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      Biomarkers of Irritable Bowel Syndrome

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          Abstract

          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.

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          Most cited references39

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          Normalization of lactulose breath testing correlates with symptom improvement in irritable bowel syndrome. a double-blind, randomized, placebo-controlled study.

          We have recently found an association between abnormal lactulose breath test (LBT) findings and irritable bowel syndrome (IBS). The current study was designed to test the effect of antibiotic treatment for IBS in a double-blind fashion. Consecutive IBS subjects underwent an LBT with the results blinded. All subjects were subsequently randomized into two treatment groups (neomycin or placebo). The prevalence of abnormal LBT was compared with a gender-matched control group. Seven days after completion of treatment, subjects returned for repeat LBT. A symptom questionnaire was administered on both days. After exclusion criteria were met, 111 IBS subjects (55 neomycin, 56 placebo) entered the study, with 84% having an abnormal LBT, compared with 20% in healthy controls (p < 0.01). In an intention-to-treat analysis of all 111 subjects, neomycin resulted in a 35.0% improvement in a composite score, compared with 11.4% for placebo (p < 0.05). Additionally, patients reported a percent bowel normalization of 35.3% after neomycin, compared with 13.9% for placebo (p < 0.001). There was a graded response to treatment, such that the best outcome was observed if neomycin was successful in normalizing the LBT (75% improvement) (one-way ANOVA, p < 0.0001). LBT gas production was associated with IBS subgroup, such that methane excretion was 100% associated with constipation-predominant IBS. Methane excretors had a mean constipation severity of 4.1, compared with 2.3 in all other subjects (p < 0.001). An abnormal LBT is common in subjects with IBS. Normalization of LBT with neomycin leads to a significant reduction in IBS symptoms. The type of gas seen on LBT is also associated with IBS subgroup.
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            Methanogenic flora is associated with altered colonic transit but not stool characteristics in constipation without IBS.

            About 35% of humans have methane-producing gut flora. Methane-producing irritable bowel syndrome (IBS) subjects are generally constipated. In animal models, methane infusion slows intestinal transit. Whether methanogenic flora alters colonic transit or stool characteristics and its relationship to constipation is unclear. The aim of this study was to examine the prevalence and association of methanogenic flora in patients with slow transit (ST) constipation and normal transit (NT) constipation and non-constipated controls. Ninety-six consecutive subjects with chronic constipation (CC) (Rome III) were evaluated with radio-opaque marker (ROM) transit studies and were classified as ST (>20% ROM retention) or NT. All constipated subjects and 106 non-constipated controls underwent breath tests to assess methane production. Baseline CH4 of >or=3 p.p.m. was used to define presence of methanogenic flora. Stool frequency and consistency were assessed using a prospective stool diary. Correlation analyses were performed. Forty-eight subjects had ST and 48 had NT. Prevalence of methanogenic flora was higher (P<0.05) in ST (75%) compared to NT (44%) or controls (28%). ST patients had higher methane production compared to NT and controls (P<0.05). NT patients also produced more methane compared to controls (P<0.05). There was moderate(P<0.05) correlation among baseline, peak, and area under the curve (AUC) of methane response with colonic transit but not with stool characteristics. Presence of methanogenic flora is associated with CC. Methane production after carbohydrate challenge and its prevalence were higher in ST than NT, although stool characteristics were similar in both groups. Methane production correlated with colonic transit, suggesting an association with stool transport but not with stool characteristics.
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              Methanogens, Methane and Gastrointestinal Motility

              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.
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                Author and article information

                Journal
                J Neurogastroenterol Motil
                J Neurogastroenterol Motil
                Journal of Neurogastroenterology and Motility
                Korean Society of Neurogastroenterology and Motility
                2093-0879
                2093-0887
                January 2017
                01 January 2017
                : 23
                : 1
                : 20-26
                Affiliations
                [1 ]Department of Internal Medicine, Ilsan Hospital, Dongguk University, Goyang, Gyeonggi-do, Korea
                [2 ]GI Motility Program, Division of Gastroenterology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
                Author notes
                [* ]Correspondence: Mark Pimentel, MD, FRCP(C), GI Motility Program, Division of Gastroenterology, Cedars-Sinai Medical Center, 8730 Alden Drive, Suite 240E, Los Angeles, CA 90048, USA, Tel: +1-310-423-6143, Fax: +1-310-423-8356, E-mail: pimentelm@ 123456cshs.org
                Article
                jnm-23-020
                10.5056/jnm16135
                5216630
                27817184
                c18bdd19-132a-4411-be02-a5ccc819edb9
                © 2017 The Korean Society of Neurogastroenterology and Motility

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 21 August 2016
                : 16 September 2016
                : 02 October 2016
                Categories
                Review

                Neurology
                biomarkers,constipation,diarrhea,irritable bowel syndrome
                Neurology
                biomarkers, constipation, diarrhea, irritable bowel syndrome

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