Posted 11/6/2013 5:23 PM (GMT -5)
For those interested, here are excerpts from clinical research that discusses how bad gut bacteria (or an overgrowth in the small intestine called SIBO) can cause changes in the immune system, cause allodynia and hyperalgesia, and and various other symptoms of Fibromyalgia. (For those suffering with IBS, IBD or Crohn's and Fibromyalgia, this somewhat explains the connection.)
Alterations in Intestinal Microbial Flora and Human Disease
Mohamed Othman, Roberto Agüero, Henry C. Lin
Curr Opin Gastroenterol. 2008;24(1):11-16.
Purpose of review: To highlight the evidence supporting the role of altered commensal gut flora in human disease. While the contribution of the indigenous gut microbial community is widely recognized, only recently has there been evidence pointing to indigenous flora in disease.
Recent findings: This review discusses recent evidence pointing to the role of altered commensal gut flora in such common conditions as irritable bowel syndrome and inflammatory bowel disease. Recent studies document the intricate relationship between the vast population of microbes that live in our gut and the human host. Since increased intestinal permeability and immune activation are consequences of an altered host-gut microbial relationship, what are the clinical effects of this shift in relationship?
Summary: We focus on the example of an abnormal expansion of gut microbial flora into the small bowel or small intestinal bacterial overgrowth and discuss the effects of bacterial overgrowth on the human host in acute pancreatitis, bacterial gastroenteritis, irritable bowel syndrome, inflammatory bowel disease, hepatic encephalopathy, and FIBROMYALGIA and burn injury. The identification of the underlying role of altered commensal gut microbiota in these and other human diseases could lead to novel diagnostic and therapeutic strategies that would improve clinical outcome.
Our intestinal microbial flora includes a variety of microorganisms, predominantly bacteria, which colonize the gut of all living organisms. Colonization of the gut begins at birth with the first exposure to the flora of the birth canal. Shortly after birth, hundreds of species of bacteria and archaea establish themselves in the human gastrointestinal tract.[1,2] For decades the importance in human health of gut microbes, commonly referred to as commensal flora, despite advanced knowledge of the microbial world, has been underappreciated. The adult human intestine is home to more than 400 species of microbes, which normally remain confined to the distal gut where the concentration of organisms is approximately 1011 organisms per gram of content (colon) but surprisingly just 100-2 organisms per gram of content in the proximal small intestine. The gut microflora is essential for the development of both the digestive tract itself as well as our immune system, required for the development of tissues such as Peyer's patches and the production of immunoglobulin A. The gut microflora is physically separated from the host by a thin intestinal epithelial barrier. The 'tight junctions' between the cells of the intestinal barrier precisely regulate the transport of molecules while prohibiting the migration of microorganisms;[5,6] however, this selective permeability can be altered directly by bacteria or indirectly via cytokines produced by the immune response of the host.[6,7] One example of the effect of gut microbes on the host is small intestinal bacterial overgrowth (SIBO), described as a proliferation of the distal gut bacterial population, proximally, into the small intestine. SIBO may permit or facilitate translocation of those bacteria or bacterial components (antigen) across the intestinal barrier, with negative consequences to health. In this review, we focus on the effect of altered gut microbiota, as exemplified by SIBO, on the human host in the settings of acute pancreatitis, bacterial gastroenteritis, irritable bowel syndrome, inflammatory bowel disease, hepatic encephalopathy, FIBROMYALGIA and burn injury.
There are numerous pathogenic organisms responsible for acute bacterial gastroenteritis. These microbes not only activate the immune response of the host but also alter the composition of the gut microflora.[21••] A complication of acute gastrointestinal infection is the subsequent development of irritable bowel syndrome (IBS). about a quarter of IBS patients recall an episode of acute gastroenteritis prior to the onset of their IBS. Furthermore, the incidence of IBS is higher among patients who experienced an episode of acute bacterial gastroenteritis relative to those who have not.[22] In a large prospectively conducted cohort study, the relative risk for developing IBS following bacterial gastroenteritis was 11-fold greater than that of the control population.[23] The relationship between acute gastroenteritis and IBS may be due to either altered gut microbiota, bacterial overgrowth (SIBO), or a change in the part of the host as a consequence of an acute episode of gastrointestinal infection. Three months following recovery from an acute gastroenteritis caused by Campylobacter jejuni, 27% of rats had SIBO as confirmed by quantitative PCR targeting microbial DNA.[24] This finding in animals recovering from acute bacterial gastroenteritis is consistent with a growing body of evidence pointing to SIBO as the underlying cause of IBS.[10] There is also evidence of abnormal microbial fermentation in IBS patients as shown by increased excretion of microbially produced gases (hydrogen or methane) on the exhaled breath of IBS patients, compared with controls, after ingestion of lactulose, a nondigestible substrate during a lactulose breath test (LBT).[9,25,26] Although prevalence of an abnormal lactulose breath test in IBS patients varies, in a randomized, placebo-controlled study of patients meeting Rome I criteria for IBS, the prevalence of an abnormal LBT was 84%.[27] Different breath test methods and instrumentation place the prevalence of an abnormal breath test in IBS patients in the range of 30-78%.[28,29] Treating IBS patients with nonabsorbable antibiotics resulted in complete resolution of IBS symptoms in those patients who achieved a normalized breath test.[28]
87 IBS patients were given either rifaximin, a nonabsorbed oral antibiotic that acted primarily in the small intestine, or placebo. In this study, symptom improvement persisted through the entire 10-week observation period following discontinuation of the 10-day antibiotic treatment. Since symptom-directed treatment rapidly disappears upon cessation of treatment, such sustained improvement is only possible if the treatment were to be directed, instead, at the underlying cause of the symptoms of IBS and that cause were to be an antibiotic-sensitive mechanism such as SIBO. The relationship between SIBO and intestinal motility was supported by the finding of reduced frequency of cycling of interdigestive motility in patients with IBS.[35] Impaired intestinal motility may be a key element in the loss of containment of the microflora, resulting in SIBO.
The relationship between acute gastroenteritis, SIBO and IBS can be understood by considering the activation of host immunity by microbes and symptoms as consequences of immune activation. An additional piece of evidence supporting the idea of altered gut microbiota is the histological finding of immune activation in both IBS patients with a history of acute gastroenteritis and in IBS patients without such history.[36] In animal models, infection of the gastrointestinal tract by nematodes resulted in an alteration of the intestinal myenteric neurons, suggesting an additional mechanism for symptoms in IBS patients.[37]
Gastrointestinal inflammation overall is one of the most important factors that influence the quantity and quality of human intestinal flora. This interaction is illustrated by inflammatory bowel disease (IBD). For example, the dominant bacterial flora in patients with IBD differs from healthy patients; similarly, the dominant bacterial flora in patients with ulcerative colitis differs from those diagnosed with Crohn's disease.[38] Differences in microbiota were also found contrasting the bacteria isolated from mucosal biopsies of inflamed versus noninflamed tissue of newly diagnosed and untreated patients.[39••] The contribution of an abundance or reduction of bacteria such as those from the genus Clostridium or the phylum Bacteroidetes in the pathogenesis of these diseases remains to be established. The microflora of IBD patients produces greater amounts of metabolic products (e.g. ammonia and short-chain fatty acids) than the microflora of healthy controls.[40] The microflora isolated from inflamed mucosa of IBD patients was also found to trigger the production of interleukin (IL)-12, interferon-ϒ and IL-10, which are important mediators of inflammation in IBD.[41] Similarly, increased T-cell response to bacterial antigens has been reported.[42] Perhaps the strongest argument for the role of commensal gut microbes in IBD is that researchers were unable to demonstrate the development of colitis in knockout mouse models of IBD when the animals were kept germ free. Specifically, even IL-10 knockout mice would not develop their usual severe intestinal inflammation if raised in a germ-free environment.[43]
Probiotic organisms and the microflora itself have the ability to shift the inflammatory response in favor of the host; bacteria such as Bifidobacterium bifidum and Lactobacillus spp. have been shown to suppress T-cell responses in both an IBD animal model and in patients as well.[44••,45] A recent Cochrane review,[46•] however, suggested that probiotics did not have a statistically significant effect in maintaining remission in Crohn's disease patients. The use of probiotics has also been investigated in the setting of IBS in several RCTs,[47] with promising results reported by O'Mahony et al. [48] using B. infantis.
Animal studies suggest a relationship between bacterial toxins and hypersensitivity. In a rat model, exposure to endotoxin resulted in local inflammation and hyperalgesia.[60] Similarly, exposure to lipopolysaccharide induced visceral hypersensitivity in rats.[61] Although the mechanism of endotoxin-induced hyperalgesia is not completely understood, a recent animal study demonstrated that exposure to endotoxin increased the production of prostaglandins and simultaneously decreased nitrous oxide production, resulting in inflammatory hyperalgesia.[62]
FiBROMYALGIA, a condition of musculoskeletal hypersensitivity, provides us with a fascinating model on the link between gut bacteria and somatic hypersensitivity. Between 30 and 75% of patients with fibromyalgia also have symptoms meeting the criteria for IBS.[63] Somatic hypersensitivity was demonstrated in IBS and fibromyalgia patients, suggesting that somatic hypersensitivity could be a common feature of the two disorders.[64] The role of gut microbes in FIBROMYALGIA is suggested by the finding that of 42 patients with the condition, all of them tested positive for hydrogen/methane production, as determined by LBT, a finding similar to a previous study in IBS in which 84% of patients had an abnormal LBT.[27,65] These observations suggest that SIBO is a common feature in both disorders and that altered gut microbiota in SIBO may play a role in the induction of somatic or visceral hypersensitivity, with affected patients meeting the diagnostic criteria for IBS, FIBROMYALGIA or both disorders.[6
Animal studies have long established that burns or thermal injury caused an increase in bacterial translocation.[66,67] Burn injuries induce epithelial apoptosis leading to atrophy of the intestinal mucosa followed by bacterial translocation.[68] What is observed is an 'imbalance' in the microflora following thermal injury in rats with decreased proportions of Bifidobacterium spp. relative to the abundance of Gram-negative organisms (e.g. E. coli), followed by bacterial translocation and sepsis.[69,70] Most notable was that animals supplemented with oral Bifidobacterium spp. had a decreased incidence of bacterial translocation.[69]
Increased intestinal permeability or leaky gut is also more common among burn victims.[71] The severity of the burn injury was found to directly correlate with the degree of increased intestinal permeability.[72] Although it was demonstrated in animal models that bacteria translocate to mesenteric lymph nodes and enter the circulation through portal blood,[70] a prospective human trial failed to detect a significant level of bacteria, bacterial endotoxin or inflammatory markers in the portal circulation of patients with major trauma in the presence of inflammatory-mediated lung injury.[73] This finding led to the recent gut-lymph hypothesis, which argues that endothelial permeability is selectively higher in the mesenteric lymph nodes and that portal circulation passes inflammatory markers via the thoracic duct to the lung rather than through the liver, causing acute lung injury.[74] This hypothesis is further supported by the prevention of acute lung injury in posthemorrhagic rats by ligation of the mesenteric lymphatic system.[75]
The human microflora has a significant impact on health and human disease, far more than ever realized. The host response to SIBO and bacterial translocation may explain the clinical findings of several pathological conditions. Recognizing the interactive nature of host and gut flora is vital to the diagnosis and treatment of these disorders.