Traditionally, irritable bowel syndrome (IBS) has not been regarded as an organic disease, and the pathophysiology of IBS is heterogeneous. Currently, the diagnosis of IBS is based upon the Rome diagnostic criteria. The performance of these criteria is only modest in predicting IBS, and moreover their validation is lacking. Additionally, as functional symptoms are common in the general population, healthy controls or volunteers are difficult to define and there is currently no definition of “normal” in the Rome criteria. Due to the weaknesses of the current diagnostic criteria, patients and doctors expect new gold standard diagnostic tools. Various etiologic mechanisms result in potential biomarkers. The focus of this research has been to find non-invasive biomarkers from serum, breath gas, and fecal materials. Though biomarkers should be based on biological and pathogenic processes, most biomarkers for IBS have been developed to identify organic diseases and therefore eliminate IBS. To date, these types of biomarkers for IBS have been disappointing. The purposes of developing biomarkers include improvement of diagnosis, differentiation from other organic diseases, and discrimination of IBS subtypes. A true mechanistic biomarker would make it possible to rule in IBS, rather than to rule out other organic diseases. New serologic biomarkers for diarrhea-predominant IBS have been introduced based on the pathophysiologic findings from a rat model and validation in a large-scale clinical trial. Further investigations of abnormal organic findings from each subtype of IBS would enable the development of new, simple subtype-specific biomarkers.
Biomarkers* ; Constipation ; Diagnosis ; Diarrhea ; Discrimination (Psychology) ; Humans ; Irritable Bowel Syndrome* ; Models, Animal ; Volunteers

Ongoing efforts to improve clinical trial design in irritable bowel syndrome have been hindered by high placebo response rates and ineffective outcome measures. We assessed established strategies to minimize placebo effect as well as the various approaches to placebo effect which can affect trial design. These include genetic markers such as catechol-O-methyltransferase, opioidergic and dopaminergic neurobiologic theory, pre-cebo effect centered on expectancy theory, and side effect unblinding grounded on conditioning theory. We reviewed endpoints used in the study of IBS over the past decade including adequate relief and subjective global relief, emphasizing their weaknesses in fully evaluating the IBS condition, specifically their motility effects based on functional net value and relative benefit-harm based on dropouts due to adverse events. The focus of this review is to highlight ongoing efforts to improve clinical trial design which can lead to better outcomes in a real-world setting.
Catechol O-Methyltransferase ; Genetic Markers ; Humans ; Irritable Bowel Syndrome* ; Outcome Assessment (Health Care) ; Patient Dropouts ; Placebo Effect* ; Placebos

Gut microbiota and their metabolites like bile acid (BA) have been investigated as causes of irritable bowel syndrome (IBS) symptoms.Primary BAs are synthesized and conjugated in the liver and released into the duodenum. BA biotransformation by gut microbiota begins in the intestine and results in production of a broad range of secondary BAs. Deconjugation is considered the gateway reaction for further modification and is mediated by bile salt hydrolase, which is widely expressed by the gut microbiota. However, gut bacteria that convert primary BAs to secondary BAs belong to a limited number of species, mainly Clostridiales. Like gut microbiota modify BA profile, BAs can shape gut microbiota via direct and indirect actions. BAs have prosecretory effects and regulates gut motility. BAs can also affect gut sensitivity. Because of the vital role of the gut microbiota and BAs in gut function, their bidirectional relationship may contribute to the pathophysiology of IBS. Individuals with IBS have been reported to have altered microbial profiles and modified BA profiles. A significant increase in fecal primary BA and a corresponding decrease in secondary BA have been observed in IBS with predominant diarrhea. In addition, primary BA was positively correlated with IBS symptoms. In IBS with predominant diarrhea, bacteria with reduced abundance mainly belonged to the genera in Ruminococcaceae and exhibited a negative correlation with primary BAs. Integrating the analysis of the gut microbiota and BAs could better understanding of IBS pathophysiology. The gap in this field needs to be further filled in the future.

Background/Aims: We performed a systematic review and meta-analysis evaluating the symptomatic response rate to antibiotics in patients with small intestinal bacterial overgrowth (SIBO). Similarly, we performed a meta-analysis on the symptomatic response to antibiotics in irritable bowel syndrome (IBS) patients with and without SIBO. Methods: MEDLINE, EMBASE, Web of Science, and Cochrane databases were searched from inception to March 2021. Randomized controlled trials and prospective studies reporting dichotomous outcomes were included. Results: There were 6 studies included in the first meta-analysis comparing the efficacy of antibiotics to placebo or no antibiotic. This included 196 patients, of whom 101 received antibiotics and 95 received placebo or no antibiotics. Significantly more patients improved with antibiotics (relative risk [95% CI] = 2.46 [1.33-4.55], P = 0.004). There were 4 studies included in the analysis comparing symptomatic response rates in IBS patients with or without SIBO with 266 IBS patients, of whom 172 had SIBO and 94 did not. The pooled response rate for symptomatic response was 51.2% in the SIBO group vs 23.4% in the no SIBO group, respectively. Significantly more IBS patients with SIBO responded to antibiotics compared to those without SIBO (relative risk [95% CI] = 2.07 [1.40-3.08], P = 0.0003). Conclusions Antibiotics appear to be efficacious in treating SIBO, although small sample sizes and poor data quality limit this interpretation. Symptomatic response rates also appear to be higher in IBS patients with SIBO. This may be the first example of precision medicine in IBS as opposed to our current empiric treatment approach. Large-multicenter studies are needed to verify the results.

BACKGROUND/AIMS: Recent studies reveal that acute gastroenteritis can precipitate irritable bowel syndrome (IBS) symptoms leading to the concept of post-infectious IBS. However, the overall contribution of gastroenteritis to the total IBS prevalence is unknown. In this exercise we try to estimate the contribution of gastroenteritis in IBS using the published literature and a longitudinal approach. METHODS: Existing literature was reviewed to determine the incidence of IBS after gastroenteritis, the rate of remission over time, data on rates of gastroenteritis in a given population and any patterns of resistance to these effects in human populations. This produced 3 models. The first assumed all humans were susceptible to gastroenteritis and its ability to produce IBS. The second assumed (using meta-analysis data) that 90% of humans in a given outbreak would be resistant to this effect. The third model used a high gastroenteritis exposure rate as might be seen in military deployment. RESULTS: In model 1, the prevalence was unrealistically high with an eventual steady state of 43.6% of the population affected by IBS. In a very conservative approach (model 2), steady state was achieved after 10 years to an overall prevalence of 8.9%. Interestingly, based on a high 1 year exposure rate such as military deployment, the maximum prevalence (steady state) was reached before 1 year suggesting high risk. CONCLUSIONS: Although hypothetical in approach, based on conservative estimates in existing literature the contribution of gastroenteritis to the overall prevalence of IBS is substantial.
Gastroenteritis ; Humans ; Incidence ; Irritable Bowel Syndrome ; Military Personnel ; Prevalence

BACKGROUND/AIMS: In high-resolution manometry lower esophageal sphincter pressure (LESP) is measured relative to intragastric pressure, however Gastric Marker(TM) (GM) location used to determine resting LESP is not well established with hiatal hernia (HH). We test the hypothesis that measured resting LESP varies with HH based on GM location. METHODS: Subjects with HH > or = 2 cm were included. The eSleeve(TM) was adjusted to span only the LES, excluding the crural diaphragm (CD). Resting LESP was determined by placing the GM below and above the CD (in the position yielding the highest resting LESP). Resting pressure across the lower esophageal sphincter (LES) to CD and pressure in the HH relative to subdiaphragmatic intragastric pressure were also measured. RESULTS: HH > or = 2 cm was present in 98 patients (mean length 2.7 cm). LESP decreased when GM was moved from below the CD into the HH: respiratory minimum LESP 7.5 +/- 1.1 to 3.6 +/- 0.9 mmHg; P < 0.001, mean LESP 17.7 +/- 1.3 to 13.7 +/- 1.1 mmHg; P < 0.001. When the eSleeve encompassed the LES and CD, the respiratory minimum pressure was 12.2 +/- 0.9 mmHg and mean pressure was 23.9 +/- 1.0 mmHg pressure (P < 0.001 for both). Pressure in the hernia pouch was greater than intragastric pressure: respiratory minimum 3.0 +/- 0.7 mmHg and mean 9.0 +/- 0.8 mmHg (P < 0.001 for both). pH studies showed a trend toward an association between abnormal distal esophagus acid exposure and lower resting LESP. CONCLUSIONS: GM placement in the HH produces lower resting LESPs. This may provide a more physiologic representation of LESP in HH.
Catheters ; Diaphragm ; Esophageal Sphincter, Lower ; Esophagus ; Gastroesophageal Reflux ; Hernia ; Hernia, Hiatal* ; Humans ; Hydrogen-Ion Concentration ; Manometry

Anaerobic fermentation of the undigested polysaccharide fraction of carbohydrates produces hydrogen in the intestine which is the substrate for methane production by intestinal methanogens. Hydrogen and methane are excreted in the flatus and in breath giving the opportunity to indirectly measure their production using breath testing. Although methane is detected in 30%-50% of the healthy adult population worldwide, its production has been epidemiologically and clinically associated with constipation related diseases, like constipation predominant irritable bowel syndrome and chronic constipation. While a causative relation is not proven yet, there is strong evidence from animal studies that methane delays intestinal transit, possibly acting as a neuromuscular transmitter. This evidence is further supported by the universal finding that methane production (measured by breath test) is associated with delayed transit time in clinical studies. There is also preliminary evidence that antibiotic reduction of methanogens (as evidenced by reduced methane production) predicts the clinical response in terms of symptomatic improvement in patients with constipation predominant irritable bowel syndrome. However, we have not identified yet the mechanism of action of methane on intestinal motility, and since methane production does not account for all constipation associated cases, there is need for high quality clinical trials to examine methane as a biomarker for the diagnosis or as a biomarker that predicts antibiotic treatment response in patients with constipation related disorders.
Adult ; Animals ; Breath Tests ; Carbohydrates ; Constipation ; Diagnosis ; Fermentation ; Flatulence ; Gastrointestinal Motility* ; Gastroparesis ; Humans ; Hydrogen ; Intestines ; Irritable Bowel Syndrome ; Methane* ; Methanococcus

BACKGROUND/AIMS: Campylobacter jejuni infection is a leading cause of acute gastroenteritis, which is a trigger for post-infectious irritable bowel syndrome (PI-IBS). Cytolethal distending toxin (CDT) is expressed by enteric pathogens that cause PI-IBS. We used a rat model of PI-IBS to investigate the role of CDT in long-term altered stool form and bowel phenotypes. METHODS: Adult Sprague-Dawley rats were gavaged with wildtype C. jejuni (C+), a C. jejuni cdtB knockout (CDT-) or saline vehicle (controls). Four months after gavage, stool from 3 consecutive days was assessed for stool form and percent wet weight. Rectal tissue was analyzed for intraepithelial lymphocytes, and small intestinal tissue was stained with anti-c-kit for deep muscular plexus interstitial cells of Cajal (DMP-ICC). RESULTS: All 3 groups showed similar colonization and clearance parameters. Average 3-day stool dry weights were similar in all 3 groups, but day-to-day variability in stool form and stool dry weight were significantly different in the C+ group vs both controls (P < 0.01) and the CDT- roup (P < 0.01), but were not different in the CDT- vs controls. Similarly, rectal lymphocytes were significantly higher after C. jejuni (C+) infection vs both controls (P < 0.01) and CDT-exposed rats (P < 0.05). The counts in the latter 2 groups were not significantly different. Finally, c-kit staining revealed that DMP-ICC were reduced only in rats exposed to wildtype C. jejuni. CONCLUSIONS: In this rat model of PI-IBS, CDT appears to play a role in the development of chronic altered bowel patterns, mild chronic rectal inflammation and reduction in DMP-ICC.
Adult ; Animals ; Bacterial Toxins ; Campylobacter Infections ; Campylobacter jejuni ; Colon ; Gastroenteritis ; Humans ; Inflammation ; Interstitial Cells of Cajal ; Irritable Bowel Syndrome ; Lymphocytes ; Models, Animal ; Phenotype ; Rats ; Rats, Sprague-Dawley ; Weights and Measures