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Do you know the difference between fiber and prebiotics? A new ISAPP infographic explains

Many people think prebiotics and fiber are the same thing. But according to leading scientists, they’re not. Fiber and prebiotics are both dietary tools to promote health, but you need to know some key differences between these two types of nutrients in order to make the best decisions for your health.

This new infographic summarizes what fiber and prebiotics have in common, and how they are different (including their distinct effects on the gut microbiome). And most importantly of all: you’ll learn how to get them in your daily diet so you can take advantage of their proven health benefits.

The infographic was written by ISAPP board of directors with input from several outside experts and coordinated by the ISAPP science translation committee.

ISAPP Releases a Mission-Based Summary of 2018 Activities

The mission of ISAPP is to advance scientific excellence in probiotics and prebiotics. ISAPP is an independent, science-based voice for the probiotic and prebiotic fields. The newly released short summary details ISAPP’s accomplishments in 2018 based around the core value of Stewardship, Advancing the Science, and Education. See here for the summary, also featuring ISAPP’s recent publications.

Thank you to the ISAPP Board of Directors for their leadership, dedication and scientific expertise, making these accomplishments possible.

Thank you to the Industry Advisory Committee for their ongoing support of ISAPP, providing the resources needed for ISAPP to accomplish its mission to advance the science of probiotics and prebiotics.

Click here to see the 2018 Summary.

See all Annual Reports and Short Summaries here.

YOGURITO –the Argentinian social program with a special yogurt

Dra. María Pía Taranto, CERELA-CONICET, Argentina and Prof. Seppo Salminen PhD, University of Turku, Finland

It is widely accepted that technologies play a central role in the processes of social change. The Argentinian experience has documented that yogurt can be a promising tool for promoting social development.  The program is called “Scholar Yogurito, the social probiotic” and the probiotic product is called “Yogurito”. This social program began with the development of a probiotic food, in the form of yogurt. This yogurt contains the probiotic strain Lactobacillus rhamnosus CRL1505, whose functional and technological characteristics are widely documented by CERELA-CONICET researchers. These researchers conducted clinical studies that demonstrated that the consumption of this probiotic product improves natural defenses and prevents respiratory and intestinal infections, the infectious events of greatest relevance in childhood. The “Yogurito Social Program” benefits some 300,000 schoolchildren in the province of Tucumán and some 50,000 in other provinces and municipalities of Argentina. This social transfer project, implemented in 2008 in the province of Tucumán, is a paradigm of interaction between the scientific sector, the manufacturing sector and the state, to improve the quality of life of highly vulnerable populations.

The social and economic implications for such translational research are significant and especially pertinent for people living in poverty, with malnutrition and exposure to environmental toxins and infectious diseases including HIV and malaria. This example of probiotic applications illustrates the power of microbes to positively impact the lives of women, men, and children, right across the food value chain. The researchers are looking for grants that would enable them to compare outcomes of schools given Yogurito to schools with no participation in the program.

 

Additional reading:

Julio Villena, Susana Salva, Martha Núñez, Josefina Corzo, René Tolaba, Julio Faedda, Graciela Font and Susana Alvarez. Probiotics for Everyone! The Novel Immunobiotic Lactobacillus rhamnosus CRL1505 and the Beginning of Social Probiotic Programs in Argentina. International Journal of Biotechnology for Wellness Industries, 2012, 1, 189-198.

Reid G, Kort R, Alvarez S, Bourdet-Sicard R, Benoit V, Cunningham M, Saulnier DM, van Hylckama Vlieg JET, Verstraelen H, Sybesma W. Expanding the reach of probiotics through social enterprises. Benef Microbes. 2018 Sep 18;9(5):707-715. doi: 10.3920/BM2018.0015.

 Senior Researcher Maria Pia Taranto and the Yogurito product

 

Maria Luz  Ovejero, a teacher at Primary School 252 Manuel Arroyo y Pinedo, explains probiotics to 4-6 year old children in Tucuman province in Argentina

Where does our food come from – why should we care?

Dr. Karen Scott, The Rowett Institute, University of Aberdeen,  Scotland

The food we eat feeds our microbes, gives us energy and nutrition, and keeps us healthy. The choices we make about our food clearly affects our health, but also has a huge effect on the world around us. We need to make more effort to choose correctly.

Sometimes it seems that everywhere we look, someone has an opinion on what we should be eating. Television is full of programmes telling us how and what to cook – suitable for a range of abilities. In supermarkets we are continually targeted with special offers and promotions, encouraging us to buy things we do not need, that are not on our shopping list. In magazines there are page long adverts, letting us know many reasons why our lives will be enriched if we purchase product Y, and perhaps even how we will be missing out if we do not. Even newspapers print articles telling us which foods are “super” this week, and will endow us with youthful skin, long life, and/or a svelte figure. Next week there will be another article with a new superfood, and one demoting last week’s superfood to the “standard” food, or even demonising it completely.

Yet even with all this focus on what we should be eating, do we really care about where our food comes from? Shouldn’t we really be more concerned with the provenance and sustainability of our food, rather than whether it is “super”?

Quinoa is a grain with a high nutrient content, high protein content (including all nine essential amino acids) and is also a source of some essential micronutrients and vitamins. By popular measures, a “superfood”. Quinoa is primarily grown in South America (Peru, Chile and Bolivia) where it is an important dietary staple. The increased demand and resultant export of quinoa has contributed considerably to the Peruvian economy. On the other hand, the cost increases associated with the increased worldwide demand means that the local Andean population now struggle to afford to include this healthy food in their own diets. Additionally the enlarged land area now used for quinoa production has reduced the amount of land available to grow alternative crops, and this reduced diversity has a negative impact on soil quality and on wildlife. Not so “super”.

Another healthy food-fad with a negative environmental impact is avocado. The current demand for avocados as part of the ‘green smoothie’ revolution has resulted in considerable deforestation in Mexico to make way for avocado plantations. Avocado trees also need a lot of water, which, given that they are frequently grown in climates with problems of drought, is clearly not sustainable.

The other factor is price – we are constantly persuaded that we should be looking for the best deal, getting those “2-for-1 offers”, or buying our food in the specific supermarket “saving you the most on your weekly shop”. The reality is that we spend a smaller % of our income on food today than we ever have – and this is not because we eat less, far from it. But if we think about it, it is not the large supermarket that loses money when it introduces offers. Buy one get one free offers on, for example fruit, usually mean that the farmer is only getting paid for one of every two oranges sold. Is this fair? If you ask a people doing their food shopping if they think that milk should cost more than water – most people would say “yes of course”. Yet at the milk counter in the supermarket they automatically reach for the “special offer”, cheapest product. Sometimes the farmer gets paid less for the milk he sells the supermarket than it costs to produce. Again if you asked people in the shop if they thought this was fair, they would no doubt say no, but they still reach for the “special offer”, cheapest product. This is already driving smaller dairy farmers out of business. Is this what we want? We as consumers, as well as the supermarkets, have to take responsibility.

Similarly with meat products and eggs. Most people, when asked about the best and most humane ways to look after animals on farms, prefer the low density, outside methods often depicted in children’s story books. Yet when we reach the meat counter in the supermarket we are more likely to reach for the cheaper product than the one from the farm which assures humane conditions, but which may cost twice as much. Such farming methods are more expensive to run, so the products have to cost more. We have to make more effort to include our instinctive morality when we are actually making purchases of food.

We have also become accustomed to being able to buy anything, at any time of year. If we want to buy fruit that is out-of-season in our own country, it will be in-season somewhere else and can be flown across the world for display in our local supermarket. When we ask people if they care about global warming – most will agree that it is a big problem, threatening the world. Yet they will buy specific fruits or vegetables that have been flown 1000s of miles, in aeroplanes contributing CO2 emissions, without a thought. Locally produced food, eaten in season, completely avoids this non-essential contribution to global warming.

Feeding our microbes is easy – they just eat our leftovers. But perhaps we also need to think about them. Food produced in intensively farmed conditions contains more pesticide and antibiotic residues than foods produced less intensively. Depending where we live, imported foods may have fewer controls on additives and production methods than those produced locally. Although specific studies have not been carried out to gauge the effect of such residues on our microbes, it is likely that there will be an effect. The healthy compounds in fruits develop best when they are allowed to ripen on the bush/tree and are not harvested unripe and then transported across the world. Our ancestors ate fresh foods in season and produced locally. People living in remote areas of the modern world without access to the diverse range of foods in a supermarket have a more diverse, healthy microbiota than those of us consuming “western diets”. Our microbes do not need, and potentially do not want, intensively produced foods.

Many of us are in the fortunate position of being able to afford to pay a bit more for our food, and thus to support it being produced in the way we would prefer if we stopped to think about it. This is why we DO have to stop to think and not automatically reach for the cheapest product on the shelf.  If we do not support farmers who are producing food in the most humane way, they will go out of business and we will be left with no choice but to buy mass-produced, often imported, food. Is this really what we want?

We have become so accustomed to paying less for our food, and looking for bargains, that we seem to care less about the quality and provenance than the price. Unless we change our outlook we will affect whole populations and environments forever. We need to stop the disconnect between our thoughts about what our foods should be, and what we actually buy, and we need to do it before it is too late.

Conference Focusing on the Microbiome in Women

By Prof. Gregor Reid, University of Western Ontario

It started with an idea for a mini symposium as an add-on to the PhD defence of Jessica Younes in 2015. It would be an event that focused on the impact of microbes on women’s health.

It had never been done before. Held in Artis, the Amsterdam Zoo and Microbiology museum, the 2015 conference attracted close to 100 people.

Following two more successful meeting in The Netherlands, “Women and their Microbes” is now coming to North America.

On March 6th and 7th next year an exciting program awaits at McMaster University’s campus in Hamilton, Ontario, a 90 minute drive from downtown Toronto.

See the program here.

Last year, I was happy to pass membership on the organizing committee to young clinicians and scientists such as Dr. Ruben Hummelen, who along with Jessica, have prepared an outstanding and practical program for 2019. Winclove B.V. remains the key sponsor, and ISAPP continues to add its voice.

As you will see from the program, there are a number of internationally recognized speakers, but also some outstanding Canadians you may not have had the pleasure to yet hear. The first day has split sessions with an emphasis on clinical practice. The second day features aspects of pregnancy influenced by microbes, including the exciting gut-brain axis research.

It is a great opportunity for scientists who have enjoyed ISAPP meetings and for members of our Students and Fellows Association to participate. At only $50 for students and $120 for faculty, you’ll be hard pressed to find a meeting with such value for money.

 

International Dairy Summit 2018 in Daejeon in South Korea

By Prof. Seppo Salminen PhD, University of Turku, Finland

The International Dairy Federation (IDF) convenes annual meetings that bring together scientists and industry professionals to discuss issues foremost to the production of safe and nutritious dairy products globally. Since probiotics find a home in so many dairy foods worldwide, ISAPP and IDF have some overlapping interests.

ISAPP president, Prof. Seppo Salminen of University of Turku, spoke at IDF’s International Dairy Summit 2018 on the potential for fermented foods to fight diseases and improve nutrition. He emphasized that many fermented foods contain a diverse collection of live microorganisms, which likely support our gut microbiota, perhaps even promoting gut microbiota resilience. Further, he stated, “Fermented dairy products, especially yoghurt, which combines milk, microbial starter cultures and pre-digested nutrients for human use, can be considered for future food-based dietary guidelines or recommendations focusing on beneficial microbe intake for gastrointestinal and other health effects.”

Another speaker, Prof Bruno Pot, discussed the global situation with regard to health claims for fermented dairy products. He focused on the situation in the European Union, where the only allowed health claim for probiotics is the benefit from live bacteria (Lactobacillus bulgaricus and Streptococcus thermophilus) in yoghurt reducing symptoms of lactose maldigestion. He reported that yoghurt is becoming a mainstream food in Asia. Key growth drivers in Asia are the perceptions that yoghurt is a healthy product with its beneficial impact on the digestive and immune systems, and they offer a good source of protein and calcium. The symposium also explored ways to enrich food through product development and innovation, particularly to provide nourishment for vulnerable populations. The potential for new ingredients such as milk protein hydrolysate-calcium complexes as calcium sources in yoghurt production was recognized.

David Everett, Chair of IDF’s Standing Committee on Dairy Science and Technology, reported: “Holding the 6th edition of the Symposium on Fermented Milks in Asia is of tremendous value as the scientific research on fermented dairy and the interest in these products is growing in the region.”

Forthcoming changes in Lactobacillus taxonomy

Mary Ellen Sanders PhD, Executive Science Officer, ISAPP

I was privileged to be included in a small meeting of scientists, both academic and industry, who met last week in Verona to discuss changes in Lactobacillus taxonomy. The first objectives of the meeting were to clarify with industry the need for the proposed changes and to clarify the methodology that will be used. The second objectives were to discuss at large potential consequences and approaches to address them.

Changes to the Lactobacillus genus

Experts from the Taxonomic Subcommittee for Lactobacilli, Bifidobacteria and Related Organisms agreed that the genus Lactobacillus is too heterogeneous and dividing this genus into several genera is inevitable. The need for this taxonomic ‘correction’ has been known for a long time, but until recently, the methodologies needed to reliably group the current Lactobacillus species into new genera were not available. But earlier this year, a paper by Salvetti et al (2018) analyzed 269 Lactobacillus and related (e.g., Pediococcus, Leuconostoc, Fructobacillus, Oenococcus) species and showed that the Lactobacillus genus comprises 10 phylogroups (see box). Each of these phylogroups represents at least one new genus. These same 10 phylogroups were observed using three separate approaches [phylogenetic analysis of 16S ribosomal DNA sequences, whole genome sequence analysis, leading to the comparison of 72 shared housekeeping genes (the core genome), and the comparison of average amino acid identity and percentage of conserved proteins], providing strong evidence that these groupings are robust. Commercially important Lactobacillus probiotic strains span at least 7 of those newly defined phylogroups; food fermentation lactobacilli cover even more.

lactobacillus_info

Although these 10 phylogroups were identified by this study, the current genus Lactobacillus could ultimately be resolved into 10 or up to 23 genera, depending on the cut-off values used for the different approaches. If researchers choose to split the genus into fewer new genera, it increases the chance that taxonomic changes will be needed in the nearer future. If they split the genus into more genera, it increases the chance that nomenclature will remain stable.

The names of the new genera are not decided. New names must be published (or validated) in the International Journal of Systematic and Evolutionary Microbiology. The authors of the publication will propose the new genus names. All species will be retained and their species names will not change. To minimize disruption, researchers will try to propose new genera names that begin with the letter “L”. Because “Lactobacillus” is a masculine Latin noun, the new genus names must be masculine for the species names to be retained.

A silver lining

Critics of these changes may suppose that adhering to taxonomic convention is their only purpose. But a classification system that better reflects genetic relatedness of the species may reap other benefits. As evidence for clinical benefits accumulates (summarized in open access review “Probiotics for Human Use”, 2018) and investigations provide insight into probiotic mechanisms of action, a clearer image of mechanisms and functions associated with particular taxonomic groups may emerge. The concept of core, shared benefits that were not strain-specific but linked to higher taxonomic groupings was explored in two ISAPP publications [Hill et al. (2014) and more in depth in Sanders et al. (2018)]. Reconsideration of clinical evidence and its relationship to new genera might prove enlightening.

What can be done to minimize confusion?

The meeting attendees brainstormed potential complications that might result from changing genus names. Company representatives in general considered that internal changes could be managed, although resources would be required to update names on all different paperwork and labels associated with commercial products (for example, marketing materials, product information, certificates of analysis, labeling, import/export certificates). The 2002 WHO/FAO probiotic guidelines, as well as the 2017 CRN/IPA guidelines, indicate that the genus, species and strain designation should be included on product labels. Further, the name used should reflect current nomenclature. This requirement is reflected in some national regulations. Therefore, genus name changes will necessitate label changes.

Further, it was emphasized that a clear document should be prepared and endorsed by reputable organizations (EFSA, NIH, FDA, medical organizations, and others). The document should: (a) indicate the name changes, (b) provide a clear, concise statement of why the changes were needed, and (c) emphasize that only the names, not the strains, would be different. This could be leveraged by companies to communicate with all stakeholders. End-users of probiotic products would likely not be a significant communication challenge. Authorities involved with probiotic safety (FDA with GRAS and EFSA with QPS) likely will manage these changes, as they are science-based. More of a concern was communication with other regulators, both at the level of national agencies responsible for probiotic-specific regulations (including countries with positive lists of species that are acceptable as probiotics) as well as authorities involved in import/export of product. Some potential issue with intellectual property may be envisaged, especially in a transition period during which the new names are not routinely used yet.

The bottom line: Name will change but the strains will stay the same 

The current Lactobacillus genus will be split into at least 10, and perhaps as many as 23, genera. No species names will change, but many species – including commercially important ones – will have a different genus names, hopefully beginning with the letter “L”.  Because of the tremendous heterogeneity of the current Lactobacillus genus, Prof. Paul O’Toole concluded his presentation saying “the status quo is not an option.” Some disruptions can be expected from this massive change, but the probiotic field would benefit from embracing these changes and developing strategies to minimize any difficulties resulting from them.

 

Additional information:

The International Committee on Systematics of Prokaryotes (ICSP) and the International Code of Nomenclature of Bacteria are responsible for the naming of bacteria. The subcommittee of the ICSP responsible for naming lactobacilli is the Taxonomic Subcommittee for Lactobacilli, Bifidobacteria and Related Organisms.

The meeting was convened by the Lactic Acid Bacteria Industrial Platform and chaired by Esben Laulund of Chr Hansens, who also chairs IPA Europe. A full report of meeting conclusions is expected to be published in a scientific journal by the end of 2018. Abstracts and program will to be posted on the LABIP website in due time.

The taxonomic hierarchy for Lactobacillus currently is: Domain: Bacteria; Division/Phylum: Firmicutes; Class: Bacilli; Order Lactobacillales; Family: Lactobacillaceae; Genus: Lactobacillus. The lowest order of taxonomy is the subspecies; the strain designation has no official standing in nomenclature. There are currently over 230 recognized species of Lactobacillus, and approximately 10 new species are added each year.

ISAPP Releases New Infographic – Probiotic Checklist: Making a Smart Selection

Not all products labelled “probiotic” are true probiotics. ISAPP just released a new infographic focused on helping consumers make smart selections when examining probiotic products. The infographic addresses identifying products backed by science, effective dosing, and more.

See and download the full infographic here.

See all ISAPP infographics here.

 

happy_baby

Probiotics and D-lactic acid acidosis in children

Prof. Hania Szajewska PhD, The Medical University of Warsaw, Department of Paediatrics, Poland and Prof. Seppo Salminen PhD, Faculty of Medicine, Functional Foods Forum, University of Turku, Finland

See related post ‘Brain Fogginess’ and D-Lactic Acidosis: Probiotics Are Not the Cause

In their recent study, Rao and colleagues1 incriminated probiotics in the induction of D-lactic acidosis (1). Many who benefit from probiotics could be frightened—on the basis of this report—into stopping them, with potentially negative impacts on their health (2). Some probiotic bacteria, including some specific components of the intestinal microbiota, may produce D-lactic acid. Indeed, if plasma D-lactic acid rises sufficiently, it is clinically relevant, causing D-lactic acidosis. D-lactic acidosis has mainly been observed in subjects with short bowel syndrome. However, some authorities have regulated the use of D-lactic acid producing bacteria in infant and weaning foods, but the reasoning for normal infant population has been debated. Even in adults, the safety of D-lactic acid producing bacteria has been challenged, but apart from short bowel patients no evidence on clinical problems has been reported (3).

For this reason, we conducted a review and examined whether D-lactic acid-producing bacteria, acidified infant formulas and fermented infant formulas were potential causes of paediatric D-lactic acidosis (4).

We identified five randomised controlled trials conducted between 2005-2017 with 544 healthy infants. Additionally, some case reports and experimental studies were considered. No clinically relevant adverse effects of D-lactic acid-producing probiotics or fermented infant formulas in healthy children were identified. The only known cases of paediatric D-lactic acidosis were observed in patients with short bowel syndrome (4). It is of importance that human milk also contains lactic acid bacteria and bifidobacteria, some of which may produce D-lactic acid. Some stress situations, such as exercise, may elevate human milk lactate concentrations.  Thus, breast milk D-lactate content needs to be analysed more carefully to compare with fermented infant formulas.

Taken together, our results suggest that neither the probiotics that were evaluated in the studies we reviewed nor fermented infant formulas cause D-lactic acidosis in healthy children.

 

  1. Rao, S. S. C., Rehman, A., Yu, S. & Andino, N. M. Brain fogginess, gas and bloating: a link between SIBO, probiotics and metabolic acidosis.  Transl. Gastroenterol.9, 162 (2018). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6006167/
  2. Sanders, M. E., Merenstein, D. & Merrifield, C. A. Probiotics for human use.  Bull.43, 212–225 (2018). https://onlinelibrary.wiley.com/doi/10.1111/nbu.12334
  3. Quigley E.M.M, Pot B., Sanders M.E. ‘Brain fogginess’ and D-lactic acidosis: probiotics are not the cause. Transl. Gastroenterol.9, 187 (2018). https://www.nature.com/articles/s41424-018-0057-9
  4. Łukasik, J., Salminen S., Szajewska H. Rapid review shows that probioticsand fermented infant formulas do not cause D-lactic acidosis in healthy children. Acta Pediatrica 107, 1322-1326 (2018). https://www.ncbi.nlm.nih.gov/pubmed/29603358

FDA/NIH Public Workshop on Science and Regulation of Live Microbiome-based Products: No Headway on Regulatory Issues

September 20, 2018

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

On September 16, 2018, the US Food and Drug Administration’s Center for Biologics Evaluation and Research (CBER) and National Institute of Allergy and Infectious Diseases (NIAID) collaborated on the organization of a public workshop on “Science and Regulation of Live Microbiome-based Products Used to Prevent, Treat, or Cure Diseases in Humans”.  I was present at this meeting along with ISAPP vice-president, Prof. Daniel Merenstein MD, who lectured on the topic of probiotics and antibiotic-associated diarrhea.

Prof. Dan Merenstein speaking at CBER/NIAID conference

While regulatory issues are often discussed at other microbiome conferences, the fact that this meeting was organized by the FDA suggested it was a unique opportunity for some robust discussions and possible progress on regulatory issues involved with researching and translating microbiome-targeted products. The regulatory pathways to drug development seem clear enough, but regulatory issues for development of functional foods or supplements are less clear. Jeff Gordon and colleagues have previously pointed out regulatory hurdles to innovation of microbiota-directed foods for improving health and preventing disease (Greene et al. 2017), and at the 2015 ISAPP meeting, similar problems were discussed (Sanders et al. 2016).

The meeting turned out to be mostly about science. Some excellent lectures were given by top scientists in the field (see agenda below), but discussion about regulatory concerns was a minimal component of the day. Questions seeding the panel discussions focused on research gaps, not regulatory concerns: an unfortunate missed opportunity.

Bob Durkin, deputy director of the Office of Dietary Supplements (CFSAN), left after his session ended, suggesting he did not see his role as an important one in this discussion. One earlier question about regulatory perspectives on prebiotics led him to comment that the terms ‘probiotic’ and ‘prebiotic’ are not defined. From U.S. legal perspective he is correct, as there are no laws or FDA regulations that define these terms. But from a scientific perspective, such a statement is disappointing, as it shows the lack of recognition by U.S. regulators of the widely cited definitions developed by top researchers in these fields and published in 2014 and 2017, respectively.

Two issues not addressed at this meeting will require clarification from the FDA:

The first is how to oversee human research on foods or dietary supplements. CBER’s oversight of this research has meant most studies are required to be conducted under an Investigational New Drug (IND) application. From CBER’s perspective, these studies are drug studies. However, when there is no intent for research to lead to a commercial drug, the IND process is not relevant. Even if endpoints in the study are viewed as drug endpoints by CBER, there should be some mechanism for CFSAN to make a determination if a study fits legal functions of foods, including impacting the structure/function of the human body, reducing the risk of disease, or providing dietary support for management of a disease. When asked about this, Durkin’s reply was that CFSAN has no mechanism to oversee INDs. But the point was that without compromising study quality or study subject safety, it seems that FDA should be able to oversee legitimate food research without forcing it into the drug rubric. CBER acknowledged that research on structure/function endpoints is exempt from an IND according to 2013 guidance. But FDA’s interpretation of what constitutes a drug is so far-reaching that it is difficult to design a meaningful study that does not trigger drug status to them. For example, CBER views substances that are given to manage side effects of a drug, or symptoms of an illness, as a drug. Even if the goal of the research is to evaluate a probiotic’s impact on the structure of an antibiotic-perturbed microbiota, and even if the subjects are healthy, they consider this a drug study. With this logic, a saltine cracker eaten to alleviate nausea after taking a medication is a drug. Chicken soup consumed to help with nasal congestion is a drug. In practice, many Americans would benefit from a safe and effective dietary supplement which they can use to help manage gut disruptions. But in the current regulatory climate, such research cannot be conducted on a food or dietary supplement in the United States. There are clearly avenues of probiotic research that should be conducted under the drug research oversight process. But for other human research on probiotics, the IND process imposes research delays, added cost, and unneeded phase 1 studies, which are not needed to assure subject safety or research quality. Further, funders may choose to conduct research outside the United States to avoid this situation, which might explain the low rate of probiotic clinical trials in the United States (see figure).

The second issue focuses on actions by CBER that have stalled evidence-based use of available probiotic products. This issue was discussed by Prof. Merenstein in his talk. He pointed out that after the tragic incident that led to an infant’s death from a contaminated probiotic product (see here; and for a blog post on the topic, see here), CBER issued a warning (here) that stated that any probiotic use by healthcare providers should entail an IND. This effectively halted availability of probiotics in some hospital systems. For example, at Johns Hopkins Health-system Hospitals, the use of probiotics is now prohibited (see below). Patients are not allowed to bring their own probiotics into the hospital out of concern for the danger this poses to other patients and staff. This means that a child taking probiotics to maintain remission of ulcerative colitis cannot continue in the hospital; an infant with colic won’t be administered a probiotic; or a patient susceptible to Clostridium difficile infection cannot be given a probiotic. Available evidence on specific probiotic preparations indicates benefit can be achieved with probiotic use in all of these cases, and denying probiotics can be expected to cause more harm than benefit.

It might be an unfortunate accident of history that probiotics have been delivered in foods and supplements more than drugs. The concept initially evolved in food in the early 1900’s, with Metchnikoff’s observation that the consumption of live bacilli in fermented milk had value for health. Probiotics have persisted as foods through to the modern day, likely because of their safety. The hundreds of studies conducted globally, including in the U.S. until 10-15 years ago, were not conducted as drug studies, even though most would be perceived today as drug studies by CBER. This has not led to an epidemic of adverse effects among study subjects. True, serious adverse events have been reported, but the overall number needed to harm due to a properly administered probiotic is negligible.

According to its mission, the FDA is “…responsible for advancing the public health by helping to speed innovations that make medical products more effective, safer, and more affordable and by helping the public get the accurate, science-based information they need to use medical products and foods to maintain and improve their health.” Forcing human research on products such as yogurts containing probiotics to be conducted as drug research, when there is no intent to market a drug and when the substances are widely distributed commercially as GRAS substances, does not advance this mission. Further, CBER actions that discourage evidence-based use of available probiotics keeps effective and safe products out of the hands of those who can benefit.

A robust discussion on these issues was not part of the meeting earlier this week.  Researchers in the United States interested in developing probiotic drugs will find CBER’s approaches quite helpful. Yet researchers interested in the physiological effects of, or clinical use of, probiotic foods and supplements will continue to be caught in the drug mindset of CBER. CFSAN does not seem interested. But without CFSAN, human research on, and evidence-based usage of, probiotic foods and supplements will continue to decline (see figure), to the detriment of Americans.

Human clinical trials on “probiotic”
1992-September 20, 2018

 

 

 

ISAPP-initiated systematic review and meta-analysis shows the association of probiotic consumption with reduced antibiotic prescriptions

At the ISAPP meeting in Turku, Finland in 2016, scientists convened a working group led by Dan Merenstein of Georgetown University (USA) along with Irene Lenoir-Wijnkoop of University of Utrecht (the Netherlands) and Danone Research. In their discussions, the group identified a gap in the literature: a systematic review of randomized, controlled trials to determine how antibiotic prescriptions are associated with probiotic consumption for the prevention of common acute infections. The protocol was registered with PROSPERO (registration number CRD42016052694).

The analysis, authored by ten scientists, was recently published—and results showed that infants and children who received probiotics were at least 29% less likely to be prescribed antibiotics. Find the paper here in the European Journal of Public Health.

ISAPP scientists say probiotics deserve consideration as a public health intervention that may reduce the widespread over-prescription of antibiotics.

See the ISAPP press release here, and the Georgetown University press release here.

See here for media coverage of this paper:

http://www.microbiometimes.com/scientific-analysis-shows-probiotic-use-is-associated-with-fewer-antibiotic-/

https://www.pharmacytimes.com/resource-centers/vitamins-supplements/daily-probiotics-may-reduce-kids-need-for-antibiotics

https://www.news-medical.net/news/20180914/Probiotics-could-reduce-the-need-for-antibiotics.aspx

Clinical evidence and not microbiota outcomes drive value of probiotics

By ISAPP Board of Directors, plus Prof. Francisco Guarner and Dr. Bruno Pot

September 10, 2018

Two recent papers have generated much adverse publicity for the probiotic field. Headlines driven by sensationalism, not data, claim “Probiotics labelled ‘quite useless’” (BBC) and “Probiotics ‘not as beneficial for gut health as previously thought’” (The Guardian). The quotes are from author Eran Elinav, who generalizes the study findings to all ‘probiotics’ as a class – a generalization that ignores that specific probiotic are meant for specific purposes. This research was published this month in Cell (here and here).

The scope of these papers is limited to microbiome data; no clinical endpoints are assessed. Without clinical evidence, it is not possible to conclude about the tested probiotic’s usefulness, and it is certainly not possible to conclude about probiotic usefulness in general. Stating that probiotics are ‘quite useless’ or ‘not as beneficial’ is, quite simply, wild and factually inaccurate. The authors discount the existing body of evidence for probiotic health benefits, including Level 1 placebo-controlled, randomized trials. Cochrane reviews (the gold standard used by physicians and public health policy makers) of the totality of evidence show that specific probiotics can prevent antibiotic associated diarrhea (AAD) and C. difficile diarrhea. This evidence has been translated into evidence-based recommendations for probiotics issued by medical groups. Regardless of an effect on the microbiota, these are established, evidence-based benefits of probiotics.

No clinical endpoints tracked in either study

What these papers provide is extensive data about the impact of one product containing 11 common probiotic species on different microbiome measures. To the authors’ credit, they analyzed mucosal and luminal samples from humans, in addition to samples from stool.  Nonetheless, the probiotic definition [live microorganisms that, when administered in adequate amounts, confers a health benefit on the host (Hill et al 2014)] does not require that probiotics function via interaction with the microbiota, nor is there much evidence that they alter the microbiota composition in an appreciable manner. Absence of impact on microbiome measures is not evidence that probiotics lack clinical or physiological effects. Probiotics function via many mechanisms that might not be revealed by the measures made in these papers.

Methodological concerns

A careful reading of this paper reveals many methodological concerns.

The extensive data in the paper is an assortment of different types of analyses. For example, for a beta-diversity metric, they sometimes use weighted Unifrac, sometimes unweighted Unifrac, and sometimes Bray-Curtis, without an explanation for their choice. These approaches to presenting the data can give very different results. With the transcriptomics data, sometimes the authors choose samples from the duodenum and sometimes the jejunum. For example, in figure 6, panels C-E compare the difference in gene expression between the naïve group and the treatment in the duodenum, whereas in panels F-H they compare the antibiotic state with the treatment in the jejunum. Such an approach leads the reader to speculate that the authors picked the metrics and data that best fitted the story they wanted to tell. In a well-conducted clinical trial, the statistical plan is registered before the study starts, to assure readers that the scientific process of advancing a hypothesis and designing a study to test the hypothesis is respected.

The probiotic was not administered to human subjects until 7 days after the treatment with antibiotics commenced, after the damage by the antibiotics has been done. Dozens of human studies with specific probiotics have documented that probiotics prevent AAD or C. difficile infection. In most clinical trials, the probiotic is administered together with the antibiotics. A recent meta-analysis concluded that “administration of probiotics closer to the first dose of antibiotic reduces the risk of (Clostridium difficile infection) by >50% in hospitalized adults.” (Emphasis added) The approach in the Suez et al paper is not consistent with the aforementioned clinical studies, with how probiotics are used in clinical practice or with the knowledge of how probiotics most likely prevent AAD. When provided on the same days as antibiotics, probiotics have the opportunity to prevent overgrowth of opportunistic, antibiotic-resistant microbes by competitive exclusion in the ecosystem. Therefore, the microbiome findings of Suez et al likely cannot be applied to clinical trials with such different time course of antibiotic/probiotic administration.

Several conclusions about the effect of probiotics on the microbiota were based on relative abundance measures, which do not relate to actual bacterial numbers or metabolic activity of all relevant species in the gut.

The antibiotic treatment used was potent for a study population that would otherwise not need antibiotics. Volunteers were administered oral ciprofloxacin 500 mg bi-daily and oral metronidazole 500 mg tri-daily for a period of 7 days. They are both very strong and indiscriminate antibiotics, having a severe impact on the gut microbiota.  One could question if this drug therapy might have a different impact on the microbiome of a healthy person compared to a patient likely to receive this treatment, i.e., one whose microbiota ecosystem is disrupted by disease or fever.

The probiotic product

A serious issue is that the authors chose a product for this study that has no demonstrated clinical benefits. At a minimum, the product used for this study should have evidence for impact on antibiotic associated conditions, including symptoms or emergence of opportunistic pathogens. The 3 (possibly 2, as the latter 2 appear to be the publication of the same data) human studies conducted on this product (here, here and here), showed no clinical benefit. Thus, the investigators tested the potential benefits of a product for which no benefits had been previously shown. Further, the papers do not adequately describe the product; only a total count (25 billion) is given; counts of each strain – through the end of the administration period – should have been provided. Furthermore, the authors state about the product that “B. longum was probably represented by two strains.” This constitutes imprecise characterization unacceptable in a well-defined probiotic product.

Appearance of author bias

The conclusions reached in the papers promote a personalized approach to probiotic use. In an article on the BBC, the lead author stated, “In the future probiotics will need to be tailored to the needs of individual patients. And in that sense just buying probiotics at the supermarket without any tailoring, without any adjustment to the host, at least in part of the population, is quite useless.” The authors did not disclose they are involved with a company promoting this personalized approach.

Probiotic colonization

The authors suggest that their finding that probiotics do not colonize long term is noteworthy. In fact, researchers in this field have known this for 30 years: most probiotics do not colonize or become established as part of the resident microbiota. A 2016 paper by Madonado-Gomez et al was notable precisely because a Bifidobacterium longum strain was found that did persist. In most cases, probiotic effects are likely mediated by transient effects.

Responders and non-responders

A well-established concept in medicine is that some people respond clinically and physiologically to interventions and others don’t. This is the case with much of probiotic as well as pharmaceutical literature. (See review on responders and non-responders to probiotics by Reid et al.) An individual’s response is likely impacted by diet, resident microbes, host genes and host physiology/health. The validity of a personalized approach to probiotic administration remains to be determined, as evidence for a clinical benefit to the approach is needed. Microbiome data alone are not sufficient.

Need for future research

In the Cell publications, the authors acknowledge their study was limited due to lack of clinical endpoints and the testing of only a single product. It is unfortunate that the press marched ahead with inflammatory stories about the negative effects of probiotics based on such paltry evidence. The scientific community understands that this is one study, on a small number of human subjects, by one research group. Sweeping conclusions cannot be made. There are many hypotheses that can be generated from this study that can lead to follow up studies, which we hope will ensue.

Conclusions

Hundreds of human trials have demonstrated clinical benefits of probiotics and several evidence-based recommendations have been issued by medical organizations. Of course, not all studies are positive. Not all probiotics work for all conditions. But the safety record of probiotics administered to healthy as well as many patient populations is well-established. Numerous media outlets have reported on these two studies as if they are proof that probiotics are useless at best and harmful at worst. This irresponsible reporting may lead people who are benefitting from probiotics to stop using them, potentially causing real harm.

The erroneous interpretation of the current study and previous research by the primary author is disingenuous, as he states,  “Contrary to the current dogma that probiotics are harmless and benefit everyone, these results reveal a new potential adverse side effect of probiotic use with antibiotics that might even bring long-term consequences.” This comment and the papers’ conclusions are not corroborated by the totality of safety and efficacy clinical evidence on probiotics, which includes thousands of probiotic-treated subjects. In comparison, the data in Suez et al come from microbiome assessments from only eight probiotic-treated subjects.

Furthermore, this paper evaluated just one product of limited provenance and containing a combination of multiple, incompletely characterized strains. This is in sharp contrast to numerous studies of precisely characterized strains demonstrating well-defined and beneficial engagements with the host. Zmora and colleagues and Suez and colleagues are to be congratulated on their attempts to characterize in detail the impact of one probiotic product on a perturbed, human microbiome. We look forward to further such studies employing well-characterized strains with demonstrated clinical benefits and including relevant clinical endpoints.

Additional reading:

ISAPP comments: International Group of Probiotic Scientists Weighs in on Flawed Conclusions From New Scientific Papers

American Gastroenterological Association response: AGA’s Interpretation of the Latest Probiotics Research

Response by Prof. Gregor Reid:  Trying to Close the Stable Door After the Horse Has Bolted

Role of citizen science in research on fermented foods

By Prof. Sarah Lebeer, Universiteit Antwerpen

Spontaneous vegetable fermentations, with their rich flavors and potential health benefits, are regaining popularity among chefs and the general public. Famous Michelin star chefs, such as Belgium’s Kobe Desramaults, have implemented fermented vegetables in their recipes and offer fermented vegetable juices as non-alcoholic alternatives to wine. Serendipity was surely at play when I made contact with Kobe and his team, and had the opportunity to explore the microbial life of many of his fermented food and beverages.

Thanks to this spontaneous collaboration, I became intrigued by fermented vegetables as a promising alternative to dairy probiotic matrices. They have several benefits:

  • they are lactose-free
  • they contain no milk allergens
  • they are naturally vitamin-, antioxidant- and fiber-rich
  • they are vegan, satisfying the growing dietary trend

 

Together with prof. L. De Vuyst – a fermented food specialist from the VUB University in Brussels – we attracted a talented PhD student Sander Wuyts to study Lactobacillus’ role in the spontaneous fermentation process of carrot juices. I admit that fermented carrot juice is not the tastiest beverage I ever drank, but the fermentation process turned out to be scientifically intriguing: it appeared to be a robust, man-made microbial ecosystem dominated by lactic acid bacteria. We now often use this fermentation process in my lab as a model to study various aspects of niche-adaptation and niche-flexibility of lactic acid bacteria (LAB). And if you mix carrot juice with another fresh vegetable juice, such as cucumber, you’ll be surprised by its interesting light acidic flavor!

But perhaps the most rewarding part about our fermented-vegetables project was that we managed to carry out a Citizen Science project with the Flemish name, Ferme Pekes. You could translate it as ‘Fantastic Carrots’ 😊. Forty citizens volunteered to set up their own carrot juice fermentations at home and delivered with great enthusiasm samples of different time points. The carrots originated from their own garden, the supermarket or organic stores. Our analysis indicated that origin or organic compared to conventional product did not impact the microbial community composition. But we also could show that the LABs – first Leuconostoc then Lactobacillus – out-competed the undesirable Enterobacteriaceae after 3 to 13 days of fermentation. Longer times were needed for carrots derived from winter storage.

Our analyses (phylogenetic placement and comparative genomics, which was recently published in Applied and Environmental Microbiology) also indicated that a high LAB diversity was achieved in the different spontaneous fermentations. This is of interest if you believe it is important to let our immune system come into contact with a large and naturally diverse dose of beneficial bacteria. This idea has been promoted through the years as the hygiene hypothesis or microbial deprivation theory and aligns perfectly with the surge of interest in the health benefits of naturally fermented foods. See the recent ISAPP blog from Prof. Colin Hill, who advocates for the idea of a recommended daily allowance of consumption of live microbes.  (See also a related ISAPP blog here.) Such guidelines should be taken with precaution: the fermentations must be done properly with regard to food safety (see ISAPP blog on Making Safe Fermented Foods at Home).

Citizen Science refers to projects where citizens are actively involved in scientific studies, although it has various definitions and descriptions. In our case, it allowed us to obtain a much larger and more diverse set of samples than we could have created in the lab. Furthermore, the opportunity to directly (on e.g. workshops for adults and kids or at delivery of their samples) or indirectly (as a response to articles in the popular press) communicate with citizens helped us greatly in identifying which other research questions might be of importance for the general public. This approach is increasingly implemented in the fermented food and microbiome field. There are examples of fantastic projects such as on sourdough from Rob Dunn, Benjamin Wolfe and colleagues, the Global FoodOmics initiative and the Flemish Gut Flora project, which will also be presented by Dr. Gwen Falony at our next ISAPP meeting in Antwerp. I am not aware of a Citizen Science project in the probiotic or prebiotic area, but it might be a good idea for a joint ISAPP initiative, for science communication, the creation of richer datasets, validation/confirmation of probiotic efficacy, inspiration for future research questions, for example.

‘Brain fogginess’ and D-lactic acidosis: probiotics are not the cause

Mary Ellen Sanders PhD, Executive Science Officer, International Scientific Association for Probiotics and Prebiotics

Bruno Pot PhD, Research Group of Industrial Microbiology and Food Biotechnology, Faculty of Sciences and Bioengineering Sciences, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium

See here for ISAPP letter to the Clinical and Translational Gastroenterology editor regarding this paper.

See related post Probiotics and D-Lactic Acid Acidosis in Children

Rao and colleagues incriminated probiotics in the induction of D-lactic acidosis in their paper titled “Brain fogginess, gas and bloating: a link between small intestinal bacterial overgrowth (SIBO), probiotics and metabolic acidosis” (Rao et al. 2018). Eamonn Quigley MD, Bruno Pot, microbiologist and I on behalf of ISAPP authored a letter to the editor of Clinical and Translational Gastroenterology (currently In Press), summarizing many medical and other concerns with the study design, execution and conclusions.

It is regrettable that one poorly controlled paper can lead to such negative backlash on the probiotic field. Respectable media outlets including Newsweek, Science Daily, Psychology Today, the Daily Mail, MSN.com, and others blindly reported the results of this study without critical analysis of the paper. These stories advance the opinion that probiotics are potentially harmful and should be sold only as drugs. This flies in the face of many scientific studies that document safety compounded with safe, worldwide consumption for decades of probiotic foods and supplements.

Bifidobacterium as a genus does not yield D-lactate as a metabolic end product. Some Lactobacillus species do (Table 19.1 in Pot 2014). Among common probiotic Lactobacillus species, the following are classified as species that can produce D-lactic acid: L. acidophilus, L. gasseri, L. delbrueckii subsp. bulgaricus (one of the 2 yogurt starter culture bacteria), L. fermentum, L. lactis, L. brevis, L. helveticus, L. plantarum and L. reuteri.  Individual strains within each species may vary with regard to levels of D-lactic acid produced.

The observational nature of the Rao et al. paper precludes any conclusive link between probiotic consumption and symptoms observed.  The authors acknowledge that they have only established an association between probiotic use and the symptoms, but the misleading paper title suggests an intention to indict probiotics, even in the absence of evidence.  It is much more likely that the patient population with underlying SIBO in this study sought relief from their gut symptoms by use of probiotics rather than the probiotics being the cause of their symptoms.

D-lactic acidosis is a rare but serious condition, typically occurring in people with short bowel syndrome. These patients should know that D-lactate-producing probiotics are not recommended for them. In people with a normal gut, D-lactate produced by members of the gut microbiota – including some probiotics – is metabolized by other members of the gut microbiota and does not accumulate. Thus, under normal circumstances, D-lactic acidosis does not result from consumption of D-lactic acid-producing probiotics. The patients in the Rao et al. study showed very low levels of D-lactic acid, calling into question if these SIBO patients were even acidotic.  Moreover, the D-lactic acid that was present was not proven to be a result of probiotic growth. This is important, as intestinal bacteria including Escherichia coli also produce D-lactic acid. In cases of SIBO, numerous metabolites are produced in the small intestine (including alcohol), leading to a variety of SIBO symptoms, possibly including the poorly defined phenomenon of “brain fogginess”.  Many issues that should have been were not addressed in the Rao et al. paper.

The real tragedy with the publication of this paper is that – similar to many such media scares in the past – it is may cause harm.  The sensationalist headlines may dissuade safe probiotic use in people who can truly benefit from them. Scientists and clinical researchers – both academic and from industry – must remain diligent in assessment and reporting of any probiotic harms. However, the Rao et al. paper is not an example of this.

Reference:

Pot B. 2014. The genus Lactobacillus. Chapter 19. In Lactic Acid Bacteria: Biodiversity and Taxonomy, First Edition. Edited by Wilhelm H. Holzapfel and Brian J.B. Wood. 2014 John Wiley & Sons, Ltd.

Other reading:

Mack D. 2004. D(-)-lactic acid producing probiotics, d(-)-lactic acidosis and infants. Canadian J Gastroenterol. 18:671-5. (ISAPP-commissioned paper)

Łukasik J, Salminen S, Szajewska H. Rapid review shows that probiotics and fermented infant formulas do not cause d-lactic acidosis in  healthy childrenActa Paediatr. 2018 Aug;107(8):1322-1326. doi: 10.1111/apa.14338. Epub 2018 Apr 24.

cber

CBER to hold public workshop on regulation of biologics

FDA’s Center for Biologics Evaluation and Research (CBER) is convening a public workshop Sept 17 in Rockville MD on the Science & Regulation of Live Microbiome-Based Products Used to Prevent, Treat, or Cure Diseases in Humans. It is now open for registration (free). See here for the program and here for additional info.

The evidence for efficacy, the safety and the regulatory framework for probiotics other live microbiome based products will be discussed. Prof. Dan Merenstein MD, ISAPP’s current Vice President, will speak on evidence, research and clinical use of probiotics for antibiotic associated diarrhea. Although the title suggests the meeting will focus on drugs, Dr. Bob Durkin from the Center for Food Safety and Applied Nutrition (CFSAN) of the FDA will speak on probiotic foods and dietary supplements.

This workshop is an opportunity for stakeholders to share with FDA and NIH concerns regarding the regulatory approach to probiotics adopted by the FDA. The path for development of probiotic drugs is reasonably clear. But the road to develop probiotic foods, supplements or microbiome-based dietary strategies to compensate for deficient microbiota is less so. These products are intended to improve gut function, nutritional status, immune status, metabolic properties and more. These are legal functions for foods and supplements, but the FDA doesn’t seem to see it that way.

The FDA has for the most part has approached probiotics as drugs (Sanders et al. 2016). Since probiotics are live microbes, and since CBER deals with drugs that are derived from living sources, CBER often oversees human research on probiotics. But there is no mechanism within CBER to oversee foods and supplements, and hence, human research on probiotics tends to be shunted into the investigational new drug (IND) process. But, the legal definitions of drugs and foods overlap – both can impact the structure/function of the human body and both can reduce the risk of disease. So conducting such research on probiotic foods – and not as part of the IND rubric – should be possible. Perhaps progress on this front can be achieved in the CBER workshop in September.

In a press announcement, FDA Commissioner Scott Gottlieb MD shared FDA perspective on probiotics and promoted this CBER conference. A couple of issues are noteworthy in this announcement by Gottlieb. First, the term ‘probiotic’ is used. Over the years, the FDA largely avoided use of this term, instead favoring the term live biotherapeutic product (LBP). But these terms are not synonymous. Probiotic is defined as a live microorganisms that, when administered in adequate amounts, confers a health benefit on the host (Hill et al. 2014). It spans multiple regulatory categories. A LBP is by definition a drug. The fact that Gottlieb used the term ‘probiotic’ may signal that he recognizes that not all probiotics are drugs. Second, Gottlieb’s announcement shows awareness that probiotics are legitimate components in foods and dietary supplements and states that the FDA is “committed to working with industry on efforts to provide information that can help consumers make more informed choices about these products.” This is a welcome statement to many researchers involved in probiotic foods and supplements in the United States. It suggests that the FDA is willing to look beyond probiotics as LBPs and develop regulatory approaches for research and claims appropriate to foods and supplements.

Innovation in this field, which has the potential to benefit many people globally, requires regulatory approaches that do not obstruct. Participation in this workshop may lead to improvements that both protect public safety and facilitate academic and industry researchers in the United States on the path to discovery.

 

Additional information:

Sanders ME, Shane AL, Merenstein DJ. Advancing Probiotic Research in Humans the United States: Challenges and strategies. Gut Microbes 7(2):97-100.

Warning letter from CBER: Dietary Supplements Containing Live Bacteria or Yeast in Immunocompromised Persons: Warning – Risk of Invasive Fungal Disease. Posted 12/09/2014.

rdamicrobes

Recommended daily allowance (RDA) for microbes?

By Prof. Colin Hill, Alimentary Pharmabiotic Centre, Food for Health Ireland, University College Cork

In this months’ issue of The Biochemist (August 2018) I explored the concept of whether or not there could be a health benefit to ingesting large numbers of safe microbes in our diet (see the open access article here).  This was an effort, though I should stress not a scientifically rigorous effort, to consider the long history of encounters between humans and ingested microbes.

This opinion piece was prompted by a series of open questions which have often puzzled me.  Why is so much of our immune system focussed on the gut?  Why not simply let the microbes and food constituents pass through and get digested without such strict surveillance?  Surely it would be more metabolically favourable to only react to those microbes that breach our epithelial barriers?  Why does our enteric nervous system devote so much of its resources to the gut?  Why is there a generally beneficial effect of many probiotics across so many health conditions?  Why is mother’s milk designed to promote the growth of microbes?

Could the solution to all of these questions be down to a very simple answer? Because the gut ‘expects and requires’ constant encounters with microbes for full functionality. Given that humans evolved into a microbial world, and that we have consumed a diet rich in microbes for most of our evolutionary history, it makes sense that our enteric systems would be designed to appropriately deal with microbes of all types, selecting out those which can cause damage and destroying them, accommodating those which will become part of our microbiomes and letting the rest pass through.  Surely we are monitoring and controlling our ‘microbial’ organ in the same way that our eukaryotic organs are monitored and controlled.

Could it be that the rise in autoimmune diseases could be, at least in part, due to an immune system primed to expect more microbes than it currently sees?  Should we recommend that a daily dose of safe microbes should be included in dietary guidelines – in the form of more safe raw foods, more fermented foods and more probiotics? It must be emphasized that some serious pathogens must be controlled or eliminated from food – not ALL live microbes are safe. But the goal can be to process only when needed for safety reasons, so foods can be a source of the safe microbes they harbour.

Lots of questions, and not many answers.  But I for one am taking account of this concept in my daily diet and am deliberately eating more microbes – I’ll let you know how it goes!

ISAPP publishes new paper on “Human Use of Probiotics”

ISAPP, working with the British publication Nutrition Bulletin, published an open access paper on “Human Use of Probiotics”.

The paper provides an overview of probiotics in the 21st Century, summarizes health conditions where actionable evidence on probiotic use exists, considers fermented food in the context of probiotics, and provides some regulatory and marketplace perspective.

“Most reviews covering health benefits of probiotics focus on specific conditions in depth. In this paper we try to include all benefits with compelling evidence,” Sanders says.

Access the paper here.

2018 Annual Meeting Report Now Available

The meeting report for the Annual Meeting June 5-7th 2018 ISAPP in Singapore is now available, featuring overviews of the speakers and discussion group conclusions.

Two days of plenary talks focused on the latest science featuring prebiotic and probiotic use in: pediatrics, oral health, allergy immunotherapy, the gut microbiome throughout life, synbiotics, liver disease, honey bee health, chronic gut disorders, and more. The meeting also featured an interesting talk about the changes coming in the nomenclature of the genus Lactobacillus.

The plenary, open sessions were followed by a Discussion Forum on June 7th for invited experts and Industry Advisory Committee Members. The discussion groups focused on:

  • Harmonizing Global Probiotic and Prebiotic Food/Supplement Regulation
  • Fermented Foods for Health: East Meets West
  • Potential Value of Probiotics and Prebiotics to Treat or Prevent Serious Medical Issues in Developing Countries
  • Prebiotics as Ingredients: How Foods, Fibres and Delivery Methods Influence Functionality

Finally, there were over 70 posters presented at the meeting featuring the latest prebiotic and probiotic research from around the world.

Slides and abstracts for the meeting can be found on the ISAPP website under the “Annual Meetings” tab, available to meeting participants only.

smile

Probiotics for oral health: start young

By Dr. Mary Ellen Sanders

Prof. Wim Teughels from the Department of Oral Health Sciences, Leuven University, spoke at the 2018 ISAPP meeting on the topic of probiotics and prebiotics for oral health. He embraced the opportunity to speak to this audience in part hoping he could convince researchers to consider incorporating oral health endpoints in their future clinical trials.

He did a spot-on lecture, which precisely summarized available evidence for probiotics and prevention of dental caries, management of periodontal disease and reduction of Streptococcus mutans in the oral cavity. This area of research is gaining traction (see here).

One study he discussed is particularly interesting by Stensson et al. 2014 tracked caries in children at 9 years of age. This single-blinded, placebo-controlled study administered L. reuteri ATCC 55730 to mothers during the last month before their baby’s birth and to the children through age one. The number of children receiving the L. reuteri probiotic without caries was significant higher (82%) than in the placebo group (58%).  Although there are studies available that show a larger impact, the interesting aspect of this study is that it tests a very early intervention in life that seems to have an effect up to 9 years later. It is an important paper because it opens up the notion of early interventions in life, during microbial ecology development. The main message here is you don’t need to wait until there are teeth to start working on dental health later in life. In fact, interventions for dental health can start during pregnancy and by this:

We do not know what would have happened if the probiotics were given during the whole 9 years of life. Dentists who are interested in prevention should be interested in such data.

Several meta-analyses have summarized data for dental caries and management of periodontal disease. These reviews are useful in that they summarize the totality of evidence. But combining data on different strains might not be justified, as different strains may utilize different mechanisms to achieve effects, and therefore should not be considered as the same intervention. See here, here, here and here.

In sum, there appears to be a growing body of evidence that probiotic administration may impact several indicators of oral health: dental caries, gingivitis and periodontitis. More research is needed to understand the impact of probiotic supplementation on the oral microbiota and if clinical benefits are mediated by microbiota changes. It’s also important to understand which strains will deliver the strongest benefits, although L. reuteri has several, positive studies, and the importance of dose and temporal factors with dosing.

live-dead-probiotics

Dead bacteria – despite potential for benefit – are NOT probiotics

This blog is a re-posting of a blog initially published on www.usprobiotics.org on July 5. By Dr. Mary Ellen Sanders

At the 2018 International Scientific Association of Probiotics and Prebiotics (ISAPP) meeting in Singapore, two renowned speakers reported unpublished research documenting the health benefits of dead bacteria.

Prof. Hill showed that an inactivated Lactobacillus strain reduced anxious behavior, reduced cortisol levels, and impacted the microbiome in a mouse model. Prof. Patrice Cani showed that heat-killed Akkermansia muciniphila were sufficient to ameliorate obesity and diabetes in mice. Both professors made the point that these microbial preparations were not probiotics.

Prof. Colin Hill is the lead author on the oft-cited and -downloaded (over 40,000 times) ISAPP consensus paper reaffirming the definition of probiotics, which emphasizes that probiotics must be alive when administered. This, of course, does not preclude health effects of dead bacteria. One just must remember that dead bacteria are NOT probiotics. Many different types of microbe-derived substances such as metabolites, cell wall fragments, enzymes, and neurochemicals, can have beneficial physiological effects. A 2016 review by de Almada et al. lists a couple dozen published studies of physiologically active dead bacteria.

Preserving the long-accepted definition of probiotics as ‘live microbes’ is important to the many stakeholders involved in the field. Consumers should be able to purchase a product labeled as ‘probiotic’ and know that it contains an effective level of live microbes. Regulators should know that a product without an adequate level of live microbes is fraudulent if called a probiotic. Scientists should be able to use the term and have reviewers and readers understand that they are referring to functions of live microbes. An agreed-upon definition enables us to be precise when discussing an issue. Saying that because dead bacteria have a health effect and they should be called ‘probiotics’ is like saying that because vitamin D has a health benefit, the term ‘vitamin A’ should include vitamin D.

What are implications of the fact that dead microbes may have health effects?

Stewards of the probiotic field can expect increased frustration with popular press writers. I’ll use a recent example to make this point. The June 2018 Cooking Light Magazine /Special Gut Health Issue included an article that lists sourdough bread as a top probiotic-containing fermented food. When the error about misusing the term ‘probiotic’ to describe a food that contained no live probiotic bacteria was pointed out to the editor by Jo Ann Hattner, MPH RD author of Gut Insight, Cooking Light chose to ignore advice from an expert and justify their mistake by using an irrelevant observation that both live and dead cells in probiotic products may generate beneficial biological responses. Apparently, the expertise she derived from a paper that described the “probiotic paradox” trumped the considered opinions of global expert scientists/researchers and the FAO/WHO, who agree that probiotics must be alive when administered. It’s quite a simple concept. It is true that some dead microbes may have some health benefit (although evidence of such an effect is much lower than that available from controlled human trials on actual probiotics), but they are NOT probiotics.

Confusion. Some audiences will be confused by the idea that probiotics that are killed can have health benefits. Inaccurate writers, such as the Cooking Light author above, will perpetuate this error. This is unfortunate, since the probiotic concept is a long-standing one, backed by much mechanistic and clinical evidence. Conflating probiotics with dead bacteria will lead to confusion over important aspects of an effective probiotic product.

Overages.  It is not uncommon for commercial products to be formulated with live microbes at time of manufacture that far exceed the number claimed on the label. This is to assure that the product meets label claim at the end of shelf life, as probiotics often die to some extent during storage. Sometimes this ‘overage’ can reach 10-fold more than the level guaranteed on the product, although more typically it’s 2- to 5-fold. If over the course of shelf life the viable count drops to label claim, then dead microbes may comprise as much as 90% of the microbes present. We don’t know if these dead bacteria – although no longer probiotics – have physiological benefits, as no studies have been conducted on this form of inactivated cells, but it’s an interesting possibility. When we study a probiotic product, perhaps that product needs to be characterized by both the level of live and dead microbes that are present. Means of inactivation, such as heat, pressure, irradiation, or sonication, may impact the physiological activity of the resulting dead cells.

Opportunity.  Keeping probiotics alive in commercial products is a challenge. Research such as Prof. Cani’s targets an expanded range of microbes – many isolated from the human GI tract – that cannot be easily grown and stabilized in commercial products. Further, these microbes lack the history of safe use that food-associated microbes have, and so administration of high numbers of these next-generation probiotics will require proof of safety. If these microbes can be killed and still deliver health benefits, the commercialization process could be simplified.

ISAPP may need to consider convening another consensus panel to address these newly emerging terms, such as postbiotic and paraprobiotic. Then we can all be on the same page when using these terms, which have important scientific, nutritional and clinical impact. Of course, even if ISAPP does this, authors may still choose to ignore it.

efficacyvseffectiveness

Efficacy and Effectiveness Studies

By Michael D. Cabana, MD, MPH

In the world of clinical trials, reproducibility (or consistency) of results across different clinical trials improves clinicians’ confidence in an intervention (Hill, 1965).  However, when reviewing the evidence for a probiotic or prebiotic supplement, the results are sometimes conflicting.  One study claims an intervention may work.  Another study claims that an intervention may not work. So how does the clinician deal with this situation?

To know how much confidence to place in any claim of benefit, clinicians need to consider the totality of the evidence and the quality of the studies. One tool is the systematic review process, which in an unbiased manner searches for all studies for a particular intervention, and when possible, combines results into a meta-analysis. The ‘summary’ of these data point to either an effect or no effect. The best way to combine data is using an individual patient-data meta-analysis (IPDMA). In addition, a clinician should determine whether the clinical trial is an effectiveness study or an efficacy study (Singal 2014).

 

Efficacy or Effectiveness?   

Efficacy studies ask, “does the intervention work in a defined (usually an “ideal”) setting?”  In general, the inclusion criteria for study participants will be very selective.  Patient adherence tends to be closely monitored. The clinicians conducting the trial may be specially trained in the intervention and its application. The intervention occurs in an ideal setting and the risk of other confounding interventions (e.g., unusual diets, concurrent treatments) will be limited.

On the other hand, effectiveness studies ask, “Does the intervention work in a real-world setting?”  The inclusion criteria for study participants tends to be less selective.  Patient adherence to the protocol is not necessarily strictly enforced. The clinicians conducting the trial tend to be representative of the typical physicians who would treat this condition.  The intervention occurs in a more ‘real-world’ setting where the presence of other confounding factors may be present.

For example, two relatively recent studies both examined the effect of a probiotic intervention, L. reuteri DSM 17938 for the treatment infant colic.  A study conducted by a team in Italy (Savino et al. 2010) noted that the intervention reduced colic symptoms; however, the study conducted by a team in Australia (Sung et al. 2014) showed no effect on colic.

Why the different results? In the Italian study, all the infants were breastfed.  In addition, the breastfeeding mothers limited their dairy intake.  The infants tended to be younger (mean age 4.4 weeks) and tended not to have other treatments for colic or gastrointestinal symptoms.  In contrast, the infants in the Australian study were breastfed or formula fed. The infants were older (median age 7.4 weeks) and were more likely to have been exposed to other treatment for gastrointestinal symptoms (such as histamine-2 blocker or proton pump inhibitors).  The infants were recruited from many different settings such as the emergency department.

Although both the Italian and the Australian study evaluated the same probiotic intervention for the same condition, the studies offer different information in terms of efficacy and effectiveness.  Describing a study as either an “efficacy” study or an “effectiveness” study is not always dichotomous.  Rather, these studies exist on a spectrum, from being more like an efficacy study versus more like an effectiveness study. In the example above, the Italian study had stricter criteria and fewer confounding factors.  As a result, it would tend to be classified as an efficacy study.  The Australian study enrolled infants with colic who were older and had a greater likelihood to be exposed to other interventions.  This study would tend to be classified as more of an effectiveness study.  The fact that the Australian study was a null study does not mean that the intervention was not effective in the ‘real world’.  Rather, for the patients enrolled, the treatment was not effective when used in that particular setting and context.  Perhaps you may encounter infants with colic who have feeding history and medical history more like the infants from the Italian study. Understanding the context of the studies helps identify those characteristics that may or may not apply to the infants with colic who you may treat in your clinic.

 

Which is better: Efficacy or Effectiveness?

When developing a new or experimental intervention, an efficacy study might be important to increase the likelihood of detecting a positive change.  However, “real world” factors may make a difference in how a product is used.  Perhaps an intervention might be inconvenient (due to multiple doses throughout the day) or unpalatable for the patient.  Perhaps the dosing regimen is complicated and the primary care providers don’t apply the correct dosing for patients. In these cases, an effectiveness study might be a better guide to how useful the intervention will be in clinical practice.

As a final note, it can be tempting to simply read the abstract of a clinical trial to assess the results of a study.  However, in many instances the crucial details of the study (e.g., how the study participants were selected, who was included or excluded, what type of clinical setting was used) are buried in the methods section of the study.  Patient diet, exposure to other treatments and comorbid conditions are all common confounding factors encountered in trials evaluating supplements.  When reading through the literature and understanding if a study is applicable to your practice, be sure to understand the full context and purpose of the study.  “Was this study useful for determining clinical efficacy or clinical effectiveness?” is an important question for readers of probiotic and prebiotic clinical trials. Keeping this question in mind may help you better resolve what may appear to be inconsistency among clinical trials.

East meets West at ISAPP’s first meeting in Asia

By Mary Ellen Sanders, PhD

The International Scientific Association for Probiotics and Prebiotics (ISAPP) recently convened its first meeting held in Asia, with the modern hub of Singapore as a host city. The meeting featured a two-day open registration meeting, attended by nearly 250 scientists, health professionals, and industry representatives, and a third day of smaller discussion groups by invitation. The meeting provided a rare opportunity for non-members to attend. It provided a dynamic forum for sharing different clinical experiences and regulatory nuances amongst the continents, as well as allowing attendees to better appreciate the research being performed in the Asian region.

Here are a few speaker highlights:

 

Mimi Tang MD

Tang presented the results of a double-blind, randomized controlled trial examining the effect of probiotic supplementation combined with oral immunotherapy (OIT) to decrease the risk of peanut allergy in children. Peanut allergy is one of the fastest growing food allergies in children. In the Probiotic and Peanut Oral ImmunoTherapy [PPOIT] study, children randomized to the intervention group had increased rates of sustained responsiveness to peanut several weeks after discontinuation of the treatment. Tang discussed the implications of the study, as well as current, larger clinical trials that are building upon these findings.

 

Dr. Bruno Pot

The Lactobacillus genus is taxonomically abnormally heterogeneous. Currently, the 231 Lactobacillus species range from a genome size of 1.23 – 4.91 megabases, have a GC content of 32-57% and an average nucleotide identity that is typical for a family or worse. Such ranges are far beyond what is acceptable for a bacterial genus. Experts are recommending that the current genus should be split into 12 new genera. Some well-known lactobacilli would be re-named, which may have important repercussions commercially and legally.

 

Profs. Colin Hill and Patrice Cani

Hill described how lactase in yogurt cultures improves lactose digestion; he emphasized how mechanisms that drive probiotic activity are complex. Some scientists are searching for a single molecule that drives probiotic health benefits—but it is unlikely to be found.

Hill noted even inactivated (non-living) microbes may have health effects—for example, a study showed that a dead Lactobacillus strain reduced anxious behavior, reduced cortisol levels, and impacted the microbiome in a mouse model. Work by Prof. Patrice Cani showed that heat-killed Akkermansia muciniphila were sufficient to ameliorate obesity and diabetes in mice. Does this suggest that we will need to start quantifying probiotics based on biomass as well as CFU?

 

Profs. Hani El-Nezami, Gregor Reid and Akihito Endo

These three speakers illustrated the important impact of environmental toxins (extremely potent aflatoxins, pesticides, and heavy metals) on humans and wildlife. They showed how certain probiotic strains can decrease aflatoxin absorption and even degrade them; sequester heavy metals and pesticides to reduce their uptake; and enhance resistance to honey bee colony collapse disorder that threatens the world’s food supply.

 

Prof. Wim Teughels

To date, 11 studies have been published on probiotics with a low ‘number needed to treat’ for prevention of dental caries in infants, toddlers, and adults. One study showed the benefits of administered L. reuteri, following children for nine years after they were treated as infants before any teeth had emerged. Also, data exist for probiotics influencing other oral health endpoints, including periodontal infections, oral candida infections, and halitosis.

 

The discussion groups on day three of the conference addressed a range of topics:

  • Possibilities to harmonize global probiotic and prebiotic regulations—Chaired by Seppo Salminen (Finland), Yuan Kun Lee (Singapore), and Gabriel Vinderola (Argentina)
  • Fermented foods for health: East meets West—Chaired by Bob Hutkins (USA), Paul Cotter (Ireland), and Liu Shao Quan (Singapore)
  • Potential value of probiotics and prebiotics to treat or prevent serious medical issues in developing countries—Chaired by Daniel Merenstein (USA), Reuben Wong (Singapore), and Colin Hill (Ireland)
  • Prebiotics as ingredients: How foods, fibres and delivery methods influence functionality—Chaired by Glenn Gibson (England) and Karen Scott (Scotland)

 

These workshops often produce peer-reviewed publications based on the discussion outcomes, so stay tuned for these developments. (See here for a list of ISAPP publications.)

The full meeting report is being developed and will be posted on the ISAPP website shortly.

The 2019 meeting will return to ISAPP’s normal format, hosted by Dr. Sarah Lebeer in Antwerp, Belgium.

 

seppo

Welcome Seppo Salminen – ISAPP’s New President

An interview with Prof. Seppo Salminen

ISAPP President 2018-2021

 

1) What are your goals as the next president of ISAPP? 

My goal is to work together with the board and the members to advance excellence in the science of probiotics and prebiotics and to share research and conclusions with as wide an audience as possible. It is also my goal to leverage ISAPP’s scientific  expertise to work with organizations to promote  evidence-based applications of probiotics and prebiotics to advance health and well-being of people.

2) What do you hope to see the organization accomplish during your tenure?

ISAPP is engaged now in North America, Europe and Asia so maybe we can be really be global and reach out to South America and  connect with researchers in Africa as we have done with Professor Reid earlier. I would like to work toward common goals with more industrial, scientific and regulatory experts from different parts of the world.

3) What changes do you foresee in the field of probiotics and prebiotics in the next few years?

 I foresee rapid development in probiotics and prebiotics. There will be novel microorganisms developed and novel sources of prebiotics and this direction leads to challenges in safety evaluation and efficacy demonstration  as well as communication of the results to larger audiences.

4) How did you originally become involved in ISAPP?

I was originally invited to one ISAPP meeting, then to the next one, then to the third one and at the end was invited to be a member of the board, which I considered a special honour!

5) Which ISAPP meeting was your favorite so far?

They all have been excellent, but some I remember (each for different reasons) are the ones in Barcelona, New York, Chicago and Berkeley – and now Singapore. Of course, the one in Turku, Finland as well – when you help organize a meeting like that you certainly remember even on a minute-by-minute basis.

Thank you Prof. Salminen and welcome!

2018_Singpaore

ISAPP’s First Meeting in Asia is a Huge Success

June 5-7th 2018 ISAPP held it’s first Asian meeting in Singapore. This open registration meeting was a huge success with over 240 attendees from 34 countries.

Two days of plenary talks focused on the latest science featuring prebiotic and probiotic use in: pediatrics, oral health, allergy immunotherapy, the gut microbiome throughout life, synbiotics, liver disease, honey bee health, chronic gut disorders, and more. The meeting also featured an interesting talk about the changes coming in the nomenclature of the genus Lactobaccilus.

The plenary, open sessions were followed by a Discussion Forum on June 7th for invited experts and Industry Members. The discussion groups focused on:

  • Harmonizing Global Probiotic and Prebiotic Food/Supplement Regulation
  • Fermented Foods for Health: East Meets West
  • Potential Value of Probiotics and Prebiotics to Treat or Prevent Serious Medical Issues in Developing Countries
  • Prebiotics as Ingredients: How Foods, Fibres and Delivery Methods Influence Functionality

Finally, there were over 70 posters presented at the meeting featuring the latest prebiotic and probiotic research from around the world.

Next year, ISAPP will be hosting an invite-only meeting in Antwerp, Belgium – May 14-16, 2019. To attend this meeting, join ISAPP as an Industry Member.

      

karen_scott

ISAPP’s Outgoing President: Karen Scott

Dr. Karen Scott of the Rowett Institute of the University of Aberdeen has served as the ISAPP President for the last three years. During her time as President, ISAPP has seen some incredible growth and accomplishments, and the organization is so grateful for her leadership.

Last year, under Karen’s leadership, ISAPP produced a prebiotic consensus panel paper, which remains one of the highest cited papers in nature reviews gastroenterology and hepatology.

In addition, over the last three years the Science Translation Committee has produced nine infographics, four videos, monthly blog posts, and a monthly newsletter focused on disseminating clinical and consumer information on probiotics and prebiotics.

Karen led three successful ISAPP Annual Meetings – Turku in 2016, Chicago in 2017, and ISAPP’s first meeting in Asia which took place in Singapore in 2018. All of these meetings followed her acting as local host for the 2014 ISAPP meeting in Aberdeen.

ISAPP’s mission to educate resulted in numerous outreach activities over the last three years including continuing education opportunities, webinars, the USP expert panel on probiotics, and regulator engagements. In terms of advancing the science, under Karen’s leadership ISAPP has published 21 peer-reviewed articles on probiotics and prebiotics.

Finally, industry involvement in ISAPP has remained strong and steady during Karen’s term, with 40-45 industry members from around the world. These industry members support ISAPP’s activities and participate in the annual meeting each year to hear about the latest probiotic and prebiotic science available.

Thank you so much Karen for your dedication and hard work to advance scientific excellence in probiotics and prebiotics.