A key characteristic of a probiotic is that it remains alive at the time of consumption. Yet scientists have known for decades that some non-living microorganisms can also have benefits for health: various studies (reviewed in Ouwehand & Salminen, 1998) have compared the health effects of viable and non-viable bacteria, and some recent investigations have tested the health benefits of pasteurized bacteria (Depommier et al., 2019).
Since non-viable microorganisms are often more stable and convenient to include in consumer products, interest in these ‘postbiotic’ ingredients has increased over the past several years. But before now, the scientific community had not yet united around a definition, nor had it precisely delineated what falls into this category.
An international group of scientists from the disciplines of probiotics and postbiotics, food technology, adult and pediatric gastroenterology, pediatrics, metabolomics, regulatory affairs, microbiology, functional genomics, cellular physiology and immunology met in 2019 to discuss the concept of postbiotics. This meeting led to a recently published consensus paper, including this definition: “a preparation of inanimate microorganisms and/or their components that confers a health benefit on the host”.
Thus, a postbiotic must include some non-living microbial biomass, whether it be whole microbial cells or cell components.
Below is a Q&A with four of the paper’s seven ISAPP-linked authors, who highlight important points about the definition and explain how it will lay the groundwork for better scientific understanding of non-viable microbes and health in the years ahead.
Why was the concept of postbiotics needed?
Prof. Seppo Salminen, University of Turku, Finland:
We have known for a long time that inactivated microorganisms, not just live ones, may have health effects but the field had not coalesced around a term to use to describe such products or the key criteria applicable to them. So we felt we needed to assemble key experts in the field and provide clear definitions and criteria.
Further, novel microbes (that is, new species hitherto not used in foods) in foods and feeds are being introduced as live or dead preparations. The paper highlights regulatory challenges and for safety and health effect assessment for dead preparations of microbes.
Can bacterial metabolites be postbiotics?
Prof. Gabriel Vinderola, National University of Litoral, Argentina:
Postbiotics can include metabolites – for example, fermented products with metabolites and microbial cells or their components, but pure metabolites are not postbiotics.
Can you expand on what is not included in the category of postbiotics?
Dr. Mary Ellen Sanders, ISAPP Executive Science Officer, USA:
The term ‘postbiotic’ today is sometimes applied to components derived from microbial growth that are purified, so no cell or cell products remain. The panel made the decision that such purified, microbe-derived substances (e.g. butyrate) should be called by their chemical names and that there was no need for a single encompassing term for them. Some people may be surprised by this. But microbe-derived substances include a whole host of purified pharmaceuticals and industrial chemicals, and these are not appropriately within the scope of ‘postbiotics’.
For something to be a postbiotic, what kinds of microorganisms can it originate from?
Prof. Gabriel Vinderola, National University of Litoral, Argentina:
A postbiotic must derive from a living microorganism on which a technological process is applied for life termination (heat, high pressure, oxygen exposure for strict anaerobes, etc). Viruses, including bacteriophages, are not considered living microorganisms, so postbiotics cannot be derived from them.
Safety and benefits must be demonstrated for its non-viable form. A postbiotic does not have to be derived from a probiotic (see here for a list of criteria required for a probiotic). So the microbe used to derive a postbiotic does not need to demonstrate a health benefit while alive. Further, a probiotic product that loses cell viability during storage does not automatically qualify as a postbiotic; studies on the health benefit of the inactivated probiotic are still required.
Vaccines or substantially purified components and products (for example, proteins, peptides, exopolysaccharides, SCFAs, filtrates without cell components and chemically synthesized compounds) would not qualify as postbiotics in their own right, although some might be present in postbiotic preparations.
What was the most challenging part of creating this definition?
Dr. Mary Ellen Sanders, ISAPP Executive Science Officer, USA:
The panel didn’t want to use the term ‘inactive’ to describe a postbiotic, because clearly even though they are dead, they retain biological activity. There was a lot of discussion about the word ‘inanimate’, as it’s not so easy to translate. But the panel eventually decided it was the best option.
Does this definition encompass all postbiotic products, no matter whether they are taken as dietary supplements or drugs?
Prof. Hania Szajewska, Medical University of Warsaw, Poland:
Indeed. However, as of today, postbiotics are found primarily in foods and dietary supplements.
Where can you currently find postbiotics in consumer products, and what are their health effects?
Prof. Hania Szajewska, Medical University of Warsaw, Poland:
One example is specific fermented infant formulas with postbiotics which have been commercially available in some countries such as Japan and in Europe, South America, and the Middle East for years. The postbiotics in fermented formulas are generally derived from fermentation of a milk matrix by Bifidobacterium, Streptococcus, and/or Lactobacillus strains.
Potential clinical effects of postbiotics include prevention of common infectious diseases such as upper respiratory tract infections and acute gastroenteritis. Moreover, fermented formulas have the potential to improve some digestive symptoms or discomfort (e.g. colic in infants). In addition, there is some rationale for immunomodulating, anti-inflammatory effects which may potentially translate into other clinical benefits, such as improving allergy symptoms. Still, while these effects are likely, more well-designed, carefully conducted trials are needed.
What do we know about postbiotic safety?
Dr. Mary Ellen Sanders, ISAPP Executive Science Officer, USA:
Living microbes have the potential, especially in people with compromised health, to cause an infection. But because the microbes in postbiotics are not alive, they cannot cause infections. This risk factor, then, is removed from these preparations. Of course, the safety of postbiotics for their intended use must be demonstrated, but infectivity should not be a concern.
What are the take-home points about the postbiotics definition?
Prof. Seppo Salminen, University of Turku, Finland:
Postbiotics, which encompass inanimate microbes with or without metabolites, can be characterized, are likely to be more stable than live counterparts and are less likely to be a safety concern, since dead bacteria and yeast are not infective.
Read the postbiotic definition paper here.
See the press release about this paper here.
View an infographic on the postbiotic definition here.
See another ISAPP publication on postbiotics here.
The Human Mycobiome: An ISAPP mini-symposium
/in News, ISAPP Science Blog /by KCISAPP announces an open registration mini-symposium on the human mycobiome.
Although the contribution of the intestinal microbiome in human physiology is well-studied, the specific role of intestinal fungi, the gut mycobiome, is not well understood. Yet they may play an important role in shaping host development and health. For example, the evidence that fungi are involved in development of chronic inflammatory diseases is building. Further, a healthy gut microbiome is likely a major line of defense against the detrimental spread of fungi from the intestinal environment to other parts of the body, or unwanted establishment of fungi in the gut itself. This mini-symposium features six short lectures that will explore different aspects of the human mycobiome, including research, clinical and industry perspectives.
Mini-symposium schedule, July 1, 2021
Houston, TX
Weill Cornell Medical College, TX
The webinar was held on July 1, 2021 — see the recording here:
A roundup of the ISAPP consensus definitions: probiotics, prebiotics, synbiotics, postbiotics and fermented foods
/in ISAPP Science Blog /by KCBy Dr. Mary Ellen Sanders, PhD, ISAPP Executive Science Officer
ISAPP has long recognized the importance of precise definitions of the ‘biotic’ family of terms. As a scientific organization working to advance global knowledge about probiotics, prebiotics, synbiotics, postbiotics and fermented foods, we believe carrying out rigorous scientific studies—and comparing one result to another—is more difficult if we do not start with a clear definition of what we are studying.
Over the past 8 years, ISAPP has endeavored to bring clarity to these definitions for scientists and other stakeholders. ISAPP board members have met with other top experts representing multiple perspectives and specialties in the field to develop precise, useful and appropriate definitions of the terms probiotics, prebiotics, synbiotics, postbiotics and fermented foods. The definitions of these first four terms have all entailed the requirement that the substance be shown to confer a health benefit in the target host. Fermented foods have multitudes of sensorial, nutritional and technological benefits, which drive their utility. A health benefit is not required.
The problem with health benefits
The definitions provide significant advantages for the scientific community in terms of clarity but complexity arises when the same definitions are accepted by regulatory agencies. This requirement for a health benefit as part of the probiotic definition has been rigorously implemented in the European Union. Currently, with the exception of a few member states, the term probiotic is prohibited. The logic is that since a health benefit is inherent to the term probiotic and since there are no approved health claims for probiotics in the EU*, the term ‘probiotic’ is seen to be acting as a proxy for a health claim. This has frustrated probiotic product companies who believe they have met the scientific criteria for probiotics, yet cannot identify their product as a probiotic in the marketplace because they have not received endorsement of their claims by the EU. This is not an issue resulting from an unclear definition, since probiotics surely should provide a health benefit, but rather from a lack of agreement as to what level of evidence is sufficient to substantiate a health benefit.
ISAPP remains committed to the importance of requiring a health benefit for the ‘biotic’ family of terms (outlined in the table below). It’s clear that all of these definitions are meaningless unless the requirement that they confer a health benefit is considered as essential by all stakeholders. One could reasonably discuss whether the required levels of evidence for foods and supplements are too high in some regulatory jurisdictions, but the value of these substances collapses in the absence of a health benefit.
Summary of ISAPP consensus definitions
With the publication of the most recent ISAPP consensus paper, this one on postbiotics, I offer a summary below of the five consensus definitions published by ISAPP. Each definition is part of a comprehensive paper resulting from focused discussions among experts in the field and published in Nature Reviews Gastroenterology and Hepatology (NRGH). These papers are among the top most viewed of all time on the NRGH website and are increasingly cited by scientists and regulators.
Table. Summary of ISAPP Consensus Definitions of the ‘Biotics’ Family of Substances. Probiotics, prebiotics, synbiotics and postbiotics have in common the requirement for a health benefit. They may apply to any target host, any regulatory category and must be safe for their intended use. Fermented foods fall only under the foods category and no health benefit is required.
No mechanism is stipulated by the definition.
*Actually, there is one approved health claim in the EU for a probiotic: Scientific Opinion on the substantiation of health claims related to live yoghurt cultures and improved lactose digestion (ID 1143, 2976) pursuant to Article 13(1) of Regulation (EC) No 1924/2006
Do new product formats need new clinical trials?
/in ISAPP Science Blog /by KCBy Marla Cunningham, Metagenics Global R&D Innovation Manager and 2021 ISAPP Industry Advisory Committee representative
Let’s assume a hypothetical clinical study has been published with positive impacts of a yoghurt containing Lacticaseibacillus rhamnosus strain XYZ in children with atopic dermatitis. If the strain is now to be incorporated into a fruit drink, at the clinically trialled dose throughout shelf life, can it be expected to have the same health benefits? Can the probiotic yoghurt study provide primary support of efficacy claims on the probiotic fruit drink? Such a question is highly relevant to the challenges that food and supplement manufacturers within the ISAPP community face daily in product development.
This important scientific and regulatory question is addressed in a new ISAPP-driven collaborative article, originating from opinions and data presented at the industry-organised Learning Forum at the 2019 ISAPP annual meeting in Antwerp. The paper, published online April 21 in Trends in Food Science and Technology, reviewed preclinical and clinical evidence for an impact of product matrix on functionality of probiotics and prebiotics.
The article notes it is well-recognised that heat, pH and moisture are key factors causing degradation in probiotics and prebiotics, and such factors currently weigh heavily in formulation design and quality assurance processes for these products. Beyond such impacts on degradation, some evidence suggests that ingredients in the product matrix can affect probiotic and prebiotic functionality in vitro, for example via the binding of proteins or carbohydrates to structural components of prebiotics or altering activity of effector molecules on probiotics.
However, clinical trials do not provide convincing evidence that observed preclinical interactions are significant in vivo. Head-to-head clinical trials comparing product formats are rare, meaning that direct evidence that product formats can influence a clinical endpoint is lacking. To address this gap, researchers are encouraged to consider comparing different matrixes in future clinical trials. Yet, while differences in study factors (such as populations, interventions and doses) limit conclusions that can be drawn from comparing across clinical studies, meta-analyses in general suggest a robustness of effect across a broad range of delivery matrices for given clinical endpoints.
Preclinical assessments are useful, but limited. Attempts to replicate findings from highly controlled preclinical experiments often fail because preclinical assessments cannot capture the complexity of the physiology or the individual factors inherent to the human subject. It makes sense that any impact of physicochemical interaction between probiotics or prebiotics with a product matrix may not be revealed in vivo. If we consider the almost infinite number of variations that could make up a study subject’s (or consumer’s) diet, probiotics and prebiotics are in fact being delivered in a variety of matrices every day, with substantially greater potential for physiochemical interactions in the digestive tract outside of product formulation variables. Add to this interindividual differences in human physiology and microbiome, and the overall impact of product formulation differences on the expression of a clinical effect in an end consumer may be smaller still.
This broader perspective suggests that even if it were ethically and practically possible, unrestrained investment into the repetition of clinical trials for each new product format may not be the answer to provide a high degree of confidence for translation of clinical trial evidence to any given consumer. Instead, research dollars may be better spent in the short term on mechanistic and clinical studies investigating the relative impact of factors determining individual response to probiotic and prebiotic intervention, including factors intrinsic to the host as well the product formulation.
Nonetheless, it is critical that any extrapolation of evidence across product formats is supported by a solid scientific rationale. As such, the article provides recommendations for a practical path forward to demonstrate essential equivalence between product formats, utilising in vitro and in vivo tests, and clinical trials where justified. Such an approach is intended to provide reasonable assurance of scientific substantiation and may also go some way to meeting the expectations of regulatory authorities across the globe (reviewed within).
The open access article can be found here.
Behind the publication: Understanding ISAPP’s new scientific consensus definition of postbiotics
/in ISAPP Science Blog /by KCA key characteristic of a probiotic is that it remains alive at the time of consumption. Yet scientists have known for decades that some non-living microorganisms can also have benefits for health: various studies (reviewed in Ouwehand & Salminen, 1998) have compared the health effects of viable and non-viable bacteria, and some recent investigations have tested the health benefits of pasteurized bacteria (Depommier et al., 2019).
Since non-viable microorganisms are often more stable and convenient to include in consumer products, interest in these ‘postbiotic’ ingredients has increased over the past several years. But before now, the scientific community had not yet united around a definition, nor had it precisely delineated what falls into this category.
An international group of scientists from the disciplines of probiotics and postbiotics, food technology, adult and pediatric gastroenterology, pediatrics, metabolomics, regulatory affairs, microbiology, functional genomics, cellular physiology and immunology met in 2019 to discuss the concept of postbiotics. This meeting led to a recently published consensus paper, including this definition: “a preparation of inanimate microorganisms and/or their components that confers a health benefit on the host”.
Thus, a postbiotic must include some non-living microbial biomass, whether it be whole microbial cells or cell components.
Below is a Q&A with four of the paper’s seven ISAPP-linked authors, who highlight important points about the definition and explain how it will lay the groundwork for better scientific understanding of non-viable microbes and health in the years ahead.
Why was the concept of postbiotics needed?
Prof. Seppo Salminen, University of Turku, Finland:
Can bacterial metabolites be postbiotics?
Prof. Gabriel Vinderola, National University of Litoral, Argentina:
Can you expand on what is not included in the category of postbiotics?
Dr. Mary Ellen Sanders, ISAPP Executive Science Officer, USA:
For something to be a postbiotic, what kinds of microorganisms can it originate from?
Prof. Gabriel Vinderola, National University of Litoral, Argentina:
What was the most challenging part of creating this definition?
Dr. Mary Ellen Sanders, ISAPP Executive Science Officer, USA:
Does this definition encompass all postbiotic products, no matter whether they are taken as dietary supplements or drugs?
Prof. Hania Szajewska, Medical University of Warsaw, Poland:
Where can you currently find postbiotics in consumer products, and what are their health effects?
Prof. Hania Szajewska, Medical University of Warsaw, Poland:
What do we know about postbiotic safety?
Dr. Mary Ellen Sanders, ISAPP Executive Science Officer, USA:
What are the take-home points about the postbiotics definition?
Prof. Seppo Salminen, University of Turku, Finland:
Read the postbiotic definition paper here.
See the press release about this paper here.
View an infographic on the postbiotic definition here.
See another ISAPP publication on postbiotics here.
Children and dogs in a household share gut microbes – and these microbes are modified by a canine probiotic
/in Consumer Blog, ISAPP Science Blog /by KCFrom longtime family pets to ‘pandemic puppies’, dog ownership is seemingly more popular than ever. In households with children, scientists have found that a pet dog is one of the environmental factors that influences the gut microbiota in early life – but can the microbes that children and dogs share be modified?
A new study from ISAPP president Prof. Seppo Salminen (University of Turku, Finland) and colleagues recently explored the impact of a household dog on children’s gut microbiota, before and after the dogs were given a canine probiotic. Not only did the gut microbiota of dogs and children in the same household share features in common, but also the gut microbes of both shifted after dogs received a probiotic.
The study, which was part of a larger investigation, looked at families with at least one member who had allergic disease. Thirty-one of the families in the current study had dogs, and 18 families (the control group) did not. From each household, the fecal microbiota of one child (aged 5 or under) was tested. The fecal microbiota of the dogs was tested, and further, they received either a probiotic containing 3 canine-derived strains, or placebo.
The data supported previous observations that dogs and children share gut microbes: the children living with dogs had a distinct fecal microbiota composition. The most striking microbiota differences were a higher abundance of Bacteroides and short-chain fatty acid producing bacteria.
Moreover, when the household dogs were given a probiotic, both the dogs and the children living with them showed a gut microbiota shift, with a reduction in Bacteroides. (The exact probiotic strains were not tracked in the feces of either the dogs or the children.)
Were the changes beneficial? It’s not certain, since health outcomes in the children were not part of the study. But these findings provide more evidence for the effect of home environments and pets on the gut microbiota of children, and highlight the modifiability of both the dog’s and children’s gut microbiota. The ability to modify a child’s gut microbiota is of particular interest in the early years, when gut microbiota / immune interactions have the potential to shape health through the lifespan.
The study authors conclude, “Our promising data invite the idea that the compositional development of the gut microbiota in children is potentially modifiable by indirect changes in household pets and justify the further search of novel modes of intervention during critical period when the scene is set for the consolidation of the child later health.”
What’s a Clinician to do When the Probiotic Recommendations from Medical Organizations Do Not Agree?
/in ISAPP Science Blog /by KCBy Prof. Hania Szajewska, MD, Department of Paediatrics, The Medical University of Warsaw, Poland
The scientific literature on probiotics is growing rapidly, with newly published studies continually adding to the sum of information about the probiotic strains that confer health benefits in specific populations.
In research, we make hypotheses. Eventually, they are resolved by collecting data or they are replaced by more refined, or entirely new, hypotheses. This process usually unfolds over an extended period of time. Along the way, medical and scientific organizations may decide to take ‘snapshots’ of the evidence to-date and develop guidelines based on available published studies. Unfortunately, disagreements can occur about the meaning of the data, sometimes leading to differences in the guidelines developed by various organizations.
But clinicians cannot always wait for the data to provide a crystal-clear picture. They want answers to guide their clinical practice. Hence the question: Should probiotics be used if guidelines do not agree on the use of probiotics for a certain indication, or on the strains to be used?
Take, for example, the current situation relevant to pediatric practice. Here I discuss two recommendation documents: one developed by the European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN), and another developed by the American Gastroenterological Association (AGA).
Acute diarrhea
In 2020, the ESPGHAN Working Group (WG) on Probiotics identified 16 systematic reviews and meta-analyses published since 2010, which included more than 150 RCTs. The WG made weak (also known as conditional) recommendations for (in descending order in terms of the number of trials evaluating any given strain):
The WG made a strong recommendation against L helveticus R0052 & L rhamnosus R0011 (moderate certainty of evidence) and a weak (conditional) recommendation against Bacillus clausii strains O/C, SIN, N/R, and T (very low certainty of evidence)1.
In contrast, also in 2020, the AGA, based on the evaluation of 89 trials, made a conditional recommendation against the use of probiotics in children from North America with acute infectious gastroenteritis (moderate quality of evidence)2. The rationale for the negative AGA recommendation was that the majority of the studies were performed outside North America. Moreover, two large, high-quality null trials, performed in Canada and US, questioned the efficacy of the probiotics evaluated in these studies, for the management of children with acute gastroenteritis 3,4.
Prevention of necrotizing enterocolitis
Another example of discordant guidelines relates to necrotizing enterocolitis (NEC) in preterm infants. NEC is one of the most severe and life-threatening gastrointestinal diseases to occur in preterm infants, particularly those with a birth weight <1,000 g. The factors involved in the pathogenesis of NEC include formula feeding rather than breastfeeding, intestinal hypoxia–ischemia, and colonization of the gut with pathogenic microbiota5.
In 2020, both ESPGHAN6 and AGA2 published their recommendations on the use of probiotics for preventing NEC. While both were based on pair-wise systematic reviews and network meta-analyses7, their conclusions differed. The only probiotic strain that was recommended by both societies was L rhamnosus GG ATCC 53103. With regard to L reuteri DSM 17938, the ESPGHAN did not formulate a recommendation for or against it, while the AGA conditionally recommends it.
Why do guidelines differ?
Many factors contribute to the discrepancy in guidelines developed by various organizations. In the case of probiotics, they may be due to these differences:
What should clinicians do when the guidelines are not consistent?
Back to the question asked earlier: Should probiotics be routinely used if guidelines from the scientific or medical organizations do not agree on the use of probiotics?
One approach may not fit all. However, in the case of acute infectious diarrhea in children, both the AGA and ESPGHAN formulated a conditional recommendation: in the first case, it is negative; in the second, positive. It is important to note that the interpretation of a conditional recommendation for and a conditional recommendation against is similar. For clinicians, both mean that different choices will be appropriate for different people. Clinicians should help each patient make decisions consistent with the patient’s preferences. For patients, it means that the majority of individuals in this situation would want the suggested course of action, but many would not8.
Taken together, the recommendations communicate that probiotics may be beneficial, although not essential, in the treatment of acute diarrhea in young children. The use of certain probiotics with documented efficacy may be considered in the management of acute diarrhea in young children.
With regard to the prevention of NEC, the AGA and ESPGHAN guidelines agree that certain probiotics reduce the risk of NEC in preterm infants. However, based on their analyses and the included / excluded studies they differ in the recommended strains; additionally, not all of the strain combinations are available everywhere. Therefore, it seems reasonable to choose a probiotic that is included in the recommendations of both societies (if available). One example is L. rhamnosus GG.
In general, organizations should be commended for taking on the daunting task of evaluating the probiotic evidence – both the quality of the studies and the positive or negative results – in order to generate recommendations. Until further well-conducted studies make the answer clearer, clinicians must live with some ambiguity and use the recommendations in the best way possible to inform their daily decisions with individual patients.
REFERENCES
See here for a published comment on this topic in The American Journal of Gastroenterology.
ISAPP publishes continuing education course for dietitians
/in News, ISAPP Science Blog /by KCFor dietitians, it’s often difficult to find practical, up-to-date resources with a scientific perspective on probiotics, prebiotics, synbiotics and fermented foods. ISAPP is pleased to announce a new resource to fill this need – a Special Continuing Education Supplement in Today’s Dietitian titled, “Evidence-based use of probiotics, prebiotics and fermented foods for digestive health”. This free continuing education course also includes infographic summaries, links to supplementary information, and even some favourite recipes. US dietitians can earn 2.0 CPEUs for completing this self-study activity.
The resource was written by dietitian and assistant professor Dr. Hannah D. Holscher, along with two ISAPP board members, Prof. Robert Hutkins, a fermented foods and prebiotics expert, and Dr. Mary Ellen Sanders, a probiotic expert.
“We hope this course will give dietitians an overview of the evidence that exists for probiotics, prebiotics, synbiotics and fermented foods, and help explain some of the practical nuances around incorporating them into their practice,” says Sanders. “In addition, we believe that this course will be a scientifically accurate overview that can counter prevalent misinformation. It can serve as a useful resource for diverse array of professionals active in this field.”
What’s the evidence on ‘biotics’ for health? A summary from five ISAPP board members
/in Consumer Blog, ISAPP Science Blog /by KCEvidence on the health benefits of gut-targeted ‘biotics’ – probiotics, prebiotics, synbiotics, and postbiotics – has greatly increased over the past two decades, but it can be difficult to sort through the thousands of studies that exist today to learn which of these ingredients are appropriate in which situations. At a recent World of Microbiome virtual conference, ISAPP board members participated in a panel that provided an overview of what we currently know about the health benefits of ‘biotics’ and how they are best used.
Here’s a summary of what the board members had to say:
Dr. Mary Ellen Sanders: Probiotics and fermented foods
Prof. Dan Merenstein, MD: Probiotics – How do I know what to prescribe for adult health?
Prof. Glenn Gibson: Prebiotics and Synbiotics
Prof. Hania Szajewska, MD: Biotics for pediatric use
Prof. Gabriel Vinderola: Postbiotics
In Memoriam: Todd Klaenhammer
/in ISAPP Science Blog, News /by KCBy Mary Ellen Sanders and Colin Hill
We all suffered a devastating loss this past Saturday with the death of Prof. Todd Klaenhammer, aged 69.
Todd was a larger-than-life figure in the scientific field of genetics of lactic acid bacteria. Todd’s 38-year career started at the age of 26, when he joined North Carolina State University as an assistant professor in 1978. His research and teaching awards are too numerous to count, as the phrase goes, but of special note was his election in 2001 to the U.S. National Academy of Sciences. Later he also received the O. Max Gardner award, given to one researcher in the North Carolina University system “who has made the greatest contribution to the welfare of the human race.”
Gregor Reid, Todd Klaenhammer, Colin Hill and Paul Ross in Tromso, Norway.
For those of us fortunate enough to work closely with him, it was a privilege to witness his mind at work, making those leaps in understanding in real time as he furiously forged ahead of the data while designing strategies to test his theories. He saw the potential for probiotics when few others were interested. He led the field in phage resistance, in bacteriocin research, and in basic lactic acid bacterial genetics. When many preferred to study the more genetically accessible lactococci he went with the much more recalcitrant lactobacilli. The discoveries he made were all the more notable because he always maintained a relatively small laboratory group, not moving to the large team-based approaches that are more common today. He was a fierce competitor, but was warm and generous when his friends and rivals made scientific advances. His willingness to take on challenges was truly inspirational, and his scientific intellect was the rock-solid foundation for everything he achieved in a legendary career.
As a founding board member for ISAPP, serving on the board from 2002 to 2016, Todd helped shape ISAPP’s development. He had a great influence on ISAPP leadership, nudging Prof. Colin Hill to serve as president and nominating Prof. Sarah Lebeer to the board. He, along with Prof. Jeff Gordon, organized the National Academy of Sciences Sackler Symposium “Microbes & Health” in conjunction with the 2009 ISAPP annual meeting at the Beckman Center in Irvine CA. Later, one of ISAPP’s finest moments was the gala dinner during the 2015 ISAPP meeting in Washington DC, which Todd hosted at the National Academy of Sciences Great Hall.
Colin Hill, Todd Klaenhammer, Dymphna Hill and Mary Ellen Sanders at dinner after the 2012 ISAPP annual meeting in Cork, Ireland.
Todd seemed especially happy when he was able to help young scientists succeed in science. His “work hard, play hard” ethic and his fierce dedication made positions in his lab coveted. Competition for a space in his lab became steeper as the years went by. The best and the brightest students and postdocs found their way to his lab over the years, and he was extremely proud of all that those in his lab accomplished.
Todd always welcomed the opportunity to connect with his many colleagues and friends. He was rarely without a story to share – watching his Ford Bronco start to sink into the lake with his cherished golden retriever paddling in the back was a favorite. The listening throng always radiated congeniality. He could work a crowd.
Saying goodbye to Todd will be hard for so many of us across the globe. We will miss his good humor, his friendship, his constant encouragement of others to excel, and his hustle to make sure they did.
Rest in peace, Todd. We will try to continue to make you proud.
Mary Ellen Sanders was a graduate student in the Klaenhnammer lab from 1978-1983. Colin Hill was a postdoc in the Klaenhammer lab from 1988-1990.
Todd Klaenhammer (second from left) with other participants in the 2010 ISAPP meeting in Barcelona.
Designing Probiotic Clinical Trials: What Placebo Should I Use?
/in ISAPP Science Blog /by KCBy Daniel J. Merenstein, MD, Professor, Department of Family Medicine and Director of Research Programs, Georgetown University Medical Center, Washington DC
Specifying a placebo is one of the most important decisions for a clinical trialist. The first trial I led was a study giving Benadryl to kids to see if it helped them sleep. We spent hours working with our pharmacist on the placebo to make sure it had the same sweet cherry taste of the active drug, Benadryl. We didn’t want parents to be able to determine whether they were randomized to Benadryl or the placebo by comparing the study product to what they had at home. Do study subjects really do this? Yes. Early in my career I was helping an orthopedist who was putting pain pumps directly into a patient’s ankle post-surgery in order to see if it would decrease oral narcotic usage. One of our first patients pulled his pump out, tasted the medicine and called us late at night complaining he was in the saline (placebo) group.
When undertaking a study on probiotics, and specifically probiotic yogurts, we can debate for weeks about the best placebo. Our intervention is yogurt fortified with an additional probiotic. Therefore, our intervention yogurt contains both the starter lactic acid bacteria and the probiotic. So assuming we want both groups to get nutritionally equivalent yogurt that can be blinded our placebo options could be as follows. Note that in recent years, we have become more cognizant that dead microbes may not be biologically inactive.
We chose regular yogurt (the first option above) and now about eight papers later, I would say that about 50% of reviewers question our choice.
There are many reasons the placebo needs to be well considered, including the specific research question under consideration. But an important one is clinical equipoise, “a state of genuine uncertainty on the part of the clinical investigator regarding the comparative therapeutic merits of each arm in a trial”, as defined Freedman 1987. Thus, for example in a study of a new hypertension drug, one cannot use a placebo that has no chance of lowering a patient’s blood pressure as a comparator as that is ethically indefensible. Instead, a well proven hypertension drug will be studied versus the new experimental drug.
For most of my career the goal in my studies was to pick a placebo that was as inactive as possible that still smelled, looked and tasted like my active intervention. However, the times are changing. When I started working there were fewer than 200 randomized controlled clinical probiotic trials retrievable from PubMed; today the number is over 2,300. Well that means we have gone beyond merely recognizing the value of probiotics in different indications, to detailed comparisons of different probiotic and non-probiotic interventions, so one has to consider how inactive their placebo is for probiotic intervention trials.
In 2020 the American Gastrointestinal Association came out with recommendations and guidelines after they conducted a thorough review of probiotic evidence. (See ISAPP blog ISAPP take-home points from American Gastroenterological Association guidelines on probiotic use for gastrointestinal disorders.) For three indications, they recommended using select probiotics over no or other probiotics, in populations of preterm low birthweight infants, patients receiving antibiotics, and patients with pouchitis. So what does this mean for trials evaluating one of these indications? It means that the placebo should be an active control, a probiotic versus probiotic trial.
Today if I’m asked what placebo should be used, my first question is what indication are you studying? If you are studying infant colic or preterm low birthweight infants, I think you need an active control, such as another probiotic. (Colleagues and I suggested this for probiotic studies on necrotizing enterocolitis in 2013.) If you are studying anxiety, then an inert placebo makes the most sense since insufficient evidence exists for any probiotic for this endpoint as yet. In the case of antibiotic associated diarrhea, it will be a much longer discussion as the data are not clear, but it would be reasonable for an IRB to argue that your placebo should be another probiotic. It is not ethical to deny a placebo group an effective intervention if one is available.
So in the last 15 years of my career the answer to what placebo should I use has greatly changed. As probiotic research has advanced, so has the evidence base for usage. As we proceed with research we now need to consider conducting our clinical trials differently. This is just another example of how probiotic evidence has matured over a relatively short period of time.
Five things scientists should know about the future of probiotics and prebiotics
/in ISAPP Science Blog /by KCBy Marla Cunningham, Metagenics Global R&D Innovation Manager and 2021 ISAPP Industry Advisory Committee representative
As anyone connected with probiotics and prebiotics knows – there’s a lot happening in this space.
After a well-attended discussion group at the 2019 ISAPP Annual Meeting in Antwerp, a collaboration of 16 industry and academic scientists came together to produce a broad overview of current and emerging trends that were covered in this discussion. Just released online by Trends in Microbiology, the open access paper identifies some top trends across multiple spheres of influence on the future of probiotics and prebiotics.
These and other trends create a rich and evolving landscape for scientists within the field and provide the promise of a bright future for prebiotics and probiotics.
Reference:
Cunningham, M., Azcarate-Peril, M. A., Barnard, A., Benoit, V., Grimaldi, R., Guyonnet, D., Holscher, H. D., Hunter, K., Manurung, S., Obis, D., Petrova, M. I., Steinert, R. E., Swanson, K. S., van Sinderen, D., Vulevic, J., & Gibson, G. R. (2021). Shaping the Future of Probiotics and Prebiotics. Trends in microbiology, S0966-842X(21)00005-6. Advance online publication. https://doi.org/10.1016/j.tim.2021.01.003
The Microbiome — Can it aid in the diagnosis and therapy of irritable bowel syndrome (IBS)?
/in Consumer Blog, ISAPP Science Blog /by KCBy Eamonn M M Quigley, MD FRCP FACP MACG FRCPI MWGO
Lynda K and David M Underwood Center for Digestive Disorders, Houston Methodist Hospital and Weill Cornell Medical College, Houston, Texas
Irritable bowel syndrome (IBS) is one of the most common gastrointestinal disorders and seems to be prevalent across the globe1. Although non-fatal, IBS impacts on quality of life, personal relationships and productivity and can impose a significant socioeconomic burden on the individual as well as on society at large. Despite considerable effort there is still no test to diagnose IBS and, in clinical practice, the diagnosis commonly rests on the presence of characteristic symptoms, such as those defined by the Rome criteria2, in an individual in which alternate diagnoses have been excluded or deemed unlikely. The concern of the IBS sufferer and his/her physician is that because IBS symptoms are relatively non-specific (abdominal pain, altered bowel habit and bloating) a diagnosis based on symptoms alone may miss “something serious”.
Several challenges confront those who attempt to design a diagnostic test or new therapy for IBS. First, IBS is not a homogeneous disorder; symptoms, their severity and impact vary considerably. Second, symptoms tend to fluctuate over time with periods of calm interposed between episodes of much distress. Third, it is almost certain that IBS is multifactorial with various factors contributing to a variable extent in each sufferer. Over the years, genetic predisposition, gut motility and sensation, how the brain senses activity in the gut, and how the body responds to stress have all been invoked to explain the development of symptoms in IBS. While all of these factors undoubtedly contribute, none has yielded a diagnostic test.
One concept, that of the gut-brain axis, has served as a useful paradigm to explain IBS symptoms with dysfunction at various points along the axis, which extends all the way from the cerebral cortex to gut muscle, nerve and mucosa and back again, variably contributing to the presentation of IBS in different individuals3,4. Now, connections between the gut and the brain have been extended to include a new participant, the microbiome. This leads to the concept of the microbiome-gut-brain axis, whereby bacteria resident in the gut could impact on the “big brain” and even contribute to neurological and neuropsychiatric disease5. There is substantial experimental data to indicate that gut microbes influence components of the gut barrier, the intestinal immune system and the neuromuscular apparatus of the gastrointestinal tract, as well as central nervous system structure and function6.
Could the gut microbiome produce a diagnostic test for IBS?
That microbiota might be a factor in IBS was first suggested by the observation that IBS could develop de novo in the aftermath of acute enteric bacterial, viral or parasitic infections7. More recently, modern sequencing technology has been applied to fecal and colonic microbiota in IBS with the aim of determining relationships between a variety of clinical and demographic parameters and microbiota. Although data remain limited, and not always consistent, it is evident that IBS patients have an altered fecal microbiota relative to healthy individuals8. Currently available data are fraught with challenges in interpretation – small study populations, variations in patient selection and methodology, not to mention a failure to account for such confounders as diet, stool form and consistency, therapy, co-morbid psychopathology and symptom severity. Nonetheless, some overall patterns have emerged: the fecal and colonic mucosal microbiota are different in IBS and the fecal microbiota may not only predict severity9, but also responsiveness to one common intervention – the low fermentable oligo-, di- and monosaccharides and polyols (FODMAP) diet10. It is now abundantly clear that the expectation that a single microbial signature might typify IBS was naïve.
Recent progress
While we are not yet able to diagnose IBS using the microbiome, some very interesting observations have resulted from applying the highest quality microbiome science to what was once regarded as fringe and unimportant.
In the first of these studies, Kashyap’s lab, and its collaborators, employed a multi-omics approach in a longitudinal study of a reasonably large cohort of IBS sufferers and were able to identify IBS subtype-specific and symptom-related variations in microbial composition and function and to relate certain bacterial metabolites with physiological mechanisms relevant to IBS in the host11. A disturbed microbiome or an aberrant host response to the microbiome might well involve the generation of intraluminal molecules with biological effects on motility, sensation, gut barrier function, immune activation and, of course, communication with the central nervous system. A very high level of methodological complexity was needed to identify these relationships since IBS symptoms vary not only between individuals but over time within individuals.
IBS sufferers have been telling us for decades that having a meal often makes their symptoms worse. Various explanations have been advanced to explain this phenomenon ranging from an exaggerated gastro-colonic reflex to food allergy and intolerance. A recent paper from Aguilera-Lizarraga and colleagues reveals just how complicated this story might well be – involving an interaction between bacterial infection, dietary antigens and immunoglobulin (Ig)E and mast cell responses in the host. In a mouse model, infection with Citrobacter rodentium led to a breakdown in oral tolerance to the food antigen ovalbumin which resulted in the development of an IgE antibody-mediated response locally in the colon and ultimately to diarrhea and visceral hypersensitivity, a common feature of IBS12. They went on to show that the injection of some common food antigens (soy, wheat, gluten and milk) into the rectosigmoid mucosa of IBS sufferers resulted in edema and mast cell activation. It was notable that the development of visceral hypersensitivity in the mouse model did not appear to be related to any change in the resident microbiome or to ongoing chronic inflammation but seemed to be a very specific interaction between the original infectious insult, loss of oral tolerance and the subsequent development of IgE antibodies to a dietary antigen. The net result was the activation of neural pathways responsible for visceral hypersensitivity. These findings certainly extend our understanding of post-infection IBS, but to what extent they relate to IBS, in general, remains to be determined.
To date the focus on studies of the microbiome in IBS (or, for that matter, in most disease entities) has been on bacteria. Das and colleagues expanded their microbiota inquiry to consider the contributions of fungi (the mycobiome) to IBS13. They found significant differences in mycobiome diversity between IBS sufferers and control subjects but the mycobiome could not differentiate between IBS subtypes. Interestingly, mycobiome alterations co-varied with those in the bacteriome but not with dietary habits. Unfortunately, as has been the case with studies of bacterial populations, these changes in the mycobiome proved “insufficient for clinical diagnosis”.
Based on the assumption that gut microbial communities are disturbed in IBS and considering the success and overall excellent safety record of fecal microbiota transplantation/transfer (FMT) in the management of severe or recurrent Clostridioides difficile infection, it should come as no surprise that FMT has been employed in IBS14-24. Results to date have been mixed and, for now, preclude a recommendation that FMT be adopted to treat IBS. Two observations are of note. Both are derived from a randomized double-blind, placebo-controlled, clinical trials where the instillation of the patient’s own feces served as the control. First, the positive clinical results in the studies by El-Salhy and his colleagues seem to relate to the use of a “super-donor”20. Second, the report from Holvoet and colleagues suggests that the baseline microbiome of the recipient predicted response to FMT albeit in a very unique group of IBS sufferers21. Indeed, it appears that a successful FMT, in IBS, is associated with the normalization of a number of components of the colonic luminal milieu22-24. Herein may lie clues to guide the future use of “bacteriotherapy” in IBS.
Conclusions
It should come as no surprise, given advances in techniques to study the microbiota coupled with exciting data from animal models, that the paradigm of the microbiota-gut-brain axis has been proposed as relevant to IBS. The possibility that a disturbed microbiome, or an aberrant host-response to that same microbiome, might be relevant to IBS and could impact on the CNS is now being contemplated seriously as an avenue to understand disease progression and treatment as well as to open new diagnostic and therapeutic possibilities on this challenging disorder. As much of the extant data comes from animal models one must remain cautious in their interpretation – no single animal model can recapitulate the IBS phenotype. The bi-directionality of microbiota-gut-brain interactions must also be remembered – the complex interactions between inflammation and the gut microbiota exemplify how a disease state can impact on the microbiota. With regard to interventions, there are many intriguing approaches, but still a long way to go to achieve personalized pharmabiotic therapy for that very special individual – the IBS sufferer.
References
ISAPP board members look back in time to respond to Benjamin Franklin’s suggestion on how to improve “natural discharges of wind from our bodies”
/in News, Consumer Blog /by KCBenjamin Franklin, born in 1706, was a multi-talented politician and scientist best known for his discoveries related to electricity. Historians say he was scientifically pragmatic—aiming not just to advance theories, but to solve the most vexing problems of the day.
In 1780, when Franklin read about the intellectual contests being held by The Royal Academy of Brussels (today known as the Royal Flemish Academy of Belgium for Science and the Arts – KVAB), he took it upon himself to write an amusing letter that contained a suggestion for an important scientific challenge: “To discover some Drug wholesome & not disagreable, to be mix’d with our common Food, or Sauces, that shall render the natural Discharges of Wind from our Bodies, not only inoffensive, but agreable as Perfumes.”
Over two centuries later, the organization was prompted for a reply. Writer Brian Van Hooker wrote to the KVAB: ‘I am a writer at MEL Magazine and I am working on a piece about a letter that Benjamin Franklin sent to your organization’s predecessor, the Royal Academy of Brussels, 240 years ago. The letter was entitled “Fart Proudly,” and I’m reaching out to see if anyone at your organization might like to issue a reply to Mr. Franklin’s letter’.
Brian Van Hooker summarized: “In other words, Mr. Franklin, they’re working on it and, perhaps sometime within the next 240 years, your dream of non-smelly farts might just come true.”
The KVAB response to Benjamin Franklin concluded: “Your letter is a ripple through time. It may not surprise you that scientific questions can have effects across decades and even centuries. This idea remains the tacit hope of many scientists working together for the progress of humanity. We have not yet invented a reverse time machine, but we send our answer along with your question forward in time, hoping that it may inspire future scientists as your question inspired us.”
Read the MEL Magazine article here.
Read more about gut microbiota & intestinal gas here.
Video Presentation: Behind the scenes of the consensus panel discussion on the definition of fermented foods
/in ISAPP Science Blog /by KCNumerous misunderstandings and questions exist around the concept of fermented foods. For example:
The first step in answering these questions is for scientists to come to agreement on what constitutes a fermented food. A new global definition of fermented foods was recently published by 13 interdisciplinary scientists from various fields—microbiology, food science and technology, immunology, and family medicine. In their paper in Nature Reviews Gastroenterology & Hepatology, fermented foods are defined as: “foods and beverages made through desired microbial growth and enzymatic conversions of food components”.
The panel discussion and the definition of fermented foods are covered in this video presentation by the paper’s first author Prof. Maria Marco, from the Department of Food Science and Technology at the University of California, Davis. This presentation was originally given at the virtual ISAPP 2020 annual meeting.
The new definition is intended to provide a clearer conceptual understanding of fermented foods for the public and industry, with the authors expecting that in the years ahead, scientists will undertake more hypothesis-driven research to determine the extent that various fermented foods improve human health and precisely how this occurs. More studies that address fermented foods in promoting health will be useful for establishing the importance of fermented foods in dietary guidelines.
The panel acknowledged that regulations on fermented foods from country to country are mainly concerned with food safety — and that, when properly made, fermented foods and their associated microorganisms have a long history of safe use.
ISAPP ha estado trabajando en colaboración con la Sociedad de Enterocolitis Necrotizante
/in Consumer Blog, News /by KCLa Asociación Científica Internacional para Probióticos y Prebióticos (ISAPP, por sus siglas en inglés), ha estado trabajando en colaboración con la Sociedad de Enterocolitis Necrotizante (NEC Society) en el desarrollo de una infografía sobre el rol de los probióticos en la prevención de la Enterocolitis Necrotizante (ECN).
La ECN es una enfermedad intestinal que puede poner en peligro la vida principalmente en bebés prematuros. Esta enfermedad produce un proceso inflamatorio que puede provocar daños en el tejido intestinal e incluso la muerte.
La leche materna de la madre del bebé es la forma más importante de ayudar a disminuir el riesgo de ECN. La leche pasteurizada de madres donantes es la segunda mejor opción. Adicionalmente, suministrar probióticos a bebés prematuros, junto con la leche materna, puede reducir el riesgo de ECN.
Los probióticos son microorganismos vivos que, cuando se administran en cantidades adecuadas, confieren un beneficio para la salud del huésped.
Los padres con hijos con riesgo de desarrollar ECN pueden consultar a los responsables de la Unidad de Cuidados Intensivos, sobre la posibilidad de utilizar probióticos para contribuir a prevenir el desarrollo de ECN.
ISAPP ha preparado una infografía en español con mayor información sobre este tema, la cual se puede encontrar aquí.
Can fermented or probiotic foods with added sugars be part of a healthy diet?
/in Consumer Blog, ISAPP Science Blog /by KCBy Dr. Chris Cifelli, Vice President of Nutrition Research, National Dairy Council, Rosemont IL, USA
What about added sugar in fermented or probiotic foods? I am almost always asked this question whenever I give a nutrition presentation, no matter the audience. It’s not a surprising question as people care about what they eat and, often, are looking for ways to reduce their intake of sugar. Yet, if someone wants to add fermented or probiotic foods such as yogurt, kefir or kombucha to their diet, they often find the products available to them contain sugar as an added ingredient.
Should these products be part of you and your family’s healthy eating plan even if they have added sugar? The simple answer – yes, they likely can still fit into a healthy eating plan.
According to the U.S. Food and Drug Administration, ‘added sugars’ are defined as sugars that are either added during the processing of foods or are packaged separately as sugars (e.g. the bag of sugar you buy to make your treats). Added sugars in the diet have received attention because of their link to obesity and chronic disease risk. The World Health Organization, American Heart Association, Dietary Guidelines for America, and American Diabetes Association all recommend reducing added sugar intake to improve overall health. While data from the US National Health and Nutrition Examination Survey (NHANES) has shown that consumption of added sugar decreased from the 2007-2010 to the 2013-2017 surveys, the most recent Dietary Guidelines Advisory Committee report noted that the mean usual consumption of added sugars was still 13% of daily energy in 2015-16, which exceeds recommendations of 10%.
Including fermented foods in one’s diet may be important for overall health. The recent ISAPP consensus paper on fermented foods indicated that fermented foods, especially the live microbes contained in them, could benefit health in numerous ways, such as by beneficially modulating the gut microbiota or the immune system. Similarly, foods with added probiotics may confer health benefits ranging from impacting digestive health to metabolic parameters, depending on the probiotic contained in the product. Our understanding of the gut microbiota continues to evolve, but one thing is for certain: it is important for health. This provides a compelling reason to find ways to include these foods in healthy eating patterns.
So, back to the question at hand. Should you reduce or eliminate fermented foods and foods with probiotics from your diet if they have added sugars? Just like a “spoonful of sugar helps the medicine go down,” a little added sugar to improve the palatability of nutrient-dense foods is okay. Indeed, government and health organizations all agree that people can eat some sugar within the daily recommendations (which is 10% of total daily calories), especially in foods like yogurt or whole-grain cereals, or other healthy foods. And, there is no scientific evidence to show that the sugar in these products reduces the health benefits associated with eating foods like yogurt or probiotics. Human studies assessing health benefits of probiotic foods typically use products with added sugar, yet health effects are still observed.
The next time you are out shopping you can choose your favorite fermented or probiotic-containing food guilt free, as long as you’re watching your overall daily intake of sugar. But, if are you are still concerned, then choose plain varieties to control your own level of sweetness or you could opt for a probiotic supplement to avoid the sugar. Whether you go with the sweetened or unsweetened version of your favorite fermented food, you’ll not only get the benefit of the live microbes in these products but also the nutritional benefit that comes with foods like yogurt.
The future is microbial: A post-pandemic focus on identifying microbes and metabolites that support health
/in Uncategorized, Consumer Blog, ISAPP Science Blog /by KCBy Prof. Maria Marco, Department of Food Science and Technology, University of California Davis, USA
The COVID-19 pandemic has been a sobering reminder of the significance that microorganisms have on human life. Despite the tremendous scientific and medical advances of the twentieth century, our best precautions against the virus have been to practice the oldest and most simplistic of all public health measures such as washing hands and maintaining physical distance from others. At the same time, the effectiveness of the new SARS-CoV-2 vaccines and the speed in which they were developed show how sophisticated and advanced our understanding of viruses has become. Taken together, the limitations and successes of responses to the pandemic underscore the power of investment in microbiology research. This research, which was first catalyzed by the pioneering work of Louis Pasteur, Robert Koch, and contemporaries in the late 1800s, was the basis for the overall reduction in infectious diseases during the twentieth century. Continued investment in these efforts will prepare us for the next pandemic threat.
Beyond pathogens to health-promoting microbes
As our attention turns to the promise of the New Year, we may also take this moment to appreciate the fact that microorganisms can also do good. Our “microbial friends” were first promoted by the lauded biologists Élie Metchnikoff, Henry Tissier, and Issac Kendall at the turn of the twentieth century. Since then, nearly another century passed before the power of microorganisms to benefit human health reached wider acceptance.
Marked by the emergence of laboratory culture-independent, nucleic-acid based methods to study microbial communities, there is now excitement in the identification of microorganisms that are important for health promotion. This interest is catalyzed by the urgency to find ways to prevent and treat cardiovascular diseases, cancers, and other non-communicable, chronic conditions that are now the leading causes of death worldwide. Much like the pressure to address infectious diseases as the primary cause of mortality prior to the twentieth century, so too is the need today for sustained research investments in studying how certain microorganisms contribute to, or may be essential for, preventing and treating the greatest threats to public health in the modern era.
Exemplified by the growing number of human microbiome studies, it is now broadly understood that the human microbiome contributes positively to digestive, immune, and endocrine systems function. Systematic reviews and meta-analyses of clinical trials support the use of probiotics for a variety of conditions and there are positive associations between the consumption of fermented dairy foods and good metabolic health. To understand how microbes can be beneficial, numerous mechanisms have been proposed (for example, modulation of the immune system and production of neurochemicals that can impact the gut-brain axis), and these mechanisms apply to both autochthonous microbiota and probiotics alike. However, our understanding of exactly how this occurs lags far behind what is currently known about microorganisms that cause harm.
Identifying microbes & metabolites that maintain health
The future of beneficial microbes is in identifying the specific, health-promoting metabolites, proteins, and other compounds that they make. Presently only a handful of such examples are known. Perhaps most recognized are the short chain fatty acids, butyrate, propionate, and acetate, which are known to bind specific human cell receptors to modulate numerous cell pathways including those that affect metabolism. Other microbial compounds generated as intermediate or end products of microbial metabolism (such as metabolites of amino acids), secondary metabolites (such as bacteriocins), and bacterial cell surface constituents (such as certain membrane proteins) were shown to benefit health, although a more complete description of mechanistic details for their effects remains to be discovered. Precise mechanistic descriptions of “beneficial factors”, or the microbial enzymatic pathways and molecules that induce desired cellular and systemic responses in the human body, will be pivotal for elucidation of the precise ways microorganisms sustain health and well-being (for more detail on this topic see here).
Based on what we know about the complexity of the human microbiome and the now many decades of probiotics research, this effort will require innovation and multi-disciplinary coordination. Just as early microbiologists raced to address the high rates of mortality due to microbial pathogens, we are in a new age where again microorganisms are regarded as emerging public health threats. However, we now have to our advantage the knowledge that not all microorganisms cause harm but instead the majority may offer solutions to the greatest health challenges of the twenty-first century.
Creating a scientific definition of ‘fermented foods’
/in Consumer Blog, ISAPP Science Blog /by KCBy Prof. Maria Marco, Department of Food Science and Technology, University of California Davis, USA
A panel of scientific experts was recently convened by ISAPP to discuss the state of knowledge on fermented foods. While there was much agreement on the underlying microbiological processes and health-related properties of those foods and beverages, our conversation on definitions led to sustained debate. So what exactly is a fermented food?
The word “ferment” originates from fervere, which in Latin means to boil. According to the Merriam-Webster dictionary, the verb ferment is defined as “to undergo fermentation or to be in a state of agitation or intense activity”. Fermentation is defined as both a chemical change with effervescence and as an enzymatically controlled anaerobic breakdown of energy-rich compounds (such as a carbohydrate to carbon dioxide and alcohol or to an organic acid). In biochemistry, fermentation is understood as an ATP-generating process in which organic compounds act as both electron donors and acceptors. In industry, fermentation means the intentional use of bacteria and eukaryotic cells to make useful products such as drugs or antibiotics. As you can see, there are clearly many meanings implied in “ferment” and “fermentation”. We add onto this by defining how those words apply to foods.
As our ISAPP panel began to deliberate the definition of fermented foods, it quickly became clear how difficult reaching consensus can be! Even though many panel members shared similar academic backgrounds and scientific expertise, finding agreement on the definition required several rounds of debate and some consuming of fermented foods and beverages along the way. Finally, we defined fermented foods and beverages as being “foods made through desired microbial growth and enzymatic conversions of food components” (see the published consensus paper here).
This definition is very specific by requiring microbial growth and enzymatic processes for the making of those foods. Activity of the endogenous enzymes from the food components or enzymes added to the food is not enough for a food to be regarded as fermented. Similarly, foods made by only adding vinegar or “pickling” should not be called fermented. The definition acknowledges the essential roles of microorganisms for making fermented foods but does not require their presence or viability at the time of consumption.
On the other hand, our definition does not restrict fermented foods to only those foods and beverages made using microorganisms using metabolic pathways implicit in the strict biochemical definition. Yogurt and kimchi made using lactic acid bacteria relying on fermentative energy metabolism are included as much as koji and vinegar, foods made using fermentation processes that employ fungi and bacteria that perform aerobic respiratory metabolism.
Each word in a definition needs to be carefully calibrated. The best example of this in our definition of fermented foods is the word “desired”. Unlike a food that is spoiled as a result of microbial growth and enzymatic activity, food fermentations generate wanted attributes. Other words such as “intentional”, “desirable”, or “controlled” may also be used to describe this meaning. However, those words also have caveats that not all fermented foods are made “intentionally”, at least in the way that they were first prepared thousands of years ago. Qualities of fermented foods may be “desirable’ in some cultures but not others. While some fermentations are “controlled”, others are spontaneous, requiring little human input.
The process of discussing the definition with a group of scientific experts was enlightening because it required us to deconstruct our individual assumptions of the term in order to reach agreement on descriptions and meaning. With a definition in hand, we can use a shared language to study fermented foods and to communicate on the significance of these foods and beverages in our diets. There will also certainly be more “fermenting” of these concepts to improve our knowledge on the production and health impacting properties of fermented foods for years to come.
Find the ISAPP press release on this paper here.
Read about another ISAPP-led publication on fermented foods here.
Learn more in a webinar on the science of fermented foods here.
Ambient yogurts make a global impact
/in Consumer Blog, ISAPP Science Blog /by KCBy Prof. Bob Hutkins, PhD, University of Nebraska Lincoln, USA
Quick, which country consumes the most yogurt? Must be France? Or the Netherlands? Maybe Turkey? The United States, perhaps? Try none of the above: the answer is China.
While many other countries consume way more yogurt than China on a per capita basis, China’s population gives it an advantage, with 1.4 billion potential consumers. And yogurt has become one of the most popular snack foods in China. It’s especially trendy among young and affluent urbanites. Indeed, total consumption of yogurt in China now exceeds that of France, the Netherlands, Turkey, and the United States, combined!
Whereas per capita consumption of yogurt in China in 2000 was around 1 kg per person per year, it’s now approaching 5 kg. Yogurt consumption even exceeds that of fluid milk.
Considering that dairy consumption was virtually non-existent in China for thousands of years, this trend is nothing short of a cultural phenomenon. While some of the yogurt consumed in the country is produced by domestic manufacturers, yogurt and yogurt ingredients are also being imported from other countries in the region, including New Zealand and Australia.
There is, however, one major difference between yogurt typically consumed in China and the products consumed in other regions. Indeed, ambient yogurt, short for “yogurt-based product for ambient distribution”, is all the rage in China.
Ambient yogurt and yogurt drink products, as the name implies, are stable at room temperature. This is achieved by heat-treating the yogurt after fermentation. Many ambient yogurts are aseptically processed similar to ultra-high-temperature processed (UHT) products, leaving the product commercially sterile (i.e. without live microbes) and stable for up to a year. In China, these products can still be labeled as yogurt.
Not only are these ambient yogurt products convenient for retailers, but also, a cold-chain infrastructure, often absent in rural areas of China, is not necessary during transport and distribution. Perhaps for this reason, ambient yogurts are also being introduced in other regions, including Africa, South America, and the Middle East.
The popularity of yogurt in China, in the absence of a live microbe label declaration, is evidently due to the ‘healthy’ virtues or halo effect ascribed to yogurt, because of its high protein, calcium, and vitamin content. Perhaps there are also postbiotic benefits in the yogurt – this would be an interesting topic for research. But the novel flavors, textures and grab-and-go convenience, especially for drinkable yogurt products, also appeals to teens and young adults.
Traditionalists balk at the very idea of heat-treating yogurt and inactivating the live microorganisms. In some countries, such products cannot even be labeled as yogurt. In the U.S., these products can be labeled as yogurt but must be further labeled as “heat-treated”.
In reality, consumers’ expectation of live microbes in yogurt is so ingrained that heat-treated yogurts are nearly impossible to find in the United States. Indeed, yogurt, kefir, and other cultured milk and non-dairy products are promoted, in part, on the high number of viable microbes they contain. Probiotics are added to more than 90% of the yogurts sold in the United States.
According to international CODEX standards, yogurt must be made with Lactobacillus delbrueckii subsp. bulgaricus and Streptococcus thermophilus, AND must contain at least 107 CFU/g “through to the date of minimum durability after the product has been stored under the storage conditions specified in the labeling”. Any other labeled bacteria must be present at a minimum of 106 CFU/g. The CODEX standards have been widely adopted, although some countries have lower minimum levels.
Interestingly, and despite appeals by yogurt manufacturers, the U.S. Food and Drug Administration does not require minimum numbers of CFUs for yogurt. They have been considering changes that would be consistent with CODEX for more than a decade. In regions that do not require the CODEX standards, the International Dairy Foods Association offers the Live & Active Cultures (LAC) seal, which requires 107 CFU/g of yogurt cultures at time of manufacture.
The China National Food Safety Standard for Fermented Foods does specify a minimum Lactobacillus count of 106 CFU/g, but importantly, also includes the following footnote:
Such products, however, must be labeled as heat-treated. It should be noted that there is still a substantial market for more traditional (chilled) yogurt containing live microorganisms. Still, ambient yogurts account for most of the yogurt consumed in China.
Given the relatively flat yogurt market in Europe and the United States, it should not be surprising that this rapidly growing market in China has attracted so much attention. The China Nutrition Society and government policymakers have recommended that consumers increase dairy consumption to 3 times higher than current levels. That means a lot more yogurt will be consumed in China.
Translated, that means, from culture companies to processing and packaging industries, there will continue to be plenty of interest, innovation, and investment in yogurt for the Chinese population. For example, new generation yogurt products have recently been introduced with the claim of having 90 days’ shelf-life and containing live probiotic bacteria.
Still, whether by new or traditional technologies, the availability and consumption of live microbes in yogurt and other cultured products may be expected to increase as Chinese consumers become more informed about their health benefits. Perhaps, as cold-chain infrastructure also improves, these live yogurts may become a bigger part of the yogurt culture in China.
‘Probiotic’ on food labels in Europe: Spain adopts a pioneering initiative
/in ISAPP Science Blog, News /by KCBy Silvia Bañares, PhD in commercial law, attorney Barcelona Bar Association, Spain; and Miguel Gueimonde, Departamento de Microbiología y Bioquímica de Productos Lácteos, IPLA-CSIC, Villaviciosa, Asturias, Spain.
The word ‘probiotic’ has been absent from food products in most countries in Europe for years. Authorities there concluded that the word is an implied health claim, which is a reasonable position based on the probiotic definition: live microorganisms that, when administered in adequate amounts, confer a health benefit on the host. The argument proceeds: since there are no health claims approved for probiotics by the European Union, the word is not allowed on food labels. However, the logic fails since in 2010 ESFA actually did approve a health claim for probiotics – although they didn’t use the term ‘probiotic’. This claim was for yogurt cultures improving lactose digestion. But nonetheless, restrictions on using the word ‘probiotic’ have endured.
Recently, akin to positions taken by Italy (here and here) and ostensibly the Czech Republic (as stated here), Spanish authorities have determined that the term ‘probiotic’ may be used.
In October 2020 the Spanish Health Authority (AESAN) delivered a new decision related to the use of the term “probiotic” in foodstuffs. According to it:
This new decision completely differs from the previous one (February 2020), which forbade the use of “probiotic/s” term in food products. Surprisingly, both documents are extremely similar in their reasoning.
However, the new Guidance contains some points that might be relevant for the future:
This statement is clearly aligned with Regulation EU 2019/515 [7] (related to mutual recognition principle) and a recent Commission Regulation (Implementing Regulation 2020/1668), which develops the previous one [8]. According to these dispositions, any competent authority suspending market access should notify the legitimate public interest grounds for such suspension. Therefore, Spain would find quite difficult to reject a foodstuff labelled as “probiotic” in another EU country when it is legally sold as such. Hence, it can be said that Spain has adopted a pioneering initiative that maybe could be followed by other EU Member States.
Italy and the Czech Republic have allowed use of the term ‘probiotic’ on foods – perhaps simply because they considered it to be the right thing to do – but they did not make the convincing legal argument made by Spanish authorities. The rationale presented by Spain could likely be easily adopted by other EU countries as well. Perhaps the Spanish initiative will motivate the EU Commission and EFSA to reach a consensus about this word.
Two decades ago, with a rapidly growing list of probiotic-containing products reaching the market worldwide, there was increasing concern by consumers about how to distinguish among the different probiotic strains available and how to know which products have evidence for different health benefits. This, together with the interest of scientist and industry for clear rules and fair competence, prompted the EU Commission to regulate the area and the Regulation EC n° 1924/2006 on nutrition and health claims made on foods was developed. In its preamble this Regulation states, “to ensure a high level of protection for consumers and to facilitate their choice, products put on the market must be safe and adequately labelled” and recognises that “general principles applicable to all claims made on foods should be established in order to ensure a high level of consumer protection, give the consumer the necessary information to make choices in full knowledge of the facts, as well as creating equal conditions of competition for the food”. Therefore, consumer protection and facilitating informed purchase choices was in the forefront of the Regulation, in an attempt to satisfy the concerns and demands that consumers had leveraged.
Subsequent interpretation of the Regulation EC n° 1924/2006 led to the conclusion that the term “probiotic” was a health claim and, as a consequence, should not be used in product labelling. Different countries, such as Italy or the Czech Republic, reacted to this by developing national regulations allowing the probiotic food labelling. Now Spain, on the basis of mutual recognition principle, accepts its use as well.
However, this new situation makes relevant again the challenges that consumers had identified two decades ago: how to differentiate among the different available probiotic products and make an informed, purposeful purchase. This unsolved issue should now be addressed. In this context, we advocate for the development of easy-to-use guidelines targeted to regular consumers, not to clinicians or scientists, to provide consumers with the necessary tools to make their choice.
Related article: Spanish agency approves use of term ‘probiotic’ on food and supplements
References:
[1] https://www.aesan.gob.es/AECOSAN/web/seguridad_alimentaria/subdetalle/probioticos.htm
[2] Translation by the authors
[3] https://ec.europa.eu/food/sites/food/files/safety/docs/labelling_nutrition_claim_reg-2006-124_guidance_en.pdf
[4] Guidance on the implementation of Regulation n° 1924/2006 on nutrition and health claims made on foods conclusions of the Standing Committee on the Food Chain and Animal Health /14/12/2007
[5] Translation by the authors
[6] Translation by the authors
[7] Commission Implementing Regulation (EU) 2020/1668 of 10 November 2020 specifying the details and functionalities of the information and communication system to be used for the purposes of Regulation (EU) 2019/515 of the European Parliament and of the Council on the mutual recognition of goods lawfully marketed in another Member State.
[8] Regulation (EU) 2019/515 of the European Parliament and of the Council of 19 march 2019 on the mutual recognition of goods lawfully marketed in another Member State and repealing regulation (EC) nº 764/2008
ISAPP collaborates with NEC Society to help parents understand the role of probiotics in reducing the risk of necrotizing enterocolitis
/in Consumer Blog, News /by KCBy Dr. Mary Ellen Sanders, PhD, ISAPP Executive Science Officer
To date, over 50 clinical trials on probiotics and necrotizing enterocolitis have been published. Medical organizations have considered the trials completed to date and have provided guidance (ESPHGAN) and recommendations (American Gastroenterological Association) for implementing probiotics in clinical practice.
As important as the science on this issue are the perspectives from parents of babies who have suffered from NEC or are at risk of developing the disease. Such parents consistently point to the need for credible and balanced educational materials about this condition. Recently, ISAPP has been fortunate to work with the NEC Society to develop materials that will help inform parents.
Also, a recent ISAPP blog Probiotics to Prevent Necrotizing Enterocolitis: Moving to Evidence-Based Use by Dr. Ravi Patel MD, a neonatologist on the NEC Society’s Scientific Advisory Council, summarizes the state of the science supporting this use, including both controlled efficacy trials and post-implementation surveys.
The NEC Society is a nonprofit organization – the only US group dedicated to NEC – with the stated mission of “building a world without necrotizing enterocolitis (NEC) through research, advocacy, and education.” They advocate for families affected by NEC by bringing together critical stakeholders to improve understanding, prevention, and treatment for NEC. Jennifer Canvasser founded the NEC Society in 2014 after her son, Micah, died from complications of NEC just before his first birthday. Micah was born at 27-week’s gestation, placing him at increased risk of NEC. Despite Micah’s risk factors and his parents asking the care team to consider offering Micah probiotics, he was not treated with probiotics. Although it is impossible to know if probiotics could have changed Micah’s course, his parents feel that more could have been done to better protect Micah from the devastation of NEC. Micah’s photo is featured in the new infographic co-created by ISAPP and the NEC Society.
“It is vital for healthcare providers to support NICU parents in understanding the protective and risk factors associated with NEC,” Canvasser shared. “Parents are the most important members of their baby’s care team. For parents to effectively engage and contribute, they need to be supported in accessing and understanding important information related to their child’s health. This new resource on probiotics and NEC will help to ensure that NICU parents are informed and feel encouraged to ask questions so they can best advocate for their child.”
The NEC Society intends to use the new infographic as a resource available to NICU parents and providers. It will be downloadable from the websites of both the NEC Society and ISAPP, and it will be shared via both social media platforms. Once in-person events are possible again, print versions will be made available. ISAPP will also work with the NEC Society’s Scientific Advisory Council to explore how we can further disseminate this resource to NICUs.
Read more about the efforts of the NEC Society here:
Head of the Herd: Jennifer Canvasser, Founder and Director, Necrotizing Enterocolitis (NEC) Society
Family Reflections: harnessing the power of families to improve NEC outcomes
10 Things All Parents of NICU Babies Need to Know
9 Things You Need to Know About Necrotizing Enterocolitis
New ISAPP-led paper calls for investigation of evidence for links between live dietary microbes and health
/in ISAPP Science Blog, Consumer Blog /by KCThe past two decades have brought a massive increase in knowledge about the human gut microbiota and its links to human health through diet. And although many people perceive that regular consumption of safe, live microbes will benefit their health, the scientific evidence to date has not been sufficiently developed to justify adding a daily recommended intake of live microbes to food guides for different populations.
Recently, a group of seven scientists, including six ISAPP board members, published their perspective about the value of establishing the link between live dietary microbes and health. They conclude that although the scientific community has a long way to go to build the evidence base, efforts to do this are worthwhile.
The collaboration on this review was rooted in an ISAPP expert discussion group held at the 2019 annual meeting in Antwerp, Belgium. During the discussion, various experts presented evidence from their fields—addressing the potential health benefits of live microbes in general, rather than the narrow group of microbial strains that qualify as probiotics.
Below, the authors of this new review answer questions about their efforts to quantify the relationship between greater consumption of live microbes and human health.
Why is it interesting to look at the potential importance of live microbes in nutrition?
Prof. Joanne Slavin, PhD, RD, University of Minnesota
Humans need proper nutrition to survive, and a lack of certain nutrients creates a ‘deficiency state’. Is this the case for live microbes?
Dr. Mary Ellen Sanders, PhD, ISAPP Executive Science Officer
Why think about intake of ‘live microbes’ in general, rather than intake of probiotic & fermented foods specifically?
Prof. Maria Marco, PhD, University of California Davis
What are dietary sources of live microbes? And do we get microbes in foods besides fermented & probiotic foods?
Prof. Bob Hutkins, PhD, University of Nebraska Lincoln
What’s the evidence that a greater intake of live microbes may lead to health benefits?
Prof. Dan Merenstein, MD, Georgetown University
Why is it difficult to interpret past data on people’s intake of live microbes and their health?
Prof. Colin Hill, PhD, University College Cork
Databases of dietary information have data on people’s intake of live microbes, but what are the limitations of our available datasets?
Prof. Dan Tancredi, PhD, University of California Davis
See ISAPP’s press release on this paper here.
Update on harmonized guidelines for probiotics being developed by the Codex Alimentarius
/in ISAPP Science Blog, News /by KCBy Prof. Gabriel Vinderola, PhD, Associate Professor of Microbiology at the Faculty of Chemical Engineering from the National University of Litoral and Principal Researcher from CONICET at Dairy Products Institute (CONICET-UNL), Santa Fe, Argentina
In December 2017, at the 39th session of the Codex Committee on Nutrition and Foods for Special Dietary Uses (CCNFSDU) in Berlin, members of the Committee agreed to include in the agenda a discussion of harmonized guidelines on probiotics for use in foods and food supplements. Argentina supported this initiative and proposed itself to lead the work, building a guideline based on the present Argentinian framework on probiotics.
The first draft of the document was presented in 2018. Some countries supported the work to develop harmonized guidelines with a definition and minimum requirements for characterization, quality, and labeling, while other countries did not support the initiative, arguing that there was no perceived need to start this new work, it was not a priority for the Committee at that moment, and the document should be revised to provide more clarity on the need to start work on this topic.
Early in 2019, Argentina convened a panel of local experts to contribute to the discussion of the paper based on the issues raised in the first round of revision. I participated in that panel.
In November 2019, at the 41th meeting of the CCNFSDU, an updated version of the paper was presented. This revision clarified that the goal of the work was to produce a regulatory framework for the use of probiotics in food and food supplements. This objective is in line with the purpose of the Codex Alimentarius to guarantee safe and quality food and to ensure equity in international food trade.
In the course of the debate, some delegations favored the topic, stressing the value of regulatory harmonization within the Codex. They pointed out that framework could be based on the existing probiotic definition and guidelines of FAO and WHO, providing clear guidance and principles focused on the use of probiotics as ingredients. Delegations that opposed the new work noted that the Codex had already adopted principles and guidelines of a similar (horizontal) nature on issues such as labeling, claims, contaminants, safety and hygiene covering all foods, including food supplements, and that probiotic-specific regulations were not needed. FAO and WHO had also conducted work in this area.
After the debate, the Committee considered that the document presented needed further clarification, especially with regard to the scope and the issues raised in the discussion. Finally, it was agreed that Argentina and Malaysia would revise the document to be presented at the next plenary meeting of the Committee (42th meeting), to be held in November 2020. It was agreed that in order to assess the need to work on this topic, the new proposal should include a justification for additional probiotic-specific criteria in accordance with the mechanism for assigning Committee priorities.
Due to the COVID-19 pandemic, the 42th meeting has been postponed until November 2021, and a deadline of March 2021 was set for submitting the revised paper to the CCNFSDU.
The information reported in this post was kindly provided by Andrea Moser, Argentinian representative at the Codex Committee on Nutrition and Foods For Special Dietary Uses.
Locally produced probiotic yogurt for better nutrition and health in Uganda
/in Consumer Blog, News /by KCBy Prof. Seppo Salminen, Director of Functional Foods Forum, University of Turku, Turku, Finland
Can locally produced probiotic yogurt be a way to increase the health and wealth of people in resource-poor areas of Uganda? Recently Dr. Nieke Westerik, a researcher from the Netherlands, partnered with a local Ugandan team to explore a yogurt production and distribution program similar to one that had previously proved successful in low-income areas of Argentina.
Since 2008, “Yogurito Social Program” has been operating in Argentina and now some 350,000 schoolchildren in less developed provinces enjoy the benefits of daily probiotic yogurt developed locally. Dr. Westerik (Free University of Amsterdam and Yoba 4 Life Foundation), with support from former ISAPP board member Prof. Gregor Reid, has now helped adapt the program to local needs in Uganda, making use of a well-known probiotic (Lacticaseibacillus rhamnosus GG) plus a yogurt starter (produced by the Yoba 4 Life Foundation) for production of the yogurt. The probiotic’s health effects have been demonstrated in human intervention studies.
The team worked on technical training and quality control of the locally produced yogurt, developing a production protocol suitable for Ugandan small-scale manufacture of probiotic fermented foods. Dr. Westerik’s team then conducted two clinical studies that demonstrated that the consumption of this probiotic product improved natural defenses and prevented respiratory infections (e.g. the common cold) and intestinal infections, which are the infectious conditions of greatest relevance in childhood in Uganda.
Yogurt is a new tool for individuals in developing areas of Uganda to achieve better health through diet, with potentially significant social and economic implications. Both the Ugandan and Argentinian experiences illustrate the power of microbes to positively impact the lives of women, men, and children. Given the positive results from these two different contexts, such activities could be replicated in other geographical areas—with either dairy, vegetable, or grain fermentations used locally with defined, well-studied starter cultures.
Further 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.
Westerik N. 2020. Locally produce probiotic yoghurt for better nutrition and increased incomes in Uganda. PhD thesis, Free University of Amsterdam, The Netherlands.
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. Beneficial Microbes, 9 (5): 707-715.
YOGURITO –the Argentinian social program with a special yogurt
Probiotics to Prevent Necrotizing Enterocolitis: Moving to Evidence-Based Use
/in ISAPP Science Blog /by KCBy Ravi Mangal Patel, MD, Msc, Associate Professor of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta. rmpatel@nullemory.edu Twitter: @ravimpatelmd
Necrotizing enterocolitis (NEC) is one of the most lethal neonatal diseases, yet most people have never heard about it. The disease primarily affects preterm infants and is characterized by the development of intestinal inflammation. Clinically, the disease often manifests with an infant developing feeding intolerance or abnormal abdominal exam findings. The diagnosis is confirmed by abdominal x-ray or ultrasound. One of the key diagnostic radiographic findings is pneumatosis, which is air in the lumen of the bowel caused by gas-producing bacteria.
Dr Ravi Mangal Patel
NEC accounts for 1 out of every 10 deaths in US neonatal intensive care units. Among extremely preterm infants (those born at 22-28 weeks’ gestation) in the US, NEC is the most common single cause of death between 2 weeks and 2 months of age. Many infants with NEC undergo surgery to remove diseased bowel and those who recover and survive are at risk for long-term neurodevelopmental impairment and short bowel syndrome.
Decades of research into NEC have identified several key risk factors, including formula feeding, inconsistent feeding, abnormal intestinal oxygenation and [gut microbiota] dysbiosis. Studies have shown that dysbiosis, or abnormal intestinal colonization, is an important antecedent risk factor for the development of NEC. These studies have found that infants who develop NEC have an increase or bloom in the relative abundance of proteobacteria, compared to those who do not develop NEC. These proteobacteria, which contain a lipopolysaccharide coating, may lead to inflammation through their interaction with Toll-like receptor 4.
Given the role of dysbiosis in NEC, efforts to intervene by provision of probiotics to prevent NEC is a rational and extensively studied intervention, with over 63 randomized trials enrolling ~15,000 infants to date. The aforementioned meta-analysis, along with several others (Table 1), show probiotic supplementation results in large magnitude reductions in the risks of NEC and death and more modest reductions in the risks of late-onset sepsis. However, there is more limited data on extremely preterm infants and the quality or certainty of evidence for probiotics for the prevention of NEC was low in a recent Cochrane review.
Source: https://doi.org/10.1053/j.sempedsurg.2017.11.008
In the United States, an increasing number of centers have begun to routinely provide probiotics, with the greatest increase in use beginning in 2015. Observational studies evaluating routine probiotic use show benefits that are similar in magnitude to those from randomized trials, supporting the external validity of the results from the trials. This includes a large recent evaluation of probiotic use in the United States. Around the world, probiotic use is highly variable, from 100% of NICUs in New Zealand, 68% of NICUs in Germany, to 12% in the UK, 21% in Canada and 14% in the United States. Some of the variability in clinical use may be related to the uncertainty regarding the quality of commercially available probiotic products and need for clarity regarding strain-specificity of effects. There are many considerations both for and against routine use of probiotics to prevent NEC (Table 2). Current probiotic dietary supplements do not undergo FDA’s premarket review and approval requirements for safety and effectiveness or have to meet manufacturing and testing standards for drugs, and the potential risks were highlighted by a case of an infant death from a contaminated supplement. There is currently no FDA-approved live biotherapeutic product to prevent NEC.
Source: doi: 10.1016/j.earlhumdev.2019.05.009
Recent recommendations and guidance from ESPHGAN and the AGA also demonstrate that some medical organizations recognize the strength of the data in support of probiotic use to prevent NEC. It has been over two decades since the first study demonstrating the benefit of probiotic supplementation to prevent NEC in preterm infants. Now, more than ever, the evidence continues to accumulate regarding the beneficial effects of probiotic use in preterm infants as a compelling strategy to reduce the risks of both NEC and death. Therefore, considering the balance of potential risks and benefits including data from both randomized trials and routine implementation studies, my opinion is that the cumulative evidence to date supports routine probiotic use to prevent NEC and death in preterm infants.
As important is considering the parent voice regarding probiotic use. The NEC Society is a non-profit focused on NEC that has worked to incorporate the voice of the patient-family in clinical decisions.
Disclosures: Dr. Patel serves on the data-safety monitoring board of the Connection Study, which is a trial examining the use of an investigational probiotic to decrease the risk of NEC.
For further information, see this seminar by Dr. Patel: Practical Consideration for Probiotics in the NICU