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Popular media, misinformation and ‘biotics’

/in News /by KC

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

Encountering misinformation is all too easy when seeking understanding of probiotics, prebiotics, synbiotics, and postbiotics (collectively, ‘biotics’). It can be perpetuated both by proponents and detractors. Through this lens, I’m prompted to comment on some high profile pieces making news recently. A Washington Post article Probiotic supplements may do the opposite of boosting your gut health was published on March 28, 2023, by Anahad O’Connor. This author was then interviewed for a CBS video story Studies find that probiotics can harm gut health on March 30, 2023.  Then, a National Geographic article Probiotics, prebiotics, postbiotics. What’s the difference? was published on the same day.

These pieces appropriately acknowledge the availability of evidence linking probiotics to human benefits. Yet the points raised about potential harms from probiotics and a misunderstanding of what ‘biotic’ substances really are deserve comment.

Harms of probiotics

Amid a backdrop of marketing and media messaging lauding the many benefits of probiotics, reporters are understandably drawn to the counter message that ‘probiotics can harm gut health’. Safety must always be rigorously assessed, as encouraged by a 2023 ISAPP paper focused on emerging issues in probiotic safety (see here). However, the claims of harm made – although generated from studies in humans – are not based on clinical endpoints. Instead they are based on either microbiome endpoints (Suez et al. 2018) or on post hoc analysis of biomarker outcomes (Wastyk et al. 2023). The limitations of the Suez et al. 2018 study were discussed in more detail previously (See: Clinical evidence and not microbiota outcomes drive value of probiotics). This paper evaluated the effect of one multi-strain probiotic product and is the only paper I am aware of that shows that probiotics inhibit microbiome recovery after antibiotic treatment. The paucity of supporting evidence for the harm supposedly documented in this paper is not mentioned in the stories. It is noteworthy that in the Wastyk et al. 2023 paper the authors acknowledge that the study did not achieve its primary objectives, and in referring to their post hoc analysis (including the ‘evidence’ for harm), they specifically acknowledge that such analysis is not conclusive evidence:  “We next leveraged aspects of our study design … in a discovery analysis process to reveal trends that could inform possible … hypotheses for future studies.” These studies are best used for generating hypotheses requiring further study.

Another criticism that was leveraged as evidence that probiotics cause harm is that probiotics reduce microbiota diversity. Any probiotic-induced reduction in diversity of fecal microbiota has not been shown to be associated with harm. Further, most studies show no significant overall changes in microbiome composition in response to traditional probiotic administration. However, it should be understood that the value of diversity as a marker of health remains unproven. The evidence is from observational studies and only shows associations, not causality.

 You can’t both object to criticisms based only on microbiome data but then promote probiotics based on it.

As stated, relying on microbiota endpoints to advance the idea that probiotics cause harm is not justified. But I cannot escape the fact that probiotic proponents in part contribute to this thinking. When probiotics are marketed as being able to ‘balance the microbiota’, without clinical data to substantiate a benefit, aren’t they promoting the same limited science?

Adherence to definitions of biotics needed

ISAPP has rigorously considered and offered definitions for probiotics, prebiotics, synbiotics, postbiotics and fermented foods (see here for a summary), which have been presented in highly cited reviews in Nature Reviews Gastroenterology and Hepatology (see here, here, here, here and here). These efforts were undertaken to advance a common understanding of these terms, so that precision can be attained in communications on them.

This objective has been far from realized. Misuse of these terms continues on product labels, in scientific publications, and in popular press communications.

The articles cited above compelled me to offer some take home messages for those responsible for accurately communicating science:

  • “Prebiotics + probiotics = postbiotics”, a heading in the National Geographic article, is completely wrong.

Probiotics are: Live microorganisms that, when administered in adequate amounts, confer a health benefit on the host

Prebiotic is: A substrate that is selectively utilized by host microorganisms conferring a health benefit on the host

Postbiotic is: Preparation of inanimate microorganisms and/or their components that confers a health benefit on the host

  • Fermented foods are not the same as probiotics. Most fermented foods have not been proven to improve health (associative studies have suggested, but in most cases not proven, health benefits), many do not retain live microbes, and most are not made with microbes characterized to the strain level. All these are requirements to meet the definition of a probiotic. See here, here and here for clear discussions of this issue.
  • Fermented foods are not the magic bullet that many portray them as. Yes – for that subset of fermented foods that retain live microbes – they may contribute a diversity of live microbes to the diet. ISAPP has recently researched this area (see recent ISAPP publications here and here). And yes, they are tasty. However, the evidence level for benefits of traditional fermented foods is nowhere near the level for probiotics. Still, healthcare professionals critical of evidence supporting probiotic benefits commonly recommend fermented foods.
  • Postbiotics do not refer to ‘metabolites from probiotics’. See here for why ISAPP focused the definition of postbiotic on inactivated microbes with or without their metabolites.
  • In simplistic language, prebiotics can be viewed as food for beneficial microbes, but, typically, prebiotics target the normal microbes in the gut, not probiotics. See here.

Conclusion

Both the positive and negative effects of probiotics based on microbiome assembly can be misrepresented in the press, by some marketing claims, and sometimes in scientific literature. The field will benefit from communications that acknowledge the limitations of available science. Further, it’s important for clarity in communication that the field coalesces around established definitions and honor the criteria needed to meet those definitions. Additionally, scientists and medical professionals should apply the same scrutiny and critical thinking to fermented foods as they do to probiotics.

ISAPP encourages healthy debate, critical review of new studies and innovative research. Since ISAPP’s mission is focused on promoting the science of these substances, journalists are invited to reach out as needed to ISAPP for an evidence-based perspective on this evolving field (www.ISAPPscience.org).

How to navigate probiotic evidence and guidelines for pediatric populations

Episode 20: How to navigate probiotic evidence and guidelines for pediatric populations

/in Podcast, Season Two /by Laura

How to navigate probiotic evidence and guidelines for pediatric populations

 

Podcast: Play in new window | Download

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The Science, Microbes & Health Podcast 

This podcast covers emerging topics and challenges in the science of probiotics, prebiotics, synbiotics, postbiotics and fermented foods. This is the podcast of The International Scientific Association for Probiotics and Prebiotic (ISAPP), a nonprofit scientific organization dedicated to advancing the science of these fields.

How to navigate probiotic evidence and guidelines for pediatric populations, with Dr. Hania Szajewska

Episode summary:

In this episode, the ISAPP podcast hosts talk about evidence and guidelines for probiotics in pediatric populations, with Prof. Hania Szajewska MD PhD, of the Department of Paediatrics at the Medical University of Warsaw, Poland. They talk about some of the inconsistencies between different medical organizations’ guidelines for pediatric probiotic use, and how clinicians can move forward with recommendations based on the best available evidence.

 

Key topics from this episode:

  • Guidelines exist on probiotic use for gastroenterological issues in children, but there are differences (especially regarding acute gastroenteritis) between guidelines from different medical societies: European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) and The American Gastroenterological Association (AGA).
  • Realistic expectations are necessary when prescribing probiotics. Different probiotics have different benefits, but they are not a ‘magic bullet’. For example, the evidence shows certain probiotics for acute gastroenteritis reduce diarrhea by an average of one day. This could have a big impact on the quality of life of the end user, but for clinicians it may not sound like a lot so they must set expectations accordingly.
  • The market is overflowing with probiotic products, many of which do not have proven efficacy. This makes it difficult for end users and healthcare professionals to distinguish the best products.
  • Always look for evidence-based probiotics with documented efficacy for the indication for which they are intended.
    • Physicians have the ethical duty to prescribe evidence-based products (that is, clinically proven, effective products).
    • The exact strains and doses matter.
  • Formal training and education of healthcare professionals regarding the beneficial effects of microbes, the microbiome, and probiotics are currently lacking.
  • Is it more valuable to know probiotics’ mechanism of action, or to have evidence from clinical trials that they are effective?
    • Ideally we would have both, but since we don’t know the exact mechanism for all probiotics, positive evidence from clinical trials is crucial. 
    • We also need to make clear to healthcare professionals and end users what to expect from taking probiotics. For example, some probiotics reduce the chances of developing antibiotic-associated diarrhea by 50%. For colic, some probiotics can reduce the crying time by half an hour. These are modest benefits but for the affected individual they may be impactful.
  • For vulnerable populations such as preterm infants, we need high-quality products with proven safety and efficacy.

 

Episode abbreviations and links:

 

About Prof. Hania Szajewska: 

Hania Szajewska, MD, is Professor and Chair of the Department of Paediatrics at the Medical University of Warsaw and the Chair of the Medical Sciences Council. Among her various functions, she served as the Editor-in-Chief of the Journal of Pediatric Gastroenterology and Nutrition; a member of the Council and then as the General Secretary of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN); the Secretary of the ESPGHAN Committee on Nutrition. Most recently, she joined the Board of Directors of the International Scientific Association for Probiotics and Prebiotics (ISAPP). Prof. Szajewska has broad interests in pediatric nutrition but her research focuses on the effects of early nutritional interventions on later outcome; and the gut microbiota modifications such as with various biotics (probiotics, prebiotics, synbiotics, postbiotics). She is or has been actively involved in several European Union-funded research projects. She is an enthusiastic advocate for the practice of evidence-based medicine. Prof. Szajewska has co-authored more than 400 peer-reviewed publications and 30 book chapters. Citations >18,141. Hirsch index 72 (WoS, March 2023).

Questioning the existence of a fetal microbiome, with Dr. Kate Kennedy

Episode 19: Questioning the existence of a fetal microbiome

/in Podcast, Season Two /by Laura

Questioning the existence of a fetal microbiome, with Dr. Kate Kennedy

 

Podcast: Play in new window | Download

Subscribe: Apple Podcasts | Google Podcasts | Spotify | RSS

The Science, Microbes & Health Podcast 

This podcast covers emerging topics and challenges in the science of probiotics, prebiotics, synbiotics, postbiotics and fermented foods. This is the podcast of The International Scientific Association for Probiotics and Prebiotic (ISAPP), a nonprofit scientific organization dedicated to advancing the science of these fields.

Questioning the existence of a fetal microbiome, with Dr. Kate Kennedy

Episode summary:

In this episode, the ISAPP podcast hosts tackle the debate on the existence of a fetal microbiome, with guest Kate Kennedy PhD of McMaster University in Canada. They talk about Kennedy’s recent co-first-authored paper in Nature, which concludes that it is not biologically plausible that the fetus harbors live microorganisms, and that previous microbial sequencing studies on the fetal microbiome did not account for the many sources of contamination.

 

Key topics from this episode:

  • During the last 10 years, a lively debate has emerged on whether humans harbor living microorganisms prior to birth. Some scientists have looked at fetal and placental tissues and amniotic fluid, and have ostensibly detected microbial DNA. But those results are being questioned, with the argument that the signals being found are not biologically plausible.
  • Kennedy et al. published an article in Nature that re-analyzed data and brought in experts from different related fields to help interpret the data. The conclusion is that the fetal microbiome does not exist. Previous studies have likely seen contamination during sampling, since it’s nearly impossible to collect samples in a sterile way following vaginal delivery; contamination can happen at different stages so stringent controls are needed across all these areas of potential contamination. Furthermore, live microorganisms in the fetus does not fit with what we already know in related fields of science.
  • The popularity of microbiome research may have made scientists interested in this topic, although sequencing by itself may not be sufficient to settle the question of whether a fetal microbiome exists.
  • Human cells have Mitochondrial DNA, which is bacterial in origin. In 16S rRNA gene sequencing, there is some overlap in what is amplified, and this could include mitochondrial DNA, giving misleading results. This was not accounted for in some of the initial fetal microbiome studies.
  • Bringing together disparate disciplines is inherently challenging. It’s very important to work to understand each other and understand the host and biological situation you’re dealing with.
  • If there were even small numbers of bacteria present in the fetus it would have huge implications for our understanding of fetal biology and immunology. One question would be: how is the fetus limiting growth of any microbes it harbors?
  • Despite the likelihood that the fetal microbiome does not exist, the fetus is not unprepared for the microbial onslaught after birth. The maternal microbiota and immune system can educate the fetus immunologically in the absence of fetal colonization.

 

Episode abbreviations and links:

 

About Dr. Kate Kennedy: 

Kate completed her PhD on the role of the maternal gut microbiome in perinatal programming in the lab of Dr. Deborah Sloboda at McMaster University. She previously completed her BSc and MSc in Biology at the University of Waterloo. Her research explores host-microbiome relationships in pregnancy, early-life, and aging to understand their role in modulating health and disease risk.  

Episode 17: Using metabolomics to learn about the activities of gut microbes

/in Podcast, Season Two /by Laura

 

Podcast: Play in new window | Download

Subscribe: Apple Podcasts | Google Podcasts | Spotify | RSS

The Science, Microbes & Health Podcast 

This podcast covers emerging topics and challenges in the science of probiotics, prebiotics, synbiotics, postbiotics and fermented foods. This is the podcast of The International Scientific Association for Probiotics and Prebiotic (ISAPP), a nonprofit scientific organization dedicated to advancing the science of these fields.

Using metabolomics to learn about the activities of gut microbes, with Dr. Anisha Wijeyesekera

Episode summary:

In this episode, the ISAPP podcast hosts address the topic of metabolomics with Dr. Anisha Wijeyesekera, PhD, a Lecturer in the Department of Food and Nutritional Sciences at the University of Reading, United Kingdom. Dr. Wijeyesekera gives an overview of how metabolic profiling works, including the information provided by different biological samples, and discusses how metabolomics can be used to piece together the contributions of microbes to host health.

 

Key topics from this episode:

  • Dr. Wijeyesekera introduces the field of metabolomics and describes it as an essential part of systems biology. Metabolic profiling provides a real-time snapshot of the multiple metabolic processes going on in a system at the time the sample was collected.
  • Metabolites are the end products of metabolism; the gut microbiota is the most metabolically active of the microbiomes in the human body.
  • Methodology depends on what information you hope to uncover from your samples. Different biological samples (e.g. stool, urine, plasma) provide different pieces of information; this is cross-referenced with information on metabolic pathways.
  • One application of metabolomics is in identifying biomarkers that can predict patient outcomes. Identifying differences in microbes as well as metabolites could lead to the development of dietary-based supplements for patients to take alongside clinical treatments.
  • Changes in microbial composition may not be that meaningful if the bugs that change are doing the same thing in the end; this is what metabolomics helps uncover.
  • Metabolomics gives you insights into mechanisms when you have a probiotic or prebiotic trial with clinical outcomes. 
  • Short-chain fatty acids are metabolites that are frequently associated with health; changes in these is a clue that the gut microbiota has been impacted by the intervention.
  • Bile acids are metabolites that come from diet. Microbes convert primary bile acids to secondary, which circulate throughout the body. You can measure bile acids to see how gut microbiota are affected by an intervention.
  • Metabolomics is very promising and may be used in more probiotic and prebiotic studies in the future.

 

Episode abbreviations and links:

 

About Dr. Anisha Wijeyesekera:

Anisha is a Lecturer in the Department of Food and Nutritional Sciences at the University of Reading, United Kingdom. She previously worked at Imperial College London, where she also obtained her PhD (in Biochemistry). Anisha’s research applies a combined microbial and metabolic phenotyping approach, to better understand the tripartite relationship between diet, gut microbiota and human health. At the University of Reading, she conducts in vitro and in vivo studies for functional assessment of the gut microbiota, particularly in response to prebiotics and probiotics. The ultimate aim is to use this information to tailor nutritional or other interventional therapy to improve health outcomes.

Episode 16: The honey bee microbiome and potential for probiotics

/in Podcast, Season Two /by Laura

 

Podcast: Play in new window | Download

Subscribe: Apple Podcasts | Google Podcasts | Spotify | RSS

The Science, Microbes & Health Podcast 

This podcast covers emerging topics and challenges in the science of probiotics, prebiotics, synbiotics, postbiotics and fermented foods. This is the podcast of The International Scientific Association for Probiotics and Prebiotic (ISAPP), a nonprofit scientific organization dedicated to advancing the science of these fields.

The honeybee microbiome and potential for probiotics, with Dr. Brendan Daisley

Episode summary:

In this episode, the ISAPP podcast hosts cover the honey bee microbiome with Brendan Daisley, PhD, who is currently a post-doctoral fellow at the University of Guelph in Canada. Daisley explains how the honeybee microbiome is unique, why it’s important for bee health, and the potential for probiotic applications as well as the practicalities of how live microorganisms are delivered to hives.

 

Key topics from this episode:

  • Daisley’s research is motivated by declining bee populations and finding ways to find ways to stop this.
  • He originally researched how probiotics could have detoxification functions in humans; this led to the question of whether probiotics could help reduce the toxicity of pesticides in bees and possibly affect resistance to infectious diseases.
  • Each individual bee has a microbiome of its own. Unlike other insects, bees have a core, defined microbial community in their guts.
  • Surprisingly, no one has successfully derived a completely germ-free honey bee. Microbiota-depleted bees do exist, however.
  • Research is ongoing on how microbes may even enable life in bee species — e.g. the recent finding that pupation in stingless bees is triggered by fungi.
  • Bees are affected by pesticides; many pesticides also have antimicrobial effects, but regulatory agencies do not track these effects.
  • Supplementing bees with beneficial strains of microbes can improve bee health and resistance to infectious diseases. However, no good baseline studies have been done on the bee gut, so it’s difficult to know what’s ‘normal’ and what is missing. The Canadian Bee Gut Project aims to determine this.
  • It’s possible to try finding bees that may have had less exposure to pesticides, but it’s difficult to determine past exposure because bees are traded and sent all over the world.
  • Wolbachia is a valuable endosymbiont for bees, and acts like a ‘secondary mitochondria’ in their cells. Currently it is hardly ever found in honey bees, possibly because of chronic exposure to tetracycline.
  • Probiotics can be delivered to bees using a “BioPatty” or a spray-based formula; the delivery method is very important. Supplementing the hive with certain probiotics can suppress outbreaks of American Foulbrood disease when they happen.
  • Daisley and colleagues used 3 probiotic strains, which remain present in the bee host for several weeks. 
  • As far as potential prebiotics for bees, it has been observed that pollen fibers can beneficially modulate the honey bee microbiome.
  • The healthy honey bee microbiome should be dominated by lactic acid bacteria.

 

Episode abbreviations and links:

 

About Dr. Brendan Daisley:

Dr. Brendan Daisley is a postdoc at the University of Guelph (Allen-Vercoe lab) and the current President of the Students and Fellows Association of ISAPP. He graduated from his PhD in Microbiology & Immunology at Western University in 2021 (supervisor: Dr. Gregor Reid), during which he received several national awards including the Armand Frappier Outstanding Student Award, adjudicated by The Canadian Society of Microbiologists. Brendan has a broad range of experience in environmental application of probiotics to honey bees and, notably, he was the first to introduce the theory of ‘missing microbes’ within the field of honey bee microbiome research. During his PhD, he helped coordinate several large field trials across North America (mostly in Ontario and California) showing that supplementation of probiotic lactobacilli strains to honey bees could improve colony-level health outcomes. During his postdoc work, he has developed a microbiome database tool (BEExact) for improved detection of uncultivated ‘microbial dark matter’, established a bioreactor model of the honey bee gut microbiome (the RoBEEgut), and co-founded the Canadian Bee Gut Project (https://beegutproject.uoguelph.ca) – a nationwide crowdsourcing initiative that aims to deeply sequence thousands of bee microbiome samples to increase our knowledge on the multifactorial drivers of honey bee mortality.

Why researchers need to understand more about the small intestinal microbiome

/in ISAPP Science Blog /by KC

By Prof. Eamonn M. M. Quigley, MD, The Methodist Hospital and Weill Cornell School of Medicine, and Prof. Purna Kashyap, MD, Mayo Clinic

The phrase “gut microbiota” properly refers to the microorganisms living throughout the entire digestive tract, including the mouth and the upper digestive tract, through the length of the small intestine as well as the large intestine. Yet the vast majority of scientific studies on the gut microbiota make conclusions based only on stool samples, meaning that the contributions to health and disease of microorganisms from most of the digestive tract are largely unexplored.

Researchers have established that the microorganisms throughout different parts of the digestive tract vary greatly. In particular, the microorganisms living in the small intestine are fewer in number than those in the colon. They are less diverse, and they change more over time because of their dynamic environment (fluctuations in oxygen, digestive secretions, dietary substrates, among other influences).

The dynamic composition and biologic functions of the small intestinal microbiome in health and disease are mostly unknown. Research has been hampered by the difficulty in obtaining samples from this area of the digestive tract and, in particular, its more distal reaches. Participants in a 2022 ISAPP discussion group argued, however, there are some good reasons to dedicate more effort to investigation of the small intestinal microbiome:

  • The small intestine has critical homeostatic functions in relation to nutrient digestion and absorption, immune engagement and interactions with the enteric and central nervous systems, as well as the neuroendocrine system. Each of these could be influenced by microbiota-host interactions. Important locations for these interactions include the gut barrier and mucosa- or gut-associated lymphoid tissue. The nature of microbiota-host interactions in these particular areas needs to be better understood, as they could have implications for systemic host health.
  • Diet plays a critical role in symptom generation in many gastrointestinal disorders; it is important to better understand diet-microbe interactions in the gut lumen to determine how the small intestinal microbiome may be contributing to diet-triggered symptoms.
  • A disordered small intestinal microbiome is commonly implicated in the pathogenesis of various gastrointestinal and non-gastrointestinal symptoms, from irritable bowel syndrome to Alzheimer’s disease, through the much-disputed concept of small intestinal bacterial overgrowth (SIBO). A precise definition of the normal small intestinal microbiome is a prerequisite to the accurate diagnosis of SIBO and linking it with various disease states.

How can we gain more information on the small intestinal microbiome? Our group tackled the limitations of current definitions and diagnostic methods, noting that this field may be advanced in the near future by new technologies for real-time sampling of intestinal gases and contents. The group discussed optimal methods for the sampling of small intestinal microbes and their metabolic products—noting that a full range of ‘omics technologies applied in well-defined populations could lead to further insights. In the meantime, the gastroenterologists in our group advised restraint in the diagnosis of SIBO and the need to exert caution in identifying it as the cause of symptoms. Clinical progress in this area is best achieved through the application of modern molecular methods to the study of human small intestinal microorganisms.

The gut mycobiome and misinformation about Candida

/in ISAPP Science Blog /by KC

By Prof. Eamonn Quigley, MD, The Methodist Hospital and Weill Cornell School of Medicine, Houston

As a gastroenterologist, I frequently meet with patients who are adamant that a Candida infection is the cause of their ailments. Patients experiencing a range of symptoms, including digestive problems, sometimes believe they have an overgrowth of Candida in their gastrointestinal (GI) tract and want to know what to do about it. Their insistence is perhaps not surprising, given how many many websites and social media ‘gurus’ share lists of symptoms supposedly tied to Candida infections. Even cookbooks exist with recipes specifically tailored to “cure” someone of Candida infection through dietary changes. Some articles aim to counter the hype – for example, an article titled “Is gut Candida overgrowth actually real, and do Candida diets work?” Yet patients are too often confused about the evidence on Candida and other fungi in the GI tract. In a 2021 ISAPP presentation on the gut mycobiome, I provided a clinical perspective on fungal infections and the related evidence base.

Fungal infections do occur

Much of the misinformation I encounter on Candida infections focuses on selling a story that encourages people to blame Candida overgrowth as the cause of their symptoms and undertake expensive or complicated dietary and supplement regimens to “cure” the infection. This is not to say that fungal infections do not take place in the body. Fungal infections, from Candida or other fungi, frequently occur on the nails or skin. Patients taking oral or inhaled steroids may develop Candida infections in the oropharynx and esophagus. Immunocompromised patients also face a greater risk of Candidiasis and Candidemia—these include HIV patients; patients undergoing chemotherapy; transplant patients; and patients suffering from malnutrition.

Fungal infections are rare in the GI tract

Regardless, instances of documented Candida infection in the GI tract remain few in number. One study published in the 90s reported 10 patients hospitalized with severe diarrhea1. These patients suffered from chronic illness, underwent intense antimicrobial treatment or chemotherapy, and faced severe outcomes such as dehydration—and clinicians consistently identified the growth of Candida albicans in the patient fecal samples. Other studies on the matter lack the clinical evidence to conclude that fungal infections drive GI disease. A study examining small intestinal fungal overgrowth identified instances of fungal overgrowth among 150 patients with unexplained symptoms2. However, the lack of documentation of response to an antifungal treatment protocol makes it difficult to attribute the observed symptoms to the presence of fungal organisms.

 The gut mycobiome in IBS

The gut microbiome has taken centre stage in common discourse about gut health. In line with this movement, my colleagues at Cork investigated the fungal members of the gut microbiome – that is, the gut mycobiome – in the guts of patients diagnosed with irritable bowel syndrome (IBS)3 to ascertain whether there was any correlation with symptoms. This effort revealed DNA sequences belonging to many fungal species. However, no significant differences in the number of fungal species were observed between IBS patients and volunteers. A smaller study done on a Dutch cohort, on the other hand, detected significantly reduced total fungal diversity among IBS patients4. So, it’s not yet clear whether mycobiome differences exist across populations with IBS.

Studying the gut mycobiome for further insights

The few studies that have examined the human gut mycobiome expose the need to answer basic questions about the fungal components of the gut microbiome. For instance, what is the gut mycobiome composition among people not suffering from GI-related symptoms? Efforts to answer these questions would require longitudinal sample collection to account for the high turnover of microbes in the GI tract. We would also need to perform stool measures not typically performed in the clinic to better correlate fungal overgrowth with GI-related symptoms. Overall, any gut mycobiome study requires careful and detailed experimental design.

We also have to consider where the gut mycobiome originates. A recent study in mSphere showed that the increased amount of DNA belonging to S. cerevisiae in stool samples coincided with the number of times subjects consumed bread and other fungi-rich foods5. S. cerevisiae also failed to grow in lab conditions mimicking the gut environment after 7 days of incubation. These findings suggest that the fungi identified in gut mycobiome profiles are not persistent gut colonizers, but transient members of the gut microbiome that come from the food we digest or our saliva.

A survey of the literature on the gut mycobiome and fungal infections in the GI tract highlights the need to conduct more studies on the role fungi play in gut and overall health. My clinical approach when I encounter someone claiming to have GI symptoms caused by Candida infection is a skeptical, yet empathetic response. Through proper communication of the evidence, we can investigate the origin of symptoms together and identify the best treatment methods for any GI-related disease, whether caused by fungal infections or not.

ISAPP held a mini-symposium featuring six short lectures that explore different aspects of the human mycobiome, including research, clinical and industry perspectives. See here for the replay, with Dr. Quigley’s talk at 1:12:30.

References

(1)        Gupta, T. P.; Ehrinpreis, M. N. Candida-Associated Diarrhea in Hospitalized Patients. Gastroenterology 1990, 98 (3), 780–785. https://doi.org/10.1016/0016-5085(90)90303-i.

(2)        Jacobs, C.; Coss Adame, E.; Attaluri, A.; Valestin, J.; Rao, S. S. C. Dysmotility and Proton Pump Inhibitor Use Are Independent Risk Factors for Small Intestinal Bacterial and/or Fungal Overgrowth. Aliment Pharmacol Ther 2013, 37 (11), 1103–1111. https://doi.org/10.1111/apt.12304.

(3)        Das, A.; O’Herlihy, E.; Shanahan, F.; O’Toole, P. W.; Jeffery, I. B. The Fecal Mycobiome in Patients with Irritable Bowel Syndrome. Sci Rep 2021, 11 (1), 124. https://doi.org/10.1038/s41598-020-79478-6.

(4)        Botschuijver, S.; Roeselers, G.; Levin, E.; Jonkers, D. M.; Welting, O.; Heinsbroek, S. E. M.; de Weerd, H. H.; Boekhout, T.; Fornai, M.; Masclee, A. A.; Schuren, F. H. J.; de Jonge, W. J.; Seppen, J.; van den Wijngaard, R. M. Intestinal Fungal Dysbiosis Is Associated With Visceral Hypersensitivity in Patients With Irritable Bowel Syndrome and Rats. Gastroenterology 2017, 153 (4), 1026–1039. https://doi.org/10.1053/j.gastro.2017.06.004.

(5)        Auchtung, T. A.; Fofanova, T. Y.; Stewart, C. J.; Nash, A. K.; Wong, M. C.; Gesell, J. R.; Auchtung, J. M.; Ajami, N. J.; Petrosino, J. F. Investigating Colonization of the Healthy Adult Gastrointestinal Tract by Fungi. mSphere 2018, 3 (2), e00092-18. https://doi.org/10.1128/mSphere.00092-18.

 

 

Improving the quality of microbiome studies – STORMS

/in ISAPP Science Blog /by KC

By Mary Ellen Sanders, PhD, ISAPP Executive Science Officer

In mid-March I attended the Gut Microbiota for Health annual meeting. I was fortunate to participate in a short workshop chaired by Dr. Geoff Preidis MD, PhD, a pediatric gastroenterologist from Baylor College of Medicine and Dr. Brendan Kelly MD, MSCE, an infectious disease physician and clinical epidemiologist from University of Pennsylvania. The topic of this workshop was “Designing microbiome trials – unique considerations.”

Dr. Preidis introduced the topic by recounting his effort (Preidis et al. 2020) to review evidence for probiotics for GI endpoints, including for his special interest, necrotizing enterocolitis (NEC). After a thorough review of available studies testing the ability of probiotics to prevent morbidity and mortality outcomes for premature neonates, he and the team found 63 randomized controlled trials that assessed close to 16,000 premature babies. Although the effect size for the different clinical endpoints was impressive and clinically meaningful, AGA was only able to give a conditional recommendation for probiotic use in this population.

Why? In part, because inadequate conduct or reporting of these studies led to reduced confidence in their conclusions. For example, proper approaches to mitigate selection bias must be reported. Some examples of selection bias include survival bias (where part of the target study population is more likely to die before they can be studied), convenience sampling (where members of the target study population are not selected at random), and loss to follow-up (when probability of dropping out is related to one of the factors being studied). These are important considerations that might influence microbiome results. If the publication on the trial does not clearly indicate how these potential biases were addressed, then the study cannot be judged as low risk of bias. It’s possible in such a study that bias is addressed correctly but reported incompletely. But the reader cannot ascertain this.

With an eye toward improving the quality and transparency of future studies that include microbiome endpoints, Dr. Preidis shared a paper by a multidisciplinary team of bioinformaticians, epidemiologists, biostatisticians, and microbiologists titled Strengthening The Organization and Reporting of Microbiome Studies (STORMS): A Reporting Checklist for Human Microbiome Research.

Dr. Preidis kindly agree to help the ISAPP community by answering a few questions about STORMS:

Dr. Preidis, why is the STORMS approach so important?

Before STORMS, we lacked consistent recommendations for how methods and results of human microbiome research should be reported. Part of the problem was the complex, multi-disciplinary nature of these studies (e.g., epidemiology, microbiology, genomics, bioinformatics). Inconsistent reporting negatively impacts the field because it renders studies difficult to replicate or compare to similar studies. STORMS is an important step toward gaining more useful information from human microbiome research.

One very practical outcome of this paper is a STORMS checklist, which is intended to help authors provide a complete and concise description of their study. How can we get journal editors and reviewers to request this checklist be submitted along with manuscripts for publication?

We can reach out to colleagues who serve on editorial boards to initiate discussions among the editors regarding how the STORMS checklist might benefit reviewers and readers of a specific journal.

How does this checklist differ from or augment the well-known CONSORT checklist?

Whereas the CONSORT checklist presents an evidence-based, minimum set of recommendations for reporting randomized trials, the STORMS checklist facilitates the reporting of a comprehensive array of observational and experimental study designs including cross-sectional, case-control, cohort studies, and randomized controlled trials. In addition to standard elements of study design, the STORMS checklist also addresses critical components that are unique to microbiome studies. These include details on the collection, handling, and preservation of specimens; laboratory efforts to mitigate batch effects; bioinformatics processing; handling of sparse, unusually distributed multi-dimensional data; and reporting of results containing very large numbers of microbial features.

How will papers reported using STORMS facilitate subsequent meta-analyses?

When included as a supplemental table to a manuscript, the STORMS checklist will facilitate comparative analysis of published results by ensuring that all key elements are reported completely and organized in a way that makes the work of systematic reviewers more efficient and more accurate.

I have been struck through the years of reading microbiome research that primary and secondary outcomes seem to be rarely stated up front. Or if such trials are registered, for example on clinicaltrials.gov, the paper does not necessarily focus on the pre-stated primary objectives. This approach runs the risk of researchers finding the one positive story to tell out of the plethora of data generated in microbiome studies. Will STORMS help researchers design more hypothesis driven studies?

Not necessarily. The STORMS checklist was not created to assess study or methodological rigor; rather, it aims to aid authors’ organization and ease the process of reviewer and reader assessment of how studies are conducted and analyzed.  However, if investigators use this checklist in the planning phases of a study in conjunction with sound principles of study design, I believe it can help improve the quality of human microbiome studies – not just the writing and reporting of results.

Do you have any additional comments?

One of the strengths of the STORMS checklist is that it was developed by a multi-disciplinary team representing a consensus across a broad cross-section of the microbiome research community. Importantly, it remains a work in progress, with planned updates that will address evolving standards and technological processes.  Anyone interested in joining the STORMS Consortium should visit the consortium website (www.stormsmicrobiome.org).

See related blog:   ISAPP take-home points from American Gastroenterological Association guidelines on probiotic use for gastrointestinal disorders

 

Hands holding mobile phone

Virtual events continue to fill gaps as in-person meetings are being planned

/in News /by KC

Prof. Bob Hutkins, PhD, University of Nebraska – Lincoln, USA

For scientists, annual meetings provide coveted opportunities to hear about the latest scientific advances from expert researchers, and they are where students and trainees get to present their research, often for the first time. Of course, meeting and socializing with colleagues, both new and old, during breaks and evening sessions is also an important part of these conferences.

Yet over the past two years, most occasions to meet face-to-face were canceled. Virtual meetings became the new normal and, even though a poor substitute for in-person gatherings, provided opportunities to connect and share emerging science. As we anticipate being together again in person – hopefully for 2022 meetings – take note of three upcoming conferences to fill the gap. Each of these feature meetings are related to the gut microbiome, diet, and health.

(1) In October, the Agriculture and Health Summit: Cultivating Gut Health at the Crossroads of Food & Medicine is a FREE three-day virtual conference that brings together a unique combination of researchers, industry leaders and thought leaders from the biomedical and agricultural sectors for important conversations about the future of human health. The event will provide a rare opportunity for individuals with diverse areas of expertise to discuss opportunities and challenges in creating ‘foods for health’ through the gut microbiome, working toward solutions in nutrition and medicine. More information can be found here. Among the presenters are ISAPP Executive Science Officer, Mary Ellen Sanders, and board members, Dan Merenstein and Bob Hutkins.

 

(2) Then in November, a Nature-sponsored online conference called Reshaping the Microbiome through Nutrition will be held. According to the website, “this conference will bring together researchers working on the microbiome and nutrition to discuss how our microbiota use and transform dietary components, and how these nutrients and their products influence host health throughout life, including effects on development and infectious and chronic diseases. A central theme of the meeting will be how diet and dietary supplements could be harnessed to manipulate the microbiome with the aim of maintaining health and treating disease”. More information is found here.

(3) Another meeting in November is organized across ten centers/institutes at the NIH and the Office of Dietary Supplements and the Office of Nutrition Research. This two-day conference November 5 and 8, titled Precision Probiotic Therapies—Challenges and Opportunities, features a Keynote address by Prof. Jeff Gordon, from the Washington University School of Medicine. ISAPP president Prof. Dan Merenstein, Georgetown University School of Medicine, is also presenting. To register for this FREE meeting, see here.

 

In this current era, interest in how diet (including probiotics, prebiotics, and fermented foods) influences the microbiome and affects human and animal health has never been greater, as is evident by these and other similarly-themed conferences.

ISAPP is planning its next annual by-invitation meeting, to be held in person.

 

The Microbiome — Can it aid in the diagnosis and therapy of irritable bowel syndrome (IBS)?

/in Consumer Blog, ISAPP Science Blog /by KC

By 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.

  1. Lessons from multi-omics

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.

  1. Food-related symptoms – linking bacteria, food antigens and the immune response

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.

  1. Beyond bacteria

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”.

  1. Fecal microbiota transplantation and IBS

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

  1. Sperber AD, Bangdiwala SI, Drossman DA, et al. Worldwide Prevalence and Burden of Functional Gastrointestinal Disorders, Results of Rome Foundation Global Study. Gastroenterology 2020 [epub ahead of print].
  2. Lacy BE, Mearin F, Change L, et al. Bowel Disorders. Gastroenterology 2016;150:1393-1407.
  3. Camilleri M, Di Lorenzo C. Brain-gut axis: from basic understanding to treatment of IBS and related disorders. J Pediatr Gastroenterol Nutr. 2012;54:446-53.
  4. Camilleri M. Physiological underpinnings of irritable bowel syndrome: neurohormonal mechanisms. J Physiol. 2014;592:2967-80.
  5. Quigley EMM. Microbiota-Brain-Gut Axis and Neurodegenerative Diseases. Curr Neurol Neurosci Rep 2017;17:94.
  6. Mayer EA, Tillisch K, Gupta A. Gut-brain axis and the microbiota. J Clin Invest. 2015;125:926-38.
  7. Klem F, Wadhwa A, Prokop LJ, et al. Prevalence, Risk Factors, and Outcomes of Irritable Bowel Syndrome After Infectious Enteritis: A Systematic Review and Meta-analysis. Gastroenterology. 2017;152:1042-1054.
  8. Pittayanon R, Lau JT, Yuan Y, et al. Gut Microbiota in Patients WithIrritable Bowel Syndrome-A Systematic Review. 2019;157:97-108.
  9. Tap J, Derrien M, Törnblom H, et al. Identification of an Intestinal Microbiota Signature Associated With Severity of Irritable Bowel Syndrome. Gastroenterology. 2017;152:111-123.
  10. Bennet SMP, Böhn L, Störsrud S, et al. Multivariate modelling of faecal bacterial profiles of patients with IBS predicts responsiveness to a diet low in FODMAPs. Gut 2018;67:872-81.
  11. Mars RAT, Yang Y, Ward T, et al. Longitudinal Multi-omics Reveals Subset-Specific Mechanisms Underlying Irritable Bowel Syndrome. 2020;183:1137-1140.
  12. Aguilera-Lizarraga J, FlorensMV, Viola MF, et al. Local immune response to food antigens drives meal-induced abdominal pain. Nature 2021;590:151-156.
  13. Das A, O’Herlihy E, Shanahan F, et al. The fecal mycobiome in patients with Irritable Bowel Syndrome. Sci Rep 2021;11:124.
  14. Myneedu K, Deoker A, Schmulson MJ, Bashashati M. Fecal microbiota transplantation in irritable bowel syndrome: A systematic review and meta-analysis. United European Gastroenterol J. 2019;7:1033-1041.
  15. Halkjær SI, Christensen AH, Lo BZS, et al. Faecal microbiota transplantation alters gut microbiota in patients with irritable bowel syndrome: results from a randomised, double-blind placebo-controlled study. 2018;67:2107-2115.
  16. Johnsen PH, Hilpüsch F, Cavanagh JP, et al.Faecal microbiota transplantation versus placebo for moderate-to-severe irritable bowel syndrome: a double-blind, randomised, placebo-controlled, parallel-group, single-centre trial. Lancet Gastroenterol Hepatol. 2018;3:17-24.
  17. Aroniadis OC, Brandt LJ, Oneto C, et al. Faecalmicrobiota transplantation for diarrhoea-predominant irritable bowel syndrome: a double-blind, randomised, placebo-controlled trial. Lancet Gastroenterol Hepatol. 2019;4:675-685.
  18. Johnsen PH, Hilpüsch F, Valle PC, Goll R. The effect of fecal microbiota transplantation on IBS related quality of life and fatigue in moderate to severe non-constipated irritable bowel: Secondary endpoints of a double blind, randomized, placebo-controlled trial. 2020;51:102562.
  19. Lahtinen P, Jalanka J, Hartikainen A, et al. Randomised clinical trial: faecalmicrobiota transplantation versus autologous placebo administered via colonoscopy in irritable bowel  Aliment Pharmacol Ther. 2020;51:1321-1331.
  20. El-Salhy M, Hatlebakk JG, Gilja OH, et al. Efficacy of faecal microbiota transplantation for patients with irritable bowel syndrome in a randomised, double-blind, placebo-controlled study. Gut. 2020;69:859-867.
  21. Holvoet T, Joossens M, Vázquez-Castellanos JF, et al. FecalMicrobiota Transplantation Reduces Symptoms in Some Patients With Irritable Bowel Syndrome With Predominant Abdominal Bloating: Short- and Long-term Results From a Placebo-Controlled Randomized Trial. 2021;160:145-157.
  22. Mazzawi T, Hausken T, Hov JR, et al. Clinical response tofecal microbiota transplantation in patients with diarrhea-predominant irritable bowel syndrome is associated with normalization of fecal microbiota composition and short-chain fatty acid levels. Scand J Gastroenterol. 2019;54:690-699.
  23. Goll R, Johnsen PH, Hjerde E, et al. Effects offecal microbiota transplantation in subjects with irritable bowel syndrome are mirrored by changes in gut microbiome. Gut Microbes. 2020;12:1794263.
  24. El-Salhy M, Valeur J, Hausken T, Gunnar Hatlebakk J. Changes infecal short-chain fatty acids following fecal microbiota transplantation in patients with irritable bowel  Neurogastroenterol Motil. 2020:e13983.

 

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 Consumer Blog, News /by KC

Benjamin 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’.

Since ISAPP board member Prof. Sarah Lebeer (University of Antwerp, Belgium) is a KVAB Belgian Young Academy alumna with microbiome knowledge, Bert Seghers from the Academy asked her to help draft a reply. However, since the gut microbiome is not her main area of expertise, she consulted her fellow ISAPP board members. For example, Bob Hutkins, author of a popular ISAPP blog post on intestinal gas, immediately sent her a paper entitled Identification of gases responsible for the odour of human flatus and evaluation of a device purported to reduce this odour with the comment: “The next time a graduate student complains about their project, refer them to this paper and the 5th paragraph of the methods”—a paragraph that describes how scientists in the experiment were tasked with rating the odor of flatus and differentiating between the different smells of sulphur-containing gases.

But it was the answer of Prof. Glenn Gibson (University of Reading, UK) that was incorporated into the ‘formal’ reply to Franklin’s suggestion. “Your suggested topic on improving flatulence odour is amusing, but indeed also very relevant. An outstanding answer to the contest as you formulate it would be ground-breaking,” wrote Profs. Lebeer and Gibson. They noted that gases in the intestine are mainly released by the bacteria living there—but especially the sulphate reducing bacteria contribute to the “traditional” smell due to their production of noxious H2S —and that advances in probiotic and prebiotic science could one day lead to reduced (and “nicer smelling”) gas production by switching hydrogen gas production to methane or even acetate and away from H2S.

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.

Growing interest in beneficial microbes and fermented foods in Argentina

/in Consumer Blog, ISAPP Science Blog /by KC

By Prof. Gabriel Vinderola PhD, Associate Professor of Microbiology at the Faculty of Chemical Engineering from the National University of Litoral and Principal Researcher from CONICET at Dairy Products Institute (CONICET-UNL), Santa Fe, Argentina

Awareness of gut microbes, fermented foods and probiotics has been on the rise in Argentina. Nutritionists and influencers, who in recent years have begun promoting a healthier lifestyle, are leveraging their social networks to post how-to instructions for making fermented foods, advice to promote a ‘healthier’ microbiota, and information on the potential role of probiotics and prebiotics in human health. But are these news items and recommendations based on science? Not always! I’ve been fortunate to have had the opportunity to make sure the science is correctly communicated to a broad audience on the microbiome, fermented foods, probiotics and prebiotics.

In Argentina, for the last 50 years, there has been on the air a TV show with a particular format: the hostess, Miss Mirtha Legrand, invites 4-6 people to have lunch every Sunday, talking about politics, economy, popular culture, arts and even science for 3 hours. According to her, this is the longest continuously running TV program in the world. Every Sunday several thousands of people from Argentina, Uruguay and Paraguay tune in. In October 2019, I was invited to join the table and to comment about the invisible world inside and around us. We discussed how we can profit from bacteria through fermented foods and probiotics, and how to feed our gut microbes with prebiotics. In fact, in 2019, I gave more than 40 talks on this topic to scientific audiences at conferences, as courses for Ph.D. students, as seminars and as workshops. These efforts are targeted not only to local scientists and students, but also to children in schools, local sport clubs in small towns, gyms and hospitals. The interest in friendly bugs is wide-ranging and varied, and fueled by information from radio and TV programs.

“Having lunch with Mirtha Legrand”, a talk show on television for more than 50 years in Argentina, where the discussion on beneficial microbes was brought to the table by Prof. Gabriel Vinderola (far right). Mirtha Legrand, now 93 years old, is in the center (October 3rd, 2019).

The enthusiasm of the audience was immediately evident. Lots of messages came by email, WhatsApp, Facebook or Instagram. People were anxious to know more, inquiring about trustworthy sources to read scientific-based but “easy-to-understand” material, posing specific questions about their gut feelings, where to get these probiotics and prebiotics or how to make fermented foods in a safe manner. Fortunately, the ISAPP infographics on probiotics and prebiotics were already available in Spanish, translated by Miguel Gueimonde (Spain) and me, and these were a welcome resource. Yet people still wanted more information, and asked more and more specific questions.

Spurred by such widespread interest, I contacted a local lawyer-turned-chef, Ana Milena Giacomini, who left behind her professional law career to open a small restaurant with a menu heavily based on fermented foods. She features such delights as home-made yoghurt, chucrut, kimchi, sugary kefir, fermented hummus, sourdough bread, pancakes made out of fermented rice flour, kombucha, kvass and a gasified drink from fermented ginger. With her, we organized 4-hour workshops, which are currently on hold due to COVID-19. These workshops feature Ana preparing some of these fermented foods live, followed by tasting, while I explain the science and microbiology behind them. I share factors related to the identity, safety, stability, and potential health effects of these products. I emphasize the differences between fermented foods and probiotics, while discussing the potential value of incorporating fermented foods, probiotics and prebiotics to the daily diet as a way to promote gut health. I provide more specific information on health effects for which robust meta-analyses are available to support the microbes’ use, such as prevention of antibiotic-associated diarrhea in children, treatment of infant colic, prevention of allergies, and downregulation of intestinal inflammation. Other workshops with different chefs from different locations in Argentina are in line for when the coronavirus pandemic ends.

Part of the four-course dinner containing fermented foods prepared by chef Martin Russo. The starter consisted of fermented carrots and hummus, served on sourdough bread (pictured).

These workshops are expected to be attended by 30-35 people each time. Nutritionists are interested in giving sound responses to their clients, who hear about these topics in the media or in social networks. But also, people come who want to learn how to make fermented foods, where to find probiotics and prebiotics, or to gain clear guidance on how to incorporate live bacteria to their diets. Other health professionals (gastroenterologists, pediatricians), educators and even people from the industry also attend.

 

The dessert was ice cream balls covered by the mother of vinegar (transparent circle on the top), rinsed and sweetened.

Most people interested in attending these workshops have narrow experience with fermented foods, only being familiar with such things as yoghurt, cheese, wine or beer. Some of them do not know that these foods are indeed fermented, or do not have a clear idea what fermentation is about. Most of them also have a very limited awareness, or even misinformation, about probiotics and prebiotics. These workshops offer the possibility for the curious to learn and to taste new foods, to get insights on the science behind fermented foods, probiotics and prebiotics, and to learn the differences between them in a science-based manner in an “easy-to-follow language”. These encounters are a great way to expand the interest by the general public on the invisible world inside and around us.

The past decade of probiotics and prebiotics research: ISAPP board members share their perspectives.

/in Consumer Blog, ISAPP Science Blog /by KC

By ISAPP board members, compiled by Kristina Campbell

Scientific progress in the field of probiotics and prebiotics, as in any other field, often seems to occur one tiny step at a time. Yet over the course of several years, these tiny steps can add up to significant progress.

Current members of the ISAPP board of directors hold academic positions across North America, and Europe, representing some of the experts at the forefront of scientific innovation in probiotics and prebiotics. Their collective experience encompasses functional foods, fermentations, microbial ecology, microbial genetics, immunology, and clinical medicine, including pediatrics, family medicine and gastroenterology. As we enter into 2020 and a new decade, these board members have taken a moment to reflect on how far they and their colleagues have come over the past ten years, by answering the question: What changes have occurred in the domains of research, applications, and awareness about probiotics and prebiotics?

ISAPP board members, 2019 annual meeting

Available scientific methods and tools

The change that stood out the most to the ISAPP board members over the past decade was the rapid expansion of available scientific methods and tools – from gene sequencing technology to CRISPR-Cas to bioinformatic approaches. These exciting developments have enabled scientists to obtain more information, and to do it both quickly and economically. In the words of the board members:

“Advances in sequencing technology [have] revolutionized our ability to understand the gene repertoire of each individual probiotic strain (whole genome sequencing) and the interplay with the microbiome (metagenomics). This has been really energizing to the field, but has also meant that competence in bioinformatics has become an essential tool for probiotic and prebiotic scientists.”

“A decade ago, human studies on prebiotics would look at changes in the gut microbiota using fairly laborious procedures. Nowadays, the analysis is much more extensive and straightforward to do, and probably more accurate… The biggest change has been the capability to assess not only composition of the microbiota but also its functionality. So, today, the trials include metabonomics as well as assessments of health effects (through changes in particular symptoms and /or biomarkers such as blood lipids, microbial products, immune and inflammatory status). That way, we get a far better picture of what prebiotics can do.”

“In 2010 we only had DGGE to characterize the genome and were trying to figure out how to implement 16S amplicon sequencing. Now we are implementing shotgun & shallow shotgun sequencing for similar prices. In 2010, we did only work on 3-4 probiotic lactobacilli for molecular research, now we work on 400-500 lactobacilli. We do comparative genomics and functional analyses at much larger scale. And in 2010, we paid almost 10000 euro just to sequence one genome of lactobacilli, with limited analysis, now a few hundred euro for sequencing.”

Probiotics and prebiotics for microbiome modulation

Because of the rapid advancements in scientific tools and techniques during the past decade, as mentioned above, many more research groups are endeavoring to study the microbial communities that relate to probiotics and prebiotics. Gut microbiota are of great interest—not least because, among the strategies for microbiome modulation, probiotics and prebiotics are two of the leading candidates. Moreover, microbiome data can help researchers understand the context of probiotics and prebiotics in the gut and in different environments. In particular, many clinical trials of probiotics and prebiotics now include a microbiota-related measure. Novel species and strains for food use may be identified from gut microbiota studies, although safety and efficacy assessment will form challenges for regulatory bodies. Board members said:

“My collaborators and I initiated our first human clinical trials with prebiotics in 2008 and published several papers in 2010 and 2011. These early papers were among the first in which high throughput 16S DNA sequencing was used to assess how the human gut microbiota was affected by the prebiotic, GOS. Although this is now a routine method in the field, in 2008, having a Roche 454 pyrosequencer in the lab was very special, and we were astounded to be able to identify and measure abundances of the main members of the gut microbiota. Having these large data sets also led us to realize the importance of what was at the time the “new” field of bioinformatics that was critical in analyzing and reporting the data. This research showed that GOS was bifidogenic (with high specificity) in healthy adults, but was also subject-dependent. Thus, the results clearly showed there were prebiotic responders and non-responders. This remains an important area of research for my group.”

“The decade started with general excitement that ‘dysbiosis’ of the gut microbiota is involved in just about every human health problem, and has turned into re-remembering that correlation is not causation and microbiota patterns are often driven more by random factors or factors unrelated to disease than by microbiology.”

“It’s worth noting that in 2020, the well-controlled probiotic studies showing health benefits in humans are still more convincing and valuable than the studies showing any ‘beneficial’ effects on the human microbiota.”

“Over the past decade we have witnessed a tremendous explosion in our understanding of the microbiome and its interactions with us, its host. Progress in translating this knowledge into new treatments has been slower but glimmers of encouragement have appeared and we look forward to the next decade when interventions that modulate the microbiome to benefit our health will be based on a true understanding of how they act and will be selected to the maximal benefit of each individual.”

Probiotic mechanisms of action

Probiotic mechanisms of action are a perennial hot topic within the scientific community—and many had hoped that the new suite of scientific tools at scientists’ disposal would significantly advance this area of research during the past decade. But according to one ISAPP board member:

“In 2010 I would have confidently predicted that by 2020 we would have much more of a mechanistic understanding of probiotic mechanisms [and] the importance of strain effects… But this simply has not happened.  The field has become more biologically and computationally complex and many millions have been spent on research, but I still don’t think we can answer the fundamental question we faced in 2010, and in 2000, and in 1990 – what makes one a strain a probiotic, while another is not?”

But in the views of other board members:

“Through genomic and metabolomic studies we are identifying differences between strains that function at different sites and what properties are important for their probiotic function.”

“Identify[ing] the key effector molecules turned out to be more complex [than] we thought 10 years ago. It has become clear to me that probiotic mechanisms of action are per definition complex and multifactorial, because they are living microbes having thousands of molecules that all play a role. Yet, there is clearly an hierarchy of effector molecules.”

Probiotic and prebiotic applications

In general, microbiome studies of the past decade have led to a better appreciation of the ubiquity and complexity of microbial communities—not just those associated with different human body sites, but also those occupying every possible niche on Earth. ISAPP board members reflect:

“In 2010, I was mainly studying probiotics for the gut and vagina, now we have explored probiotics for the skin, respiratory tract, animals, plants, isolates from fermented vegetables that can boost vegan probiotic formulations etc., and other areas.”

“Two areas of research I am doing I’d never have imagined in 2010 are in honey bees and Chinook salmon and against environmental chemicals, administering probiotics.”

Public awareness of probiotics and prebiotics

Numerous studies and surveys show the general public has more awareness than ever of probiotics – and increasingly, of prebiotics too. Individuals receive their information through many different channels, both digital (e.g. blogs, websites) and non-digital (e.g. magazines, product packaging). The past decade also saw the creation of valuable evidence-based resources, such as the Clinical Guides available in the US and Canada, and resources from World Gastroenterology Organisation and from ESPGHAN (probiotics for pediatric acute gastroenteritis, pediatric nosocomial diarrhea, preterm infants, and pediatric AAD). These resources have been enabled by a critical mass of studies that have examined the efficacy of various probiotic strains for certain indications. One board member says:

“From a clinical perspective, the biggest change for us has been that the general public knows so much about probiotics; now we are doing a lot less educating of docs and patients about the concepts behind our probiotic studies.”

But there’s still work to be done:

“The term probiotic is now widely known, but still too often people are misinterpreting what it means, or generalizing the whole field instead of recognizing strain and product differences. We need to continue to educate and clarify to keep the messaging on track.”

“There is still lack of knowledge that not all probiotics are equal. The clinical effects and safety of any single probiotic or combination of probiotics should not be extrapolated to other probiotics. The same applies to prebiotics.”

“Choosing a probiotic continues to be a major hurdle for the consumer – for every probiotic strain that is well characterized, studied in detail in appropriate disease models, and shown to be effective in clinical trials there are hundreds that would fail to pass even the most basic tests of quality control. We must help the consumer to make informed choices.”

 

It seems that, while the past decade has been a fruitful time for probiotics and prebiotics research and public awareness, scientists still have a lot of work to do. In the 2020s they will use the tools available to them, and continue to develop new ones, to gain more detailed and multi-faceted information about probiotic strains and prebiotic compounds—and about the context in which they operate (for instance, the gut microbiome), to ultimately confer benefits on human health.

Probiotics, Prebiotics and Globobiotics!

/in Consumer Blog, featured, ISAPP Science Blog /by ISAPP

By Prof. Colin Hill, PhD, APC Microbiome Ireland, University College Cork, Ireland

Growing up I could not imagine what the world would look like in 2020, but I was convinced it would be amazing. The future was exciting, new planets and solar systems would be explored, diseases would be cured, and everyone would have sufficient food and shelter.  I sometimes think my generation may have been born at the most perfect time in human history (for someone brought up in a first world country at any rate).  We avoided the major world wars which our parents and grandparents endured, we had the benefits of cheap airfares so we could travel the world as tourists, not as armies. Oil was cheap and plentiful. Access to education was widely available. We benefited from antibiotics while they were still effective.  Gender inequalities and racism began to be addressed, even though there is still a long way to go. Computers became commonplace and the internet provided access to almost unlimited sources of information.

But here we are in 2020, and now things do not look so promising. Perhaps cynicism is a natural by-product of getting older, but now the future seems to be presented in apocalyptic terms. Climate change, antibiotic resistance, ageing populations, the paradoxes of increasing obesity and increasing hunger, exploding populations, depletion of natural resources and pollution of our oceans. Watching nature programmes hosted by the incomparable David Attenborough has changed from generating a sense of awe at the wonders of the natural world to a sense of despair as to what we are doing to it. Australia is literally on fire as I write this!  Can our planet survive the onslaught of the projected 10 billion humans by 2050 – each one hungry for a share of finite resources?  Is this really going to be the legacy from my generation to the next – a dystopian future without hope and optimism?

But it’s a New Year and a new decade, and I really want to be hopeful. I am encouraged by the fact that we are gradually beginning to come to grips with this new reality. The UN Sustainable Development Goals provide a roadmap guiding societies and individuals as to how to make a contribution. Attitudes are changing.  Too slowly for sure, but we do seem to be at a tipping point.

But what has this tirade have to do with prebiotics and probiotics, you may ask? Well, everything of course. One of the things that really gives me hope is our growing understanding of how humans are simply occupying space in a microbial world. If we squander our opportunity and destroy our planet in terms of human habitation, microbes will carry on for billions of years to come. We should remember that we can only live on Earth because all of the oxygen we breathe is the result of billions of years of microbial metabolism, that most of the carbon cycling on earth is due to microbes, and that every natural system on Earth depends on microbes. Of course we are also inhabited by a vast ecosystem of microbes (our microbiomes) that are required for our health and wellbeing, and we live in environments shaped by microbes. Understanding this will help us to live in harmony with our microbial world, rather than constantly forcing our poor planet to deliver our short term needs.

How can microbes help us to achieve sustainability and restore a healthy ecosystem? I believe that there are many opportunities. By 2050 I predict that we will be using microbes to restore productivity to land damaged by excessive use and pollution.  We will be using microbes to clean our oceans of plastic waste. We will improve food production without using chemicals, and we will have certainly reduced food waste (it is estimated that one third of all the food we produce on earth is lost to spoilage, much of it caused by microbes). We will have reduced methane emissions by manipulating the rumen microbiome in domesticated ruminants. We can look forward to a world where we can work with microbes to restore and replenish our atmosphere by unlocking the enormous potential of microbes to scavenge and store carbon. We will have reduced our reliance on antibiotics and will have found microbiome-friendly solutions to prevent and treat infection. We will have developed probiotics and prebiotics that will help us to address metabolic diseases, we will be using bacteriophage to sculpt microbiomes, while psychobiotics will be helping to prevent age related loss of brain function.

Given that the world is a microbial ecosystem, I propose that in the same way we can treat our human ecosystems with prebiotics and probiotics to improve or restore health, we can think in terms of developing microbial solutions to improve or restore planetary health. Because we haven’t had one in at least a month, I propose yet another new term; globobiotics. Globobiotics would be defined as “live microorganisms, microbial products or substrates selectively utilized by microorganisms, that are used in a manner that contributes to the sustainability of our planet”.

We’ve had the Stone Age, the Iron Age, the Oil Age, the Atomic Age and the Information Age, welcome to the Microbial Age!

Those probiotics may actually be helping, not hurting

/in Consumer Blog, ISAPP Science Blog /by KC

By Mary Ellen Sanders PhD, Executive Science Officer, ISAPP, and Gregory B. Gloor PhD, Department of Biochemistry, Schulich School of Medicine and Dentistry, The University of Western Ontario, London

 

A recent Wall Street Journal essay posits that probiotics are harmful, but does so by misrepresenting probiotic and microbiome science in some important ways.

The focus of this essay was an anecdotal report showing that consuming probiotic products (the composition of which was not disclosed), as well as making other dietary modifications, was associated with lower fecal microbiota diversity. This equates, in the author’s mind, to an “unhealthier gut” and leads to the sensational article title “Those Probiotics May Actually Be Hurting Your ‘Gut Health’”.

How important is fecal microbiota diversity to gut health? There is no evidence in humans that increased gut microbiota diversity is causally linked to any better health outcome. In hunter-gatherer populations, the diversity of the gut microbiome cycles seasonally with diet, yet both the low and high diversity microbiomes are presumably equally ‘healthy’. Many different gut diseases are associated with microbiota compositions that differ from those from healthy subjects. But importantly, we don’t know if the different microbiota is the cause of or the result of the disease. So contrary to the author’s assertion, to speak of gut health is not to speak “really…about the gut microbiome”. Scientists don’t even know what a “healthy microbiome” looks like (see review here).

Perhaps more importantly, it is not at all surprising that consuming high numbers of a few probiotics would result in lower fecal microbial diversity. Probiotics typically survive intestinal transit and are observed in fecal samples when the microbiota is measured. A quirk of measuring the microbiome is that it is typically measured as relative abundance, and the thing about relative abundance is that as the number of one microbe goes up, others appear to decline. They don’t decline in absolute number, but their percentage of the total measured is reduced and hence our ability to detect them is also reduced. So, when you add probiotic microbes to your gut microbiota, and then measure the species present, the probiotic organisms appear at the expense of others. As illustrated in the figure, the probiotic species will appear to displace many rare species because the probiotic species comprise a high percentage of the total population. Although the other resident bacteria are all still there, they are more difficult to detect because they are now below the detection limit after probiotics were added to the community.

 

We are not aware of any evidence that probiotics will increase the diversity of fecal microbiota. In fact, based on the rationale above, we expect that probiotics may appear to decrease fecal microbiota diversity. Does that mean probiotics are harmful? No.

The author glosses over another weakness in his anecdotal report. He treats his fecal microbiota as if it is equivalent to his gut microbiota. Fecal samples represent a terminal microbial community with diminishing nutrients and many dead, but measurable, bacteria. This community is much different from what occurs farther upstream in the colon, and likely has little in common with small intestinal microbial communities. Granted, this is a weakness of much research on the gut microbiome, but discerning scientific reporting should call this what it is: fecal microbiota, not gut microbiome.

Are probiotics actually good for us? To answer this question, consult the literature that evaluates specific probiotics for the health outcome that interests you. Some good evidence exists for several clinical endpoints including antibiotic-associated diarrhea, reduced risk of C. difficile, treatment of colic in infants, reduced incidence in upper respiratory tract infections, and others (see review here).

We agree with one conclusion of the essay, that eating a diverse, whole-food, high-fiber diet likely promotes gut health. But there is nothing new about this recommendation and it seems hardly worth column space in the Wall Street Journal.

 

 

The small intestinal ‘mysteriome’: A potentially important but uncharted microbiome

/in Consumer Blog, ISAPP Science Blog /by KC

By Eamonn MM Quigley MD FRCP FACP MACG FRCPI, Lynda K and David M Underwood, Center for Digestive Disorders, Division of Gastroenterology and Hepatology, Houston Methodist Hospital, Houston, Texas, USA

 

Over recent years, countless publications have documented the status of the microbiota of the gastrointestinal tract by examining fecal samples. While this approach does provide a “snapshot” or representation of what is going on in the gut, and especially in the colon, it is a crude measure of the complex interactions between micro-organisms in the gut, as well as between these same microorganisms and us (their hosts). Fecal samples comprise a terminal microbial ecosystem, characterized by depletion of readily fermentable substrates, with a concomitant change in microbial composition, even compared to those farther upstream in the colon. It is unlikely, for example, that studies using fecal samples provide a full picture of what happens when bacteria (or other microorganisms) “talk” to the lining of the gut (the mucosa) or interact with the immune system of the intestine. Even less likely is that they provide any insights into bacterial populations in the small intestine, where most of the digestion of food and absorption of nutrients takes place. The small intestine also possesses the most abundant immune tissue of the entire gastrointestinal tract.

Yet, details of which bacteria actually inhabit this long and important organ, the small intestine, are sketchy. This lack of knowledge has apparently not restricted much theorizing and speculation about the role of an overgrowth of colonic-type bacteria (referred to as small intestinal bacterial overgrowth – SIBO) in the small intestine in many symptoms, disorders, and diseases. According to one especially popular theory – the “leaky gut” hypothesis – the list of conditions is nearly endless. The “leaky gut” hypothesizes that dysbiosis in the small intestine (in other words SIBO) and a disruption of the gut barrier leads to “leakage” of bacteria and bacterial products into the circulation causing inflammation, allergy, and autoimmunity.

There are several leaps of faith involved in “leaky gut” including, of course, the definition and diagnosis of SIBO. Traditional methods of diagnosing SIBO (obtaining fluid samples directly from the upper small intestine or a variety of breath tests) are fraught with problems and, in essence, have precluded a universally accepted definition of SIBO.

Fundamental to this dilemma is the definition of the normal small intestinal microbiome – how can we diagnose abnormal when we do not know the limits of normality? I would contend that, while there are situations where it is undoubted (based on the clinical context and various laboratory and other findings) that SIBO is an issue, there are countless more instances where SIBO is over-diagnosed and incorrectly implicated as the cause of an individual’s symptoms. This is an important issue as it can lead to the inappropriate use of antibiotics – something we all wish to avoid.

There is some good news – clever techniques exist for obtaining uncontaminated fluid samples from the small intestine, a capsule technology that permits live sampling of intestinal gases (generated by bacteria) as it traverses the intestine and the application, at last, of high-throughput sequencing, metagenomics, metabolomics, and metatranscriptomics to small intestinal microbiota suggest that the accurate definition of the normal small intestinal microbiome is not far off. At that time, we can all agree on an accurate and clinically meaningful definition of SIBO.

 

Prebiotics do better than low FODMAPs diet

/in Consumer Blog, featured, ISAPP Science Blog /by ISAPP

By Francisco Guarner MD PhD, Consultant of Gastroenterology, Digestive System Research Unit, University Hospital Vall d’Hebron, Barcelona, Spain

Bloating and visible abdominal distention after meals is a frequent complaint of people suffering from irritable bowel syndrome, but even generally healthy people sometimes have these complaints. These symptoms are thought to be due to fermentation of food that escapes our digestive processes. Some sugars and oligosaccharides end up at the far end of our small bowel and cecum, where they become food for our resident microbes.

To manage this problem, medical organizations recommend antibiotics to suppress the microbial growth in our small intestine (known as small intestinal bacterial overgrowth or SIBO) or avoidance of foods that contain fermentable oligosaccharides, disaccharides, monosaccharides and polyols, called a low “FODMAP” diet. These approaches are generally successful in reducing symptoms, but do not provide permanent relief: symptoms typically return after the strategies are stopped.

Even worse, both approaches are known to disrupt the entire gut microbial ecosystem (not only at small bowel and cecum). Whereas a healthy microbial gut ecosystem has many different types of bacteria, antibiotics deplete them.  The low FODMAP diet deprives beneficial bacteria (such as Faecalibacterium, Roseburia, Bifidobacterium, Akkermansia, Lactobacillus and others) of the food they like to eat, and these species wane (see here).

Prof. Glenn Gibson, a founding father of prebiotic and synbiotic science, suggested that increasing ingestion of certain prebiotics could increase levels of bifidobacteria. These bifidobacteria in turn could prevent excessive gas production since they are not able to produce gas when fermenting sugars.  (Instead, bifidobacteria product short chain fatty acids, mainly lactate, which are subsequently converted to butyrate by other healthy types of bacteria, such as Faecalibacterium and Roseburia.)

Prof. Gibson’s hypothesis was tested in pilot studies where volunteers ingested a prebiotic known as galacto-oligosaccharide (Brand name: Bimuno). Healthy subjects were given 2.8 g/day of Bimuno for 3 weeks. At first, they had more gas: significantly higher number of daily anal gas evacuations than they had before taking the prebiotic (see here). The volume of gas evacuated after a test meal was also higher. However, after 3 weeks of taking the prebiotic, daily evacuations and volume of gas evacuated after the test meal returned to baseline. The microbe populations also started to recover. The relative abundance of healthy butyrate producers in fecal samples increased and correlated inversely with the volume of gas evacuated. This suggested that the prebiotic induced an adaptation of microbial metabolism, resulting in less gas.

Then researchers launched a second study, also in healthy volunteers, to look at how the metabolic activity of the microbiota changed after taking this prebiotic. They showed that adaptation to this prebiotic involves a shift in microbiota metabolism toward low-gas producing pathways (see here).

A third controlled study (randomized, parallel, double-blind), this time in patients with functional gastrointestinal disorders with flatulence, compared the effects of the prebiotic supplement (2.8 g/d Bimuno) plus a placebo diet (mediterranean-type diet) to a placebo supplement plus a diet low in FODMAPs. The study subjects were divided between these 2 diets, which they consumed for 4 weeks (see here). Both groups had statistically significant reductions in symptom scores during the 4-week intervention. Once subjects stopped taking the prebiotic, they still showed improved symptoms for 2 additional weeks (at this point, the study was completed). However, for subjects on the low-FODMAP diet, once the diet was stopped, symptoms reappeared. Very interestingly, these 2 diets had opposite effects on fecal microbiota composition. Bifidobacterium increased in the prebiotic group and decreased in the low-FODMAP group, whereas Bilophila wadsworthia (a sulfide producing species) decreased in the prebiotic group and increased in the low-FODMAP group.

The bottom line conclusion is that a diet including intermittent prebiotic administration might be an alternative to the low FODMAP diets that are currently recommended for people with functional gut symptoms, such as bloating and abdominal distention. Since low FOD MAP diets are low in fiber, the prebiotic option may provide a healthier dietary option.

 

  1. Halmos EP, Christophersen CT, Bird AR, Shepherd SJ, Gibson PR, Muir JG. Diets that differ in their FODMAP content alter the colonic luminal microenvironment. Gut. 2015;64(1):93–100.
  2. Mego M, Manichanh C, Accarino A, Campos D, Pozuelo M, Varela E, et al. Metabolic adaptation of colonic microbiota to galactooligosaccharides: a proof-of-concept-study. Aliment Pharmacol Ther. 2017;45(5):670–80.
  3. Mego M, Accarino A, Tzortzis G, Vulevic J, Gibson G, Guarner F, et al. Colonic gas homeostasis: Mechanisms of adaptation following HOST-G904 galactooligosaccharide use in humans. Neurogastroenterol Motil. 2017;29(9):e13080.
  4. Huaman J-W, Mego M, Manichanh C, Cañellas N, Cañueto D, Segurola H, et al. Effects of Prebiotics vs a Diet Low in FODMAPs in Patients With Functional Gut Disorders. Gastroenterology. 2018;155(4):1004-7.

 

Additional reading:

Halmos EP, Christophersen CT, Bird AR, Shepherd SJ, Gibson PR, Muir JG. Diets that differ in their FODMAP content alter the colonic luminal microenvironment. Gut. 2015;64(1):93–100.

Mego M, Manichanh C, Accarino A, Campos D, Pozuelo M, Varela E, et al. Metabolic adaptation of colonic microbiota to galactooligosaccharides: a proof-of-concept-study. Aliment Pharmacol Ther. 2017;45(5):670–80.

Mego M, Accarino A, Tzortzis G, Vulevic J, Gibson G, Guarner F, et al. Colonic gas homeostasis: Mechanisms of adaptation following HOST-G904 galactooligosaccharide use in humans. Neurogastroenterol Motil. 2017;29(9):e13080.

Huaman J-W, Mego M, Manichanh C, Cañellas N, Cañueto D, Segurola H, et al. Effects of Prebiotics vs a Diet Low in FODMAPs in Patients With Functional Gut Disorders. Gastroenterology. 2018;155(4):1004-7.

Halmos EP, Gibson PR. Controversies and reality of the FODMAP diet for patients with irritable bowel syndrome. J Gastroenterol Hepatol. 2019 Jul;34(7):1134-1142. doi: 10.1111/jgh.14650. Epub 2019 Apr 4.

 

 

“A healthy woman, a healthy baby, a healthy generation” lessons learned from the 4th Annual Women and their Microbes Conference

/in featured, ISAPP Science Blog /by Mary Ellen Sanders

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

The 4th annual Women and their Microbes conference took place at the beginning of March celebrating the International Women’s day. The first-ever conference outside Europe in Hamilton, Canada brought together top scientists to discuss the importance of women’s health through the prism of women’s specific microbiomes. The theme of the conference was Microbiome Management in Pregnancy with a uniquely designed high-quality program translating the latest research into the clinical setting. I was honored to serve on the organizing committee for this meeting, and I provide highlights below.

Our health starts long before birth. The developing fetus receives information from the mother in the form of hormones and nutrients and uses these to predict the external environment. The fetus then uses this information to adapt its development to better its chances of survival after birth. However, the developing fetus can be “misinformed.” This happens through the maternal factors such as her use of drugs, stress, and diseases such as obesity and asthma. For example, both absolute maternal weight and weight gain during pregnancy affect microbiota development in infants (Carmen Collado et al., 2010). Maternal microbiota can also shape the immune system of the newborns. Therefore, keeping women on the right course before pregnancy and healthy during pregnancy must be a priority. This will later be translated into a healthier life for the infant through adulthood. Many of us associate healthy pregnancy with women taking the right nutrients and minerals such as folic acid, B12 vitamins, and iron and we are not wrong. But microbes also play an essential role in health. Microbes are a crucial factor providing nutrients, immune protection and regulating host physiology. Particular strains of Lactobacillus sp. and Bifidobacteria sp. can produce vitamin B12 and folic acid in the gut (Magnusdottir et al., 2015), which may be very beneficial during pregnancy. Of interest, this production increases when paired with prebiotics. Not only that, but microbes are increasingly recognized as important in reproduction, pregnancy, and development. Fertilization doesn’t happen in a sterile environment. Distinct bacterial communities are present in the female reproductive tract, but semen health and male fertility are also important (Weng et al., 2014). So don’t forget the “Y” in the equation – fathers also play a role in the health of their offspring. Gestational tissue microbes can also play an important role in development. More research is needed to better understand these microbiomes and the extent to which they can be influenced by maternal diet and health state.

What if the things go wrong – adverse pregnancy outcomes. Preterm birth is an ongoing challenge with rates steadily growing and with limited approaches for prevention. It results in 75% of neonatal morbidity and mortality. High numbers (55-80 %) of preterm births are associated with dysbiosis and a shift of the vaginal microbiota towards a more diverse state (Freitas et al., 2018). It seems likely that the vaginal microbiome can protect against adverse pregnancy outcomes. However, it appears that both antibiotics and probiotic therapy used to date are not effective at preventing preterm birth. “How to prevent adverse pregnancy outcomes?” is a million dollar question. We need a highly discriminatory diagnostic test that defines versions of ‘abnormal’ vaginal microbiomes. This test needs to be significantly associated with adverse health outcomes. The type of abnormal profile that results in preterm birth needs to be distinguishable from other possible ‘abnormal’ profiles. Such a diagnostic tool needs to be simple enough for a clinical environment and cost-effective. We need to have a safe intervention that can ‘treat’ or normalize a microbiome ideally preconception or early pregnancy.

Where do probiotics fit? Probiotics and prebiotics can enhance the nutrient status of the mother via increasing micronutrient and mineral absorption. During pregnancy, about 3.6% of North American women, 14% of The Netherlands women and 23% of Australian women consume probiotics. A lot of studies focus on the role of probiotics for preventing Group B Streptococcus infections, maternal obesities, postpartum depression, and mastitis. Although results are promising, more studies are needed to make clear conclusions and select the best strains for each condition. Importantly, currently used probiotics do not appear to pose safety concerns for pregnant and lactating women. Nevertheless, consumers’ knowledge regarding probiotics is not very precise. This confusion often may stem from a probiotic market with many different manufacturers, some of which are not legitimate, selling products that are not well defined, with very little clinical evidence. A major effort in educating clinicians, pharmacists and the consumers has been made by creating probiotic guidelines. Dragana Skokovic Sunjic has been working in the last ten years in publishing and updating the “probiotic chart.” The probiotic chart summarizes commercially available probiotic supplements or foods sold in Canada or the USA that have published clinical evidence for the particular strain(s) present in each product. Of note, for products containing multiple strains, evidence must be provided for the specified combination and not extrapolated from the evidence for the separate probiotic strains. At present these guidelines are used by primary care providers, specialists (pediatrics, GI), academic teaching hospitals, universities and others.

With the increasing number of microbiome studies, we are witnessing a paradigm shift in the scientific literature with more people focusing on the importance of microbes in human health. Women’s health is a cornerstone for successful reproduction, with important implications for the health of the next generation. Initiatives such as Women and their Microbes are crucial to link the science and medicine together to bring awareness within the healthcare and academic community.

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

/in featured, News /by Mary Ellen Sanders

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

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

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

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

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

See here for the full news article about the award.

Challenges ahead in the probiotic field – insights from Probiota2019

/in featured, ISAPP Science Blog /by Mary Ellen Sanders

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

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

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

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

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

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

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

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

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

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

/in featured, ISAPP Science Blog, News /by Mary Ellen Sanders

February 20, 2019

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

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

Prof. Gloor’s slides are available here.

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

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

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

Some suggestions for improving outcomes were offered:

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

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

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

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

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

Humpty Dumpty and the Microbiome

/in featured, ISAPP Science Blog /by Mary Ellen Sanders

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

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

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

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

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

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

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

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

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

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

 

  1. Hill et al., 2014. Expert consensus document: The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the scope and appropriate use of the term probiotic.  Nat. Rev. Gastroenterol. Hepatol. 11, 506.
  2. Gibson et al., 2017. Expert consensus document: The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics.  Nat. Rev. Gastroenterol. Hepatol. 14, 491.
  3. Sarkar et al., 2016. Psychobiotics and the Manipulation of Bacteria–Gut–Brain Signals.  Trends in Neurosciences 39, 763
  4. Marchesi JR and J. Ravel. 2015. The vocabulary of microbiome research: a proposal.  Microbiome 3, 31
  5. http://worldmicrobiomeday.com/glossary-of-microbiome-terms/

I have IBS – should I have my microbiome tested?

/in Consumer Blog, featured, ISAPP Science Blog /by Mary Ellen Sanders

By Prof.  Eamonn Quigley, MD. The Methodist Hospital and Weill Cornell School of Medicine, Houston

I am a gastroenterologist and specialize in what is referred to as “neurogastroenterology” – a rather grandiose term to refer to those problems that arise from disturbances in the muscles or nerves of the gut or in the communications between the brain and the gut.  Yes, the gut has its own nervous system – as elaborate as the spinal cord – which facilitates the two-way communication between the brain and gut.

The most common conditions that I deal with are termed functional gastrointestinal disorders (FGIDs) among which irritable bowel syndrome (IBS) is the most frequent. I have cared for IBS sufferers and been involved in IBS research for decades. But while much progress has been made, IBS continues to be a frustrating problem for many sufferers. No, it will not kill you, but it sure can interfere with your quality of life. Dietary changes, attention to life-style issues (including stress) and some medications can help but they do not help all sufferers all of the time. It is no wonder, therefore, that sufferers look elsewhere for relief. Because, symptoms are commonly triggered by food, there are a host of websites and practitioners offering “food allergy” testing even though there is minimal evidence that food allergy (which is a real problem, causes quite different symptoms and can be fatal) has anything to do with IBS. Nevertheless, sufferers pay hundreds of dollars out of pocket to have these worthless tests performed.

Now as I sit in clinic I am confronted by a new phenomenon – microbiome testing. I cringe when a patient hands me pages of results of their stool microbiome analysis. Has their hard-earned money been well spent? The simple answer is no. Let me explain. First, our knowledge of the “normal” microbiome is still in evolution so we can’t yet define what is abnormal – unless it is grossly abnormal. Second, we have learned that many factors, including diet, medications and even bowel habit can influence the microbiome.  These factors more than your underlying IBS may determine your microbiome test results.  Third, while a variety of abnormalities have been described in the microbiome in IBS sufferers, they have not been consistent. Someday we may identify a microbiome signature that diagnoses IBS or some IBS subgroups – we, simply, are not there yet. Indeed, our group, together with researchers in Ireland and the UK, are currently involved in a large study looking at diet, microbiome and other markers in an attempt to unravel these relationships in IBS.

There have been a lot of exciting developments in microbiome research over the past few years. One that has caused a lot of excitement comes from research studies showing that the microbiome can communicate with the brain (the microbiome-gut-brain axis). It is not too great a leap of faith to imagine how such communications could disturb the flow of signals between and brain and the gut and result in symptoms that typify IBS. We also know that some antibiotics and probiotics can help IBS sufferers. Indeed, about 10% of IBS suffers can date the onset of their symptoms to an episode of gastroenteritis (so-called post-infection IBS). All of this makes it likely that the microbiome has a role in IBS; what we do not know is exactly how. Is the issue a change in the microbiome? Is it how we react to our microbiome? Is it the bacteria themselves or something that they produce? Could our microbiome pattern predict what treatments we will respond to? These are fascinating and important questions which are being actively studied. In the meantime, I feel that microbiome testing in IBS (unless conducted as part of a research study) is not helpful.

 

Related Reading:

Microbiome analysis: hype or helpful?

Why microbiome tests are currently of limited value for your clinical practice

Here’s the poop on getting your gut microbiome analyzed

 

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

/in Consumer Blog, featured, ISAPP Science Blog /by Mary Ellen Sanders

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

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

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

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

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

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

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

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

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

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

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

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

Conference Focusing on the Microbiome in Women

/in featured, News /by Mary Ellen Sanders

By Prof. Gregor Reid, University of Western Ontario

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

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

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

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

See the program here.

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

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

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