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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.