Abstract
Diarrhea-predominant irritable bowel syndrome (IBS) is diagnosed through clinical criteria after excluding “organic” conditions, and can be precipitated by acute gastroenteritis. Cytolethal distending toxin B (CdtB) is produced by bacteria that cause acute gastroenteritis, and a post-infectious animal model demonstrates that host antibodies to CdtB cross-react with vinculin in the host gut, producing an IBS-like phenotype. Therefore, we assessed circulating anti-CdtB and anti-vinculin antibodies as biomarkers for D-IBS in human subjects. Subjects with D-IBS based on Rome criteria (n=2375) were recruited from a large-scale multicenter clinical trial for D-IBS (TARGET 3). Subjects with inflammatory bowel disease (IBD) (n=142), subjects with celiac disease (n=121), and healthy controls (n=43) were obtained for comparison. Subjects with IBD and celiac disease were recruited based on the presence of intestinal complaints and histologic confirmation of chronic inflammatory changes in the colon or small intestine. Subjects with celiac disease were also required to have an elevated tTG and biopsy. All subjects were aged between 18 and 65 years. Plasma levels of anti-CdtB and anti-vinculin antibodies were determined by ELISA, and compared between groups. Anti-CdtB titers were significantly higher in D-IBS subjects compared to IBD, healthy controls and celiac disease (P<0.001). Anti-vinculin titers were also significantly higher in IBS (P<0.001) compared to the other groups. The area-under-the-receiver operating curves (AUCs) were 0.81 and 0.62 for diagnosis of D-IBS against IBD for anti-CdtB and anti-vinculin, respectively. Both tests were less specific in differentiating IBS from celiac disease. Optimization demonstrated that for anti-CdtB (optical density≥2.80) the specificity, sensitivity and likelihood ratio were 91.6%, 43.7 and 5.2, respectively, and for anti-vinculin (OD≥1.68) were 83.8%, 32.6 and 2.0, respectively. These results confirm that anti-CdtB and anti-vinculin antibodies are elevated in D-IBS compared to non-IBS subjects. These biomarkers may be especially helpful in distinguishing D-IBS from IBD in the workup of chronic diarrhea.
Highlights
In the clinical evaluation of chronic diarrhea, common differential diagnoses include diarrheapredominant irritable bowel syndrome (D-IBS), inflammatory bowel disease (IBD) and celiac disease
There were no differences in sex distribution of IBS and non-IBS subjects; percentage of females was greater in the healthy controls, IBS and celiac groups as compared with the IBD group (P
There were no differences in anti-Cytolethal distending toxin B (CdtB) levels between healthy subjects and IBD subjects (p = 0.23); subjects with celiac disease had higher anti-CdtB levels than all other non-IBS groups (P
Summary
In the clinical evaluation of chronic diarrhea, common differential diagnoses include diarrheapredominant irritable bowel syndrome (D-IBS), inflammatory bowel disease (IBD) and celiac disease. While IBS is the most common gastrointestinal disorder with reported prevalence rates of approximately 15% of the population [7], it is considered a “functional condition” in the absence of a known “organic” biomarker. New insights into D-IBS pathogenesis have emerged, regarding the roles of acute gastroenteritis and alterations in the intestinal microbiota in the pathogenesis of this condition. D-IBS patients have alterations in their small bowel microbial flora as demonstrated by breath testing [8] as well as culture studies [9,10] and deep sequencing [11] of small bowel flora. PI-IBS may be linked to changes in the gut microbiome based on emerging animal models
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