title: Development and validation of a biomarker for diarrhea-predominant irritable bowel syndrome in human subjects.
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.
authors.affiliation: GI Motility Program, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
authors.forename: Mark
authors.initials: M
authors.lastname: Pimentel
authors.affiliation: GI Motility Program, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
authors.forename: Walter
authors.initials: W
authors.lastname: Morales
authors.affiliation: GI Motility Program, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
authors.forename: Ali
authors.initials: A
authors.lastname: Rezaie
authors.affiliation: GI Motility Program, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
authors.forename: Emily
authors.initials: E
authors.lastname: Marsh
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America.
authors.forename: Anthony
authors.initials: A
authors.lastname: Lembo
authors.affiliation: Department of Biostatistics, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
authors.forename: James
authors.initials: J
authors.lastname: Mirocha
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Leffler
authors.affiliation: GI Motility Program, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Marsh
authors.affiliation: GI Motility Program, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
authors.forename: Stacy
authors.initials: S
authors.lastname: Weitsman
authors.affiliation: GI Motility Program, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
authors.forename: Kathleen S
authors.initials: KS
authors.lastname: Chua
authors.affiliation: GI Motility Program, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
authors.forename: Gillian M
authors.initials: GM
authors.lastname: Barlow
authors.affiliation: Salix Pharmaceuticals, Inc., Raleigh, North Carolina, United States of America.
authors.forename: Enoch
authors.initials: E
authors.lastname: Bortey
authors.affiliation: Salix Pharmaceuticals, Inc., Raleigh, North Carolina, United States of America.
authors.forename: William
authors.initials: W
authors.lastname: Forbes
authors.affiliation: GI Motility Program, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
authors.forename: Allen
authors.initials: A
authors.lastname: Yu
authors.affiliation: GI Motility Program, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
authors.forename: Christopher
authors.initials: C
authors.lastname: Chang
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001323:Autoantibodies / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D003937:Diagnosis, Differential; D003967:Diarrhea / Q000097:blood* / Q000175:diagnosis / Q000276:immunology; D005260:Female; D006801:Humans; D043183:Irritable Bowel Syndrome / Q000097:blood* / Q000175:diagnosis / Q000276:immunology; D008297:Male; D008875:Middle Aged; D012372:ROC Curve; D055815:Young Adult
chemical_list: D001323:Autoantibodies; D015415:Biomarkers