Posts

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

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.

 

The science on gut microbiota and intestinal gas: Everything you wanted to know but didn’t want to ask

By Kristina Campbell, science and medical writer

Even on the days when you don’t eat a large meal of Boston baked beans, the inside of your intestines is a gas-generating factory. This serves a valuable purpose for the body when everything is working as it should, with gases being produced and eliminated through a complex set of physiological processes. But sometimes gas becomes a problem—and this is when it’s valuable to know not only what contributes to intestinal gas symptoms, but also how dietary adjustments can alleviate some of the problems.

Dr. Fernando Azpiroz, Chief of Gastrointestinal Research at the Vall d’Hebron Research Institute and Professor of Medicine, Autonomous University of Barcelona (Spain), is an expert in both the pathophysiology of the gas produced in the digestive tract and the clinical problems related to intestinal gas. Dr. Azpiroz is the author of a chapter on intestinal gas in the well-known textbook, Sleisenger and Fordtran’s Gastrointestinal and Liver Disease, which is now in its 10th edition. And for more than 20 years he has been conducting research on digestive tract function, intestinal gas, and the contributions of the gut microbiota.

ISAPP caught up with Dr. Azpiroz to ask him about everything you wanted to know—where intestinal gas comes from, when it becomes a problem, and the latest research on the dietary changes that can reduce symptoms of intestinal gas while keeping the gut microbiota intact.

In different parts of the digestive tract, where does intestinal gas come from?

For the most part, the gas in the digestive system comes from metabolic activities of the colonic microbiota.

In addition, some air enters the stomach during swallowing. Most of this air is eliminated by eructation (i.e. burping), so there is a homeostasis. There is a small air chamber in the stomach of about 20 mLs, and this is pure atmospheric air, or CO2 after recent consumption of carbonated drinks.

In the small intestine, the neutralization of acids and alkali can theoretically produce large amounts of CO2. However, it’s more in theory than measured in experimental conditions.

Other gases originate from the metabolism of the gut microbiota. The residues of the diet that are not absorbed in the small bowel pass into the colon. These are the parts of the diets that we, as humans, cannot use. These pass into the colon, and in the colon serve as substrates for colonic microbiota. Gas is produced during this process of colonic fermentation.

What types of gases are produced in the digestive tract?

The composition of intestinal gas depends on where in the gut it is produced.

In the stomach, the gas is virtually all atmospheric air or CO2.

In the small bowel, theoretically it should be CO2, although the hard data are very scarce.

And in the colon, the largest component is likely hydrogen and CO2. But the data on that are very limited, and it is not known for sure that these theories are really true. The measurements of gas composition, in the colon or even in the gas eliminated per anus are still uncertain but so far the main concept is that most of the gas is hydrogen and CO2, and methane in subjects that have a methanogenic microbiota.

How does this gas normally get eliminated?

Throughout the GI tract, particularly the colon, about 80% of the gases produced are absorbed through the mucosa, pass into the blood, and are eliminated by breath. So only about 20-25% of the volume of gases produced, particularly in the colon, are eliminated per anus.

What influences the amount of gas produced?

The amount of gas produced in different subjects depends on two factors: one is the diet—the amount of residues (i.e. fiber) in the diet—and the second is the type of microbiota, which is very individual. It varies a lot from one subject to another.

How much intestinal gas is ‘too much’?

From the point of view of patients, of symptoms, what might be relevant is the volume of gases produced, and possibly the type of gases. One evolving idea is that some gases, which are produced in very small quantities, might serve as neurotransmitters, might play a role, but so far the information we have about the role of these gases is very limited so we cannot extrapolate that to clinical use.

Very recent data indicate that symptoms occur when the GI tract has a poor tolerance to its contents, and particularly to gas.

So what is the factor that makes gas produce symptoms? Well there are two factors. One is the amount of gas, and the other one is the tolerance of the subject.

In healthy subjects, it will typically take a large amount of gas to develop symptoms, if at all.

But even small amounts of gas in patients that have a hypersensitivity of the gut and poor tolerance to contents might contribute to their symptoms. This can be seen because, if we reduce the amount of flatulogenic substances in their diet, the symptoms reduce.

This is if we just take into consideration the volume of gas produced, but there is also another factor.

If we give a high flatulogenic diet or a high-residue diet, we know, because we have measured, that we increase the volume of gas produced into the colon. However, we also increase the amount of the fecal content in the colon. So it could be that these diets produce symptoms because they increase the amount of gas, but also because other non-gaseous components, the fecal content of the colon, also are poorly tolerated.

How can someone manipulate their diet to change the amount of intestinal gas that’s produced?

A ‘challenge’ diet, or a high flatulogenic diet in healthy subjects, makes them sick. They go from being symptom-free to having some symptoms, particularly flatulence and bloating.

In patients, the effect of the diet is more accentuated. If patients consume a diet with high residues they get very symptomatic, and if these patients will reduce residues in the diet, they see quite an improvement.

What are the options for dietary change when someone has IBS or wants to reduce gas symptoms?

One thing that has been shown recently is that the effect of a low-residue diet is similar regardless of the type of diet. In the past ten years or so there’s been a major trend with the use of low-FODMAP fermentable oligo-, di-, mono-saccharides and polyols diets.

However, the effect of these complex diets is not better than the effect of any sensible and simple low-residue diet. So if you reduce legumes, veggies from the diet, and fruits, you get a similar improvement.

The problem with low-residue diets, in particular the low-FODMAP diet, is that they introduce a restriction of the substrates for the feeding of the microbiota, and this is deleterious to the microbiota. The microbiota is impoverished.

The other limitation of low-residue diet is that the moment that the patient returns to a normal diet, the symptoms come back.

There is an alternative that has been shown in the past few years, which is to use some type of prebiotics that initially—because they are fermented—produce symptoms, but after a few days they induce an adaptation of the microbiota towards a microbiota that produces less gas with normal fermentation. And down the road, these prebiotics have a positive effect on symptoms in patients. As a matter of fact, the effect on symptoms is similar to a restrictive diet. The advantage of the prebiotics is that, after interruption, …the effect is sustained at least over a few weeks. And this is because it has been shown that prebiotics serve as substrates for microbiota and induce a proliferation of beneficial organisms.

There is also some preliminary evidence that some probiotics reduce the volume of gas production and reduce digestive symptoms in patients.

Is it a good idea to test your gut microbiota when you have IBS or gas symptoms?

There are different companies that claim that by analyzing microbiota they can diagnose some functional conditions, for instance IBS. The practical application of this technology has not been demonstrated. Usually they are expensive techniques and of no value.

It’s important to understand the real value of these methodologies and take the myth out of ‘wonder’ techniques that make a diagnosis from the microbiota and claim it explains everything.

Hopefully, this might be true in the future, but not right now. And actually many of the technologies that are used for this type of analysis are suboptimal.

 A previous blog post by Dr. Bob Hutkins on diet, gut microbiota, and intestinal gas is ISAPP’s most-read blog post of all time. Read it here.

I have IBS – should I have my microbiome tested?

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 with despair 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.

If you are interested in our research study please contact me at equigley@nullhoustonmethodist.org

 

Related Reading:

Microbiome analysis: hype or helpful?

A clinician’s guide to microbiome testing

Here’s the poop on getting your gut microbiome analyzed