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A systems biology approach to irritable bowel syndrome


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A systems biology approach to irritable bowel syndrome

  1. 1. Roundoc Rx A Systems Biology Approach to Irritable Bowel Syndrome Robert Rountree, MD For far too long irritable bowel syndrome (IBS) has been viewed by conventional doctors as a purely functional disorder. For years, mainstream textbooks typically characterized IBS as a psychosomatic process in which erratic neuronal signals sent from the brain to the gut resulted in the mix of physical symptoms that include diarrhea, constipation, and abdominal pain. The diagnosis has mainly been one of exclusion in which IBS was the wastebasket term used to describe what was left after “real” diseases were ruled out. Given that, at that time, there was no known biologic cause of the disorder, the goal of treatment was symptom control, and the path to cure was alleviating patients’ nervous tendencies. In other words, it was thought that, if the person could just calm down and become less neurotic, his or her IBS symptoms might just go away. Fortunately, this attitude is beginning to change. Sophisticated molecular diagnostic techniques have shown that IBS is not a simple functional disorder. Rather, it is a multifactorial condition with several prominent overlapping subtypes, including dysbiotic, inflammatory, postinfectious, and neurochemical subtypes.1 Dysbiosis, a disruption in the normal balance of the gut flora, is increasingly being recognized as a major factor in IBS development.1–8 Furthermore, in contrast to long-held beliefs, intestinal biopsies and measurements of cytokines have shown that chronic low-level inflammation is involved in a significant percentage of cases.4 IBS can also result from food allergies or intolerances, inadequate production of hydrochloric acid and/or digestive enzymes, and dysregulation of chemical messengers in the gastrointestinal (GI) tract.3,4,9–11 A unifying model based on the concepts of functional medicine that I have discussed in several previous columns is that certain antecedents, including genetic or lifestyle factors, can predispose an individual to a health disorder such as IBS. When the GI tracts of susceptible individuals are exposed to noxious stimuli—including foods, microbes, damaged tissue, or toxins—that sets off a complex response pattern involving visceral hypersensitivity, which then engages a mixture of interacting immune, neurologic, and endocrine pathways. These pathways are mediated by endogenous chemicals (autacoids, cytokines, gut peptides, or hormones), which are, in turn, influenced by the person’s diet, hormonal state, and lifestyle. In this scenario, psychosocial issues are only one of many factors that can trigger or amplify the symptoms of IBS. In the late 1800s, Robert Heinrich Hermann Koch, MD, developed his famous postulates that established the causative relationship between a pathogenic bacterium and a specific infectious disease. These postulates were tremendously valuable in helping to diagnose and treat bacterial diseases such as tuberculosis. However, the worldview engendered by Dr. Koch’s postulates also created limitations in our thinking. It was a linear model in which a particular disease was thought to be caused by a single microbe. This model has been greatly challenged by recent scientific advances, especially nucleic acid sequencing of gut microbes, which has enabled identification of organisms that cannot be cultured in the laboratory.12 Another challenge to the Koch postulates has come from the realization that the presence of a potentially pathogenic microbe does not always translate into a clinical infection, because many people can be “asymptomatic” carriers, so other host factors must be involved before that microbe can cause overt disease. As I described in a previous column, in which I reviewed current research on the human microbiome, nucleic-acid sequencing techniques have led to the realization that there is a lot more microbial diversity in the human intestines than we ever imagined.13 Furthermore, when these techniques are utilized for individuals with GI disorders such as IBS or inflammatory bowel disease (IBD), a complex picture emerges. Instead of identifying a single microbe that is responsible for a person’s condition, scientists have found aberrant patterns in ALTERNATIVE AND COMPLEMENTARY THERAPIES DOI: 10.1089/act.2013.19610 • MARY ANN LIEBERT, INC. • VOL. 19 NO. 6 DECEMBER 2013 289
  2. 2. ALTERNATIVE AND COMPLEMENTARY THERAPIES • DECEMBER 2013 the relative amounts of bacteria, archaea, viruses, fungi, and protozoa that are present. To comprehend the meaning behind this mosaic, we have to adopt a systems biology approach that sees the gut microbiome as a community of living organisms that exerts both positive and negative influences on the intestinal tract. The question is which of those influences predominate—the good ones or the bad ones. We have to think in terms of  how imbalances in gut microbial ecology trigger or amplify disease rather than being overly focused on the search for a single pathogen. For example, one study,  in which real-time polymerase chain reaction (PCR) assays were used to evaluate the microbiotic composition of fecal samples collected from individuals with the IBS diagnosis, reported positive correlations between the severity of self-reported IBS symptoms and specific GI bacteria such as Ruminococcus torques 94% phylotype. In contrast, the amounts of Clostridium cocleatum, Collinsella aerofaciens-like, and Coprococcus eutactus were significantly reduced.2 Although the researchers concluded that these types of changes may not be the cause of IBS, they may be useful as biomarkers of the disorder.2 People Are What They Eat Some interesting and unexpected findings are emerging from gut microbiome studies around the world. For example, the human microbiome is much more fluid than was once thought. Babies largely acquire their microbiomes from their mothers. The human gut is colonized at birth and gradually achieves the size and diversity of an adult microbiome throughout the first year of life.4 Whereas we once believed that a person’s microbiome would then remain stable—with transient changes caused by disruptive factors—such as acute infections, antibiotic therapy, or conditions such as small intestinal bacterial overgrowth (SIBO)—studies have shown that long-term changes in diet, for example, can alter a person’s microbiomic profile.4,8 There is, in general, a certain mix of bacteria that creates the ideal digestive environment in the human gut. Although not yet fully defined, the “normal” human microbiome is the subject of intensive research projects, such as the Human Microbiome Project, being carried out by the National Institutes of Health (NIH) and aimed at characterizing the microbial communities present at various sites on the human body, one being the GI tract.14 Another is the American Gut, organized by the Human Food Project.15 One aim of the American Gut project is to compare the microbiomes of participants with greatly different dietary practices, whether by choice or for medical reasons. This includes carnivores; vegetarians; and people on gluten-free, low-fat, or low-carbohydrate diets. According to the website of the American Gut project, starving a mouse or switching it to a high-fat diet for just 1 day can transform the animal’s microbiome. Ongoing research has focused on understanding how the microbes in the gut communicate, interact with each other, 290 MARY ANN LIEBERT, INC. • VOL. 19 NO. 6 and interact with their human host, and in particular the human immune and neuroendocrine systems. In decoding these microbial “social networks,” researchers have discovered new molecules that help protect the lining of the intestines from chemical signals that gut flora use to communicate with each other, toxic substances produced by the microbiome, and unique components of the human immune system (such as immunoglobulin A) that interact with bacteria in the gut.7 Dysbiosis is a situation in which microbial social networks in the gut have been disrupted; this can interfere with the normal neurochemical signaling pathways in the gut submucosa. In addition to the growing body of information about dysbiosis and its role in triggering or perpetuating IBS symptoms, we have also learned more in recent years about the neuronal signaling between the brain and the gut that is believed to have a role in IBS. The conventional definition of  IBS as a functional disorder implied a primary psychoneurologic basis in which disordered signals originating in the central nervous system led to symptoms in the bowel. This brain-to-bowel pathway was believed to be responsible, at least in part, for the alternating hyper- and hypomotility, along with the visceral hypersensitivity characteristic of IBS. However, microanatomical studies have since revealed many more neuronal connections than were previously thought to exist in the gut.16 Furthermore, these studies showed that, surprisingly, a greater number of information-gathering neurons travel from the gut to the brain than in the other direction. These findings were the basis for a profoundly insightful book on the neurology of the gut, by Michael Gershon, MD,16 who referred to the intestinal nervous system as our “second brain.” The implication of these findings is that the gut is doing more than simply digesting and assimilating food—the gut is acting as an environmental sensor that gathers information about the quality of that food and the types of microbes associated with it. This information is then “packaged” and communicated back to the brain. Could it be that the intestines—and ultimately the central nervous systems—of people with IBS are just responding to the presence of microbes or chemical compounds, whether naturally occurring (such as gluten) or synthetic (such as organophosphates), that are perceived by the sensors in the gut as being potentially dangerous? In other words, perhaps IBS is the intestinal equivalent of a canary in the coal mine. Irritable Gut, Irritable Patient IBS affects 10%–20% of adults and adolescents worldwide.1,2 Although the mucosa of a person with IBS may look completely normal during colonoscopy, there is no doubt that, as the name irritable bowel syndrome implies, the person’s GI tract is chronically irritated, compromising quality of life and making the affected patient irritable as well. As previously mentioned, a patient with IBS may experience symptoms that range from mild to severe; that fluctuate in intensity; and that can include diarrhea and/or constipation, abdominal cramps
  3. 3. ALTERNATIVE AND COMPLEMENTARY THERAPIES • DECEMBER 2013 and bloating, and flatulence. It is well-documented that anxiety and/or depression tend to occur more commonly in individuals with IBS, but whether these are precursors or results of the disorder has not been clear. In fact, some studies suggest that imbalances in the gut microbiome may be the cause of anxiety or depression, rather than the reverse.17 Considering the more-recent studies that have shed light on the microbiome, dysbiosis, and the neuroanatomy of the gut, the central issue to focus on now is what is making the bowel irritable. In some individuals, the irritability results from cytokine-mediated inflammatory responses triggered by conditionally pathogenic microbes, reactions to certain foods, or chronic low-level subclinical inflammation in the gut lining resulting from persistent upregulation of immune cells. These cytokines travel through the systemic circulation before crossing the blood–brain barrier and influencing the cells of the central nervous system directly.  This scenario has been referred to as cytokine sickness.18 Activated mast cells have been found in the mucosa of individuals without IBS, so this situation is yet another mechanism that may account for subclinical inflammation. Mast cells release histamine and other inflammatory mediators in response to environmental triggers. (Note that histamine is also present in certain foods and that ingesting those foods can mimic the effects of an allergic reaction.) Given that chronic subclinical inflammation is found in many people with IBS, one of the conundrums of this disorder is that conventional anti-inflammatory drugs, such as corticosteroids or nonsteroidal anti-inflammatories, have little or no effect on the symptomatology. Perhaps it is because the underlying problem is an intrinsic defect in the way the neurons in the gut process inflammatory signals, such as disordered secretion of the neurotransmitter serotonin, 90% of which is produced by enterochromaffin cells in the gut. Enterochromaffin cells produce serotonin in response to noxious stimuli. This local increase in serotonin stimulates gut motility by activating enteric neurons, which results in expulsion of the irritant. Excessive serotonin production can cause hypermotility or diarrhea, while inadequate production can result in constipation. Yet another possibility could be that dysbiotic microbes or food components are stimulating the overproduction of signaling molecules that affect gut motility. Some of the numerous signaling molecules that have been shown to be disrupted in irritable bowel syndrome include autacoids (serotonin, histamine, eicosanoids, substance P) and neuroendocrine peptides (CCK, VIP, NPY, somatostatin).19,20 To sum up, the integrative medicine community views IBS not as a purely functional disorder, but rather as a dysfunction of the GI tract that is triggered by reactions to foods, toxins, and traumas in the context of chronic dysbiosis and intrinsic visceral hypersensitivity. A disruption in the normal balance of the gut flora is the primary ongoing pathologic phenomenon, which results in the activation of inflammatory-signaling pathways. These phenomena underlie the constellation of symptoms experienced by patients with IBS. However, as disturbing and disruptive as these symptoms may be—and there is no denying that some patients suffer quite a lot—there is no reason to believe that IBS predisposes such patients to a more serious or potentially life-threatening disorder or cancer. Don’t Skimp on the Diagnosis The initial approach to IBS remains one of excluding more serious causes of persistent intestinal symptoms. To begin with, it is important to rule out IBD, celiac or gluten sensitivity, and lactose intolerance, all of which would require a different treatment approach than IBS. A complete blood count, C-reactive protein testing, erythrocyte sedimentation rate, a complete metabolic panel, and a thyroid-function profile should all be part of the typical workup. Tests for infectious agents should include a screen for typical bacterial pathogens and Clostridium difficile toxin; protozoa such as Giardia lamblia, Entamoeba histolytica, and Blastocystis hominis; and also overgrowth of pathogenic yeasts, primarily Candida species. For patients with recurrent bloating, especially when it occurs soon after eating, a hydrogen/methane breath test can be helpful for diagnosing SIBO, a problem that is either comorbid with IBS or—for some individuals—the primary cause of IBS. Fecal calprotectin and/or lactoferrin are excellent biomarkers for differentiating between IBS (in which the levels are usually low) and IBD, infectious enteritis, or cancer. Although both tests have utility by themselves, combining the two provides more sensitivity and specificity. Patients with long-term symptoms, especially if bleeding is present, or if fecal calprotectin levels are elevated, should undergo colonoscopy to rule out the presence of ulcerative or cancerous lesions. Symptomatic Treatment If no alternative diagnoses appear to be relevant and a patient is considered to have IBS, that is where integrative and mainstream medicine begin to diverge in their approach to patient management. Symptom control to ease patients’ discomfort and improve their daily lives is certainly desirable, but does not solve the underlying problems and should not be considered the beginning and end of treatment. Conventional symptomatic treatment focuses mainly on medications, such as loperamide to alleviate diarrhea, polyethylene glycol powder or lubiprostone for constipation, anticholinergics or other antispasmodics for abdominal pain and cramps, and, if warranted, tricyclic and other antidepressants or anxiolytics. One of the most effective and extensively studied herbal remedies for IBS-related pain and spasms is enterically coated peppermint (Mentha x piperita) oil, which is typically dosed at 1–2 capsules three times per day. Another well-studied liquid phytotherapeutic formulation marketed as STW 5 (Iberogast,® Medical Futures, Inc., Richmond Hill, Ontario* [see next page footnote]), which contains a combination of nine herbs, including peppermint leaf, German chamomile (Matricaria recutita), caraway (Carum carvi), licorice (Glycyrrhiza glabra), lemon MARY ANN LIEBERT, INC. • VOL. 19 NO. 6 291
  4. 4. ALTERNATIVE AND COMPLEMENTARY THERAPIES • DECEMBER 2013 balm (Melissa officinalis), milk thistle (Silybum marianum), angelica (Angelica archangelica), celandine (Chelidonium majus), and clown’s mustard (Iberis amara) plant can be very helpful for patients with IBS.21 In a meta-analysis, 1 mL of this preparation, taken three times per day, for 1 month significantly reduced a range of symptoms associated with IBS.21 I have prescribed this formulation for many years in my clinical practice, and have found it particularly useful for alleviating dyspepsia, abdominal pain, and spasms associated with IBS. Preliminary research has shown that artichoke (Cynara scolymus) leaf extracts can decrease IBS symptoms, including dyspepsia, pain, cramping, bloating, and constipation.22 Several small studies have shown that 2–5 mg of melatonin at bedtime can reduce overall symptoms and improve quality of life for people with IBS.23 Numerous anecdotal reports indicate that 5-hydroxytryptophan (5-HTP; a precursor to the biosynthesis of serotonin and melatonin) can be beneficial for certain patients with IBS, especially those who are constipation-predominant. Going Beyond Just the Symptoms In contrast to symptomatic treatment, the concept of  looking at ways to correct the imbalance in the microbiome is still a fairly radical notion. This approach can encompass a comprehensive stool analysis to assess an individual’s gut flora; using probiotics to repopulate the bowel with healthy bacteria; and prebiotics to support the growth of the existing, desired microbial species. I like to view this approach of correcting the microbiome as being analogous to improving the conditions of a garden in which the plants are not growing well. Identifying the source of the problem and restoring the health of the soil or removing offending pathogens is essential before the plants can thrive again. In a garden, the problem may be with the pH of the soil, an unhealthy mix of bacteria, or fungal overgrowth, for example. Similarly, a microbiome/probiotic approach aims to restore the proper balance of the gut flora. The Four Rs—a Therapeutic Blueprint The most comprehensive and well–thought-out approach to treating IBS, in my opinion, is the 4-R strategy outlined by the Institute for Functional Medicine.24 The four Rs refer to Remove, Repair, Replace, and Reinoculate. Remove Remove is the first “R.” Remove potential sources of noxious stimuli that may be contributing to the person’s symptoms. This includes two main steps: (1) Look for pathogens that can be treated, such as harmful bacteria and parasites. (2) *Although the author sometimes sells this product in his clinic pharmacy, he has no financial interest in this product or the company that manufactures it. 292 MARY ANN LIEBERT, INC. • VOL. 19 NO. 6 Try to identify foods or food groups that the individual’s digestive system cannot tolerate. One source of controversy in the Remove component of the 4-R approach involves whether or not to try an aggressive, empirical course of antimicrobial therapy to “wipe the slate clean,” even when no specific pathogen is detected in a stool analysis. Because rifaximin is poorly absorbed systemically, many practitioners consider it to be the antibiotic of choice in this situation, especially for patients with symptoms consistent with SIBO, such as chronic bloating, flatulence, and abdominal cramps after eating. The antibiotic neomycin, which is also not absorbed systemically, can be added to rifaximin for severe cases. A typical course of treatment with one or both antibiotics for 10–14 days can potentially clear the gut of the fermenting bacteria and, presumably, allow it to be repopulated with a healthy microbial mix. A study of individuals undergoing upper GI endoscopy found that 19.4% had SIBO and > 67% of that group had IBS.3 SIBO was present in 37.5% of patients with IBS, in 60% of these patients with predominantly diarrhea symptoms, and in 27.3% of these patients without diarrhea. In another study, persons who were Rome I criteria positive for IBS underwent a lactulose hydrogen breath test to assess for SIBO.6 Antibiotics were administered after a positive breath test. SIBO was detected in 78% of the patients who had IBS. Among patients who were SIBO-positive, were treated with antibiotics, and had follow-up testing, IBS symptoms, such as diarrhea and abdominal pain, were significantly reduced among the patients in whom SIBO was eradicated, compared to those in whom it was not. Furthermore, 48% of the patients in whom SIBO was eradicated no longer met the Rome I criteria for IBS. Unfortunately, although it is generally well-tolerated, rifaximin is extremely expensive (well over $700 for a course of treatment), so that puts a major limitation on its use. In addition, some researchers question the wisdom of using a broad-spectrum antibiotic to correct a condition in which there may already be a decrease in microbial richness and diversity. The risk of allergic reactions or other side effects from the antibiotics should also be considered. Without a clear and powerful strategy to restore that diversity, it is possible that the SIBO or dysbiosis could rebound after the person stops taking the drug. An alternative to empirical antibiotic therapy is to use herbal antimicrobials to eliminate suspected bacterial overgrowth or imbalances. Typical options include berberine, garlic (Allium sativum), and oil of oregano (Origanum vulgare). Their advantage is that they appear to suppress pathogenic strains without wiping out healthy flora. This is based on observations of people who have taken berberine or garlic for long periods of time (months or years) without developing evidence of a disrupted microbiome. With respect to the second part of Remove—identifying offensive foods that might trigger symptoms—the best approach is to start the patient on an elimination diet. While certain blood tests are available to test for food sensitivities, these tests
  5. 5. ALTERNATIVE AND COMPLEMENTARY THERAPIES • DECEMBER 2013 tend to be fraught with difficulties. Instead, have patients start as simple a diet as possible—preferably just some rice and lightly steamed nonflatulence-producing vegetables. For people with particularly severe symptoms, I sometimes recommend bowel rest for a few days using an oligoantigenic plant protein powder. When these patients are free of symptoms, they can begin to add back in one type of food at a time. For a comprehensive description of elimination diets, I would refer readers to the excellent review by Kathie Madonna Swift, MS, RD, LDN, and Irina Lisker, BA, MD(Cand) that appeared in the October 2012, issue of this journal.25 A body of evidence has grown to support dietary management of GI symptoms, such as those linked to IBS, by restricting rapidly fermentable, short-chain carbohydrates. Some people do not absorb these carbohydrates well, especially in the small intestine, so they are fermented by bacteria, leading to distention of the bowel wall and irritation of the gut. The Fermentable Oligo-, Di- and Mono-saccharides and Polyols (FODMAP) approach, developed by Peter Gibson, MD, and Susan Shepherd, BAppSci, MNut & Diet, PhD (at Monash University in Melbourne, Australia), restricts global intake of carbohydrates, including fructose; lactose; and fructo- and galacto-oligosaccharides; and polyols such as sorbitol, mannitol, xylitol, and maltitol.26 A strict trial of the FODMAP diet is recommended for 6–8 weeks initially, and with good dietary compliance, this approach can produce a reduction of symptoms and durable efficacy.27 Details regarding the implementation of this diet were provided by Ms. Swift and Ms. Lisker in their review.25 Repair The second “R” is Repair. The notion of Repair is based on the presumption that, if dysbiosis is present, with disruption of the intestinal environment, then damage to the gut mucosa is likely to have occurred. Even once we remove the stimulus, the injury to the gut wall may persist for a very long time, so active repair measures are necessary. In celiac disease, for example, the damage can be quite severe, characterized by flattening of the villi lining the intestinal mucosa. This may not resolve for years after removal of gluten from the diet. The nutrient with the strongest research base to support its capabilities to repair the gut wall is l-glutamine. It is a primary fuel for enterocytes and can stimulate healthy enterocyte proliferation. Therapeutic administration of l-glutamine has been shown in animal studies to promote epithelial recovery in the injured small intestine.28 A typical dose of l-glutamine is 3–15 g daily. Another good therapeutic option is the short-chain fatty acid butyrate, which is formed by bacterial fermentation of certain fibers. No one would want to take butyrate orally, though— this is the chemical that gives stool its delightful aroma—so instead we provide its precursors in the form of short-chain fructo-oligosaccharides (FSO) or inulin. The bacteria in the gut then produce the butyrate by fermentation. A caveat with using these prebiotics is that they can initially cause bloating and flatulence. For that reason, the initial dose should be low— ~ 0.5–1.0 tsp daily—and increased very slowly to ~ 1 tbsp daily as tolerated. If the person has SIBO, then FOS should probably be avoided. Replace The third “R” is Replace, which involves the use of digestive enzymes and hydrochloric acid with pepsin. Given the popularity of proton-pump inhibitors (PPIs) for treating a whole range of upper GI tract symptoms, mainstream practitioners may challenge the need for giving a person hydrochloric acid. The belief is that overproduction of stomach acid is the culprit rather than underproduction of this acid. In my experience, that is simply not so. Hypochlorhydria can actually be very common, especially among elderly patients, and can compromise the ability to break down proteins and prevent the overgrowth of fermenting bacterial strains. This situation can also lead to SIBO, a condition that commonly occurs in people taking PPIs. For patients with chronic flatulence and bloating, I recommend a commercial formulation of betaine hydrochloric acid empirically, to be taken with food (at the end of a meal), and see if it helps. A typical dose is 5–20 grains per meal. When this approach does help, the effect can be remarkable. If it does not, then no harm is done. In addition, the added stomach acid can actually help rebalance the small intestine gut flora by helping sterilize the food and limit the bacteria that contribute to fermentation in the small intestines. Digestive enzymes can be derived from pancreatin, fungi (typically Aspergillus niger), or fruits such as pineapple (bromelain), or papaya (papain). Pancreatin—which contains a combination of amylase, lipase, and protease—is very potent and helps people digest a wide range of foods. It is most effective in the high pH of the small intestine. Fungal- and plant-based enzymes are much less potent than pancreatin, but offer the advantage of being active across a wide pH range. Perhaps the best studied plant-based enzyme is a-galactosidase. It was initially promoted to decrease flatulence production after eating legumes, but it is actually helpful for enhancing digestion of a wide range of vegetables. Dose ranges can vary greatly, and I have found that I generally need to recommend much higher amounts of these products than are called for on the product labels. These products can be quite effective if people use enough of them, but they are too often underdosed. I have not seen any negative effects from using higher doses than those given by the manufacturers. A combination of traditional pancreatin and fungal-based enzymes may be the best option for individuals with particularly poor digestion. Reinoculate The final “R” is Reinoculate. This involves giving prebiotics (dietary fibers such as inulin, FOS, and larch (Larix gmelinii) arabinogalactans that are fermented by host bacteria) and probiotics (live microorganisms) to deliver “good”  bacteria to the gut, along with supporting the growth of existing good bacteria. Commonly recommended probiotics for IBS are MARY ANN LIEBERT, INC. • VOL. 19 NO. 6 293
  6. 6. ALTERNATIVE AND COMPLEMENTARY THERAPIES • DECEMBER 2013 Lactobacillus spp., Bifidobacteria spp., and Propionibacterium.29 Theoretically, probiotics should be the ideal way to restore a healthy and diverse gut microbiome. They may improve the immune profile in the gut, leading to improved oral tolerance. In some studies their use has been associated with normalization of altered, proinflammatory cytokine ratios4,5,30 and reduced IBS symptoms. However, there are also a number of negative studies that have been unable to demonstrate benefit. Simply put, after years of prescribing a wide range of probiotic strains at different doses for people with IBS, the best thing I can say is that the results are inconsistent and unpredictable. In my experience, probiotics help some of the people some of the time, but the same bacterial strains do not work for everyone, and it often takes 1–3 months of consistent use before the benefits become evident. I still believe that probiotics should be included as a standard part of the treatment regimen for IBS, but determining which strain to use and at what dose is largely a matter of trial and error. My best recommendation is to always select probiotic strains that are backed by published clinical studies. Given that probiotics have such a strong potential, why have they not proven to be more effective for addressing IBS? It may be that they do not provide the precise mix of bacterial strains needed to reinoculate the microbiome in order to restore its healthy ecology. In contrast to the hit-or-miss effects of commercial probiotics, there is an intervention that is increasingly gaining recognition and that has been shown to introduce a completely new, healthy microbiome. This approach essentially reconstitutes a person’s gut flora, in many cases after a single dose. The therapy is called a fecal microbiota transplant (FMT), or human probiotic infusion.30 As described in a detailed review article by Sala Horowitz, PhD, in the April 2013 issue of this journal, FMTs have been used most often in difficult-to-treat cases of C. difficile infection and less frequently in IBD.30 Some practitioners have also been using this approach for more-severe cases of IBS. Interestingly, in April 2013, the U.S. Food and Drug Administration declared that FMT would be classified as an unapproved biologic drug that could not be used without obtaining an investigational new drug application. However, there was such a strong outcry against this regulation from both doctors and patients that the FDA backed away from its ruling a few months later. If the goal is to repopulate the bowel with a healthy microbiome, replacing the entire ecosystem of the gut via an FMT may turn out to be the most effective approach—not just for C. difficile, but also for a wide range of chronic intestinal disorders, including IBS. The main challenge at present lies in finding an extremely healthy donor with presumably normal gut flora. As I mentioned, we still do not know what exactly that looks like, so for now, recipients typically rely on family members as donors. If a person does not have bowel-related symptoms; has a negative screen for stool pathogens; does not have hepatitis B or C, or HIV infection; is not exceptionally overweight; and is otherwise generally healthy, he or 294 MARY ANN LIEBERT, INC. • VOL. 19 NO. 6 she could be a potential donor. This opens the door to future research into identifying ideal and perhaps standardized “universal” donors based on extensive microbiome testing. Another possibility would be to pool samples from multiple donors to create a “broad-spectrum” and highly diverse source material. Researchers have been experimenting with enterically coated capsules containing purified extracts of donated fecal material, which may help to overcome the “yuck” factor associated with this treatment. Conclusion In the future, making the diagnosis of IBS will require a detailed map of a patient’s microbiome—a qualitative and quantitative analysis of the microbial contents of the patient’s GI tract. The task at hand is for researchers to establish a composite view of the “normal” microbial diversity and colonization in the human gut. This will provide the information needed to differentiate a healthy and rich microbial profile from one that is pathologically imbalanced. It will also help determine the influences of genetics, geography, diet, disease, medications (especially antibiotics), environmental toxins, and other factors on microbiome profiles, so that we can design personalized interventions to restore balance and diversity. Just as genomic, bioinformatic, and other next-generation molecular and computational tools are revolutionizing many aspects of diagnostics, therapeutics, and personalized medicine, so too will these tools dramatically change our understanding of the microbiome and the way we approach poorly defined disorders such as IBS. The sophisticated techniques and tools driving these research discoveries and their clinical applications continue to evolve and yield more detailed and complete views of the microbiome and to decrease in cost so they are more broadly accessible. Concurrently, they are becoming easier to use and the results are becoming more readily interpretable, creating new opportunities for diagnosing IBS, defining the underlying dysbiosis, and monitoring the course of the disorder and the effectiveness of treatment. n References 1. Jiménez MB. Treatment of irritable bowel syndrome with probiotics: An etiopathogenic approach at last? Rev Esp Enferm Dig 2009;101:553–564. 2. Malinen E, Krogius-Kurikka L, Lyra A, et al. Association of symptoms with gastrointestinal microbiota in irritable bowel syndrome. World J Gastroenterol 2010;16:4532–4540. 3. Pyleris E, Giamarellos-Bourboulis EJ, Tzivras D, et al. The prevalence of overgrowth by aerobic bacteria in the small intestine by small bowel culture: Relationship with irritable bowel syndrome. Dig Dis Sci 2012;57:1321–1329. 4. Ghoshal UC, Shukla R, Ghoshal U, et al. The gut microbiota and irritable bowel syndrome: Friend or foe? Int J Inflamm 2012;2012:e151085. 5. Lee BJ, Bak YT. 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