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Episode 35: Investigating gut microbiome links to chronic diseases, with Dr. Purna Kashyap MBBS

/in Podcast, Season Three /by Laura

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In this episode, the ISAPP hosts discuss the gut microbiome’s role in chronic diseases with Dr. Purna Kashyap MBBS, from Mayo Clinic in Rochester, Minnesota, USA. Dr. Kashyap talks about how to discover the complex factors that trigger and perpetuate chronic diseases such as inflammatory bowel disease, zeroing in on the gut microbiome as a contributor to different aspects of gastrointestinal (GI) tract physiology.

Key topics from this episode:

  • Dr. Kashyap became interested in some of the initial studies linking the gut microbiome to chronic diseases around 2007-2008, and subsequently began to study the molecular mechanisms that underlie changes in GI tract physiology.
  • How can scientists figure out causality in chronic diseases and the role of gut microbes? Dr. Kashyap sees causality as an ongoing cascade of events in the GI tract, with no single causal factor. Both the initial triggers and the perpetuating factors can be considered part of what causes these diseases.
  • Microbes can help perpetuate a certain state in the host because once they establish themselves they serve to make the environment more conducive to their survival. In chronic diseases, the factor that triggers the microbial community configuration may not be as important as the factor(s) that perpetuate it on an ongoing basis.
  • The gut microbiome is changeable but not easy to change. Scientists need to know how the microbial community sustains itself and intervene there to change the community.
  • Even small microbiome studies can be informative if you look at who responds to the intervention and why. This information can be valuable for informing which treatments might work for which subgroups of people.
  • Dr. Kashyap encourages combining three types of research: large-scale studies on microbial metabolites and potential drug targets; clinical studies on the metabolites present in various subgroups; preclinical models studying the effects of individual metabolites.
  • Diet, microbes, and host uptake all contribute to the physiological effects of different metabolites. And for example, if a metabolite is low, knowing which microbes are present is not enough information to explain why it’s low.
  • In gastroenterology, clinicians primarily care about the gut microbiome in relation to the new treatments it makes possible. Now that FDA-approved treatments exist (standardized fecal microbiota transplants for recurrent C. difficile), clinicians may start paying more attention.
  • Does Dr. Kashyap recommend interventions to patients based on their gut microbiomes? A high-fiber diet is good for the gut microbiome and also for overall health, so he advises patients to adhere to dietary recommendations for their daily fiber intake.

Episode abbreviations and links:

Additional resources:

Why researchers need to understand more about the small intestinal microbiome. ISAPP blog.

About Dr. Purna Kashyap:

Dr. Purna Kashyap is practicing gastroenterologist and Professor of Medicine and Physiology, the Bernard and Edith Waterman Director of the Microbiome program, and Director of the germ-free mouse facility in the Center for Individualized Medicine at Mayo Clinic, Rochester, MN. The NIH funded Gut Microbiome laboratory led by Dr. Kashyap is focused on delineating the complex interactions between diet, gut microbiome, and host gastrointestinal physiology.  The laboratory uses germ-free mouse models in conjunction with measures of gastrointestinal physiology in vitro and in vivo to investigate effects of gut microbial products on host gastrointestinal function. In parallel, they use a systems approach incorporating multi-omics, patient metadata, and physiologic tissue responses in human studies, to aid in discovery of novel microbial drivers of disease. The overall goal of the program is to develop novel microbiota-targeted therapies. Dr. Kashyap has published nearly 100 peer reviewed articles including journals like Cell, Cell Host Microbe, Science Translational Medicine, Nature Communications, and Gastroenterology. He was inducted to American Society of Clinical Investigation in 2021. He has previously served on the scientific advisory board of American Gastroenterology Association Gut Microbiome Center, and on the council of American Neurogastroenterology and Motility Society. He now serves on the council and the research committee of AGA, in an editorial role for Gut Microbes and as an ad hoc reviewer on NIH study sections.

Episode 32: How microbes and mucus interact in the gut

/in Podcast, Season Two /by Laura

How microbes and mucus interact in the gut, With Dr. Mindy Engevik PhD

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How microbes and mucus interact in the gut, With Dr. Mindy Engevik PhD

Episode summary:

In this episode, the ISAPP hosts discuss mucus-microbe interactions in the digestive tract with Dr. Mindy Engevik PhD from the Medical University of South Carolina, USA. They discuss how mucus in the gut is produced and degraded, and different ways that pathogens and commensal microbes interact with the mucus layer. Dr. Engevik describes some different ways that commensal bacteria make use of mucus, as well as dietary influences on gut mucus production.

Key topics from this episode:

  • The gut epithelium has special cells called goblet cells that actively secrete mucus. In the small intestine, mucus forms a light barrier but in the colon, it forms a thicker barrier with two layers: an inner layer free of microbes, and an outer layer where mucus and microbes coexist.
  • Bacteria in the gut make use of mucus in different ways. Many microbes have the capacity to degrade mucus, and it can provide a carbon source for bacteria to survive. Even bacterial quorum sensing can be influenced by mucus.
  • Bifidobacteria increase mucus production. Akkermansia are good at degrading mucus and also increasing mucus production. Pathogens, however, degrade the mucus and cause inflammation so mucus production is suppressed.
  • Several human diseases involve a dysfunctional gut mucus layer – for example, inflammatory bowel disease.
  • Various models are used for studying mucus – for example, traditional cell lines and human intestinal organoids.
  • Dr. Engevik’s work has found interactions between Clostridioides difficile and Fusobacterium nucleatum in the gut: these bacteria can interact to form biofilms that are more antibiotic-resistant than normal.
  • Individual differences exist in gut microbes as well as glycan structure in the gut, so the best insights will likely come from understanding the entire network of microorganisms, metabolites, and mucus. 
  • Dietary components influence the gut microbiota, which influences mucus production in the gut. High dietary fiber increases the amount of mucus produced by the goblet cells. Some bacteria degrade dietary substrates, then switch over to mucus when they don’t get what they need from the diet.
  • Dr. Engvik is an avid science communicator and advocates for scientists being present on social media. She has found science communication a great way to engage with the public as well as fostering scientific collaborations. The Instagram account showing microscopy images from her lab is @the_engevik_labs

Episode links:

About Dr. Mindy Engevik PhD:

Mindy Engevik is an Assistant Professor at the Medical University of South Carolina. She has Ph.D. in Systems Biology & Physiology and an interest in microbe-epithelial interactions in the gastrointestinal tract. Her lab focuses on how commensal friendly bacteria in the human gut interact with intestinal mucus and she tries to leverage this information to treat intestinal disorders. You can follow her on Twitter at @micromindy.

Episode 31: Microbial species and strains: What’s in a name?

/in Podcast, Season Two /by Laura

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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 Prebiotics (ISAPP), a nonprofit scientific organization dedicated to advancing the science of these fields.

Microbial species and strains: What’s in a name? with Dr. Jordan Bisanz PhD

Episode summary:

In this episode, the ISAPP podcast hosts speak with Dr. Jordan Bisanz PhD, Assistant Professor of Biochemistry and Molecular Biology at Penn State University in State College, USA. They discuss how to define a bacterial strain, the diversity of strains within a species, and how genetic differences correspond with functional differences. They also talk about manipulating microbial communities for insights about health and disease.

Key topics from this episode:

  • Dr. Bisanz says just because strains within a species are genetically related doesn’t mean they do the same things. Bacteria gain and lose genes rapidly, but we don’t yet know what a lot of those genes do.
  • Natural variation in strains can be used as a tool to find out the functions of genes. 
  • Metagenomics illuminates strain-level differences, but that assumes we know what makes a strain. There’s no single accepted definition of a strain.
  • Knowing the mechanisms behind the effects of a strain on a host is important for predicting if closely related strains will have the same effect.
  • Moving forward, it could be useful to have functional information to go along with strains and their taxonomic descriptors.
  • Dr. Bisanz’s lab tests experimentally how microbial genes are gained and lost in vivo, both through wetlab experiments and computational approaches.
  • Experiments on strains are essential – for example, two strains with differences in 1000 SNPs might be functionally the same, while differences in 2-3 key SNPs might make a big difference.
  • When testing probiotic effects, you may be testing something derived from the original microbial genome but not identical. How can this be managed in industry? Understanding the mechanisms is important, strains that function similarly can qualify as the same strain.
  • A microbiome involves multiple microbes working together, acting differently from all the strains in isolation.
  • Dr. Bisanz studies tractable microbial communities: find the microorganisms that are different in a disease state compared to a healthy state, and create a synthetic community of the microbes that are absent. What are the functions of this community?
  • The challenge is that microbiologists need to be able to manipulate the microbes but cannot do this in a whole human fecal sample.
  • Is gut microbiome sequencing useful? At the level of individual, it may not provide value. But putting the data all together, in the future it may provide interesting information. The challenge with interpretation is that the microbiome is driving, but also responding to, dietary inputs.
  • In the microbiome field, gnotobiotic models (using humanized mice) need to be taken a step further than they currently go – specifying not only which microbes established in the host, but also how they could plausibly affect the mechanism.

Episode abbreviations and links:

Additional resources:

About Dr. Jordan Bisanz PhD:

Jordan Bisanz is an assistant professor of Biochemistry and Molecular Biology at the Pennsylvania State University and the One Health Microbiome Center. The Bisanz lab combines computational analyses and wet lab experimentation to understand how gut microbes interact with each other and their host. The lab specializes in coupling human intervention studies with multi ‘omics approaches and gnotobiotic models to understand how host-microbe interactions shape health generating both mechanistic insights and translational targets.

Episode 30: A systems biology perspective on the gut microbiome

/in Podcast, Season Two /by Laura

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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 Prebiotics (ISAPP), a nonprofit scientific organization dedicated to advancing the science of these fields.

A systems biology perspective on the gut microbiome, with Dr. Sean Gibbons PhD

Episode summary:

In this episode, the ISAPP hosts discuss the microbiome and systems biology with Dr. Sean Gibbons PhD, Associate Professor at the Institute for Systems Biology in Seattle, USA. Prof. Gibbons talks about exploring and manipulating the complex ecology of the microbiome with the aim of engineering outputs of this system. He describes the utility of artificial intelligence in microbiome science and how the microbiome will play a role in personalized medicine in the future, including in the delivery of probiotics and prebiotics.

Key topics from this episode:

  • Dr. Gibbons’ lab primarily focuses on designing bioinformatic tools for exploring and manipulating the complex ecology of the microbiome, and trying to shape the outputs of the system. He emphasizes the need for computational tools alongside traditional microbiological techniques, which are needed to validate computational findings.
  • From the work so far, he says probiotics appear to be efficacious but context-specific, so the effects may appear dampened in trials with heterogeneous participants.
  • He underlines that artificial intelligence (AI) is needed to integrate complexity and predict emergent outputs of a biological system that includes a microbiome. Reductionist approaches are somewhat limited because each component of a complex system may behave differently on its own.
  • Diet is a key way to deliberately manipulate the gut microbiome. Researchers are working on how to push the system in a predictable direction. One approach is to create orthogonal niches for organisms: for example, an item in the diet (such as seaweed) that could support an organism that wouldn’t otherwise be there. His lab is working on tools that predict the likelihood of engraftment of a particular organism in a complex community.
  • Reliable tools are needed to map taxonomic composition onto functional outputs.
  • Two branches existed in the history of AI: (1) extracting new knowledge using approaches such as neural nets, and (2) A symbolic AI family of modelling, in which you already have knowledge and you can use it to make predictions about a system (making use of knowledge graphs).
  • Dr. Gibbons says microbiome measurements will likely be a part of clinical medicine in the future, because the microbiome accounts for individuals’ personalized responses to some interventions that cannot be explained by any other known factor.
  • In the future, we will be able to develop tools for precision prebiotic, probiotic, and dietary interventions through metabolic modelling work. 
  • Many probiotics have great efficacy in a particular context – so one challenge ahead is to find a rational way to deploy these organisms and to prove they work well. We will need to address the regulatory challenges inherent in personalized approaches as well.

Episode links:

About Dr. Sean Gibbons PhD:

Sean Gibbons earned his PhD in biophysics from the University of Chicago in 2015. He completed his postdoctoral work at MIT in 2018. Sean is now an associate professor at the Institute for Systems Biology, in Seattle. His lab studies the ecology and evolution of microbial communities. In particular, Sean is interested in how host-associated bacterial communities influence the health and wellness of the host organism. His group designs computational and wet-lab tools for studying these complex systems. Ultimately, the Gibbons Lab aims to develop strategies for engineering the ecology of the gut microbiome to improve human health.

Episode 23: Studying microbial ecosystems and how they support health

/in Podcast, Season Two /by Laura

 

Podcast: Play in new window | Download

Subscribe: Apple 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 Prebiotics (ISAPP), a nonprofit scientific organization dedicated to advancing the science of these fields.

Studying microbial ecosystems and how they support health, with Prof. Emma Allen-Vercoe PhD

Episode summary:

In this episode, the ISAPP podcast hosts talk about microbial ecosystems with Prof. Emma Allen-Vercoe PhD from the University of Guelph in Canada. Prof. Allen-Vercoe describes how her lab brings together information from microbial sequencing and culturing to learn about the human gut microbiome and how it supports health. She discusses what we know about the industrialized gut microbiome and possible ways to improve health by manipulating it.

Key topics from this episode:

  • What the microbiome is and the suite of tools that are typically used to study it.
  • Allen-Vercoe does both sequencing and culturing in her lab as well as metabolomics, proteomics, and transcriptomics to discover on a molecular level at what the microbes are doing. They have a model system called “Robogut” to study microbial ecosystems.
  • Culturing is still crucial and it’s important for trainees in microbiology to gain experience culturing organisms that are less straightforward to grow. The late Sydney Finegold inspired others to try culturing more challenging microorganisms.
  • The challenge of culturing is matching the techniques in the lab to what happens in nature when it grows. Her lab builds metagenome-associated genomes to be able to predict the particular substrates that a certain microbe needs to grow.
  • The “missing microbes” hypothesis is that the human microbiome has been depleted over a few generations in people from industrialized societies, and this correlates with an increase in chronic diseases.
  • The Yanomami people from South America have very diverse gut microbiomes and they share certain species with other non-industrialized societies very distant from them around the world, which are not found in industrialized populations. People in industrialized societies are never exposed to these microbes, but even if they were, the microbes might not stick around because the substrates needed to sustain them  (e.g. through the diet) are absent. 
  • The industrialized microbiome is not necessarily ‘bad’ but we do have to find out more about whether the lack of certain microbes has health effects. This is possible through the Robogut system, which can perturb microbial ecosystems and look at their behavior without affecting people’s health.
  • Fecal transplants have limitations, so they’ve started to work on therapeutic ecosystems. These are “clean” or defined ecosystems that can be administered therapeutically.

Episode links:

About Prof. Emma Allen-Vercoe PhD:

Emma obtained her BSc (Hons) in Biochemistry from the University of London, and her PhD in Molecular Microbiology through an industrial partnership with Public Health England. Emma started her faculty career at the University of Calgary in 2005, with a Fellow-to-Faculty transition award through CAG/AstraZeneca and CIHR, to study the normal microbes of the human gut. In particular, she was among the few that focused on trying to culture these ‘unculturable’ microbes in order to better understand their biology. To do this, she developed a model gut system to emulate the conditions of the human gut and allow communities of microbes to grow together, as they do naturally. Emma moved her lab to the University of Guelph in late 2007, and has been a recipient of several Canadian Foundation for Innovation Awards that has allowed her to develop her specialist anaerobic fermentation laboratory further. This has been recently boosted by the award of a Tier 1 Canada Research Chair in Human Gut Microbiome Function and Host Interactions. In 2013, Emma co-founded NuBiyota, a research spin-off company that aims to create therapeutic ecosystems as biologic drugs, on a commercial scale. The research enterprise for this company is also based in Guelph.

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.

What do we mean by ‘conferring a health benefit on the host’?

/in Consumer Blog, ISAPP Science Blog /by KC

By Prof. Colin Hill, University College Cork, Ireland

Four of the Consensus definitions produced by ISAPP in recent years (see 1-4 below) finish with a similar wording, insisting that probiotics, prebiotics, synbiotics and postbiotics must “confer a health benefit on the host”. This proviso was included to explicitly reinforce the fact that the raison d’etre for these interventions is that they must demonstrably improve host health. It would perhaps be wise to just stop there and leave the interpretation of what this really means to each individual reader. But that would not make for a very long blog and I am not very wise. Furthermore, it is useful to be more precise for scientific and regulatory purposes. At least two aspects seem to be open to elaboration; what is meant by ‘host’ and what is a ‘health benefit’? I will base my thoughts on the probiotic definition, but the logic should apply equally to all four health-based definitions.

Host. According to the Google dictionary a host is ‘an animal or plant on or in which a parasite or commensal organism lives’. This means there are millions of potential host species on our planet, something that could potentially create confusion. For example, if a well characterised microbe (or microbes) is shown to provide a measurable health benefit when administered in adequate amounts in a murine model (the host) then it clearly meets the stated definition of probiotic. But only for mice! It should not be referred to as a probiotic for other species, including humans, solely based on murine evidence. This creates a situation where the same microbe can clearly meet the criteria to be a probiotic for one host but not for another. This is not simply semantics; it is of vital importance that it should not be assumed that health benefits confirmed in one host will also be realised in another without supporting evidence. Since the majority of discussions of probiotics address human applications, it may serve all stakeholders well – even if not directly mandated by the definition – if the word ‘probiotic’ was only used without qualification for microbes with measurable benefits in humans while all others should be qualified with the target host; ‘equine probiotic’, ‘canine probiotic’, or even ‘plant probiotic’.

Health benefit. Health is of course a continuum from a desirable but almost certainly unattainable state where every organ is performing optimally (something I will term ‘ideal health’) to a point where death is imminent (that I will term ‘poor health’). Of course, health is multidimensional and far more complex than a straight line between ‘ideal’ and ‘poor’ but for simplicity I will treat it as such. If we place ideal health on the left end of our straight line and poor health at the right end, then obviously any shift towards the left can be considered a health benefit. It could even be reasonably argued that if someone is gradually progressing from left to right down our imaginary line (for example, as we age) then halting or slowing down that progression could also be considered a health benefit. From this perspective every individual (not just the unwell) could potentially derive a health benefit from a probiotic, prebiotic, synbiotic or postbiotic.

The issue of cosmetic benefits is more nuanced. If an intervention improves someone’s appearance (or reduces body odour for example) it might not be considered a health benefit per se, but of course it could well have a beneficial effect on an individuals’ mental health. I will leave it to the psychologists and psychiatrists to determine how this could be convincingly demonstrated.

There is also the issue of production characteristics where the host is a food animal or a crop. If a microbial-based intervention leads to faster growth rates and increased yields should this qualify as a health benefit? My own opinion is if the intervention leads to higher productivity by preventing infections it could be considered a health benefit, but not if it simply leads to faster growth rates by improving feed conversion for example.

Can changing the microbiome be considered a health benefit? A trickier question is whether a direct effect on the microbiome could be considered as a health benefit? Every host has a microbiome of a particular configuration, richness, and diversity. I don’t think we are yet at a point where measurable changes in these general indices of microbiome composition can be termed a health benefit in the absence of a link to a more established health outcome. The consequence of any change will be microbiome-specific in any event; a reduction in diversity in the vaginal microbiome might be desirable, whereas an increase in diversity in the gut microbiome might well be considered beneficial. But what if we can measure a reproducible reduction in a specific pathobiont like Clostridioides difficile, or an increase in a microbe that is associated with good health such as Bifidobacterium? In my opinion we are arriving at a point where we can begin to refer to these impacts as a health benefit. This will become more and more relevant as we establish direct causal links between individual commensal microbes and health outcomes. Equally, an intervention that preserves microbiome structure during a disruption (e.g. infection or antibiotic treatment) could also be considered as beneficial. I don’t know if regulators are yet at the point of accepting outcomes such as these as direct health benefits, but I believe a strong case can be made.

To finish, I believe that it is a very exciting time for all of us in the field of probiotics, prebiotics, synbiotics and postbiotics, but it is really important that all of this important science is not compromised by loose language or by literal interpretations that adhere to the letter of the definitions but not to the intent. If you want to fully understand the intent of the definitions, I encourage you to read the full text of the consensus papers.

 

  1. https://doi.org/10.1038/nrgastro.2014.66
  2. https://doi.org/10.1038/nrgastro.2017.75
  3. https://doi.org/10.1038/s41575-020-0344-2
  4. https://doi.org/10.1038/s41575-021-00440-6

Is probiotic colonization essential?

/in Consumer Blog, ISAPP Science Blog /by KC

By Prof. Maria Marco, PhD, Department of Food Science & Technology, University of California, Davis

It is increasingly appreciated by consumers, physicians, and researchers alike that the human digestive tract is colonized by trillions of bacteria and many of those bacterial colonists have important roles in promoting human health. Because of this association between the gut microbiota and health, it seems appropriate to suggest that probiotics consumed in foods, beverages, or dietary supplements should also colonize the human digestive tract. But do probiotics really colonize? What is meant by the term “colonization” in the first place? If probiotics don’t colonize, does that mean that they are ineffective? In that case, should we be searching for new probiotic strains that have colonization potential?

My answer to the first question is no – probiotics generally do not colonize the digestive tract or other sites on the human body. Before leaping to conclusions on what this means for probiotic efficacy, “colonization” as defined here means the permanent, or at least long-term (weeks, months, or years) establishment at a specific body site. Colonization can also result in engraftment with consequential changes to the gut microbiota composition and function. For colonization to occur, the probiotic should multiply and form a stably replicating population. This outcome is distinct from a more transient, short-term (a few days to a week or so) persistence of a probiotic. For transient probiotics, it has been shown in numerous ways that they are metabolically active in the intestine and might even grow and divide. However, they are not expected to replicate to high numbers or displace members of the native gut microbiota.

Although some studies have shown that digestive tracts of infants can be colonized by probiotics (weeks to months), the intestinal persistence times of probiotic strains in children and adults is generally much shorter, lasting only few days. This difference is likely due to the resident gut microbiota that develops during infancy and tends to remain relatively stable throughout adulthood. Even with perturbations caused by antibiotics or foodborne illness, the gut microbiome tends to be resilient to the long-term establishment of exogenous bacterial strains. In instances where probiotic colonization or long-term persistence was found, colonization potential has been attributed more permissive gut microbiomes specific to certain individuals. In either case, for colonization to occur, any introduced probiotic has to overcome the significant ecological constraints inherent to existing, stable ecosystems.

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

This leads to the next question: Can probiotics confer health benefits even if they do not colonize? My answer is definitely yes! Human studies on probiotics with positive outcomes have not relied on intestinal colonization by those microbes to cause an effect. Instead of colonizing, probiotics can alter the digestive tract in other ways such as by producing metabolites that modulate the activity of the gut microbiota or stimulate the intestinal epithelium directly. These effects could happen even on short-time scales, ranging from minutes to hours.

Should we be searching for new probiotic strains that have greater colonization potential? By extension of what we know about the resident human gut microbiota, it is increasingly attractive to identify bacteria that colonize the human digestive tract in the same way. In some situations, colonization might be preferred or even essential to impacting health, such as by engrafting a microbe that performs critical metabolic functions in the gut (e.g. break down complex carbohydrates). However, colonization also comes with risks of unintended consequences and the loss of ability to control the dose, frequency, and duration of exposure to that particular microbe.

Just as most pharmaceutical drugs have a transient impact on the human body, why should we expect more from probiotics? Many medications need to be taken life-long in order manage chronic conditions. Single or even repeated doses of any medication are similarly not expected to cure disease. Therefore, we should not assume a priori that any observed variations in probiotic efficacy are due to a lack of colonization. To the contrary, the consumption of probiotics could be sufficient for a ripple effect in the intestine, subtly altering the responses of the gut microbiome and intestinal epithelium in ways that are amplified throughout the body. Instead of aiming for engraftment directly or hand-wringing due to a lack of colonization, understanding the precise molecular interactions and cause/effect consequences of probiotic introduction will lead to a path that ultimately determines whether colonization is needed or just a distraction.