Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You and Your Team.

Learn More →

Small Intestinal Bacterial Overgrowth

Small Intestinal Bacterial Overgrowth ContextIrritable bowel syndrome (IBS), which affects 11% to 14% of the population, is a puzzling condition with multiple models of pathophysiology including altered motility, visceral hypersensitivity, abnormal brain-gut interaction, autonomic dysfunction, and immune activation. Although no conceptual framework accounts for all the symptoms and observations in IBS, a unifying explanation may exist since 92% of these patients share the symptom of bloating regardless of their predominant complaint.Evidence AcquisitionOvid MEDLINE was searched through May 2004 for relevant English-language articles beginning with those related to bloating, gas, and IBS. Bibliographies of pertinent articles and books were also scanned for additional suitable citations.Evidence SynthesisThe possibility that small intestinal bacterial overgrowth (SIBO) may explain bloating in IBS is supported by greater total hydrogen excretion after lactulose ingestion, a correlation between the pattern of bowel movement and the type of excreted gas, a prevalence of abnormal lactulose breath test in 84% of IBS patients, and a 75% improvement of IBS symptoms after eradication of SIBO. Altered gastrointestinal motility and sensation, changed activity of the central nervous system, and increased sympathetic drive and immune activation may be understood as consequences of the host response to SIBO.ConclusionsThe gastrointestinal and immune effects of SIBO provide a possible unifying framework for understanding frequent observations in IBS, including postprandial bloating and distension, altered motility, visceral hypersensitivity, abnormal brain-gut interaction, autonomic dysfunction, and immune activation.Irritable bowel syndrome (IBS) is a common diagnosis that affects 11% to 14% of the population.Currently, IBS is a diagnosis made on the basis of meeting clinical criteria.This symptom-based approach has been used because no consistent biological marker or unifying framework has been available to explain the different symptoms and findings of IBS. The varying symptoms in IBS have led to efforts looking at differences rather than similarities between patients.Another way we have emphasized the difference rather than the similarity is in the grouping of one set of symptoms of these patients as IBS and another set of symptoms as belonging to some other diagnosis. The clinical criteria for IBS do not include the extraintestinal symptoms that are common in these patients such as fatigue or myalgia. Instead, these complaints are viewed as symptoms of other diagnoses that coexist with IBS such as chronic fatigue syndromeand fibromyalgia.This separation may be an artifact of medical specialization.As such, a unifying framework for understanding IBS that could account for both the gastrointestinal as well as the extraintestinal symptoms of these patients would warrant serious consideration.EVIDENCE ACQUISITIONOvid MEDLINE was searched through May 2004 for articles using combinations of the terms bloating, gas, IBS, post-infectious IBS, small intestinal bacterial overgrowth(SIBO), microbial translocation, bacteria, visceral hypersensitivity, immune response, autonomic dysfunction, central nervous system, intestinal motility, fibromyalgia, chronic fatigue syndrome, interstitial cystitis, lactulose and glucose breath test, and sickness behavior. Additional sources were identified by scanning through the bibliographies of articles and books. Publications reviewed ranged from randomized controlled trials to case-control studies. Although randomized controlled trials were considered to be the strongest evidence, such studies were few, so the evidence was considered to be most compelling when there was consistency among the results of multiple different studies. Quality of data was assessed by publication in a peer-reviewed journal. A few critical recent abstracts were also considered.EVIDENCE SYNTHESISPostprandial Bloating as a Unifying Symptom of IBSRegardless of whether an IBS patient is troubled predominantly by constipation, diarrhea, or pain, 92% of IBS patients complain of bloating and pain, with 89% having a bloating score of 5 or greater (out of 10).Although many IBS patients describe worsening of their symptoms by food intake,most are unsuccessful in identifying a food trigger.This extremely common complaint of postprandial bloatingsupports the possibility of a unifying pathophysiology. This symptom is associated with abdominal distension and has been corroborated by direct physical evidence of increased intestinal gas as measured by abdominal films,computed tomography of the abdomen,and plethysmographic measurement showing increased abdominal girth at the end of the day but decreased girth overnight after fasting.The possibility of a unifying explanation for IBS is further supported by reproducible x-ray findings of Koide et alin which increased intestinal gas was noted regardless of bowel movement pattern. Of note, the increased gas was localized to the small rather than the large intestine.Intestinal Gas Excretion Is Greater in IBSAlthough in some studies intestinal gas volume of IBS patients has been reported to be no different than that of healthy controls,the gas measurement in these studies was done in a fasting state. As such, no conclusion can be drawn from these studies regarding meal-induced bloating in IBS patients. In contrast, both total hydrogen production (median, 332 vs 162 mL) and maximal rate of gas excretion (2.4 mL/min vs 0.6 mL/min) were greater following lactulose ingestion in IBS patients (6 subjects) than healthy controls.This finding of a 4-fold greater rate of maximal gas excretion and greater total hydrogen excretion provided direct evidence of increased gas production in IBS in the presence of a fermentable substrate. Since the excreted gases were hydrogen and methane, this abnormal response to lactulose in IBS patients cannot be explained by a disaccharide intolerance.This group reported similar findings in another study where the 24-hour total excretion of hydrogen following lactulose was substantially greater in IBS patients (median, 333.7 mL/24 h; interquartile range, 234.7-445.67 mL) than in normal volunteers (median, 203.1 mL/24 h; interquartile range, 131.4-256 mL; P= .002) or IBS patients who failed exclusion diet (median, 204 mL/24 h; interquartile range, 111.35-289.13 mL; P= .02).Current construct models of the pathophysiology of IBS, including abnormal motility,visceral hypersensitivity,altered brain-gut interaction,autonomic dysfunction,and immune activation,do not account for the nearly universal symptom of postprandial bloating, the physical evidence of increased intestinal gas that is localized to the small intestine, the effect of probiotics on bloating,or the increased gas excretion after lactulose ingestion.Normal Intestinal Gas ProductionFrom the seminal work of Levitt,we know that the site of hydrogen production by bacterial fermentation is limited to the distal gut. The duodenum and jejunum are often sterile, and the proximal ileum may be sterile. The concentration of gut bacteria drops precipitously from 1010-12organisms per mL in the cecum to 105-8organisms per mL in the terminal ileum, 100-5in the proximal ileum, and 100-4in the jejunum and the duodenum.For fermentation to begin, food must reach these distal gut bacteria. In the normal state, the digestibility of dietary starch is the primary determinant of how much bacterial fermentation takes place in the gut (Figure 1).The elimination of the hydrogen produced by bacterial fermentation depends significantly on methanogenic and sulfate-reducing bacteria that convert hydrogen to methane and hydrogen sulfide.These organisms are highly competitive so that the stool of an individual contains high concentrations of only 1 of these 2 types of organisms.Figure 1.Distribution of Intestinal Bacterial Flora in Normal Gut and in Small Intestinal Bacterial OvergrowthA, In the normal gut, easily digestible starch undergoes complete digestion and absorption within the proximal small intestine and is not available for fermentation in the distal ileum and colon where bacterial colonization is the greatest.In contrast, gas production results from bacterial fermentation of poorly digestible starch that is not assimilated by the proximal gut. B, In small intestinal bacterial overgrowth, the concentration of bacterial flora increases proximally allowing fermentation of both easily digestible and poorly digestible starches.If Not the Food, the Problem May Be the BacteriaSince no specific food intolerance can explain the greater increase in hydrogen excretion after lactulose ingestion,the abnormal fermentation problem may not be the food but rather, the gut bacteria. If food is not moving down to the bacteria, then bacteria may be moving to the site of food assimilation for fermentation and gas production to take place. SIBO describes just such proximal expansion of gut bacteria (Figure 1) and provides a biologically plausible framework for the bloating of IBS. What evidence is there to support the role of bacterial overgrowth in IBS?Prevalence of SIBO and Effect of Antibiotic Treatment in IBSIn a study of 202 patients meeting Rome I criteria for IBS by Pimentel et al,an abnormal breath test result suggesting SIBO was found in 78%. In this uncontrolled study, when the second breath test result after antibiotic treatment became normal, consistent with successful eradication of bacterial overgrowth, symptoms were reduced enough so that only half of the patients still met clinical criteria for IBS. The possibility of bacterial overgrowth as a unifying framework for understanding the symptoms of IBS patients is further supported by reduction of both gastrointestinal and extraintestinal symptoms when eradication of SIBO was achieved.However, it is not clear at this time whether alteration of colonic bacterial flora by antibiotics may also play a role in symptom improvement.These findings were then corroborated by a double-blind, randomized, placebo-controlled study by Pimentel et alwhere 111 patients were drawn from the general IBS population, with no a priori selection on the basis of chief complaint. The prevalence of abnormal lactulose breath test result in this controlled study was 84% vs 20% in the control subjects who did not meet Rome I criteria (odds ratio, 26.2; 95% confidence interval, 4.7-103; P<.001). There was a graded effect of treatment whereby the mean (SE) normalization of global symptoms within 1 week of randomization was 11.0% (3.7%) for placebo-treated patients, 36.7% (6.1%) for antibiotic-treated patients who did not achieve bacterial eradication, and 75.0% (6.4%) for antibiotic-treated patients who also achieved bacterial eradication (P<.001, 1-way analysis of variance).This graded response is consistent with an antibiotic-sensitive pathophysiology of IBS. A similar study consistency was demonstrated by a double-blind, placebo-controlled study that showed metronidazole to be superior to placebo in relieving symptoms in IBS patients,while another recent report by Nucera et alshowed that 75% of 200 IBS patients have an abnormal lactulose-glucose breath test result consistent with the presence of SIBO.The Type of Gas May Contribute to ConstipationIf SIBO provides a unifying framework for understanding IBS patients, how does this account for the possibility of both constipation and diarrhea? The type of gas produced by gut bacteria may be an important factor. In 2 studies by Pimentel et al,excretion of methane alone was only found in constipation-predominant IBS patients. Methane as a gas slows intestinal transitand reduces postprandial plasma level of serotonin,the mediator of the peristaltic reflex.Methane excretion has been found in 65% of children with encopresis compared with 15% of the control patients.A role for gut bacteria as one of the factors in constipation is further suggested by the observation in 8 patients with chronic idiopathic constipation that stool frequency and consistency improved after a 14-day course of antibiotics.Abnormal Small Intestinal Motility May Explain SIBO in IBSBetween meals, the interdigestive motility of the upper gastrointestinal tract is characterized by a cyclical pattern of activity known as the major migrating complex (MMC).The MMC includes a period of powerful, lumen-obliterating contractions that propagates from the stomach or duodenum distally to the terminal ileum (phase III of MMC or the intestinal housekeeper wave).When compared with recordings from healthy controls, the frequency of these intestinal housekeeper waves was significantly reduced in IBS patients,which may also explain the abnormal gas retention that is observed in IBS patients.The importance of the relationship between abnormal phase III of MMC and SIBO was first described by Vantrappen et alin patients with organic gastrointestinal disorders and extended in animal and human studies to the relationship between small bowel motility and gut bacteria; small bowel motility and SIBO; and small bowel motility, SIBO, and bacterial translocation.Why Is Prevention of SIBO Important?Bacterial translocation, a known complication of SIBO,is the movement of gut bacteria from the lumen across the mucosal barrier.In rats, experimentally induced SIBO leads to the appearance of gut bacteria in the mesenteric lymph nodes and visceral organs.A potentially important consequence of bacterial translocation is immune activation. In a report of 11 patients, an increase in the number of intraepithelial lymphocytes was observed as mucosal evidence of this immune response to confirmed bacterial translocation.This adverse outcome could explain why the normal gut has defensive mechanisms in place to keep the bacterial flora away from the small intestine, particularly the bowel proximal to the ileum.Immune Activation Is Also Present in IBSMucosal evidence of an activated immune response has been reported recently in patients who develop IBS after recovering from acute gastroenteritis (postinfectious IBS)and in those without such history.Of the IBS population, 25% to 30% of patients have an antecedent history of acute gastroenteritis.In these reports, postinfectious IBS patients have an increased number of intraepithelial lymphocytes,just like the patient with documented bacterial translocation.An episode of acute gastroenteritis is not needed to explain immune activation in IBS. In a study of 77 IBS patients, an increase in the number of activated intraepithelial lymphocytes was found in almost 90% of the subjects regardless of the acuteness of their onset or their predominant gastrointestinal symptom.The magnitude of the immune activation in patients without a history of acute gastroenteritis is, in fact, even more prominent than those with that history.These observations have provided strong study consistency in support of the biological plausibility for a role of inflammation in IBS as proposed by Collins.Any framework for understanding IBS must, therefore, account for these and other observations of immune activation.The role of an underlying process that involves inflammation in IBS is further supported by observations of a genetic predisposition in some IBS patients to produce less anti-inflammatory productsor more pro-inflammatory products.Although the trigger for the immune response in IBS has not been identified, SIBO would provide a framework for understanding the activated immune response in IBS. In postinfectious IBS patients, along with immune activation, there is also increased intestinal permeability,which has a known association with SIBO in animalsand humansas the experimental correlate of the "leaky gut syndrome."Immune Response to Bacteria Explains Abnormal Motility and Visceral HypersensitivityLipopolysaccharide, an endotoxin of gram-negative bacteria, accelerates intestinal transit.This may be mediated by mast cell degranulation, immune activation, cytokine production, and the triggering of preprogrammed responses of the enteric nervous system, including hypersecretion and power peristalsisleading to diarrhea and cramping abdominal pain.Visceral hypersensitivity has been reported as a characteristic of IBS.The immune response to these bacterial products would also explain this finding. Lipopolysaccharide has also been reported to induce visceral hypersensitivity in rats.Weston et alproposed earlier that increased mast cells in the ileum of IBS patients might be linked to altered visceral perception.Similar to IBS, Fibromyalgia May Also Be Explained by SIBOIt is well recognized that there is a high degree of overlap between IBS, fibromyalgia, interstitial cystitis, and chronic fatigue syndrome.While interstitial cystitisand IBSare diagnoses associated with hypersensitivity at the level of the bladder and gut, respectively, fibromyalgia may be considered a kind of hypersensitivity at the musculoskeletal level.Although the cause of the hypersensitivity in these disorders is not well understood, the striking overlap of hypersensitivity in these functional disorders suggests the possibility of a unifying explanation. In a study of patients meeting American College of Rheumatology criteria for fibromyalgia, an abnormal lactulose breath test result suggesting SIBO was found in 42 out of 42 patients.Fibromyalgia patients had a higher breath hydrogen concentration than IBS patients. Thus, an abnormal breath test result suggesting SIBO may reflect a common pathophysiological link between fibromyalgia and IBS. The immune response to bacterial antigen in SIBO provides a framework for understanding the hypersensitivity in both fibromyalgia and IBS.CONTROVERSIESDiagnostic Approach to SIBOSince direct culture is usually considered the gold standard for the diagnosis of a bacterial disease, the use of an indirect approach such as the lactulose breath test for the diagnosis of SIBO is controversial. When it comes to diagnosing SIBO, the problem with the direct approach is one of access. While bacterial overgrowth can occur only in the more distal portions of the 300- to 500-cm length of the small intestine,direct aspiration and culture are limited by the reach of instrumentation. Since only the small intestine proximal to the ligament of Treitz is usually reached by an endoscope (∼60 cm), there is a high false-negative rate with this approach for the diagnosis of SIBO.Even with these limitations of access, Simren et alreported that 4 (12%) of 33 IBS patients had more than 100 000 colony-forming units of bacteria of colonic origin in the duodenum. While the prevalence is considerably lower than that detected by lactulose breath testing,this study provided direct confirmation of the expansion of colonic bacteria proximally all the way to the duodenum in some IBS patients. Using glucose instead of lactulose as the substrate for a breath test is similarly limited,since glucose is rapidly absorbed with the fermentable substrate removed from the lumen of the upper small intestine. In contrast, since lactulose is poorly digestible, this fermentable substrate does remain available in the lumen for fermentation by gut bacteria anywhere along the gut (Figure 2).Figure 2.Regions of Intestine Accessible by Various Diagnostic Methods to Detect Small Intestinal Bacterial Overgrowth (SIBO)Detection of SIBO depends on location of and access to bacterial flora. SIBO by culture is defined by bacterial concentration proximal to the distal ileum >105organisms per mL. In this example of SIBO, the concentration of bacterial flora in the distal jejunum and ileum has increased to that typically present in the normal colon (1011organisms per mL). Culture of intestinal flora sampled by direct aspiration, which commonly is able to access the duodenum, would not detect the region of increased bacterial flora in this example. Similarly, a breath test using glucose as the fermentable substrate would only detect bacterial flora in the duodenum and proximal jejunum because glucose is rapidly absorbed. In contrast, a breath test using lactulose, which is not absorbed by the intestine, would be able to detect bacterial flora anywhere along the gut.Interpreting a Premature Rise of Breath HydrogenA premature rise of breath hydrogen is a feature of both bacterial overgrowth and excessively rapid transit. However, 2 observations point away from rapid transit as the primary explanation for the findings by Pimentel et al.First, the time-to-rise of breath hydrogen normalized with successful eradication of SIBO by antibiotics in the IBS patients.Second, the abnormal gas profiles of the constipation-predominant IBS (slow transit) patient overlapped with that of the diarrhea-predominant IBS patients (fast transit).Role of Sugar Intolerance in IBSThere has been recent interest in fructose intolerance as a possible explanation for unexplained gastrointestinal symptoms.Interestingly, there is a similar pattern of malabsorption in IBS patients across a number of tested fermentable substrates.For many patients, the association between sugar intolerance and IBS may be related to bacterial overgrowth rather than true sugar intolerance. Nucera et alfound a high rate of disappearance of malabsorption to lactose (86.6%), fructose (97.5%), and sorbitol (90.9%) once SIBO was eradicated. Similarly, Pimentel et al reported that while the number of IBS patients with true lactose intolerance was low (16%), a much higher number (58%) had an abnormal lactose breath test result and there was a significant correlation between lactulose (SIBO) and lactose breath test result.Activated Immunity May Explain Altered Brain-Gut Interaction and Autonomic Dysfunction in IBSAbnormalities of autonomic nervous system function, including disturbed sleep,have been described in patients with IBS.Using SIBO as a framework for understanding IBS, these neural changes can be understood on the basis of 2-way triggered communications between the immune system and the autonomic nervous system.An example of this interaction is the defensive sympathetic response to stress involving immune activation of noradrenergic neurons.Using a variety of brain imaging techniques, IBS patients have been observed to exhibit a different pattern of brain response to visceral stimuli than healthy control subjects.Since inflammation in animal models leads to multiple changes in the brain, including activation of neurons as documented by Fos expression,alteration of hypothalamic-pituitary-adrenal axis including elevation of corticotropin-releasing factor (CRF) concentration,and change in neurotransmitter levels,such altered brain-gut interactions may be a part of the systemic response to a trigger of inflammation. The immune response to bacterial antigens is known to lead to sickness behaviorincluding flu-like symptoms of fatigue, anxiety, depression,and impaired cognition.Within that framework, the psychological and psychiatric comorbidity that are so common in IBSand the response of selected symptoms to cognitive-behavioral therapy or antidepressantsmay be understood.CONCLUSIONSGiven the marked variability of symptoms and findings in patients with IBS, multiple models of pathophysiology and varying treatment strategies have been proposed. In this review, the available observations on IBS were considered and synthesized in an attempt to achieve a goal of integration. In this effort, it is biologically plausible that the gastrointestinal and extraintestinal symptoms and findings of IBS have a single, unifying explanation. Specifically, SIBO provides a framework for understanding IBS by accounting for the following observations in IBS patients. Nearly all of the symptoms and findings of IBS are wholly consistent with SIBO, including postprandial bloating (which is nearly universal), physical evidence of small bowel gas irrespective of predominant symptoms, high prevalence of abnormal lactulose breath test results, dramatic reduction in symptoms when antibiotic therapy is given and breath tests subsequently normalize, altered gut motility, visceral hypersensitivity, abnormal brain-gut interactions, evidence of autonomic dysfunction, nearly uniform immune activation regardless of prior acute gastroenteritis, and extraintestinal symptoms that are often flu-like in quality.As a unifying framework for understanding IBS and other functional disorders, SIBO provides a target for exciting research that may lead to better diagnostic and treatment approaches. SIBO is a condition characterized by a chronic relapsing clinical course.Since indefinite use of antibiotics is not an attractive option, future research should be directed at understanding and controlling the interaction between host and gut bacteria.WGThompsonIrritable bowel syndrome: prevalence, prognosis and consequences.CMAJ.1986;134:111-113.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3484655&dopt=AbstractDADrossmanZLiEAndruzziUS householder survey of functional gastrointestinal disorders: prevalence, sociodemography and health impact.Dig Dis Sci.1993;38:1569-1580.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8359066&dopt=AbstractAPManningWGThompsonKWHeatonAFMorrisTowards positive diagnosis of the irritable bowel.BMJ.1978;2:653-654.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=698649&dopt=AbstractWKruisCThiemeMWeinzierlPSchusslerJHollWPaulusA diagnostic score for the irritable bowel syndrome: its value in the exclusion of organic disease.Gastroenterology.1984;87:1-7.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6724251&dopt=AbstractWGThompsonFHCreedDADrossmanFunctional bowel disorders and functional abdominal pain.Gastroenterol Int.1992;5:75-91.WGThompsonGFLongstrethDADrossmanKWHeatonEJIrvineSAMuller-LissnerFunctional bowel disorders and functional abdominal pain.Gut.1999;45(suppl 2):II43-II47.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10457044&dopt=AbstractLAAaronDBuchwaldA review of the evidence for overlap among unexplained clinical conditions.Ann Intern Med.2001;134(9 pt 2):868-881.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11346323&dopt=AbstractGTriadafilopoulosRWSimmsDLGoldenbergBowel dysfunction in fibromyalgia syndrome.Dig Dis Sci.1991;36:59-64.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1985007&dopt=AbstractSWesselyCNimnuanMSharpeFunctional somatic syndromes: one or many?Lancet.1999;354:936-939.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10489969&dopt=AbstractTNChamiMMSchusterMEBohlmanTJPullmanNKamalWEWhiteheadA simple radiologic method to estimate the quantity of bowel gas.Am J Gastroenterol.1991;86:599-602.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2028951&dopt=AbstractPJWhorwellTreatment.In: Stockbrugger R, Pace F, eds. The Irritable Bowel Syndrome Manual. London, England: Mosby-Wolfe Medical Communications; 1999:71-79.MPetitpierrePGomowskiJ-PGirardIrritable bowel syndrome and hypersensitivity to food.Ann Allergy.1985;54:538-540.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=4014782&dopt=AbstractAKoideTYamaguchiTOdakaQuantitative analysis of bowel gas using plain abdominal radiograph in patients with irritable bowel syndrome.Am J Gastroenterol.2000;95:735-741.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10710067&dopt=AbstractDGMaxtonDFMartinPJWhorwellMGodfreyAbdominal distension in female patients with irritable bowel syndrome: exploration of possible mechanisms.Gut.1991;32:662-664.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2060875&dopt=AbstractRLeaLAHoughtonBReillyPJWhorwellAbdominal distension in irritable bowel syndrome (IBS): is there a relationship to visceral sensitivity?Gastroenterology.2003;124:A-398.MJLewisBReillyLAHoughtonPJWhorwellAmbulatory abdominal inductance plethysmography: towards objective assessment of abdominal distension in irritable bowel syndrome.Gut.2001;48:216-220.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11156643&dopt=AbstractRBLasserJHBondMDLevittThe role of intestinal gas in functional abdominal pain.N Engl J Med.1975;293:524-525.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1152877&dopt=AbstractJSerraFAzpirozJRMalageladaImpaired transit and tolerance of intestinal gas in the irritable bowel syndrome.Gut.2001;48:14-19.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11115817&dopt=AbstractTSKingMEkuaJOHunterAbnormal colonic fermentation in irritable bowel syndrome.Lancet.1998;352:1187-1189.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9777836&dopt=AbstractYKChoiFCJJohlinRWSummersMJacksonSSRaoFructose intolerance: an under-recognized problem.Am J Gastroenterol.2003;98:1348-1353.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12818280&dopt=AbstractSSenKLDearTSKingJOHunterEvaluation of hydrogen excretion after lactulose administration as a screening test for causes of irritable bowel syndrome.Eur J Gastroenterol Hepatol.2002;14:753-756.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12169984&dopt=AbstractHAbrahamssonGastrointestinal motility in patients with the irritable bowel syndrome.Scand J Gastroenterol Suppl.1987;130:21-26.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3477013&dopt=AbstractJRitchiePain from distension of the pelvic colon by inflating a balloon in the irritable colon syndrome.Gut.1973;14:125-132.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=4696535&dopt=AbstractDHSSilvermanJAMunakataHEnnesMAMandelkernCKHohEAMayerRegional cerebral activity in normal and pathologic perception of visceral pain.Gastroenterology.1997;112:64-72.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8978344&dopt=AbstractAAggarwalTFCuttsTLAbellPredominant symptoms in irritable bowel syndrome correlate with specific autonomic nervous system abnormalities.Gastroenterology.1994;106:945-950.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8143999&dopt=AbstractVChadwickWChenDShuActivation of the mucosal immune system in irritable bowel syndrome.Gastroenterology.2002;122:1778-1783.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12055584&dopt=AbstractHJKimMCamilleriSMcKinzieA randomized controlled trial of a probiotic, VSL#3, on gut transit and symptoms in diarrhoea-predominant irritable bowel syndrome.Aliment Pharmacol Ther.2003;17:895-904.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12656692&dopt=AbstractMDLevittProduction and excretion of hydrogen gas in man.N Engl J Med.1969;281:122-127.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=5790483&dopt=AbstractSLGorbachIntestinal microflora.Gastroenterology.1971;60:1110-1129.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=4933894&dopt=AbstractBSDrasarMShinerGMMcLeodStudies on the intestinal flora, I: the bacterial flora of the gastrointestinal tract in healthy and achlorhydric persons.Gastroenterology.1969;56:71-79.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=4885396&dopt=AbstractKHWilsonThe gastrointestinal biota.In: Yamada T, Alpers DH, Laine L, Owyang C, Powell DW, eds. Textbook of Gastroenterology. Philadelphia, Pa: Williams & Wilkins; 1999:624-636.MDLevittMalabsorption of starch: a normal phenomenon.Gastroenterology.1983;85:769-770.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6873617&dopt=AbstractAStrocchiJFurneCEllisMDLevittMethanogens outcompetes sulphate reducing bacteria for H2 in the human colon.Gut.1994;35:1098-1101.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7926913&dopt=AbstractMPimentelEChowHCLinEradication of small intestinal bacterial overgrowth reduces symptoms in irritable bowel syndrome.Am J Gastroenterol.2000;95:3503-3506.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11151884&dopt=AbstractMPimentelEJChowHCLinNormalization of lactulose breath testing correlates with symptom improvement in irritable bowel syndrome: a double blind, randomized controlled study.Am J Gastroenterol.2003;98:412-419.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12591062&dopt=AbstractANayakDKarnadPAbrahamFPMistryMetronidazole relieves symptoms in irritable bowel syndrome: the confusion with so-called "chronic amebiasis."Indian J Gastroenterol.1997;16:137-139.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9357184&dopt=AbstractCNuceraAMLupascuMGabrielliSugar intolerance in irritable bowel syndrome: the role of small bowel bacterial overgrowth.Gastroenterology.2004;126(4[suppl 2]):A511.MPimentelAGMayerSParkEJChowAHasanYKongMethane production during lactulose breath test is associated with gastrointestinal disease presentation.Dig Dis Sci.2003;48:86-92.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12645795&dopt=AbstractHCLinMPimentelJHChenIntestinal transit is slowed by luminal methane.Neurogastroenterol Motil.2002;14:437.MPimentelYKongSParkIBS subjects with methane on lactulose breath test have lower postprandial serotonin levels than subjects with hydrogen.Dig Dis Sci.2004;49:84-87.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14992440&dopt=AbstractEBulbringRCLinThe effect of intraluminal application of 5-hydroxytryptamine and 5-hydroxytryptophan on peristalsis: the local production of 5-HT and its release in relation to intraluminal pressure and propulsive activity.J Physiol (Lond).1958;140:381-407.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=13514713&dopt=AbstractSCFiedorekCLPumphreyHBCasteelBreath methane production in children with constipation and encopresis.J Pediatr Gastroenterol Nutr.1990;10:473-477.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2162940&dopt=AbstractAFCelikJTomlinNWReadThe effect of oral vancomycin on chronic idiopathic constipation.Aliment Pharmacol Ther.1995;9:63-68.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7766746&dopt=AbstractCFCodeJAMarlettThe interdigestive myo-electric complex of the stomach and small bowel of dogs.J Physiol (Lond).1975;246:289-309.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1142245&dopt=AbstractMPimentelEESofferEJChowHCLinLower frequency of MMC is found in IBS subjects with abnormal lactulose breath test suggesting bacterial overgrowth.Dig Dis Sci.2002;47:2639-2643.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12498278&dopt=AbstractGVantrappenJJanssensJHellemansYGhoosThe interdigestive motor complex of normal subjects and patients with bacterial overgrowth of the small intestine.J Clin Invest.1977;59:1158-1166.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=864008&dopt=AbstractEHusebyeVSkarTHoverstadTIversenKMelbyAbnormal intestinal motor patterns explain enteric colonization with gram-negative bacilli in late radiation enteropathy.Gastroenterology.1995;109:1078-1089.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7557072&dopt=AbstractEHusebyePMHellstromFSundlerJChenTMidtvedtInfluence of microbial species on small intestinal myoelectrical activity and transit in germ-free rats.Am J Physiol Gastrointest Liver Physiol.2001;280:G368-G380.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11171619&dopt=AbstractVBNeiuwenhuijsAVerheemHvan Duijvenbode-BeumerThe role of interdigestive small bowel motility in the regulation of gut microflora, bacterial overgrowth and bacterial translocation in rats.Ann Surg.1998;228:188-193.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9712563&dopt=AbstractIDVan FeliusLMAkkermansKBosschaInterdigestive small bowel motility and duodenal bacterial overgrowth in experimental acute pancreatitis.Neurogastronterol Motil.2003;15:267-276.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12787336&dopt=AbstractRDBergAWGarlingtonTranslocation of certain indigenous bacteria from the gastrointestinal tract to the mesenteric lymph nodes and other organs in a gnotobiotic mouse model.Infect Immun.1979;23:403-411.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=154474&dopt=AbstractRDBergEWommackEADeitchImmunosuppression and intestinal bacterial overgrowth synergistically promote bacterial translocation.Arch Surg.1988;123:1359-1364.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3178484&dopt=AbstractNPWoodcockJRobertsonDRMorganKLGreggCJMitchellJMacFieBacterial translocation and immunohistochemical measurement of gut immune function.J Clin Pathol.2001;54:619-623.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11477118&dopt=AbstractKAGweeJCGrahamMWMcKendrickPsychometric scores and persistence of irritable bowel after infectious diarrhoea.Lancet.1996;347:150-153.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8544549&dopt=AbstractKRNealJHebdenRSpillerPrevalence of gastrointestinal symptoms six months after bacterial gastroenteritis and risk factors for development of irritable bowel syndrome: postal survey of patients.BMJ.1997;314:779-782.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9080994&dopt=AbstractKAGweeSMCollinsNWReadIncreased rectal mucosal expression of interleukin 1beta in recently acquired post-infectious irritable bowel syndrome.Gut.2003;52:523-526.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12631663&dopt=AbstractHTornblomGLindbergBNybergBVeressFull-thickness biopsy of the jejunum reveals inflammation and enteric neuropathy in irritable bowel syndrome.Gastroenterology.2002;123:1972-1979.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12454854&dopt=AbstractSPDunlopDJenkinsRCSpillerDistinctive clinical, psychological, and histological features of post-infective bowel syndrome.Am J Gastroenterol.2003;98:1578-1583.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12873581&dopt=AbstractRCSpillerDJenkinsJPThomleyIncreased rectal mucosal enteroendocrine cells, T lymphocytes, and increased gut permeability following acute Campylobacter enteritis and in post-dysenteric irritable bowel syndrome.Gut.2000;47:804-811.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11076879&dopt=AbstractSPDunlopDJenkinsKRNealRCSpillerRelative importance of enterochromaffin cell hyperplasia, anxiety, and depression in post-infectious IBS.Gastroenterology.2003;125:1651-1659.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14724817&dopt=AbstractSMCollinsGBarbaraBVallanceStress, inflammation and the irritable bowel syndrome.Can J Gastroenterol.1999;13(suppl A):47A-49A.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10202209&dopt=AbstractSMCollinsTPichePRampalThe putative role of inflammation in the irritable bowel syndrome.Gut.2001;49:734-745.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11709500&dopt=AbstractSMCollinsA case for immunological basis for irritable bowel syndrome.Gastroenterology.2002;122:2078-2080.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12055614&dopt=AbstractWMGonsalkoraleCPerreyVPravicaPJWhorwellIVHutchinsonInterleukin 10 genotypes in irritable bowel syndrome: evidence for an inflammatory component?Gut.2003;52:91-93.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12477767&dopt=AbstractPVan der VeekYDeKoonMVan den BergHVerspagetADMascleeTumor necrosis factor alpha and interleukin 10 gene polymorphisms in irritable bowel syndrome.Gastroenterology.2004;126:A52.JKMarshallMThabaneJMeddingsIncreased intestinal permeability (IP) in subjects with irritable bowel syndrome (IBS) two years after the Walkerton outbreak of waterborne gastroenteritis.Gastroenterology.2004;126(4[suppl 2]):A520.EADeitchRDSpecianRDBergEndotoxin-induced bacterial translocation and mucosal permeability: role of xanthine oxidase, complement activation and macrophage products.Crit Care Med.1991;19:785-791.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2055056&dopt=AbstractSMRiordanCJMcIverDHThomasVMDuncombeTDBolinMCThomasLuminal bacteria and small-intestinal permeability.Scand J Gastroenterol.1997;32:556-563.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9200287&dopt=AbstractDJWirthlinJJCullenSTSpatesGastrointestinal transit during endotoxemia: the role of nitric oxide.J Surg Res.1996;60:307-311.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8598659&dopt=AbstractRKGoyalIHiranoThe enteric nervous system.N Engl J Med.1996;334:1106-1115.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8598871&dopt=AbstractAMCoelhoJFioramontiLBuenoSystemic lipopolysaccharide influences rectal hypersensitivity in rats: role of mast cells, cytokines, and vagus nerve.Am J Physiol Gastrointest Liver Physiol.2000;279:G781-G790.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11005766&dopt=AbstractAPWestonWLBiddlePSBhatiaPBJMinerTerminal ileal mucosal mast cellls in irritable bowel syndrome.Dig Dis Sci.1993;38:1590-1595.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8359068&dopt=AbstractDVealeGKavanaghJFFieldingOFitzgeraldPrimary fibromyalgia and the irritable bowel syndrome: different expressions of a common pathogenetic process.Br J Rheumatol.1991;30:220-222.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2049586&dopt=AbstractADSperberYAlzmonLNeumannFibromyalgia in the irritable bowel syndrome: studies of prevalence and clinical implications.Am J Gastroenterol.1999;94:3541-3546.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10606316&dopt=AbstractAJWeinPMHannoTargets for therapy of the painful bladder.Urology.2002;59(5[suppl 1]):68-73.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12007525&dopt=AbstractPPToskesAKumarEnteric bacterial flora and bacterial overgrowth syndrome.In: Feldman M, Sleisenger MH, eds. Sleisinger & Fordtran's Gastrointestinal and Liver Diseases.6th ed. Philadelphia, Pa: Saunders; 1998:1523-1555.JJRumessenEGudmand-HoyerEBachmannTJustesenDiagnosis of bacterial overgrowth of the small intestine: comparison of the 14C-D-xylose breath test with jejunal cultures in 60 patients.Scand J Gastroenterol.1985;20:1267-1275.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3912962&dopt=AbstractMAValdovinosMCamilleriGMThomfordeCFrieReduced accuracy of 14C-D-xylose breath test for detecting bacterial overgrowth in gastrointestinal motility disorders.Scand J Gastroenterol.1993;28:963-968.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8284631&dopt=AbstractMSimrenGRingstromPAgerforzESBjornssonHAbrahamssonP-OStotzerSmall intestinal bacterial overgrowth is not of major importance in the irritable bowel syndrome.Gastroenterology.2003;124:A163-A164.FCastiglioneARispoEDi GirolamoAntibiotic treatment of small bowel bacterial overgrowth in patients with Crohn's disease.Aliment Pharmacol Ther.2003;18:1107-1112.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14653830&dopt=AbstractRGoldsteinDBravermanHStankiewiczCarbohydrate malabsorption and the effect of dietary restriction on symptoms of irritable bowel syndrome and functional bowel complaints.Isr Med Assoc J.2000;2:583-587.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10979349&dopt=AbstractWCOrrSElsenbruchMJHarnishAutonomic regulation of cardiac function during sleep in patients with irritable bowel syndrome.Am J Gastroenterol.2000;95:2865-2871.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11051361&dopt=AbstractGHaskoReceptor-mediated interaction between the sympathetic nervous system and immune system in inflammation.Neurochem Res.2001;26:1039-1044.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11699931&dopt=AbstractHBesedovskyAdel ReyESorkinMDa PradaRBurriCHoneggerThe immune response evokes changes in brain noradrenergic neurons.Science.1983;221:564-566.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6867729&dopt=AbstractNCastexJFioramontiJDucos de LahitteGLuffauJMoreLBuenoBrain Fos expression and intestinal motor alterations during nematode-induced inflammation in the rat.Am J Physiol.1998;274(1 pt 1):G210-G216.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9458792&dopt=AbstractCRivierEffect of peripheral and central cytokines on the hypothalamic-pituitary-adrenal axis in the rat.Ann N Y Acad Sci.1993;697:97-105.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8257027&dopt=AbstractSLCarlsonDLFeltenSLivnatSYFeltenAlternations of monoamines in specific central autonomic nuclei following immunization in mice.Brain Behav Immun.1987;1:52-63.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3451782&dopt=AbstractMBergJPGodboutKWKelleyRWJohnsonAlpha-tocopherol attenuates lipopolysaccharide-induced sickness behaviour in mice.Brain Behav Immun.2004;18:149-157.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14759592&dopt=AbstractHAnismanZMeraliCytokines, stress and depressive illness: brain-immune interactions.Ann Med.2003;35:2-11.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12693607&dopt=AbstractWABanksSAFarrJEMorleyEntry of blood-borne cytokines into the central nervous system: effects on cognitive processes.Neuroimmunomodulation.2002-2003;10:319-327.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12907838&dopt=AbstractDADrossmanMCamilleriEAMayerWEWhiteheadAGA technical review on irritable bowel syndrome.Gastroenterology.2002;123:2108-2131.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12454866&dopt=AbstractDADrossmanBBTonerWEWhiteheadCognitive-behavioral therapy versus education and desipramine versus placebo for moderate to severe functional bowel disorders.Gastroenterology.2003;125:19-31.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12851867&dopt=AbstractCorresponding Author:Henry C. Lin, MD, Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, 2011 Zonal Ave, HMR 101, Los Angeles, CA 90033 (henry.c.lin@usc.edu).Funding/Support:This work was supported by an unrestricted gift in support of research from the Todd & Cheri Morgan Donor Advised Fund.Role of the Sponsor:The Todd & Cheri Morgan Donor Advised Fund had no role in the design and conduct of the study; in the collection, analysis, and interpretation or preparation of the data; or in the preparation, review, or approval of the manuscript.Financial Disclosure:Dr Lin has been on the speakers' bureaus and served as a consultant for Novartis and Salix. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA American Medical Association

Small Intestinal Bacterial Overgrowth

JAMA , Volume 292 (7) – Aug 18, 2004

Loading next page...
 
/lp/american-medical-association/small-intestinal-bacterial-overgrowth-XdKvCjbxQR
Publisher
American Medical Association
Copyright
Copyright 2004 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.
ISSN
0098-7484
eISSN
1538-3598
DOI
10.1001/jama.292.7.852
pmid
15316000
Publisher site
See Article on Publisher Site

Abstract

ContextIrritable bowel syndrome (IBS), which affects 11% to 14% of the population, is a puzzling condition with multiple models of pathophysiology including altered motility, visceral hypersensitivity, abnormal brain-gut interaction, autonomic dysfunction, and immune activation. Although no conceptual framework accounts for all the symptoms and observations in IBS, a unifying explanation may exist since 92% of these patients share the symptom of bloating regardless of their predominant complaint.Evidence AcquisitionOvid MEDLINE was searched through May 2004 for relevant English-language articles beginning with those related to bloating, gas, and IBS. Bibliographies of pertinent articles and books were also scanned for additional suitable citations.Evidence SynthesisThe possibility that small intestinal bacterial overgrowth (SIBO) may explain bloating in IBS is supported by greater total hydrogen excretion after lactulose ingestion, a correlation between the pattern of bowel movement and the type of excreted gas, a prevalence of abnormal lactulose breath test in 84% of IBS patients, and a 75% improvement of IBS symptoms after eradication of SIBO. Altered gastrointestinal motility and sensation, changed activity of the central nervous system, and increased sympathetic drive and immune activation may be understood as consequences of the host response to SIBO.ConclusionsThe gastrointestinal and immune effects of SIBO provide a possible unifying framework for understanding frequent observations in IBS, including postprandial bloating and distension, altered motility, visceral hypersensitivity, abnormal brain-gut interaction, autonomic dysfunction, and immune activation.Irritable bowel syndrome (IBS) is a common diagnosis that affects 11% to 14% of the population.Currently, IBS is a diagnosis made on the basis of meeting clinical criteria.This symptom-based approach has been used because no consistent biological marker or unifying framework has been available to explain the different symptoms and findings of IBS. The varying symptoms in IBS have led to efforts looking at differences rather than similarities between patients.Another way we have emphasized the difference rather than the similarity is in the grouping of one set of symptoms of these patients as IBS and another set of symptoms as belonging to some other diagnosis. The clinical criteria for IBS do not include the extraintestinal symptoms that are common in these patients such as fatigue or myalgia. Instead, these complaints are viewed as symptoms of other diagnoses that coexist with IBS such as chronic fatigue syndromeand fibromyalgia.This separation may be an artifact of medical specialization.As such, a unifying framework for understanding IBS that could account for both the gastrointestinal as well as the extraintestinal symptoms of these patients would warrant serious consideration.EVIDENCE ACQUISITIONOvid MEDLINE was searched through May 2004 for articles using combinations of the terms bloating, gas, IBS, post-infectious IBS, small intestinal bacterial overgrowth(SIBO), microbial translocation, bacteria, visceral hypersensitivity, immune response, autonomic dysfunction, central nervous system, intestinal motility, fibromyalgia, chronic fatigue syndrome, interstitial cystitis, lactulose and glucose breath test, and sickness behavior. Additional sources were identified by scanning through the bibliographies of articles and books. Publications reviewed ranged from randomized controlled trials to case-control studies. Although randomized controlled trials were considered to be the strongest evidence, such studies were few, so the evidence was considered to be most compelling when there was consistency among the results of multiple different studies. Quality of data was assessed by publication in a peer-reviewed journal. A few critical recent abstracts were also considered.EVIDENCE SYNTHESISPostprandial Bloating as a Unifying Symptom of IBSRegardless of whether an IBS patient is troubled predominantly by constipation, diarrhea, or pain, 92% of IBS patients complain of bloating and pain, with 89% having a bloating score of 5 or greater (out of 10).Although many IBS patients describe worsening of their symptoms by food intake,most are unsuccessful in identifying a food trigger.This extremely common complaint of postprandial bloatingsupports the possibility of a unifying pathophysiology. This symptom is associated with abdominal distension and has been corroborated by direct physical evidence of increased intestinal gas as measured by abdominal films,computed tomography of the abdomen,and plethysmographic measurement showing increased abdominal girth at the end of the day but decreased girth overnight after fasting.The possibility of a unifying explanation for IBS is further supported by reproducible x-ray findings of Koide et alin which increased intestinal gas was noted regardless of bowel movement pattern. Of note, the increased gas was localized to the small rather than the large intestine.Intestinal Gas Excretion Is Greater in IBSAlthough in some studies intestinal gas volume of IBS patients has been reported to be no different than that of healthy controls,the gas measurement in these studies was done in a fasting state. As such, no conclusion can be drawn from these studies regarding meal-induced bloating in IBS patients. In contrast, both total hydrogen production (median, 332 vs 162 mL) and maximal rate of gas excretion (2.4 mL/min vs 0.6 mL/min) were greater following lactulose ingestion in IBS patients (6 subjects) than healthy controls.This finding of a 4-fold greater rate of maximal gas excretion and greater total hydrogen excretion provided direct evidence of increased gas production in IBS in the presence of a fermentable substrate. Since the excreted gases were hydrogen and methane, this abnormal response to lactulose in IBS patients cannot be explained by a disaccharide intolerance.This group reported similar findings in another study where the 24-hour total excretion of hydrogen following lactulose was substantially greater in IBS patients (median, 333.7 mL/24 h; interquartile range, 234.7-445.67 mL) than in normal volunteers (median, 203.1 mL/24 h; interquartile range, 131.4-256 mL; P= .002) or IBS patients who failed exclusion diet (median, 204 mL/24 h; interquartile range, 111.35-289.13 mL; P= .02).Current construct models of the pathophysiology of IBS, including abnormal motility,visceral hypersensitivity,altered brain-gut interaction,autonomic dysfunction,and immune activation,do not account for the nearly universal symptom of postprandial bloating, the physical evidence of increased intestinal gas that is localized to the small intestine, the effect of probiotics on bloating,or the increased gas excretion after lactulose ingestion.Normal Intestinal Gas ProductionFrom the seminal work of Levitt,we know that the site of hydrogen production by bacterial fermentation is limited to the distal gut. The duodenum and jejunum are often sterile, and the proximal ileum may be sterile. The concentration of gut bacteria drops precipitously from 1010-12organisms per mL in the cecum to 105-8organisms per mL in the terminal ileum, 100-5in the proximal ileum, and 100-4in the jejunum and the duodenum.For fermentation to begin, food must reach these distal gut bacteria. In the normal state, the digestibility of dietary starch is the primary determinant of how much bacterial fermentation takes place in the gut (Figure 1).The elimination of the hydrogen produced by bacterial fermentation depends significantly on methanogenic and sulfate-reducing bacteria that convert hydrogen to methane and hydrogen sulfide.These organisms are highly competitive so that the stool of an individual contains high concentrations of only 1 of these 2 types of organisms.Figure 1.Distribution of Intestinal Bacterial Flora in Normal Gut and in Small Intestinal Bacterial OvergrowthA, In the normal gut, easily digestible starch undergoes complete digestion and absorption within the proximal small intestine and is not available for fermentation in the distal ileum and colon where bacterial colonization is the greatest.In contrast, gas production results from bacterial fermentation of poorly digestible starch that is not assimilated by the proximal gut. B, In small intestinal bacterial overgrowth, the concentration of bacterial flora increases proximally allowing fermentation of both easily digestible and poorly digestible starches.If Not the Food, the Problem May Be the BacteriaSince no specific food intolerance can explain the greater increase in hydrogen excretion after lactulose ingestion,the abnormal fermentation problem may not be the food but rather, the gut bacteria. If food is not moving down to the bacteria, then bacteria may be moving to the site of food assimilation for fermentation and gas production to take place. SIBO describes just such proximal expansion of gut bacteria (Figure 1) and provides a biologically plausible framework for the bloating of IBS. What evidence is there to support the role of bacterial overgrowth in IBS?Prevalence of SIBO and Effect of Antibiotic Treatment in IBSIn a study of 202 patients meeting Rome I criteria for IBS by Pimentel et al,an abnormal breath test result suggesting SIBO was found in 78%. In this uncontrolled study, when the second breath test result after antibiotic treatment became normal, consistent with successful eradication of bacterial overgrowth, symptoms were reduced enough so that only half of the patients still met clinical criteria for IBS. The possibility of bacterial overgrowth as a unifying framework for understanding the symptoms of IBS patients is further supported by reduction of both gastrointestinal and extraintestinal symptoms when eradication of SIBO was achieved.However, it is not clear at this time whether alteration of colonic bacterial flora by antibiotics may also play a role in symptom improvement.These findings were then corroborated by a double-blind, randomized, placebo-controlled study by Pimentel et alwhere 111 patients were drawn from the general IBS population, with no a priori selection on the basis of chief complaint. The prevalence of abnormal lactulose breath test result in this controlled study was 84% vs 20% in the control subjects who did not meet Rome I criteria (odds ratio, 26.2; 95% confidence interval, 4.7-103; P<.001). There was a graded effect of treatment whereby the mean (SE) normalization of global symptoms within 1 week of randomization was 11.0% (3.7%) for placebo-treated patients, 36.7% (6.1%) for antibiotic-treated patients who did not achieve bacterial eradication, and 75.0% (6.4%) for antibiotic-treated patients who also achieved bacterial eradication (P<.001, 1-way analysis of variance).This graded response is consistent with an antibiotic-sensitive pathophysiology of IBS. A similar study consistency was demonstrated by a double-blind, placebo-controlled study that showed metronidazole to be superior to placebo in relieving symptoms in IBS patients,while another recent report by Nucera et alshowed that 75% of 200 IBS patients have an abnormal lactulose-glucose breath test result consistent with the presence of SIBO.The Type of Gas May Contribute to ConstipationIf SIBO provides a unifying framework for understanding IBS patients, how does this account for the possibility of both constipation and diarrhea? The type of gas produced by gut bacteria may be an important factor. In 2 studies by Pimentel et al,excretion of methane alone was only found in constipation-predominant IBS patients. Methane as a gas slows intestinal transitand reduces postprandial plasma level of serotonin,the mediator of the peristaltic reflex.Methane excretion has been found in 65% of children with encopresis compared with 15% of the control patients.A role for gut bacteria as one of the factors in constipation is further suggested by the observation in 8 patients with chronic idiopathic constipation that stool frequency and consistency improved after a 14-day course of antibiotics.Abnormal Small Intestinal Motility May Explain SIBO in IBSBetween meals, the interdigestive motility of the upper gastrointestinal tract is characterized by a cyclical pattern of activity known as the major migrating complex (MMC).The MMC includes a period of powerful, lumen-obliterating contractions that propagates from the stomach or duodenum distally to the terminal ileum (phase III of MMC or the intestinal housekeeper wave).When compared with recordings from healthy controls, the frequency of these intestinal housekeeper waves was significantly reduced in IBS patients,which may also explain the abnormal gas retention that is observed in IBS patients.The importance of the relationship between abnormal phase III of MMC and SIBO was first described by Vantrappen et alin patients with organic gastrointestinal disorders and extended in animal and human studies to the relationship between small bowel motility and gut bacteria; small bowel motility and SIBO; and small bowel motility, SIBO, and bacterial translocation.Why Is Prevention of SIBO Important?Bacterial translocation, a known complication of SIBO,is the movement of gut bacteria from the lumen across the mucosal barrier.In rats, experimentally induced SIBO leads to the appearance of gut bacteria in the mesenteric lymph nodes and visceral organs.A potentially important consequence of bacterial translocation is immune activation. In a report of 11 patients, an increase in the number of intraepithelial lymphocytes was observed as mucosal evidence of this immune response to confirmed bacterial translocation.This adverse outcome could explain why the normal gut has defensive mechanisms in place to keep the bacterial flora away from the small intestine, particularly the bowel proximal to the ileum.Immune Activation Is Also Present in IBSMucosal evidence of an activated immune response has been reported recently in patients who develop IBS after recovering from acute gastroenteritis (postinfectious IBS)and in those without such history.Of the IBS population, 25% to 30% of patients have an antecedent history of acute gastroenteritis.In these reports, postinfectious IBS patients have an increased number of intraepithelial lymphocytes,just like the patient with documented bacterial translocation.An episode of acute gastroenteritis is not needed to explain immune activation in IBS. In a study of 77 IBS patients, an increase in the number of activated intraepithelial lymphocytes was found in almost 90% of the subjects regardless of the acuteness of their onset or their predominant gastrointestinal symptom.The magnitude of the immune activation in patients without a history of acute gastroenteritis is, in fact, even more prominent than those with that history.These observations have provided strong study consistency in support of the biological plausibility for a role of inflammation in IBS as proposed by Collins.Any framework for understanding IBS must, therefore, account for these and other observations of immune activation.The role of an underlying process that involves inflammation in IBS is further supported by observations of a genetic predisposition in some IBS patients to produce less anti-inflammatory productsor more pro-inflammatory products.Although the trigger for the immune response in IBS has not been identified, SIBO would provide a framework for understanding the activated immune response in IBS. In postinfectious IBS patients, along with immune activation, there is also increased intestinal permeability,which has a known association with SIBO in animalsand humansas the experimental correlate of the "leaky gut syndrome."Immune Response to Bacteria Explains Abnormal Motility and Visceral HypersensitivityLipopolysaccharide, an endotoxin of gram-negative bacteria, accelerates intestinal transit.This may be mediated by mast cell degranulation, immune activation, cytokine production, and the triggering of preprogrammed responses of the enteric nervous system, including hypersecretion and power peristalsisleading to diarrhea and cramping abdominal pain.Visceral hypersensitivity has been reported as a characteristic of IBS.The immune response to these bacterial products would also explain this finding. Lipopolysaccharide has also been reported to induce visceral hypersensitivity in rats.Weston et alproposed earlier that increased mast cells in the ileum of IBS patients might be linked to altered visceral perception.Similar to IBS, Fibromyalgia May Also Be Explained by SIBOIt is well recognized that there is a high degree of overlap between IBS, fibromyalgia, interstitial cystitis, and chronic fatigue syndrome.While interstitial cystitisand IBSare diagnoses associated with hypersensitivity at the level of the bladder and gut, respectively, fibromyalgia may be considered a kind of hypersensitivity at the musculoskeletal level.Although the cause of the hypersensitivity in these disorders is not well understood, the striking overlap of hypersensitivity in these functional disorders suggests the possibility of a unifying explanation. In a study of patients meeting American College of Rheumatology criteria for fibromyalgia, an abnormal lactulose breath test result suggesting SIBO was found in 42 out of 42 patients.Fibromyalgia patients had a higher breath hydrogen concentration than IBS patients. Thus, an abnormal breath test result suggesting SIBO may reflect a common pathophysiological link between fibromyalgia and IBS. The immune response to bacterial antigen in SIBO provides a framework for understanding the hypersensitivity in both fibromyalgia and IBS.CONTROVERSIESDiagnostic Approach to SIBOSince direct culture is usually considered the gold standard for the diagnosis of a bacterial disease, the use of an indirect approach such as the lactulose breath test for the diagnosis of SIBO is controversial. When it comes to diagnosing SIBO, the problem with the direct approach is one of access. While bacterial overgrowth can occur only in the more distal portions of the 300- to 500-cm length of the small intestine,direct aspiration and culture are limited by the reach of instrumentation. Since only the small intestine proximal to the ligament of Treitz is usually reached by an endoscope (∼60 cm), there is a high false-negative rate with this approach for the diagnosis of SIBO.Even with these limitations of access, Simren et alreported that 4 (12%) of 33 IBS patients had more than 100 000 colony-forming units of bacteria of colonic origin in the duodenum. While the prevalence is considerably lower than that detected by lactulose breath testing,this study provided direct confirmation of the expansion of colonic bacteria proximally all the way to the duodenum in some IBS patients. Using glucose instead of lactulose as the substrate for a breath test is similarly limited,since glucose is rapidly absorbed with the fermentable substrate removed from the lumen of the upper small intestine. In contrast, since lactulose is poorly digestible, this fermentable substrate does remain available in the lumen for fermentation by gut bacteria anywhere along the gut (Figure 2).Figure 2.Regions of Intestine Accessible by Various Diagnostic Methods to Detect Small Intestinal Bacterial Overgrowth (SIBO)Detection of SIBO depends on location of and access to bacterial flora. SIBO by culture is defined by bacterial concentration proximal to the distal ileum >105organisms per mL. In this example of SIBO, the concentration of bacterial flora in the distal jejunum and ileum has increased to that typically present in the normal colon (1011organisms per mL). Culture of intestinal flora sampled by direct aspiration, which commonly is able to access the duodenum, would not detect the region of increased bacterial flora in this example. Similarly, a breath test using glucose as the fermentable substrate would only detect bacterial flora in the duodenum and proximal jejunum because glucose is rapidly absorbed. In contrast, a breath test using lactulose, which is not absorbed by the intestine, would be able to detect bacterial flora anywhere along the gut.Interpreting a Premature Rise of Breath HydrogenA premature rise of breath hydrogen is a feature of both bacterial overgrowth and excessively rapid transit. However, 2 observations point away from rapid transit as the primary explanation for the findings by Pimentel et al.First, the time-to-rise of breath hydrogen normalized with successful eradication of SIBO by antibiotics in the IBS patients.Second, the abnormal gas profiles of the constipation-predominant IBS (slow transit) patient overlapped with that of the diarrhea-predominant IBS patients (fast transit).Role of Sugar Intolerance in IBSThere has been recent interest in fructose intolerance as a possible explanation for unexplained gastrointestinal symptoms.Interestingly, there is a similar pattern of malabsorption in IBS patients across a number of tested fermentable substrates.For many patients, the association between sugar intolerance and IBS may be related to bacterial overgrowth rather than true sugar intolerance. Nucera et alfound a high rate of disappearance of malabsorption to lactose (86.6%), fructose (97.5%), and sorbitol (90.9%) once SIBO was eradicated. Similarly, Pimentel et al reported that while the number of IBS patients with true lactose intolerance was low (16%), a much higher number (58%) had an abnormal lactose breath test result and there was a significant correlation between lactulose (SIBO) and lactose breath test result.Activated Immunity May Explain Altered Brain-Gut Interaction and Autonomic Dysfunction in IBSAbnormalities of autonomic nervous system function, including disturbed sleep,have been described in patients with IBS.Using SIBO as a framework for understanding IBS, these neural changes can be understood on the basis of 2-way triggered communications between the immune system and the autonomic nervous system.An example of this interaction is the defensive sympathetic response to stress involving immune activation of noradrenergic neurons.Using a variety of brain imaging techniques, IBS patients have been observed to exhibit a different pattern of brain response to visceral stimuli than healthy control subjects.Since inflammation in animal models leads to multiple changes in the brain, including activation of neurons as documented by Fos expression,alteration of hypothalamic-pituitary-adrenal axis including elevation of corticotropin-releasing factor (CRF) concentration,and change in neurotransmitter levels,such altered brain-gut interactions may be a part of the systemic response to a trigger of inflammation. The immune response to bacterial antigens is known to lead to sickness behaviorincluding flu-like symptoms of fatigue, anxiety, depression,and impaired cognition.Within that framework, the psychological and psychiatric comorbidity that are so common in IBSand the response of selected symptoms to cognitive-behavioral therapy or antidepressantsmay be understood.CONCLUSIONSGiven the marked variability of symptoms and findings in patients with IBS, multiple models of pathophysiology and varying treatment strategies have been proposed. In this review, the available observations on IBS were considered and synthesized in an attempt to achieve a goal of integration. In this effort, it is biologically plausible that the gastrointestinal and extraintestinal symptoms and findings of IBS have a single, unifying explanation. Specifically, SIBO provides a framework for understanding IBS by accounting for the following observations in IBS patients. Nearly all of the symptoms and findings of IBS are wholly consistent with SIBO, including postprandial bloating (which is nearly universal), physical evidence of small bowel gas irrespective of predominant symptoms, high prevalence of abnormal lactulose breath test results, dramatic reduction in symptoms when antibiotic therapy is given and breath tests subsequently normalize, altered gut motility, visceral hypersensitivity, abnormal brain-gut interactions, evidence of autonomic dysfunction, nearly uniform immune activation regardless of prior acute gastroenteritis, and extraintestinal symptoms that are often flu-like in quality.As a unifying framework for understanding IBS and other functional disorders, SIBO provides a target for exciting research that may lead to better diagnostic and treatment approaches. SIBO is a condition characterized by a chronic relapsing clinical course.Since indefinite use of antibiotics is not an attractive option, future research should be directed at understanding and controlling the interaction between host and gut bacteria.WGThompsonIrritable bowel syndrome: prevalence, prognosis and consequences.CMAJ.1986;134:111-113.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3484655&dopt=AbstractDADrossmanZLiEAndruzziUS householder survey of functional gastrointestinal disorders: prevalence, sociodemography and health impact.Dig Dis Sci.1993;38:1569-1580.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8359066&dopt=AbstractAPManningWGThompsonKWHeatonAFMorrisTowards positive diagnosis of the irritable bowel.BMJ.1978;2:653-654.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=698649&dopt=AbstractWKruisCThiemeMWeinzierlPSchusslerJHollWPaulusA diagnostic score for the irritable bowel syndrome: its value in the exclusion of organic disease.Gastroenterology.1984;87:1-7.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6724251&dopt=AbstractWGThompsonFHCreedDADrossmanFunctional bowel disorders and functional abdominal pain.Gastroenterol Int.1992;5:75-91.WGThompsonGFLongstrethDADrossmanKWHeatonEJIrvineSAMuller-LissnerFunctional bowel disorders and functional abdominal pain.Gut.1999;45(suppl 2):II43-II47.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10457044&dopt=AbstractLAAaronDBuchwaldA review of the evidence for overlap among unexplained clinical conditions.Ann Intern Med.2001;134(9 pt 2):868-881.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11346323&dopt=AbstractGTriadafilopoulosRWSimmsDLGoldenbergBowel dysfunction in fibromyalgia syndrome.Dig Dis Sci.1991;36:59-64.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1985007&dopt=AbstractSWesselyCNimnuanMSharpeFunctional somatic syndromes: one or many?Lancet.1999;354:936-939.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10489969&dopt=AbstractTNChamiMMSchusterMEBohlmanTJPullmanNKamalWEWhiteheadA simple radiologic method to estimate the quantity of bowel gas.Am J Gastroenterol.1991;86:599-602.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2028951&dopt=AbstractPJWhorwellTreatment.In: Stockbrugger R, Pace F, eds. The Irritable Bowel Syndrome Manual. London, England: Mosby-Wolfe Medical Communications; 1999:71-79.MPetitpierrePGomowskiJ-PGirardIrritable bowel syndrome and hypersensitivity to food.Ann Allergy.1985;54:538-540.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=4014782&dopt=AbstractAKoideTYamaguchiTOdakaQuantitative analysis of bowel gas using plain abdominal radiograph in patients with irritable bowel syndrome.Am J Gastroenterol.2000;95:735-741.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10710067&dopt=AbstractDGMaxtonDFMartinPJWhorwellMGodfreyAbdominal distension in female patients with irritable bowel syndrome: exploration of possible mechanisms.Gut.1991;32:662-664.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2060875&dopt=AbstractRLeaLAHoughtonBReillyPJWhorwellAbdominal distension in irritable bowel syndrome (IBS): is there a relationship to visceral sensitivity?Gastroenterology.2003;124:A-398.MJLewisBReillyLAHoughtonPJWhorwellAmbulatory abdominal inductance plethysmography: towards objective assessment of abdominal distension in irritable bowel syndrome.Gut.2001;48:216-220.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11156643&dopt=AbstractRBLasserJHBondMDLevittThe role of intestinal gas in functional abdominal pain.N Engl J Med.1975;293:524-525.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1152877&dopt=AbstractJSerraFAzpirozJRMalageladaImpaired transit and tolerance of intestinal gas in the irritable bowel syndrome.Gut.2001;48:14-19.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11115817&dopt=AbstractTSKingMEkuaJOHunterAbnormal colonic fermentation in irritable bowel syndrome.Lancet.1998;352:1187-1189.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9777836&dopt=AbstractYKChoiFCJJohlinRWSummersMJacksonSSRaoFructose intolerance: an under-recognized problem.Am J Gastroenterol.2003;98:1348-1353.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12818280&dopt=AbstractSSenKLDearTSKingJOHunterEvaluation of hydrogen excretion after lactulose administration as a screening test for causes of irritable bowel syndrome.Eur J Gastroenterol Hepatol.2002;14:753-756.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12169984&dopt=AbstractHAbrahamssonGastrointestinal motility in patients with the irritable bowel syndrome.Scand J Gastroenterol Suppl.1987;130:21-26.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3477013&dopt=AbstractJRitchiePain from distension of the pelvic colon by inflating a balloon in the irritable colon syndrome.Gut.1973;14:125-132.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=4696535&dopt=AbstractDHSSilvermanJAMunakataHEnnesMAMandelkernCKHohEAMayerRegional cerebral activity in normal and pathologic perception of visceral pain.Gastroenterology.1997;112:64-72.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8978344&dopt=AbstractAAggarwalTFCuttsTLAbellPredominant symptoms in irritable bowel syndrome correlate with specific autonomic nervous system abnormalities.Gastroenterology.1994;106:945-950.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8143999&dopt=AbstractVChadwickWChenDShuActivation of the mucosal immune system in irritable bowel syndrome.Gastroenterology.2002;122:1778-1783.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12055584&dopt=AbstractHJKimMCamilleriSMcKinzieA randomized controlled trial of a probiotic, VSL#3, on gut transit and symptoms in diarrhoea-predominant irritable bowel syndrome.Aliment Pharmacol Ther.2003;17:895-904.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12656692&dopt=AbstractMDLevittProduction and excretion of hydrogen gas in man.N Engl J Med.1969;281:122-127.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=5790483&dopt=AbstractSLGorbachIntestinal microflora.Gastroenterology.1971;60:1110-1129.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=4933894&dopt=AbstractBSDrasarMShinerGMMcLeodStudies on the intestinal flora, I: the bacterial flora of the gastrointestinal tract in healthy and achlorhydric persons.Gastroenterology.1969;56:71-79.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=4885396&dopt=AbstractKHWilsonThe gastrointestinal biota.In: Yamada T, Alpers DH, Laine L, Owyang C, Powell DW, eds. Textbook of Gastroenterology. Philadelphia, Pa: Williams & Wilkins; 1999:624-636.MDLevittMalabsorption of starch: a normal phenomenon.Gastroenterology.1983;85:769-770.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6873617&dopt=AbstractAStrocchiJFurneCEllisMDLevittMethanogens outcompetes sulphate reducing bacteria for H2 in the human colon.Gut.1994;35:1098-1101.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7926913&dopt=AbstractMPimentelEChowHCLinEradication of small intestinal bacterial overgrowth reduces symptoms in irritable bowel syndrome.Am J Gastroenterol.2000;95:3503-3506.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11151884&dopt=AbstractMPimentelEJChowHCLinNormalization of lactulose breath testing correlates with symptom improvement in irritable bowel syndrome: a double blind, randomized controlled study.Am J Gastroenterol.2003;98:412-419.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12591062&dopt=AbstractANayakDKarnadPAbrahamFPMistryMetronidazole relieves symptoms in irritable bowel syndrome: the confusion with so-called "chronic amebiasis."Indian J Gastroenterol.1997;16:137-139.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9357184&dopt=AbstractCNuceraAMLupascuMGabrielliSugar intolerance in irritable bowel syndrome: the role of small bowel bacterial overgrowth.Gastroenterology.2004;126(4[suppl 2]):A511.MPimentelAGMayerSParkEJChowAHasanYKongMethane production during lactulose breath test is associated with gastrointestinal disease presentation.Dig Dis Sci.2003;48:86-92.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12645795&dopt=AbstractHCLinMPimentelJHChenIntestinal transit is slowed by luminal methane.Neurogastroenterol Motil.2002;14:437.MPimentelYKongSParkIBS subjects with methane on lactulose breath test have lower postprandial serotonin levels than subjects with hydrogen.Dig Dis Sci.2004;49:84-87.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14992440&dopt=AbstractEBulbringRCLinThe effect of intraluminal application of 5-hydroxytryptamine and 5-hydroxytryptophan on peristalsis: the local production of 5-HT and its release in relation to intraluminal pressure and propulsive activity.J Physiol (Lond).1958;140:381-407.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=13514713&dopt=AbstractSCFiedorekCLPumphreyHBCasteelBreath methane production in children with constipation and encopresis.J Pediatr Gastroenterol Nutr.1990;10:473-477.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2162940&dopt=AbstractAFCelikJTomlinNWReadThe effect of oral vancomycin on chronic idiopathic constipation.Aliment Pharmacol Ther.1995;9:63-68.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7766746&dopt=AbstractCFCodeJAMarlettThe interdigestive myo-electric complex of the stomach and small bowel of dogs.J Physiol (Lond).1975;246:289-309.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1142245&dopt=AbstractMPimentelEESofferEJChowHCLinLower frequency of MMC is found in IBS subjects with abnormal lactulose breath test suggesting bacterial overgrowth.Dig Dis Sci.2002;47:2639-2643.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12498278&dopt=AbstractGVantrappenJJanssensJHellemansYGhoosThe interdigestive motor complex of normal subjects and patients with bacterial overgrowth of the small intestine.J Clin Invest.1977;59:1158-1166.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=864008&dopt=AbstractEHusebyeVSkarTHoverstadTIversenKMelbyAbnormal intestinal motor patterns explain enteric colonization with gram-negative bacilli in late radiation enteropathy.Gastroenterology.1995;109:1078-1089.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7557072&dopt=AbstractEHusebyePMHellstromFSundlerJChenTMidtvedtInfluence of microbial species on small intestinal myoelectrical activity and transit in germ-free rats.Am J Physiol Gastrointest Liver Physiol.2001;280:G368-G380.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11171619&dopt=AbstractVBNeiuwenhuijsAVerheemHvan Duijvenbode-BeumerThe role of interdigestive small bowel motility in the regulation of gut microflora, bacterial overgrowth and bacterial translocation in rats.Ann Surg.1998;228:188-193.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9712563&dopt=AbstractIDVan FeliusLMAkkermansKBosschaInterdigestive small bowel motility and duodenal bacterial overgrowth in experimental acute pancreatitis.Neurogastronterol Motil.2003;15:267-276.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12787336&dopt=AbstractRDBergAWGarlingtonTranslocation of certain indigenous bacteria from the gastrointestinal tract to the mesenteric lymph nodes and other organs in a gnotobiotic mouse model.Infect Immun.1979;23:403-411.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=154474&dopt=AbstractRDBergEWommackEADeitchImmunosuppression and intestinal bacterial overgrowth synergistically promote bacterial translocation.Arch Surg.1988;123:1359-1364.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3178484&dopt=AbstractNPWoodcockJRobertsonDRMorganKLGreggCJMitchellJMacFieBacterial translocation and immunohistochemical measurement of gut immune function.J Clin Pathol.2001;54:619-623.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11477118&dopt=AbstractKAGweeJCGrahamMWMcKendrickPsychometric scores and persistence of irritable bowel after infectious diarrhoea.Lancet.1996;347:150-153.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8544549&dopt=AbstractKRNealJHebdenRSpillerPrevalence of gastrointestinal symptoms six months after bacterial gastroenteritis and risk factors for development of irritable bowel syndrome: postal survey of patients.BMJ.1997;314:779-782.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9080994&dopt=AbstractKAGweeSMCollinsNWReadIncreased rectal mucosal expression of interleukin 1beta in recently acquired post-infectious irritable bowel syndrome.Gut.2003;52:523-526.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12631663&dopt=AbstractHTornblomGLindbergBNybergBVeressFull-thickness biopsy of the jejunum reveals inflammation and enteric neuropathy in irritable bowel syndrome.Gastroenterology.2002;123:1972-1979.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12454854&dopt=AbstractSPDunlopDJenkinsRCSpillerDistinctive clinical, psychological, and histological features of post-infective bowel syndrome.Am J Gastroenterol.2003;98:1578-1583.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12873581&dopt=AbstractRCSpillerDJenkinsJPThomleyIncreased rectal mucosal enteroendocrine cells, T lymphocytes, and increased gut permeability following acute Campylobacter enteritis and in post-dysenteric irritable bowel syndrome.Gut.2000;47:804-811.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11076879&dopt=AbstractSPDunlopDJenkinsKRNealRCSpillerRelative importance of enterochromaffin cell hyperplasia, anxiety, and depression in post-infectious IBS.Gastroenterology.2003;125:1651-1659.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14724817&dopt=AbstractSMCollinsGBarbaraBVallanceStress, inflammation and the irritable bowel syndrome.Can J Gastroenterol.1999;13(suppl A):47A-49A.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10202209&dopt=AbstractSMCollinsTPichePRampalThe putative role of inflammation in the irritable bowel syndrome.Gut.2001;49:734-745.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11709500&dopt=AbstractSMCollinsA case for immunological basis for irritable bowel syndrome.Gastroenterology.2002;122:2078-2080.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12055614&dopt=AbstractWMGonsalkoraleCPerreyVPravicaPJWhorwellIVHutchinsonInterleukin 10 genotypes in irritable bowel syndrome: evidence for an inflammatory component?Gut.2003;52:91-93.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12477767&dopt=AbstractPVan der VeekYDeKoonMVan den BergHVerspagetADMascleeTumor necrosis factor alpha and interleukin 10 gene polymorphisms in irritable bowel syndrome.Gastroenterology.2004;126:A52.JKMarshallMThabaneJMeddingsIncreased intestinal permeability (IP) in subjects with irritable bowel syndrome (IBS) two years after the Walkerton outbreak of waterborne gastroenteritis.Gastroenterology.2004;126(4[suppl 2]):A520.EADeitchRDSpecianRDBergEndotoxin-induced bacterial translocation and mucosal permeability: role of xanthine oxidase, complement activation and macrophage products.Crit Care Med.1991;19:785-791.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2055056&dopt=AbstractSMRiordanCJMcIverDHThomasVMDuncombeTDBolinMCThomasLuminal bacteria and small-intestinal permeability.Scand J Gastroenterol.1997;32:556-563.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9200287&dopt=AbstractDJWirthlinJJCullenSTSpatesGastrointestinal transit during endotoxemia: the role of nitric oxide.J Surg Res.1996;60:307-311.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8598659&dopt=AbstractRKGoyalIHiranoThe enteric nervous system.N Engl J Med.1996;334:1106-1115.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8598871&dopt=AbstractAMCoelhoJFioramontiLBuenoSystemic lipopolysaccharide influences rectal hypersensitivity in rats: role of mast cells, cytokines, and vagus nerve.Am J Physiol Gastrointest Liver Physiol.2000;279:G781-G790.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11005766&dopt=AbstractAPWestonWLBiddlePSBhatiaPBJMinerTerminal ileal mucosal mast cellls in irritable bowel syndrome.Dig Dis Sci.1993;38:1590-1595.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8359068&dopt=AbstractDVealeGKavanaghJFFieldingOFitzgeraldPrimary fibromyalgia and the irritable bowel syndrome: different expressions of a common pathogenetic process.Br J Rheumatol.1991;30:220-222.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2049586&dopt=AbstractADSperberYAlzmonLNeumannFibromyalgia in the irritable bowel syndrome: studies of prevalence and clinical implications.Am J Gastroenterol.1999;94:3541-3546.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10606316&dopt=AbstractAJWeinPMHannoTargets for therapy of the painful bladder.Urology.2002;59(5[suppl 1]):68-73.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12007525&dopt=AbstractPPToskesAKumarEnteric bacterial flora and bacterial overgrowth syndrome.In: Feldman M, Sleisenger MH, eds. Sleisinger & Fordtran's Gastrointestinal and Liver Diseases.6th ed. Philadelphia, Pa: Saunders; 1998:1523-1555.JJRumessenEGudmand-HoyerEBachmannTJustesenDiagnosis of bacterial overgrowth of the small intestine: comparison of the 14C-D-xylose breath test with jejunal cultures in 60 patients.Scand J Gastroenterol.1985;20:1267-1275.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3912962&dopt=AbstractMAValdovinosMCamilleriGMThomfordeCFrieReduced accuracy of 14C-D-xylose breath test for detecting bacterial overgrowth in gastrointestinal motility disorders.Scand J Gastroenterol.1993;28:963-968.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8284631&dopt=AbstractMSimrenGRingstromPAgerforzESBjornssonHAbrahamssonP-OStotzerSmall intestinal bacterial overgrowth is not of major importance in the irritable bowel syndrome.Gastroenterology.2003;124:A163-A164.FCastiglioneARispoEDi GirolamoAntibiotic treatment of small bowel bacterial overgrowth in patients with Crohn's disease.Aliment Pharmacol Ther.2003;18:1107-1112.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14653830&dopt=AbstractRGoldsteinDBravermanHStankiewiczCarbohydrate malabsorption and the effect of dietary restriction on symptoms of irritable bowel syndrome and functional bowel complaints.Isr Med Assoc J.2000;2:583-587.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10979349&dopt=AbstractWCOrrSElsenbruchMJHarnishAutonomic regulation of cardiac function during sleep in patients with irritable bowel syndrome.Am J Gastroenterol.2000;95:2865-2871.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11051361&dopt=AbstractGHaskoReceptor-mediated interaction between the sympathetic nervous system and immune system in inflammation.Neurochem Res.2001;26:1039-1044.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11699931&dopt=AbstractHBesedovskyAdel ReyESorkinMDa PradaRBurriCHoneggerThe immune response evokes changes in brain noradrenergic neurons.Science.1983;221:564-566.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6867729&dopt=AbstractNCastexJFioramontiJDucos de LahitteGLuffauJMoreLBuenoBrain Fos expression and intestinal motor alterations during nematode-induced inflammation in the rat.Am J Physiol.1998;274(1 pt 1):G210-G216.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9458792&dopt=AbstractCRivierEffect of peripheral and central cytokines on the hypothalamic-pituitary-adrenal axis in the rat.Ann N Y Acad Sci.1993;697:97-105.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8257027&dopt=AbstractSLCarlsonDLFeltenSLivnatSYFeltenAlternations of monoamines in specific central autonomic nuclei following immunization in mice.Brain Behav Immun.1987;1:52-63.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3451782&dopt=AbstractMBergJPGodboutKWKelleyRWJohnsonAlpha-tocopherol attenuates lipopolysaccharide-induced sickness behaviour in mice.Brain Behav Immun.2004;18:149-157.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14759592&dopt=AbstractHAnismanZMeraliCytokines, stress and depressive illness: brain-immune interactions.Ann Med.2003;35:2-11.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12693607&dopt=AbstractWABanksSAFarrJEMorleyEntry of blood-borne cytokines into the central nervous system: effects on cognitive processes.Neuroimmunomodulation.2002-2003;10:319-327.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12907838&dopt=AbstractDADrossmanMCamilleriEAMayerWEWhiteheadAGA technical review on irritable bowel syndrome.Gastroenterology.2002;123:2108-2131.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12454866&dopt=AbstractDADrossmanBBTonerWEWhiteheadCognitive-behavioral therapy versus education and desipramine versus placebo for moderate to severe functional bowel disorders.Gastroenterology.2003;125:19-31.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12851867&dopt=AbstractCorresponding Author:Henry C. Lin, MD, Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, 2011 Zonal Ave, HMR 101, Los Angeles, CA 90033 (henry.c.lin@usc.edu).Funding/Support:This work was supported by an unrestricted gift in support of research from the Todd & Cheri Morgan Donor Advised Fund.Role of the Sponsor:The Todd & Cheri Morgan Donor Advised Fund had no role in the design and conduct of the study; in the collection, analysis, and interpretation or preparation of the data; or in the preparation, review, or approval of the manuscript.Financial Disclosure:Dr Lin has been on the speakers' bureaus and served as a consultant for Novartis and Salix.

Journal

JAMAAmerican Medical Association

Published: Aug 18, 2004

References