Irritable bowel syndrome (IBS) is the most common gastrointestinal condition, affecting 10% to 20% of adults in developed countries. Over the last few years, growing evidence has supported a new hypothesis for IBS based on alterations in intestinal bacterial composition. This article reviews the evidence for a bacterial concept in IBS and begins to formulate a hypothesis of how these bacterial systems could integrate in a new pathophysiologic mechanism in the development of IBS. Data suggesting an interaction between this gut flora and inflammation in the context of IBS is also presented.
Irritable bowel syndrome (IBS) is a chronic bowel condition characterized by abdominal pain, altered bowel function, and bloating. It is in fact the most common gastrointestinal condition, affecting 10% to 20% of adults in developed countries and accounting for 50% of all gastrointestinal office visits. Due to the high prevalence, the health care costs related to IBS are estimated to exceed $30 billion per year. Moreover, this condition has serious implications for quality of life, which have been likened to diabetes or heart disease, in young adults who should otherwise be productive and healthy. However, despite the seriousness of IBS as a health care issue, the underlying causes remain largely unknown.
Although the etiology of IBS has remained unclear, many hypotheses have emerged, based on associations between IBS and stressful life events in the past as well as altered gut sensations. The association between stress, psychological trauma, and findings of lower thresholds for rectal balloon sensation in IBS led to the concept of the brain-gut dysregulation as a hypothesis in IBS. The brain-gut concept has continued to be a fertile area of work in IBS but unfortunately, it is difficult to prove a cause-and-effect relationship between life events and IBS. In fact, the United States householder study suggested that in the community, psychological problems are not more common in subjects with IBS.
The human intestinal tract is composed of more than 500 different species of bacteria that usually function in symbiosis with the host. Although the composition and number of bacteria in the gut depends on many factors, by adulthood, if not earlier, most humans reach an established balance of type and numbers of bacteria that is unique to a given individual, much like a fingerprint. Over the last few years, growing evidence has supported a new hypothesis for IBS based on alterations in intestinal bacterial composition. Several nonmutually exclusive mechanisms may explain how altered gut flora can lead to IBS. First, gut microbes interact with the gut mucosal immune system through innate and adaptive mechanisms. Second, altered flora can lead to changes in the intestinal epithelial barrier. Third, neuroimmune and pain modulation pathways may be influenced by the flora. Fourth, changing flora can increase food fermentation and subsequent intestinal gas production. Finally, bile acid malabsorption can result from expansion of gut flora into the small bowel. For any or all of these reasons, gut flora can produce IBS-like symptoms.
Further epidemiologic and clinical data support this new bacterial concept of IBS. First, there has been growing data linking the development of IBS to an initial episode of acute gastroenteritis ; this is now termed postinfectious IBS (PI-IBS). The second area of interest in IBS related to gut microbes is the concept that IBS patients have alterations in the balance of fecal flora. It is on this basis that probiotic studies in IBS began to be conducted. The final and most promising area is that of alterations in small intestinal flora. Relevant studies suggest that IBS subjects have excessive coliform bacteria in their small intestine (otherwise known as SIBO). The link to SIBO has led to clinical trials of antibiotics in IBS. In this article the authors review the evidence for a bacterial concept in IBS, and by the end begin to formulate a hypothesis of how these bacterial systems could integrate in a new pathophysiologic mechanism in the development of IBS. In addition, there have been data to suggest an interaction between this gut flora and inflammation in the context of IBS, and this is also be presented.
Gut microbes and IBS
Altered Intestinal Flora Composition and IBS
The effect of gut microflora on gastrointestinal physiology has been most clearly demonstrated in animal experiments under controlled conditions not feasible in human studies. For example, germ-free rats had delayed gastric emptying and intestinal transit, and a prolonged interdigestive migrating motor complex (MMC) as compared with rats with conventional flora. Moreover, introduction of normal gut flora to these germ-free rats normalized their motility. Of interest, when germ-free rats were mono-associated with either Lactobacillus acidophilus or Bifidobacterium bifidum , their small intestine transit accelerated and their MMC frequency increased. Hooper and Gordon profiled gene expression patterns in germ-free mice, and showed reduction of several enteric neuron and intestinal smooth muscle genes. Subsequent mono-association with Bacteroides thetaiotaomicron , a highly adapted and abundant commensal of the human and murine colon, restored the normal expression pattern. These experiments, which involve profound changes in the gut flora of rodents, imply a critical role of the resident flora in establishing and maintaining normal intestinal function, and suggest that changes in the gut microflora can lead to significant alterations in gastrointestinal function.
Changes in gut flora of patients with gastrointestinal disorders, including IBS, have been sought for decades. Efforts have been hampered by (1) disease heterogeneity and multifactorial pathophysiology; (2) studies not controlling for diet and medication use that can influence flora composition; (3) potential fluctuations in stability of gut flora and topographic/geographic variability, both in “normal” and affected subjects; and (4) inherent limitations in methodologies to assess gut flora composition. The last challenge in this area will be overcome by evolving technology.
Although culture of the bowel flora has been the mainstay of evaluating intestinal bacterial composition, the majority of intestinal flora are nonculturable, based on fastidious requirements and limited understanding of the vast expanse of human colonizers. DNA-based strategies such as high-throughput pyro-sequencing are considered more sensitive and accurate, but are still costly and technology intensive. Despite these limitations, culture studies have consistently demonstrated a paucity of Lactobacillus and Bifidobacterium species in the feces of IBS patients compared with controls ( Table 1 ), with the exception of Tana and colleagues who noted increased Lactobacillus . Although the influence of Lactobacillus , Bifidobacterium , and other so-called beneficial bacteria have been studied extensively based on their effects on the epithelium, host immune response, and other factors, this is beyond the scope of this article. However, one finding is notable. Balb/c mice infected with a probiotic L acidophilus strain had elevated expression of several intestinal pain receptors that led to decreased visceral sensitivity.
| IBS Subjects, # | Methodology | Findings in IBS Subjects | Citation |
|---|---|---|---|
| Unsubtyped, n = 25 | Culture | Decreased Bifidobacteria and increased Enterobacteriaceae | Si et al, 2004 |
| IBS-D, n = 12 IBS-C, n = 9 IBS-M, n = 5 | Culture PCR-DDGE | Increased coliforms and aerobic bacteria/total bacteria Increased Clostridium and decreased Eubacterium | Matto et al, 2005 |
| IBS-D, n = 12 IBS-C, n = 9 IBS-M, n = 6 | Q-RTPCR | Decreased Lactobacillus in IBS-D, increased Veillonella in IBS-C | Malinen et al, 2005 |
| IBS-D, n = 7 IBS-C, n = 6 IBS-M, n = 3 | PCR-DDGE RTPCR-DDGE | Decreased Clostridium coccoides-Eubacterium rectale in IBS-C | Maukonen et al, 2006 |
| IBS-D, n = 10 IBS-C, n = 8 IBS-M, n = 6 | Q-RTPCR (nucleic acid fractionation) | Decreased Collinsella, Clostridium, and Coprococcus | Kassinen et al, 2007 |
| IBS-D, n = 14 IBS-C, n = 11 IBS-M, n = 16 | FISH | Decreased Bifidobacterium | Kerckhoffs et al, 2009 |
| IBS-D, n = 8 IBS-C, n = 11 IBS-M, n = 7 | Culture Q-RTPCR | Increased Lactobacillus Increased Veillonella | Tana et al, 2010 |
While these results sparked the use of these specific probiotics in IBS, there were inherent problems with this initial research. The results are difficult to interpret because of the failure of these studies to control for diet. A common finding in the literature related to IBS is the association between IBS and lactose intolerance. The reason for this remains unclear, yet it is recognized that more than 60% of IBS sufferers have dairy intolerance on this basis. Because dairy products are the prebiotic for Lactobacillus and Bifidobacterium species, not accounting for diet, leaves the finding of reduced counts of these organisms possibly secondary to intrinsic diet issues in IBS subjects. The ideal study of this topic would be to put IBS and controls on an identical diet for 2 weeks followed by stool evaluation. This lack of control may explain the overall failure of Lactobacillus -based treatment in IBS, as discussed later.
Recently, more sophisticated techniques have been used to examine subjects with IBS and their fecal content. In a recent study, molecular techniques were used to determine shifts in flora between IBS and controls. In addition to finding differences categorically, subjects with constipation predominant IBS (C-IBS) also appeared to have unique differences in contrast to diarrhea predominant IBS (D-IBS). Specifically, a lack of Lactobacillus and Collinsella species were seen in IBS. Of note, C-IBS subjects had an abundance of Ruminococcus . In D-IBS, a decrease in Bifidobacterium was seen. Even in this sophisticated study, however, diet was not controlled, making interpretation an ongoing issue.
Though not specifically a chronic change in intestinal microflora, acute changes may have an impact on IBS and its development. This process involves the association between IBS and acute gastroenteritis. While this is discussed in detail in this article, animal models used to study PI-IBS further suggest a link between altered gut microflora and IBS. The most characterized postinfectious model of IBS used the organism Trichinella spiralis . This parasitic mouse infection model was found to produce reduced gut motility and increased visceral sensitivity to colorectal distention, and has been likened to IBS. However, the stool flora have not been characterized in this model.
Small Intestinal Bacterial Overgrowth and IBS
SIBO is a situation whereby coliform bacterial counts in the small bowel become excessive. Symptoms of SIBO are similar to IBS. In the last decade, growing data have linked SIBO and IBS. Whereas the initial criticism of the work was a consequence of inaccuracies of breath testing as a means of diagnosing SIBO, recent work has begun to confirm the results of breath testing in IBS, supported by small bowel culture.
As early as 2000, work began to emerge suggesting that subjects with IBS have bacterial overgrowth, based on the lactulose breath test. In this initial study, SIBO was suspect in 76% of IBS subjects and although based on a prospective database, appeared to improve after antibiotic therapy using an open-label approach. In the first follow-up study to this work, a higher rate of positive lactulose breath test results (up to 84%) were identifed. This rate was noted to be far greater than in healthy control subjects. After this work was published there was a high degree of skepticism, due to the complexities of the breath-testing techniques. Now 10 years later, meta-analyses have been conducted that support the breath test findings in IBS compared with controls. In the first of 2 meta-analyses, Ford and colleagues demonstrated that IBS subjects appear to have a higher prevalence of abnormal breath test results in IBS, but only using the most conservative interpretation of the test compared with controls. The second meta-analysis used a different approach based on simply combining the results of studies using breath testing in IBS versus controls in general. This study demonstrated that IBS patients have a greater likelihood of a positive test compared with controls. When only the best studies were used (age- and sex-matched studies), the odds ratio of a positive test in IBS was 9.64 (confidence interval = 4.26–21.82) compared with controls.
Further validation of the SIBO concept in IBS is based on culture and antibiotic trials. In the largest published study of small bowel culture in IBS, aspirates of jejunal fluid in IBS were found to harbor a greater number of coliform bacteria compared with healthy controls (using >5000 coliforms/mL) ( P <.001). Studies of antibiotic response also support SIBO in IBS ( Table 2 ). Controlled trials in IBS Pimentel and colleagues, and functional bloating demonstrate successful treatment of IBS with antibiotics based on this excessive flora. Using breath testing as an outcome measure, antibiotic therapy led to improvement of SIBO, with a 75% improvement in IBS symptoms observed if normalization of the breath test is seen with antibiotics. Another controlled trial demonstrated improvement in IBS symptoms that were sustained for a full 10 weeks of follow-up after cessation of antibiotics. Taken together, these findings strongly support a role for the gut microbiome and perhaps SIBO in the pathophysiology of symptoms in a subset of IBS sufferers.
Related posts:
Inflammation and Microflora
Therapies Aimed at the Gut Microbiota and Inflammation: Antibiotics, Prebiotics, Probiotics, Synbiotics, Anti-inflammatory Therapies
Centrally Acting Therapies for Irritable Bowel Syndrome
The Role of Genetics in IBS
The Role of Diagnostic Testing in Irritable Bowel Syndrome
Emerging Pharmacological Therapies for the Irritable Bowel Syndrome
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