profesional de abogada para abrir un pequeño restaurante con un menú basado principalmente en alimentos fermentados. Ella ofrece sabrosos platos que incluyen yogur casero, chucrut, kimchi, kéfir de agua, humus fermentado, pan de masa madre, panqueques hechos de harina de arroz fermentada, kombucha, kvass y bebidas gasificadas a base de jengibre fermentado. Con ella organizamos talleres de 4 horas de duración, que actualmente están suspendidos debido a la pandemia por COVID-19. En estos talleres Ana prepara en vivo algunos de estos alimentos fermentados, para a continuación degustarlos, mientras yo explico la ciencia y la microbiología que hay detrás de ellos. Se discuten aspectos relacionados con la identidad, seguridad, estabilidad y los posibles efectos sobre la salud de estos productos. Siempre enfatizo las diferencias entre los alimentos fermentados y los probióticos, a la vez que discuto el potencial valor de incorporar alimentos fermentados, probióticos y prebióticos a la alimentación diaria como una forma de promover la salud intestinal. En estos talleres proporciono además información más específica sobre los efectos en la salud de probióticos para los que se dispone de sólidos meta-análisis que apoyan el uso de ciertos microorganismos en la prevención de la diarrea asociada a antibióticos en niños, el tratamiento de cólicos infantiles, la prevención de alergias y la reducción de la inflamación intestinal. Otros talleres con diferentes chefs de diferentes lugares de Argentina están en lista de espera para cuando esta pandemia de coronavirus termine.
Cena de cuatro pasos que incluye alimentos fermentados en cada plato, preparada por el chef argentino Martin Russo. La entrada consistía en zanahorias fermentadas y hummus, servidas en pan de masa madre.
En estos talleres se espera la asistencia de 30-35 personas cada vez. Entre ellas, nutricionistas interesados en dar respuestas adecuadas a sus pacientes, que se enteran de estos temas en los medios de comunicación o en las redes sociales. Pero también asisten personas que quieren aprender cómo hacer alimentos fermentados, dónde encontrar probióticos y prebióticos, u obtener una orientación clara sobre cómo incorporar bacterias vivas a su dieta. También asisten otros profesionales de la salud (gastroenterólogos, pediatras), docentes e incluso gente de la industria.
El postre eran bochas de helado cubiertas por la madre del vinagre (círculo transparente en la parte superior), enjuagadas y endulzadas.
La mayoría de los interesados en asistir a estos talleres tienen poca experiencia en alimentos fermentados, sólo están familiarizados con productos como el yogur, el queso, el vino o la cerveza. Es más, muchos de ellos desconocen que estos alimentos son fermentados, o no poseen una idea clara de lo que es la fermentación. La mayoría de ellos también tienen un conocimiento muy limitado, o incluso información errónea, sobre los probióticos y prebióticos. Estos talleres ofrecen la posibilidad de que personas interesadas en estos temas aprendan y prueben nuevos alimentos, de que conozcan la ciencia que hay detrás de los alimentos fermentados, los probióticos y los prebióticos, y de que aprendan las diferencias entre ellos de forma científica y en un “lenguaje fácil de seguir”. Estos encuentros son una forma de expandir el interés del público en general sobre el mundo invisible que habita dentro y alrededor nuestro.
Growing interest in beneficial microbes and fermented foods in Argentina
/in Consumer Blog, ISAPP Science Blog /by KCBy Prof. Gabriel Vinderola PhD, Associate Professor of Microbiology at the Faculty of Chemical Engineering from the National University of Litoral and Principal Researcher from CONICET at Dairy Products Institute (CONICET-UNL), Santa Fe, Argentina
Awareness of gut microbes, fermented foods and probiotics has been on the rise in Argentina. Nutritionists and influencers, who in recent years have begun promoting a healthier lifestyle, are leveraging their social networks to post how-to instructions for making fermented foods, advice to promote a ‘healthier’ microbiota, and information on the potential role of probiotics and prebiotics in human health. But are these news items and recommendations based on science? Not always! I’ve been fortunate to have had the opportunity to make sure the science is correctly communicated to a broad audience on the microbiome, fermented foods, probiotics and prebiotics.
In Argentina, for the last 50 years, there has been on the air a TV show with a particular format: the hostess, Miss Mirtha Legrand, invites 4-6 people to have lunch every Sunday, talking about politics, economy, popular culture, arts and even science for 3 hours. According to her, this is the longest continuously running TV program in the world. Every Sunday several thousands of people from Argentina, Uruguay and Paraguay tune in. In October 2019, I was invited to join the table and to comment about the invisible world inside and around us. We discussed how we can profit from bacteria through fermented foods and probiotics, and how to feed our gut microbes with prebiotics. In fact, in 2019, I gave more than 40 talks on this topic to scientific audiences at conferences, as courses for Ph.D. students, as seminars and as workshops. These efforts are targeted not only to local scientists and students, but also to children in schools, local sport clubs in small towns, gyms and hospitals. The interest in friendly bugs is wide-ranging and varied, and fueled by information from radio and TV programs.
“Having lunch with Mirtha Legrand”, a talk show on television for more than 50 years in Argentina, where the discussion on beneficial microbes was brought to the table by Prof. Gabriel Vinderola (far right). Mirtha Legrand, now 93 years old, is in the center (October 3rd, 2019).
The enthusiasm of the audience was immediately evident. Lots of messages came by email, WhatsApp, Facebook or Instagram. People were anxious to know more, inquiring about trustworthy sources to read scientific-based but “easy-to-understand” material, posing specific questions about their gut feelings, where to get these probiotics and prebiotics or how to make fermented foods in a safe manner. Fortunately, the ISAPP infographics on probiotics and prebiotics were already available in Spanish, translated by Miguel Gueimonde (Spain) and me, and these were a welcome resource. Yet people still wanted more information, and asked more and more specific questions.
Spurred by such widespread interest, I contacted a local lawyer-turned-chef, Ana Milena Giacomini, who left behind her professional law career to open a small restaurant with a menu heavily based on fermented foods. She features such delights as home-made yoghurt, chucrut, kimchi, sugary kefir, fermented hummus, sourdough bread, pancakes made out of fermented rice flour, kombucha, kvass and a gasified drink from fermented ginger. With her, we organized 4-hour workshops, which are currently on hold due to COVID-19. These workshops feature Ana preparing some of these fermented foods live, followed by tasting, while I explain the science and microbiology behind them. I share factors related to the identity, safety, stability, and potential health effects of these products. I emphasize the differences between fermented foods and probiotics, while discussing the potential value of incorporating fermented foods, probiotics and prebiotics to the daily diet as a way to promote gut health. I provide more specific information on health effects for which robust meta-analyses are available to support the microbes’ use, such as prevention of antibiotic-associated diarrhea in children, treatment of infant colic, prevention of allergies, and downregulation of intestinal inflammation. Other workshops with different chefs from different locations in Argentina are in line for when the coronavirus pandemic ends.
Part of the four-course dinner containing fermented foods prepared by chef Martin Russo. The starter consisted of fermented carrots and hummus, served on sourdough bread (pictured).
These workshops are expected to be attended by 30-35 people each time. Nutritionists are interested in giving sound responses to their clients, who hear about these topics in the media or in social networks. But also, people come who want to learn how to make fermented foods, where to find probiotics and prebiotics, or to gain clear guidance on how to incorporate live bacteria to their diets. Other health professionals (gastroenterologists, pediatricians), educators and even people from the industry also attend.
The dessert was ice cream balls covered by the mother of vinegar (transparent circle on the top), rinsed and sweetened.
Most people interested in attending these workshops have narrow experience with fermented foods, only being familiar with such things as yoghurt, cheese, wine or beer. Some of them do not know that these foods are indeed fermented, or do not have a clear idea what fermentation is about. Most of them also have a very limited awareness, or even misinformation, about probiotics and prebiotics. These workshops offer the possibility for the curious to learn and to taste new foods, to get insights on the science behind fermented foods, probiotics and prebiotics, and to learn the differences between them in a science-based manner in an “easy-to-follow language”. These encounters are a great way to expand the interest by the general public on the invisible world inside and around us.
The FDA’s view on the term probiotics, part 2: Further down the rabbit hole
/in ISAPP Science Blog, News /by KCBy James Heimbach, Ph.D., F.A.C.N., JHEIMBACH LLC, Port Royal, VA
A number of weeks ago I wrote on the ISAPP blog about US Food and Drug Administration (FDA) declining to file Generally Regarded As Safe (GRAS) notices that described the subject microorganism as a “probiotic” or “probiotic bacterium” (see The FDA’s view on the term “probiotics”). Now the FDA’s response to such GRAS notices has developed additional ramifications. Let me put them into two categories: Class 1 misdemeanors that will cause FDA to reject the notice, and Class 2 misdemeanors that will probably not prevent filing, but will cause FDA to raise questions. I should note that these thoughts are based on both my own direct experiences and my repeated telephone conference calls with FDA.
Class 1 Misdemeanors
Class 2 Misdemeanors
Good luck!
The Horses: Daily Routines in the COVID-19 Era
/in Consumer Blog /by KCBy Gregor Reid BSc (Hons), PhD, MBA, ARM CCM, Dr HS, FCAHS, FRSC
It’s dawn and as per every day, I put on my mask. It’s not the type of mask you might think in these anxious times. It’s to prepare hay bags for our two horses. Hay, filled with the dust and mold particles that frankly my lungs despise.
After preparing the hay, I then begin my walk. Our faithful dog by my side in between racing after a ball that ejects from a plastic thrower in my right hand. All around, the sounds of birds starting their day in song, zooming in to find a spot on a feeder filled with sunflower seeds and nuts. The air is cool, but it opens my lungs.
In half an hour, I will go back to our house and open up a computer screen that counts the dead and the ill from around the world. That sends me a litany of messages outlining new rules and procedures. The temptation to check savings has long passed. Not that they don’t matter. It’s just that we have to cope whatever they do.
As I walk past bare trees standing tall, itching to come alive, I think of frontline workers at hospitals being asked to check incoming sickness. Surely, managers, teachers or others could take over this public-facing role? We need to protect front-line health workers, or we won’t have them by our bedside. I know of one case where a super-highly qualified nurse was thrust into the cold air without protective gear and told to check incoming. The managers hadn’t fully understood what a virus is, how it infects and what is needed to stop it, and despite advance warning from other countries they had left the hospital and staff unprepared. The nurse had to demand personal protective equipment. Thankfully, awareness is growing. The messaging is now full-on.
Isn’t it easy to fathom what we’re all scared of? The cough, the sore throat, the fever then lungs that can’t seem to get enough air into our body? The fear of our calls not being answered, of not getting tested, and where we sit on the priority list when the ventilators are all taken? The fear of not seeing your mother again because planes won’t take you there and she’s too old to be saved.
It’s the first day of spring, so the leaves have not yet shuttered the sounds of motor vehicles on nearby roads, except today that constant hum is muted. It’s quiet outside. Humanity behind curtains. As it should be, even though we could never have imagined it.
I sit down for breakfast. Oatmeal, a probiotic milk drink that has data on fighting the flu, on top of frozen fruit melted in the microwave. A tablespoon of sunflower seeds and almonds the birds didn’t get. I pop my favourite probiotic along with a multi-vitamin perhaps only to sanctify my mind. Plus, a cup of tea, of course.
I re-read what my colleague in Britain, Glenn Gibson, has compiled. A brilliant piece on why probiotics may help us fight this coronavirus. I also wrote a commentary, well-intentioned but already met with cynicism via Twitter, that communication tool that never allows enough space to say what needs to be said, and is never enough for the addicted users.
Whatever we do to fight this miniscule blob looking only to live and multiply like the rest of us, we must do it with hope. For hope is our salvation. It is what we aspire to find. And if our time here has come to an end when we least expected it, we can still leave hope for others and tell them we tried our best to shine a light in the darkness. A light that will be their future. And if more time is given to us, then surely with every ounce of energy we will welcome the horses and the blessings of Mother Nature and pass our multitude of gifts to make the world a better place.
When I was at high school, our English teacher from the highlands had us read a poem written around the year I was born (1955) by a famous Scot, Edwin Muir. It’s called The Horses and I will leave it for you to read (substitute ‘fathers’ for ‘parents’). For Muir, these beautiful animals were creatures closest to his God. Animals to bring hope through the hours of sadness and fear.
Barely a twelvemonth after
The seven days war that put the world to sleep,
Late in the evening the strange horses came.
By then we had made our covenant with silence,
But in the first few days it was so still
We listened to our breathing and were afraid.
On the second day
The radios failed; we turned the knobs; no answer.
On the third day a warship passed us, heading north,
Dead bodies piled on the deck. On the sixth day
A plane plunged over us into the sea. Thereafter
Nothing. The radios dumb;
And still they stand in corners of our kitchens,
And stand, perhaps, turned on, in a million rooms
All over the world. But now if they should speak,
If on a sudden they should speak again,
If on the stroke of noon, a voice should speak,
We would not listen, we would not let it bring
That old bad world that swallowed its children quick
At one great gulp. We would not have it again.
Sometimes we think of the nations lying asleep,
Curled blindly in impenetrable sorrow,
And then the thought confounds us with its strangeness.
The tractors lie about our fields; at evening
They look like dank sea-monsters couched and waiting.
We leave them where they are and let them rust:
‘They’ll molder away and be like other loam.’
We make our oxen drag our rusty plows,
Long laid aside. We have gone back
Far past our fathers’ land.
And then, that evening
Late in the summer the strange horses came.
We heard a distant tapping on the road,
A deepening drumming; it stopped, went on again
And at the corner changed to hollow thunder.
We saw the heads
Like a wild wave charging and were afraid.
We had sold our horses in our fathers’ time
To buy new tractors. Now they were strange to us
As fabulous steeds set on an ancient shield.
Or illustrations in a book of knights.
We did not dare go near them. Yet they waited,
Stubborn and shy, as if they had been sent
By an old command to find our whereabouts
And that long-lost archaic companionship.
In the first moment we had never a thought
That they were creatures to be owned and used.
Among them were some half a dozen colts
Dropped in some wilderness of the broken world,
Yet new as if they had come from their own Eden.
Since then they have pulled our plows and borne our loads
But that free servitude still can pierce our hearts.
Our life is changed; their coming our beginning.
-Edwin Muir
Can probiotics and prebiotics go viral?
/in ISAPP Science Blog /by KCBy Prof. Glenn Gibson, Food Microbial Sciences Unit, Department of Food and Nutritional Sciences, The University of Reading, UK
I usually think that psychics are pretty funny and are to be avoided, but what about this from Sylvia Browne published in 2008? “In around 2020 a severe pneumonia-like illness will spread throughout the globe, attacking the lungs and the bronchial tubes and resisting all known treatments.”
Let’s hope the latter few words of this prophesy are badly wrong but, eerily, we are now living through this prediction made 12 years ago. The coronavirus (COVID-19) pandemic has dramatically changed the world in a few weeks, how we are currently behaving and how we will behave in future. I am typing this in my office at the university and have seen just one other person all morning. Who thought you could self-isolate by coming to work? It is a bit like living in a science fiction film, but this is real and very serious. Everyone is worried about themselves, family, friends, food, way of life, travel, entertainment, jobs, finance, property, ability to exercise, the more vulnerable members of society and other major challenges (not to mention toilet rolls, hand gels, soap). If we think humans run the world – then microbes may well have their own valid claim on that!
What can we do? Wait for a vaccine — science is progressing remarkably quickly on that front and it is brilliant to see. But what for now? How may we help flatten the infection curve?
I’ve always thought that the way you deal with harmful microorganisms is to attack them with other microbes, the simplest form of germ warfare (either their direct antagonism, non-specific immune effects or metabolic products). I’ve also thought that the below work from Kiel in Germany is among the most impressive studies I have seen on probiotics:
Effect of Lactobacillus gasseri PA 16/8, Bifidobacterium longum SP 07/3, B. bifidum MF 20/5 on Common Cold Episodes: A Double Blind, Randomized, Controlled Trial (2005)
Other similar research then followed. In 2015, the Cochrane group looked at the totality of such evidence available for all probiotics (Probiotics for preventing acute upper respiratory tract infections). They concluded “Probiotics were found to be better than placebo in reducing the number of participants experiencing episodes of acute URTI by about 47% and the duration of an episode of acute URTI by about 1.89 days.”
These studies convinced me that gut bacteria could mediate activities outside of their normal habitat – amazing! The German study showing a quantifiably speedier recovery from flu (almost 2 days quicker on average) and fewer symptoms (ca. 20% less), in a placebo-controlled trial involving a large number of volunteers, opened up new views for me on what probiotics could do. I must admit that I have been recommending the product to everyone I know since the COVID-19 outbreak started. By the way, if the manufacturers see this blog and you have experienced sales increasing in the Reading area or North East England (where I am from) then I am unashamedly taking the credit!! I have also been recommending a prebiotic for improved gut health, but this is no surprise since it is a product my research group first developed in 2000 and worked upon in human intervention studies until 2017.
The plot thickened yesterday, when I was made aware of this article published a few weeks ago:
2019 Novel coronavirus infection and gastrointestinal tract
For the last couple of years, I have been lucky to have worked with one of the world’s leading campaigners Alan Barnard (more later). His summary on the above paper has been sent to the UK Government, other MPs and Lords and is as follows:
In the article, the authors say:
A representative of the Government has acknowledged that they are now aware of the research. I feel this is great news in having this at least on their radar screen and that the UK may consider it as part of the mixture of responses.
As we would expect, Gregor Reid is right on the case and published an excellent opinion piece yesterday: Can bacteria help humans fight COVID-19?
Gregor says, “there is a scientific basis for probiotics helping the respiratory tract against colds and flu, and right now we’re short on therapies for COVID-19. We’re only asking for people to consider this and maybe someone to instigate a quick study. If they can get a vaccine into testing by now in the US, someone should test a probiotic versus placebo.”
Then, there is this today: Coronavirus: Australian scientists map how immune system fights virus summarising research published in Nature Medicine, that showed people are recovering from the new virus like they would from the flu. “This is important because it is the first time where we are really understanding how our immune system fights novel coronavirus,” said co-author Prof Katherine Kedzierska. She also said, “It is really key now to understand what is lacking or different in patients who have died or who have really severe disease – so we can understand how to protect them.” Well, we know that indigenous gut bifidobacteria (strains of which are used as probiotics) do decrease with age and this possibly contributes to so-called “immunosenescence” with concomitant higher risk of acquiring, and dealing with, infections. Hence, great interest in probiotic and prebiotic use for the older adults in our societies, ever since the Crownalife EU funded research which ended in 2004 (by the way, my views on the effect of Brexit to UK science and society generally are not publishable…). But guess what? – two probiotic strains used in the German cold and flu trials cited above were bifidobacteria.
I know some cleverer people than I will rubbish all of this but, in my humbly subjective view, there are too many jigsaw pieces to ignore here and I will keep on recommending the probiotic and prebiotic products.
Back to Alan, here is his new effective and striking message on COVID-19, now rolled out all over the UK:
ISAPP is delighted to work with Alan, and he attended our Antwerp conference in 2019. Together we helped set up an All Party Parliamentary Group (APPG) on the microbiome chaired by the esteemed Julie Elliot MP (whom we approached because of her boundless energy but also because she is a Sunderland AFC fan – the unequivocal professional and personal seal of approval). As part of the APPG activities, we were very pleased to welcome Lords Taylor (of Holbeach) and Haworth (of Fisherfield) to our gut model laboratories in Reading 2 weeks ago. Both their Lordships were very positive about probiotics and prebiotics, promising to help propel the messages.
A further peer, Lord Stone of Blackheath, even went as far as mentioning ISAPP in a House of Lords debate on wellbeing held on March 12th. At the end of his speech, Lord Stone said:
Do these views apply to the COVID-19 outbreak, the world’s most serious and unprecedented issue of modern times? Obviously, there is no evidence that probiotics or prebiotics directly influence COVID-19 and we may never know if they will, but a quick benefit-to-risk thought makes recommendation of some a “no brainer” for me.
The science on gut microbiota and intestinal gas: Everything you wanted to know but didn’t want to ask
/in Consumer Blog, ISAPP Science Blog /by KCBy Kristina Campbell, science and medical writer
Even on the days when you don’t eat a large meal of Boston baked beans, the inside of your intestines is a gas-generating factory. This serves a valuable purpose for the body when everything is working as it should, with gases being produced and eliminated through a complex set of physiological processes. But sometimes gas becomes a problem—and this is when it’s valuable to know not only what contributes to intestinal gas symptoms, but also how dietary adjustments can alleviate some of the problems.
Dr. Fernando Azpiroz, Chief of Gastrointestinal Research at the Vall d’Hebron Research Institute and Professor of Medicine, Autonomous University of Barcelona (Spain), is an expert in both the pathophysiology of the gas produced in the digestive tract and the clinical problems related to intestinal gas. Dr. Azpiroz is the author of a chapter on intestinal gas in the well-known textbook, Sleisenger and Fordtran’s Gastrointestinal and Liver Disease, which is now in its 10th edition. And for more than 20 years he has been conducting research on digestive tract function, intestinal gas, and the contributions of the gut microbiota.
ISAPP caught up with Dr. Azpiroz to ask him about everything you wanted to know—where intestinal gas comes from, when it becomes a problem, and the latest research on the dietary changes that can reduce symptoms of intestinal gas while keeping the gut microbiota intact.
In different parts of the digestive tract, where does intestinal gas come from?
In addition, some air enters the stomach during swallowing. Most of this air is eliminated by eructation (i.e. burping), so there is a homeostasis. There is a small air chamber in the stomach of about 20 mLs, and this is pure atmospheric air, or CO2 after recent consumption of carbonated drinks.
In the small intestine, the neutralization of acids and alkali can theoretically produce large amounts of CO2. However, it’s more in theory than measured in experimental conditions.
Other gases originate from the metabolism of the gut microbiota. The residues of the diet that are not absorbed in the small bowel pass into the colon. These are the parts of the diets that we, as humans, cannot use. These pass into the colon, and in the colon serve as substrates for colonic microbiota. Gas is produced during this process of colonic fermentation.
What types of gases are produced in the digestive tract?
The composition of intestinal gas depends on where in the gut it is produced.
In the stomach, the gas is virtually all atmospheric air or CO2.
In the small bowel, theoretically it should be CO2, although the hard data are very scarce.
And in the colon, the largest component is likely hydrogen and CO2. But the data on that are very limited, and it is not known for sure that these theories are really true. The measurements of gas composition, in the colon or even in the gas eliminated per anus are still uncertain but so far the main concept is that most of the gas is hydrogen and CO2, and methane in subjects that have a methanogenic microbiota.
How does this gas normally get eliminated?
Throughout the GI tract, particularly the colon, about 80% of the gases produced are absorbed through the mucosa, pass into the blood, and are eliminated by breath. So only about 20-25% of the volume of gases produced, particularly in the colon, are eliminated per anus.
What influences the amount of gas produced?
The amount of gas produced in different subjects depends on two factors: one is the diet—the amount of residues (i.e. fiber) in the diet—and the second is the type of microbiota, which is very individual. It varies a lot from one subject to another.
How much intestinal gas is ‘too much’?
From the point of view of patients, of symptoms, what might be relevant is the volume of gases produced, and possibly the type of gases. One evolving idea is that some gases, which are produced in very small quantities, might serve as neurotransmitters, might play a role, but so far the information we have about the role of these gases is very limited so we cannot extrapolate that to clinical use.
So what is the factor that makes gas produce symptoms? Well there are two factors. One is the amount of gas, and the other one is the tolerance of the subject.
In healthy subjects, it will typically take a large amount of gas to develop symptoms, if at all.
But even small amounts of gas in patients that have a hypersensitivity of the gut and poor tolerance to contents might contribute to their symptoms. This can be seen because, if we reduce the amount of flatulogenic substances in their diet, the symptoms reduce.
This is if we just take into consideration the volume of gas produced, but there is also another factor.
If we give a high flatulogenic diet or a high-residue diet, we know, because we have measured, that we increase the volume of gas produced into the colon. However, we also increase the amount of the fecal content in the colon. So it could be that these diets produce symptoms because they increase the amount of gas, but also because other non-gaseous components, the fecal content of the colon, also are poorly tolerated.
How can someone manipulate their diet to change the amount of intestinal gas that’s produced?
A ‘challenge’ diet, or a high flatulogenic diet in healthy subjects, makes them sick. They go from being symptom-free to having some symptoms, particularly flatulence and bloating.
In patients, the effect of the diet is more accentuated. If patients consume a diet with high residues they get very symptomatic, and if these patients will reduce residues in the diet, they see quite an improvement.
What are the options for dietary change when someone has IBS or wants to reduce gas symptoms?
One thing that has been shown recently is that the effect of a low-residue diet is similar regardless of the type of diet. In the past ten years or so there’s been a major trend with the use of low-FODMAP fermentable oligo-, di-, mono-saccharides and polyols diets.
However, the effect of these complex diets is not better than the effect of any sensible and simple low-residue diet. So if you reduce legumes, veggies from the diet, and fruits, you get a similar improvement.
The problem with low-residue diets, in particular the low-FODMAP diet, is that they introduce a restriction of the substrates for the feeding of the microbiota, and this is deleterious to the microbiota. The microbiota is impoverished.
The other limitation of low-residue diet is that the moment that the patient returns to a normal diet, the symptoms come back.
There is an alternative that has been shown in the past few years, which is to use some type of prebiotics that initially—because they are fermented—produce symptoms, but after a few days they induce an adaptation of the microbiota towards a microbiota that produces less gas with normal fermentation. And down the road, these prebiotics have a positive effect on symptoms in patients. As a matter of fact, the effect on symptoms is similar to a restrictive diet. The advantage of the prebiotics is that, after interruption, …the effect is sustained at least over a few weeks. And this is because it has been shown that prebiotics serve as substrates for microbiota and induce a proliferation of beneficial organisms.
There is also some preliminary evidence that some probiotics reduce the volume of gas production and reduce digestive symptoms in patients.
Is it a good idea to test your gut microbiota when you have IBS or gas symptoms?
There are different companies that claim that by analyzing microbiota they can diagnose some functional conditions, for instance IBS. The practical application of this technology has not been demonstrated. Usually they are expensive techniques and of no value.
It’s important to understand the real value of these methodologies and take the myth out of ‘wonder’ techniques that make a diagnosis from the microbiota and claim it explains everything.
Hopefully, this might be true in the future, but not right now. And actually many of the technologies that are used for this type of analysis are suboptimal.
A previous blog post by Dr. Bob Hutkins on diet, gut microbiota, and intestinal gas is ISAPP’s most-read blog post of all time. Read it here.
A Miracle Treatment! Or Not?
/in ISAPP Science Blog /by KCBy Daniel J. Merenstein, MD, Professor, Department of Family Medicine and Director of Research Programs, Georgetown University Medical Center, Washington DC
Here’s a scenario for a physician: A drug rep walks into your office. She has a new product she wants to talk to you about. You are super excited to talk to her as you have heard all about this product from many other sources. The data that are being reported are amazing. There are hundreds if not many more case reports of it working. People were dying and then totally recovered after being given this product. It has been witnessed and published! The efficacy is well over 90%. You are not sure there is any intervention you have ever heard of that has such amazing efficacy. She tells you that in some of the cases, the patients were very sick and despite numerous courses of antibiotics they did not improve until this new product was given. You ask for more information as you are starting to think this must be like when doctors first heard of penicillin.
The product can be taken orally but that is not the way it is generally given. She tells you that although there are 2-3 ways to administer, most hospitals are doing it the most expensive way now. (You later learn that the typical– and most expensive – approach to administering the product may not even be the best approach.) But you withhold judgement as this sounds exciting. And remember, you have been hearing all about this from so many different sources.
But as you listen, it gets a little confusing. She tells you that the makeup of the product is different in nearly every application. This makes it exciting to use, as one really never knows what is in it. It is also relatively cheap to obtain, as the patient can have a friend just bring it in for them.
Since you are trained in evidence-based medicine, you ask a few questions. It is exciting there are all sorts of case reports but what about the randomized controlled trials, and what does the FDA say about it? You ask if you can look at the trials—there is no way you can review hundreds of studies now but if she leaves them for you, you will look at them this weekend. But before she leaves you ask a few quick questions. How many of these studies are randomized? She says 10. How many use a placebo? She says 6. You tell her what you really want to do is review all the randomized placebo-controlled blinded studies, if she can just leave those.
Later in the week you go pick up the folder she left and right away are a little surprised at how light it is. It looks like there are only 3 randomized placebo-controlled blinded studies, only two of which are peer-reviewed and published. One was a positive study; overall, 91% of patients in the new drug group achieved clinical cure compared with 63% in the control group. But you realize this is not exactly a placebo-controlled trial. What they did is compare two types of the new application. Furthermore, this study was conducted at two sites and at one of the sites both the new application and the control had nearly identical rates of improvement, both over 90%. Okay so this was not a perfect study, only 46 total participants, but still pretty exciting with over 90% improvement.
The second study had three groups of 83 people. Group A (2 doses of new drug), B (2 doses of placebo) and C (1 dose of new drug and 1 placebo dose). The efficacy for these three groups was 61%, 45%, and 67%, respectively. The primary endpoint was not met (P = .152). Interestingly, Group C, which included one dose of placebo, was superior to all placebo (group B) but Group A, in which the drug was given two times, was not superior to placebo.
The third study, a Phase II trial, appears to not be peer-reviewed or published, but just reported online. However, it does appear this was far from a positive study, with 44% of subjects (26 of 59) who received the new application improving versus 53% of subjects (16 of 30) who received placebo. I have been told that this study will be published soon and that a Phase III study of this intervention was also undertaken.
Well now you are getting a little more confused. You have heard from fellow docs, the lay press, medical literature and the drug rep that this new application was over 90% effective. But it appears in the three reasonably well controlled studies, the ones from which we can really draw conclusions, only one was positive and in that study the control was not a real placebo.
Besides efficacy, you remember that one has to always consider the cost and adverse events. Maybe this new application is like recommending the Mediterranean Diet, where the efficacy from studies is limited but the adverse events are nearly non-existent. But when you do a quick PubMed search you learn that this is far from the case with this product. This application has been reported to cause very serious adverse events, including extended-spectrum beta-lactamase (ESBL)–producing Escherichia coli bacteremia resulting in one death. You look online expecting that the FDA must have some serious warnings about this new drug. You don’t find any such warnings.
You may have guessed that the product is in fact a Fecal Microbiota Transplant (FMT). Besides having a professional interest in this much-discussed treatment, I have a personal interest. Last year my son was in a Johns Hopkins Hospital with a central line and two broad-spectrum antibiotics for a bone infection. I asked them to provide him with probiotics since the number needed to treat to prevent pediatric antibiotic associated diarrhea is 9, per a 2019 Cochrane review. This review included 20 randomized, placebo-controlled studies of a single strain. However, I was told no Hopkins hospital will administer probiotics, and further, that we could not even bring in our own because of concerns for the safety of others. But no worries – if my son got recurrent C. diff infection, Hopkins would allow this great new procedure, FMT.
In medicine I cannot truly imagine a probiotic with the same evidence base as FMT receiving such widespread acceptance and escaping regulatory scrutiny. And currently used probiotics have an excellent safety record. Just imagine, if this were a new drug being sold there would be widespread condemnation of the attempt to get approval mainly based on anecdotal case reports. Shockingly, based on the level of evidence I have described many experts now think a randomized placebo-controlled trial is not even ethical for the placebo group, as of course they know FMT works.
It is a quandary. I am not opposed to FMT; I find it fascinating. But why has it been so widely accepted and why has the FDA, which in general has been very careful with probiotic applications in medicine, allowed this to proceed for recurrent C diff infection with only enforcement discretion? Both treatments administer live microorganisms, one with 31 placebo controlled randomized trials, including 8672 subjects [of C. diff prevention (number needed to prevent=42), not treatment like FMT], the other with pretty limited data. I have my thoughts, but better for you to ponder it.
Additional related content:
Webinar presenting current level of evidence for FMT: FECAL MICROBIOTA TRANSPLANTATION, AM I SURE IT WORKS? Oct 29, 2020. Presented by Prof. Daniel Merenstein, introduced by Prof. Hania Szajewska, sponsored by Centro Studi Scientifici, La Marcigliana.
The past decade of probiotics and prebiotics research: ISAPP board members share their perspectives.
/in ISAPP Science Blog, Consumer Blog /by KCBy ISAPP board members, compiled by Kristina Campbell
Scientific progress in the field of probiotics and prebiotics, as in any other field, often seems to occur one tiny step at a time. Yet over the course of several years, these tiny steps can add up to significant progress.
Current members of the ISAPP board of directors hold academic positions across North America, and Europe, representing some of the experts at the forefront of scientific innovation in probiotics and prebiotics. Their collective experience encompasses functional foods, fermentations, microbial ecology, microbial genetics, immunology, and clinical medicine, including pediatrics, family medicine and gastroenterology. As we enter into 2020 and a new decade, these board members have taken a moment to reflect on how far they and their colleagues have come over the past ten years, by answering the question: What changes have occurred in the domains of research, applications, and awareness about probiotics and prebiotics?
ISAPP board members, 2019 annual meeting
Available scientific methods and tools
The change that stood out the most to the ISAPP board members over the past decade was the rapid expansion of available scientific methods and tools – from gene sequencing technology to CRISPR-Cas to bioinformatic approaches. These exciting developments have enabled scientists to obtain more information, and to do it both quickly and economically. In the words of the board members:
Probiotics and prebiotics for microbiome modulation
Because of the rapid advancements in scientific tools and techniques during the past decade, as mentioned above, many more research groups are endeavoring to study the microbial communities that relate to probiotics and prebiotics. Gut microbiota are of great interest—not least because, among the strategies for microbiome modulation, probiotics and prebiotics are two of the leading candidates. Moreover, microbiome data can help researchers understand the context of probiotics and prebiotics in the gut and in different environments. In particular, many clinical trials of probiotics and prebiotics now include a microbiota-related measure. Novel species and strains for food use may be identified from gut microbiota studies, although safety and efficacy assessment will form challenges for regulatory bodies. Board members said:
Probiotic mechanisms of action
Probiotic mechanisms of action are a perennial hot topic within the scientific community—and many had hoped that the new suite of scientific tools at scientists’ disposal would significantly advance this area of research during the past decade. But according to one ISAPP board member:
But in the views of other board members:
Probiotic and prebiotic applications
In general, microbiome studies of the past decade have led to a better appreciation of the ubiquity and complexity of microbial communities—not just those associated with different human body sites, but also those occupying every possible niche on Earth. ISAPP board members reflect:
Public awareness of probiotics and prebiotics
Numerous studies and surveys show the general public has more awareness than ever of probiotics – and increasingly, of prebiotics too. Individuals receive their information through many different channels, both digital (e.g. blogs, websites) and non-digital (e.g. magazines, product packaging). The past decade also saw the creation of valuable evidence-based resources, such as the Clinical Guides available in the US and Canada, and resources from World Gastroenterology Organisation and from ESPGHAN (probiotics for pediatric acute gastroenteritis, pediatric nosocomial diarrhea, preterm infants, and pediatric AAD). These resources have been enabled by a critical mass of studies that have examined the efficacy of various probiotic strains for certain indications. One board member says:
But there’s still work to be done:
It seems that, while the past decade has been a fruitful time for probiotics and prebiotics research and public awareness, scientists still have a lot of work to do. In the 2020s they will use the tools available to them, and continue to develop new ones, to gain more detailed and multi-faceted information about probiotic strains and prebiotic compounds—and about the context in which they operate (for instance, the gut microbiome), to ultimately confer benefits on human health.
The FDA’s view on the term probiotics, part 1
/in ISAPP Science Blog, News /by KCBy James Heimbach, Ph.D., F.A.C.N., JHEIMBACH LLC, Port Royal, VA
James Heimbach, food and nutrition regulatory consultant
Over the past 20 years as a food and nutrition regulatory consultant, I have filed about 40 GRAS notices with the United States Food and Drug Administration (FDA), including 15 strains of probiotic bacteria and 5 prebiotics. This fall I submitted notices dealing with 4 strains of bacteria and on January 16 received a telephone call from FDA that surprised me and initially infuriated me, but which I have come to understand.
The essence of the call was that FDA was declining to file my probiotic notices because the notices had identified the subject bacteria as “probiotics” or “probiotic bacteria.” FDA suggested that I resubmit without calling the subject microorganisms “probiotics.”
As I said, I was surprised and frustrated, and I still would prefer that when FDA makes a policy swerve they would do it in a way that does not make extra work for me and delay my clients’ ability to get to market in a timely manner.
What I have had to do here is remove my advocate’s hat and put on my regulator’s hat. (I worked for FDA for a decade . . . long ago [1978 to 1988], but I still remember how to think like a regulator.) And here is the issue. Recall that GRAS is concerned with safety, not efficacy (generally recognized as safe, or GRAS), and the information provided in a GRAS notice is focused on safety (although benefits may be more-or-less incidentally covered). The reviewers at FDA are charged with assessing whether the notice provides an adequate basis to conclude that there is a reasonable certainty that no harm will result from the intended use. They are not charged, and they are not equipped, to evaluate what benefits ingestion of the substance or microorganism might provide. So they are not in a position to say whether the subject microorganism will “confer a health benefit on the host,” which is to say, they are not in a position to say whether or not it may be regarded as a probiotic. Remember, probiotics are defined as live microorganisms that, when administered in adequate amounts, confer a health benefit on the host (Hill et al. 2014).
Given that the FDA reviewers cannot say whether the notified microorganism is rightly called a probiotic, they are reluctant to sign off that they have no questions about a notice that calls it one. Regulatory agencies have to be careful; things sometimes come back to haunt them. Those who have been following FDA’s GRAS-notice response letters for a couple of decades will be aware that the agency is putting more and more disclaimers into the letters—about standards of identity, about potential labeling issues, about benefits shown in clinical trials, and about Section 201(II) of the FD&C Act.
One concern that FDA likely has is that if some issue comes up in the future regarding a claim made for benefits from use of a product containing the subject bacterium, someone may make the argument that FDA had accepted that the strain is indeed a probiotic and so it presumably confers probiotic benefits. In the case of probiotics, there are also some internal FDA politics. As ISAPP meeting attendees may already be aware, FDA’s Center for Biologics Evaluation and Research (CBER) would like to claim jurisdiction over all administration of live microorganisms, and the Center for Food Safety and Applied Nutrition (CFSAN) does not seem willing to have a confrontation.
I suspect that a similar situation obtains with the term “prebiotic.” Although I have filed a number of GRAS notices for prebiotics, they haven’t been called that; they have been called fructooligosaccharides, or tamarind seed polysaccharide, or polydextrose, or 2’-O-fucosyllactose. I don’t know how FDA would respond if a GRAS determination were filed with the substance labeled as a prebiotic.
So, I’ve decided that my sympathies lie with FDA. Until and unless a microorganism has been confirmed by competent authority to have probiotic properties when used as intended in a GRAS notice, FDA is probably correct in rejecting its right to be labeled a probiotic. If it’s any consolation, this new position by the FDA has its origin in their acknowledgment of the official scientific definition of the word “probiotic”.
When Mary Ellen Sanders (ISAPP’s Executive Science Officer) reviewed my first draft of this note, she asked what I had in mind by “competent authority,” to which I don’t have a good answer at the present time except to insist that it is not FDA’s Division of GRAS Notice Review. Thirty years ago, when I was at FDA, I was in the Office of Food Science and Nutrition, and that office was charged with making determinations of that type (although I don’t recall anything about probiotics coming before us). But FDA no longer has such an office. Until it does, or until it agrees on another source of authority on designation of microorganisms as non-CBER-domain probiotics, I suspect that CFSAN will continue to be very cautious in this area.
Read part 2 of this blog series here.
Probiotics, Prebiotics and Globobiotics!
/in Consumer Blog, featured, ISAPP Science Blog /by ISAPPBy 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
/in Consumer Blog, ISAPP Science Blog, News /by KCBy 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
/in Consumer Blog, ISAPP Science Blog /by KCBy 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
/in Consumer Blog, ISAPP Science Blog /by KCBy 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
/in ISAPP Science Blog /by KCBy 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.
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:
ISAPP helps inform UK Parliament
/in News /by KCBy Prof. Glenn Gibson, University of Reading, UK
An All Party Parliamentary Group (APPG) was inaugurated in February 2019 in the UK. Its purpose is: “to highlight the role of the gut microbiome in physical and mental health and its capacity to prevent many disorders and improve or slow others; to inform debate about how this will save money for the Treasury and NHS; and to enable communications between interested parties and relevant parliamentarians.” At this stage, over 80 MPs and Peers are currently involved, with Julie Elliott MP as chair.
iStock photo. Credit: Vladislav Zolotovby. Houses of Parliament and Big Ben at sunset, London, UK.
The APPG meetings (6 per year) provide opportunities to share information based on sound science and reality, not hype, so that parliamentarians can take appropriate action when opportunities arise. Specific experts are invited to give the evidence, and the topics discussed so far include:
Alan Barnard presents about the APPG at the 2019 ISAPP annual meeting.
Scientific advisors for the APPG are ISAPP board of directors member Dr. Glenn Gibson, Dr. Kirsty Hunter (Nottingham Trent University), and Dr. Gemma Walton (University of Reading). The secretariat is Alan Barnard. Kirsty and Alan attended the ISAPP 2019 annual meeting in Antwerp to give an overview of the aspirations and format of the APPG. The advisors use ISAPP science to drive the communications, including the organization’s review articles, consensus statements, infographics, videos, and selected working group summaries from the annual meetings. ISAPP anticipates further involvement with the APPG, including a future meeting featuring Gregor Reid’s outstanding probiotic research in the developing world.
Harmonized Probiotic Guidelines to be discussed at Codex Alimentarius meeting November 24 – 29
/in News, Uncategorized /by KCBy Mary Ellen Sanders PhD, Executive Science Officer, ISAPP
In 2017, the International Probiotics Association (IPA) proposed that Codex Alimentarius consider the topic of global harmonization of probiotics, and Argentina offered to propose an approach. The final proposal developed by Argentina is here.
This set into motion activities among many stakeholders that led to a final proposal, to be discussed at the Joint FAO/WHO Food Standards Programme, Codex Committee on Nutrition and Foods For Special Dietary Uses, Forty-first Session, Dusseldorf, Germany, being held 24 – 29 November 2019. The agenda for this meeting includes “Harmonized Probiotic Guidelines for Use in Foods and Dietary Supplements”, agenda item #11.
ISAPP has long championed the need for the term ‘probiotic’ to be used on product labels only when the scientifically recognized definition is met. In June 2018, ISAPP convened a large group of industry and academic scientists, chaired by Profs. Seppo Salminen (Finland), Yuan Kun Lee (Singapore), and Gabriel Vinderola (Argentina), to discuss global harmonization. Prof. Vinderola later served as a member of the Argentinian committee that developed the proposal now under consideration. From this discussion group, a white paper “ISAPP position statement on minimum criteria for harmonizing global regulatory approaches for probiotics in foods and supplements” was prepared, describing the minimum criteria for use of the term ‘probiotic’. These outputs frame an overall position of ISAPP on this issue: any global regulations should impose only the minimum criteria necessary to ensure truthful product labeling.
Issues such as requiring specific safety tests, stipulating specific in vitro or animal studies, or expecting manufacturers to automatically re-conduct clinical trials when changing delivery matrices, will serve to inhibit innovation and impose expensive requirements that may not be necessary.
Although probiotics can be considered unique in that they are live microorganisms, their use as dietary ingredients is not substantively different from other ingredients. Every ingredient needs specific analytical techniques and has specific requirements for identity, purity, and stability. So if truth in labeling can be assured regarding proper commercial use of the term ‘probiotic’, there may not be a need for carved-out global regulations on probiotics.
The position of the United States on this agenda item is: “The United States is still reviewing the discussion paper and has not formed a position at this time. We note however that in our view this work is lower in priority than proposed work on nutrient profiles.”
Lactobacillus bacteremia in critically ill patients does not raise questions about safety for general consumers
/in ISAPP Science Blog /by KCBy 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
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).
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.
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 biotherapeutics. Nat 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
/in ISAPP Science Blog, News, Uncategorized /by KCPast President and founding board member Prof. Gregor Reid is stepping down from the ISAPP Board in Banff in June 2020, as he retires from Western University and his Endowed Chair position at Lawson Health Research Institute the following month. In this blog post, he shares thoughts on his career and the opportunities for his replacement and for others to continue probiotic research. See here for information on the position of Research Chair in Human Microbiome and Probiotics at the Lawson Health Research Institute.
By Gregor Reid BSc (Hons), PhD, MBA, ARM CCM, Dr HS, FCAHS, FRSC
A mere blue dot. A pinhead, if that. But it’s us, all we have been and all we will be – for a while at least. The planet Earth.
Its magnificence is there for all to see.
Creative Commons Earth Illustration, 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)