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

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

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

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

Its magnificence is there for all to see.

Creative Commons Earth Illustration, Pixabay

Creative Commons Earth Illustration, by Pixabay

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

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

Photo by Andrew Pitek. Used with permission.

Just being human is a guest house1.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

References (unlike any you’ve seen before)

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

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

Researchers submit recommendations for revised Lactobacillus taxonomy

By Mary Ellen Sanders PhD, Executive Science Officer, ISAPP

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

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

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

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

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

See here for a detailed article on this topic.

new_website

ISAPP launches new website, furthering its mission of educating stakeholders on probiotic and prebiotic science

The ISAPP Board of Directors is pleased to announce the launch of the organization’s new website, which has now gone live at ISAPPscience.org. The website has been redesigned for easier navigation by different stakeholder groups—scientists, consumers, clinicians, and students—enabling ISAPP to continue with its mission of providing accurate, science-based information to its readers about probiotics, prebiotics and fermented foods.

ISAPP Executive Science Officer Dr. Mary Ellen Sanders says, “The scientists comprising the ISAPP Board of Directors realize that consumers and clinicians often struggle to find science-based information on probiotics and prebiotics. ISAPP is working to fill this gap, and we have streamlined our website to help individuals from each of these groups easily find the information they’re looking for.”

At the ISAPP annual meeting held earlier this year, advancing probiotic and prebiotic evidence to a variety of audiences was the topic of a special ‘springboard discussion’ session.

“Probiotic and prebiotic science has made significant progress in the past few decades,” says Sanders, “but this progress has not always been communicated effectively or correctly to those outside the scientific community.” Sanders continues, “Some studies describe an expanding array of health benefits but other studies show the limits of these interventions. Our goal is to counter the abundance of misinformation and be the go-to source of accurate materials about probiotics and prebiotics.”

ISAPP is building its capacity to produce more science-focused educational materials tailored to different audiences. Infographics, some of which are translated into 10 different languages, short videos and targeted blogs are featured on the new website. In coming weeks, ISAPP will make additional resources available on the website, including frequently asked questions about probiotics and prebiotics, and a downloadable white paper for clinicians. Signing up for the ISAPP newsletter is the best way to stay up to date on educational materials being added to the website.

ISAPP’s 2019 annual meeting in Antwerp, Belgium: Directions in probiotic & prebiotic innovation

Kristina Campbell, Microbiome science writer, Victoria, British Columbia

We live in a time when a simple Google search for ‘probiotics’ produces over 56.8 million hits; a time when almost everyone has heard of probiotics through one channel or another, and when an ever-increasing variety of probiotic and prebiotic products is available in different regions of the world.

The next five to ten years will be telling: will probiotics and prebiotics join the ranks of other trendy health products that experienced a wave of popularity before something else took their place? Or will they be recognized as important contributors to health through the lifespan, and establish a permanent position in the clinical armamentarium?

According to the global group of 175 academic and industry scientists who met for the ISAPP annual meeting in Antwerp (Belgium) May 14-16, 2019, one thing above all is necessary for the world to recognize the significance of probiotics and prebiotics for health: scientific innovation. Not only are technological capabilities advancing quickly, but also, new products are being evaluated by better-educated consumers who demand more transparency about the health benefits of their probiotics and prebiotics.

Participants in the ISAPP conference came together to talk about some of the leading innovations in the world of probiotics and prebiotics. Here are three of the broad themes that emerged:

Better health through the gut-brain axis

Gut-brain axis research is rapidly growing, with many investigators in search of probiotic and prebiotic substances capable of modulating brain function in meaningful ways. Phil Burnett of Oxford (UK) presented on “Prebiotics, brain function and stress: To what extent will prebiotics replace or complement drug therapy for mental health?”. Burnett approached the challenge by administering prebiotics to healthy adults and giving them a battery of psychological tests; in one experiment he found people who consumed a prebiotic (versus placebo) showed benefits that included reduced salivary cortisol and positively altered emotional bias. For those with diagnosed brain disorders, Burnett concludes from the available data that prebiotics have potential anxiolytic and pro-cognitive effects in these populations, and that prebiotics may eventually be used to complement the established treatments for some mental disorders.

Short-chain fatty acids (SCFAs) are of interest as potential modulators of brain function, but so far very little research has been carried out in this area. Kristin Verbeke of Leuven (Belgium) gave a talk entitled “Short-chain fatty acids as mediators of human health”, which covered the extent to which interventions with fermentable carbohydrates can alter systemic SCFA concentrations (rather than gut SCFA concentrations)—since the former are more relevant to effects on the brain.

Also, a students and fellows feature talk by Caitlin Cowan of Cork (Ireland) explored a role for the microbiota in psychological effects of early stress. She spoke on the topic “A probiotic formulation reverses the effects of maternal separation on neural circuits underpinning fear expression and extinction in infant rats”.

A clear definition of synbiotics

Immediately before the main ISAPP meeting, a group of experts met to propose a consensus definition of ‘synbiotic’, with the objective of clarifying for stakeholders a scientifically valid approach for the use of the increasingly-popular term. A key point of discussion was whether the probiotic and prebiotic substances that make up a synbiotic are complementary or synergistic. And if the two substances have already been tested separately, must they be tested in combination to give evidence of their health effect? The group’s conclusions, which will undoubtedly steer the direction of future R&D programs, will be published in a forthcoming article in Nature Reviews Gastroenterology & Hepatology.

Probiotics and prebiotics for pediatric populations

Probiotics and prebiotics have been studied for their health benefits in pediatric populations for many years, but in this area scientists appear to have a renewed interest in exploring new solutions. Maria Carmen Collado of Valencia (Spain) covered “Probiotic use at conception and during gestation”, explaining some of the most promising directions for improving infant health through maternal consumption of probiotics.

In recent years, technical advancements have made possible the large-scale production of some human milk oligosaccharides (HMOs); it is now an option to administer them to infants. Evelyn Jantscher-Krenn of Graz (Austria) presented a novel perspective on HMOs, with “HMOs in pregnancy: Roles for maternal and infant health”, giving a broad overview of the many ways in which HMOs might signal health status and how they might be fine-tuned throughout a woman’s pregnancy.

A discussion group on “prebiotic applications in children”, chaired by Dr. Michael Cabana of San Francisco (USA) and Gigi Veereman of Brussels (Belgium), discussed evidence-based uses of prebiotics in children in three areas: (1) prevention of chronic disease; (2) treatment of disease; and (3) growth and development. While the latter category has the best support at present (specifically for bone development, calcium absorption, and stool softening), the other two areas may be ripe for more research and innovation. The chairs are preparing a review that covers the outcomes of this discussion group.

Next year in Banff

ISAPP’s next annual meeting is open to scientists from its member companies and will be held on June 2-4, 2020 in Banff, Canada.

 

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

Thank You to ISAPP’s 2019 Industry Advisory Committee Members

by Dr. Mary Ellen Sanders

This year, a record 50 companies that are dedicated to a science-based approach to the probiotic and prebiotic industries joined ISAPP. As members of the Industry Advisory Committee (IAC), these companies provide critical insights to ISAPP’s all-academic board of directors as they leverage ISAPP to address challenges facing these and related industries.

ISAPP will welcome representatives from each IAC company at the ISAPP Annual Meeting – taking place next week May 14th-16th in Antwerp, Belgium.

Industry dues provide support for ISAPP activities, which would not be possibly without funding by our IAC members. Summaries of ISAPP activities are found here.

Thank you IAC!

ISAPP Tests the Water with a New Session Format at Annual Meeting: The Springboard

By Mary Ellen Sanders PhD, Executive Science Officer, ISAPP

Along with more traditional lectures, the distinctive five-minute rapid-fire late breaking news session and the small, topical discussion groups have been staples of the annual ISAPP meetings. This year in Antwerp, ISAPP is trying yet another innovative approach – a session we are calling “The Springboard.” The witty Prof. Glenn Gibson will chair, sure to make the session entertaining as well as inspiring.

The Springboard is a session designed to integrate audience and facilitators’ viewpoints in an interactive format. The topic:  What can scientists and industry do to spring probiotics and prebiotics into mainstream health management? Four facilitators, each focused on a different perspective (industry, politics, medical/clinical or science/research), will present their visions. The audience, which will be divided into 10 subgroups, is challenged with the task of generating innovative ways to achieve the visions.

ISAPP plans to write up the most interesting solutions for publication. Watch for the output from this new session after the 2019 ISAPP annual meeting – May 14-16.

The Art of Interpretation

By Prof. Gregor Reid, BSc Hons PhD MBA ARM CCM Dr HS, Lawson Research Institute, University of Western Ontario, Canada

It takes a certain degree of intelligence to become a scientist, and certainly hard work to be able to fund a lab and students. Yet, is it not bemusing when scientists cannot interpret simple things like definitions and the results of human studies?

I’ve written repeatedly, as have others, about the definition of probiotics (in case you forgot – “Live microorganisms that, (or which) when administered in adequate amounts, confer a health benefit on the host”),1,2 and yet people look at it and must think that ‘dead’ fits, as does ‘consume’, as does ‘colonize’. It beggar’s belief how such a simple definition can be so badly interpreted by intelligent people.

Time after time papers I review mis-write and/or misinterpret the definition. Conference after conference, I hear dieticians, pharmacists, physicians, scientists not only get the definition wrong, but say things like ‘the probiotics in kombucha’ when there are none, ‘we have lots of probiotics in our gut’ when you don’t unless you consumed them, ‘the lactobacilli need to colonize’ when this was never a prerequisite nor does it happen except in rare instances.

The interpretation gets more difficult when people use terms that are completely undefined like ‘psycho-biotics’ and ‘post-biotics’. Even ‘dead probiotics’ have been used in clinical trials – God help us when the authors can’t even define it. Why stop at killing probiotic strains? Why not just kill any bacterial strain? Even the gut-brain axis which is now mentioned everywhere in the literature is undefined and unproven. The vagus nerve links to many body sites as does the nervous system, making it exceedingly difficult to prove that brain responses are only due to the gut microbes.

Everyone can site a manuscript that has been badly analyzed, interpreted or peer-reviewed, or whose findings are overblown. But let’s not excuse this as ‘it’s just science’ or ‘it’s just the way it is.’ No, it is not. When a paper uses a product that is stated to be ‘probiotic’, there is an onus on the authors to make sure the product meets the appropriate criteria. These have been stated over and over again and reiterated this March, 2019.3

If scientists and science writers are really that smart, then how do they keep getting this wrong? How do we let a poorly analyzed paper get published and allow authors to say that Bacteroides fragilis is a probiotic that can treat autism?4,5 And when this leads to companies claiming probiotics can treat autism, why do other scientists convey cynicism for the field instead of against their colleagues and specific companies making the false claims?

Where does opinion cross the line with ignorance or stupidity? Martin Luther King Jr. must have predicted life today when he said, “Nothing in all the world is more dangerous than sincere ignorance and conscientious stupidity.”

Is it envy or anger that drives the anti-probiotic sentiments? It seems to go far beyond a difference of opinion. When the BBC and JAMA fail to comment on two much better and larger studies on the effects of probiotics published6,7 at the same time as the ones in Cell8,9 that were promoted by press releases, what is driving opinion? The science or the press releases? Are the journalists and communications’ people interpreting study results vigorously? One cannot believe they are.

In an era where anyone can write anything at any time and pass it along to the world, what are we recipients to do? Just go with our instincts? Soon, we will not know the difference between fact and fake news. The avatars will be so real, we will act on falsehoods without knowing. When all news is fake, where does that leave us as people, never mind scientists?

Manuscripts are sent for peer-review but how many reviewers are experts in bioinformatics, molecular genetics, clinical medicine, biostatistics and what happens on the front line of products to consumers or patients? Like it or not, poor studies will get out there and it will be the media who will tell the story and interpret the findings or press releases.

One must hope that confirmatory science will continue and if it fails, the writers and readers will stop citing the original incorrect report. But how often does that happen? And what are we left with?

It takes effort to object or fight back, but if we don’t then the fake news will become the norm.

Try interpreting that if you will.

 

Literature Cited

  1.  FAO/WHO. 2001. Probiotics in food.  http://www.fao.org/food/food-safety-quality/a-z-index/probiotics/en/
  2. Hill C. et al. 2014. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotics. Nat. Reviews Gastroenterol. Hepatol. 11(8):506-14.
  3. Reid G. et al. 2019. Probiotics: reiterating what they are and what they are not. Front. Microbiol. 10: article 424.
  4. Hsiao et al. 2013. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell. 155(7):1451-63.
  5. Sharon G, et al. 2016. The central nervous system and the gut microbiome. Cell. 167(4):915-932.
  6. Korpela K. et al. 2018. Probiotic supplementation restores normal microbiota composition and function in antibiotic-treated and in caesarean-born infants. Microbiome. 6(1):182.
  7. De Wolfe, T.J. et al. 2018. Oral probiotic combination of Lactobacillus and Bifidobacterium alters the gastrointestinal microbiota during antibiotic treatment for Clostridium difficile infection. PLoS One. 13(9):e0204253.
  8. Suez J. et al. (2018). Post-antibiotic gut mucosal microbiome reconstitution is impaired by probiotics and improved by autologous FMT. Cell. 2018 Sep 6;174(6):1406-1423.e16.
  9. Zmora N. et al. 2018. Personalized gut mucosal colonization resistance to empiric probiotics is associated with unique host and microbiome features. Cell. Sep 6;174(6):1388-1405.e21.

University confers Distinguished University Professor status on ISAPP board of directors member Gregor Reid

ISAPP board of directors member Dr. Gregor Reid has received a Distinguished University Professorship (DUP) award from his institution, University of Western Ontario in Canada, in honour of his exceptional scholarly career achievements. Reid, a Professor of Microbiology & Immunology, and Surgery, was aptly described as ‘a Canadian and international pioneer’ in research related to probiotics and the microbiome. A special area of research focus is how these relate to women’s health.

The many letters after Reid’s name reflect his extensive qualifications: BSc Hons, PhD, MBA, ARM CCM, Dr HS, FCAHS, FRS; he also has over 500 scientific publications to his name. But more than that, the impact of Reid’s work is seen all over the world. He has researched novel probiotic therapies that are now being used in different countries and settings, and his innovations have resulted in numerous probiotic-related patents. Reid also makes a point of empowering those in need: in Uganda, Kenya, and Tanzania, for example, he participated in a project to establish probiotic yogurt kitchens that allowed local women to further build sustainable yogurt businesses.

Reid’s connection with ISAPP goes back a long way—he hosted the first ever ISAPP meeting in London, Canada in May of 2002, and served as ISAPP’s second president. Still a dedicated member of the ISAPP board of directors, he is respected for his innovative ideas to move ISAPP forward and his incredible efficiency. As his colleagues know, no one gets more done more quickly than Gregor!

Today he is known as a steward of the proper use of the term ‘probiotic,’ a fitting description since he chaired the FAO/WHO expert consensus that published the now globally-recognized definition of the word probiotic back in 2001.

The ISAPP colleagues of Dr. Gregor Reid extend a warm congratulations on his Distinguished University Professorship award; they applaud his remarkable scientific accomplishments, his energy, and his determination to help the field advance.

See here for the full news article about the award.

New ISAPP video gives an overview of fermented foods and their health benefits

Fermented foods are not the same as probiotic-containing foods. So what’s the difference? Do both of them confer the same health benefits?

These topics are addressed in ISAPP’s latest video, which takes viewers through the scientific basics of fermented foods (see here). Yogurt, kimchi, and cheese fall into this category of foods, which are transformed by growth and metabolic activity of microbes.

Some fermented foods contain live microbes that travel through the digestive tract, interact with cells, and support the intestinal microbiota. Their potential health benefits are of interest, too: not only do fermented foods improve digestibility, but initial studies show they also improve the immune system and prevent acute illnesses.

The upshot? Naturally fermented foods are worth incorporating in your daily diet.

This educational video was commissioned by the ISAPP board of directors with input from several additional scientific experts.

ISAPP releases new video providing clarity on prebiotics and their health benefits

Consumers often assume prebiotics are the same as dietary fibers—but in fact, prebiotics have a specific scientific definition and come with unique health benefits.

In this new video produced by ISAPP (see here), you’ll get a quick overview of prebiotics: what they are, different ways you can consume them, and their scientifically demonstrated health benefits.

The video describes food sources of prebiotics, including whole grains, beans, onions, garlic, and artichokes, and how to look for prebiotics in supplement or functional food form. It also distills the science into a practical recommendation: a daily intake of 3-5 grams of prebiotics can help improve digestion, support the body’s natural defenses, improve mineral absorption, and regulate energy balance and glucose metabolism.

This educational video was commissioned by the ISAPP board of directors with input from several additional scientific experts.

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

February 20, 2019

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

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

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

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

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

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

Some suggestions for improving outcomes were offered:

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

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

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

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

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

Prof. Maria Marco joins the ISAPP board of directors

ISAPP happily announces that Prof. Maria Marco Ph.D. from the Department of Food Science and Technology at UC Davis has joined the ISAPP board of directors.

Prof. Marco has broad expertise in probiotics, prebiotics, and fermented foods. She has a special interest in lactic acid bacteria (from plant and animal sources) and the mechanisms of their interaction with their hosts.  She is one of the few researchers globally to tackle the important issue of the role of delivery matrix in probiotic functionality. She has more than 70 publications and book chapters.

Prof. Marco serves as the Chair of the Food Science Graduate Group and has mentored over 50 undergraduates, MS students, and visiting scholars, 11 PhD students, and 13 post-docs. She is active in education and public outreach on fermented foods and is a founder of a start-up company on microbial detection.

Prof. Marco serves as an Editor of mSphere and has served as the Guest Editor – Special issue on Food Biotechnology for Current Opinion in Biotechnology (2018). As guest editor of COB, she mediated publication of outcomes from several ISAPP discussion groups.

See her profile here. For more details on what her lab is up to, see here.

See here for the list of ISAPP’s all-academic board of directors.

ISAPP’s prebiotics & probiotics infographic now available in Russian

‘International’ is the first word in ISAPP’s title—and the organization takes seriously its commitment to advancing education about probiotics and prebiotics in countries around the world. ISAPP members are happy to announce that the infographic “Effects of Prebiotics and Probiotics on our Microbiota” is now available in Russian. See here.

In an effort to reach broader global populations with its science-based communications on probiotics, prebiotics and fermented foods, ISAPP is undertaking steps to translate its infographics into multiple languages. Expected in the next month are translations of ISAPP’s popular “Probiotics” and “Prebiotics” infographics, which will be available in Bulgarian, Chinese, Dutch, French, Indonesian, Italian, Polish, Portuguese, Russian, and Spanish. (See here for all available translations of ISAPP infographics.)

The translation efforts, led by Dr. Roberta Grimaldi from University of Reading (UK), are made possible by many translators who are contributing generously of their time and skills.

hospital_room

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

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

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

 

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

 

ISAPP recognizes Prof. Michael Cabana’s contributions during his board of directors tenure

Prof. Michael Cabana’s service on ISAPP’s board of directors has come to an end in 2018—and the remaining board members wish to affirm his rich legacy of contributions, which furthered ISAPP’s mission of advancing the science of probiotics and prebiotics.

Dr. Cabana, Professor of Pediatrics, Epidemiology and Biostatistics and the Director of the Division of General Pediatrics at the University of California, San Francisco (UCSF), joined the ISAPP board in 2008. He served as secretary for five years and treasurer for one year, and was local host for the 2011 ISAPP annual meeting in Berkeley, USA. He chaired discussion groups at eight different annual meetings:

  • 2009: Designing human clinical trials for probiotics
  • 2010: Prebiotics and probiotics in perinatal nutrition
  • 2012: From clinical trials to clinical guidelines:  Reconciling the evidence
  • 2013: Use of probiotics and/or prebiotics to program fetal and newborn health / first 1000 days of life
  • 2014: Infant colic:  Is there enough clinical evidence to support probiotic interventions?
  • 2015: Technology transfer and academic-industry partnerships
  • 2016: Colic update:  IPDMA and mechanisms
  • 2019: Prebiotic applications in children

 

Dr. Cabana was proactive in developing ISAPP responses to media misrepresentations of research by co-authoring letters to the editor in the New England Journal of Medicine (under review) and JAMA Internal Medicine (in press):

  • Guarner F, Cabana MD, Sanders ME. Late initiation of probiotic therapy for acute pediatric gastroenteritis may account for null results. New England J Med. Submitted.
  • Cabana MD, Salminen S, Sanders, ME. Probiotic safety – reasonable certainty of no harm. JAMA Internal Med. In Press.

As outcomes of ISAPP discussion groups or as part of other ISAPP initiatives, Dr. Cabana coauthored several papers, including:

 

Always a congenial and collaborative colleague, Dr. Cabana will be missed by the ISAPP board as he now turns his focus to other professional activities. Dr. Cabana’s UCSF lab has several ongoing trials related to the microbiome and probiotics in pediatric populations.

Prof. Hania Szajewska joins the ISAPP board of directors

ISAPP is pleased to announce that Prof. Hania Szajewska MD from the Department of Paediatrics of The Medical University of Warsaw has joined the ISAPP board of directors.

Prof. Szajewska’s depth and breadth of experience in probiotics, prebiotics, and the effects of early dietary interventions on long term health will greatly facilitate ISAPP’s ability to fulfill its mission to advance the science of probiotics and prebiotics.

In addition to conducting clinical trials on probiotics in pediatric populations, Prof. Szajewska has led numerous efforts to systematically review the totality of evidence on probiotics and prebiotics in order to develop evidence-based recommendations where warranted. She has more than 285 publications and 25 book chapters.

Prof. Szajewska serves as the Editor-in-Chief (Europe) of the Journal of Pediatric Gastroenterology and Nutrition and is involved in European Society for Paediatric Gastroenterology, Hepatology and Nutrition in numerous capacities.

Prof. Szajewska replaces Prof. Michael Cabana MD MPH, who is stepping down from the board to embrace new professional opportunities.

See here for the list of ISAPP’s all-academic board of directors.

kelly_swanson

ISAPP plans consensus panel on synbiotics

The term ‘synbiotic’ – which refers to a substance that combines both a probiotic and prebiotic – lacks a concise, modern definition. Stakeholders, including researchers, regulatory experts, consumers, marketers, industry scientists and healthcare providers, would benefit from a clear definition of synbiotics, a concise review of the state of the science of synbiotics, and a clarification of what kinds of products fall under the synbiotic scope.

ISAPP will convene a panel of top scientific experts on May 13th in Antwerp to develop a consensus around this topic. This panel will be chaired by Prof. Kelly Swanson, The Kraft Heinz Company Endowed Professor in Human Nutrition, Professor in the Department of Animal Sciences and Division of Nutritional Sciences, and Adjunct Professor in the Department of Veterinary Clinical Medicine at the University of Illinois at Urbana-Champaign. Prof. Swanson is known for his research on the mechanisms by which nutritional interventions affect health outcomes in both animals and humans. He is a co-author of the 2017 ISAPP consensus statement on the definition and scope of prebiotics.

As with the ISAPP consensus statements on probiotics (Hill et al. 2014) and prebiotics (Gibson et al. 2017), ISAPP is working with Nature Reviews Gastroenterology and Hepatology to publish the outcome of the synbiotics panel.

ISAPP’s focus on the science of probiotics and prebiotics makes it uniquely positioned to champion a panel of experts to discuss the definition and scientific justification for synbiotics.

The consensus panel members are:

  • Kelly Swanson, University of Illinois at Urbana-Champaign, USA (chair)
  • Glenn Gibson, University of Reading, UK
  • Gregor Reid, University of Western Ontario, Canada
  • Kristin Verbeke, University of Leuven (KU Leuven), Belgium
  • Nathalie Delzenne, Université Catholique de Louvain, Belgium
  • Robert Hutkins, University of Nebraska-Lincoln, USA
  • Karen Scott, University of Aberdeen, UK
  • Raylene Reimer, University of Calgary, Canada
  • Hannah Holscher, University of Illinois at Urbana-Champaign, USA
  • Meghan Azad, University of Manitoba, Canada
  • Mary Ellen Sanders, ISAPP

ISAPP’s 2019 Annual Meeting Program Released

ISAPP is pleased to announce the release of the official program for its 2019 Annual Meeting, scheduled for May 14-16, 2019, in Antwerp. Unlike the 2018 ISAPP meeting in Singapore, which was an open registration meeting, the 2019 event will comprise only invited academic experts and industry scientists from member companies. For program details, see the meeting website.

The 2019 program offers a strong lineup of probiotic, prebiotic and microbiome presentations. Featured topics include human milk oligosaccharides, learnings from the Flemish Gut Flora project, and leveraging political infrastructure to advance important science and public health messaging. Half-day breakout discussion groups are scheduled for May 15th, covering timely topics relevant to both industry and clinical practice, such as recommended dietary allowance (RDA) for live cultures, and the use of probiotics and prebiotics as adjuncts to drugs. Prof. Glenn Gibson will host the “fishbowl”, a session designed to integrate audience and experts’ perspectives in an interactive format; this year’s topic is: What can scientists and industry do to spring probiotics and prebiotics into mainstream health management?

For companies interested in participating in this meeting, now’s the time to join ISAPP and become part of its active industry advisory committee. Details on industry membership can be found here. ISAPP’s industry members help ISAPP achieve its mission of advancing the science of probiotics and prebiotics—see  here for a summary of our latest accomplishments.

Students and fellows will constitute an important presence at the annual meeting. Members of the ISAPP students and fellows association (SFA) will be keen participants, having organized a poster session as well as two SFA oral presentations. The group will also run a half-day parallel student-focused program.

The local host for ISAPP’s 2019 Annual Meeting, Prof. Sarah Lebeer, University of Antwerp, is excited to welcome her ISAPP colleagues to Antwerp. The history of Antwerp goes back to the 4th century and today the city remains an important European cultural and trade center. ISAPP Annual Meeting participants are invited to join a riverboat trip and dinner to get to know this historic city.

 

 

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.

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.

 

Minimum criteria for probiotics: ISAPP perspectives

By Mary Ellen Sanders PhD, Executive Science Officer, ISAPP

During its 2018 annual meeting (June 5-7), ISAPP convened a group of 30 participants from 13 countries to address issues associated with global harmonization of regulations for probiotics and prebiotics. This topic was of interest due to the broad international presence at this meeting, ISAPP’s first in Asia. The goal of this group was to provide regulators guidance derived from this assemblage of experts regarding the minimum criteria a probiotic food or supplement should meet. Drs. Seppo Salminen, Yuan-Kun Lee, and Gabriel Vinderola, who chaired this group, recently completed a summary titled “ISAPP position statement on minimum criteria for harmonizing global regulatory approaches for probiotics in foods and supplements”.

In December of 2017 the International Probiotic Association (IPA) presented a proposal to Codex Alimentarius – a recognized body that develops global standards and guidelines related to foods – regarding establishment of guidelines for probiotic foods. Codex Alimentarius accepted this proposal and requested that Argentina prepare draft guidelines to be considered in the 2018 session of the Codex Alimentarius  Committee on Nutrition and Foods for Special Dietary Use. ISAPP representatives and group coordinators (Sanders, Salminen and Vinderola) took part along with IPA in a scientific meeting in Argentina to present the ISAPP views to local authorities and experts.  IPA hopes that these efforts will lead to harmonized regulations since “this lack of harmonization in industry practice and legislation remains and often leads to serious issues and concerns for the probiotics industry, regulators, and even consumers in regard of quality, safety and labelling.” (Page1 of the proposal)

As the efforts of harmonization of regulations for probiotic foods through Codex progresses, ISAPP offers – through this summary document – its perspectives on minimum criteria for probiotics. The ISAPP group’s conclusions echo the principles outlined in the IPA proposal. Our hope is that this ISAPP document will provide useful perspective to local regulators. As of this writing, Prof. Salminen has delivered this document to the Codex representative at the Finnish Ministry of Agriculture and Food. We hope that further dissemination of the perspectives in this document will contribute to a science-based approach to global harmonization of regulations for probiotics.

See the document for the list of minimum criteria.

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.

 

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