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.

Enhancing Diagnostic Performance of Symptom-Based Criteria for Irritable Bowel Syndrome by Additional History and Limited Diagnostic Evaluation

“…20 One biomarker that is available for use in clinical practice currently was examined for its ability to differentiate IBS-D from inflammatory bowel disease, celiac disease, or health. 19 In this study, antibodies to cytolethal toxin B, a toxin commonly produced by Campylobacter 24 and outperformed symptom-based diagnostic criteria alone in a previous metaanalysis. 12 Tibble et al also demonstrated a high diagnostic accuracy of the Rome I criteria in combination with both a fecal calprotectin and a small intestinal permeability ratio.…”

“…[15][16][17][18][19] Some of the proposed biomarkers (which are unfortunately not widely available) may also serve as therapeutic targets and enhance outcomes. Despite this, a systematic review and meta-analysis that evaluated all generally available approaches to diagnose IBS demonstrated that biomarkers alone performed similarly to symptom-based criteria, 20 while adding to the cost of care.…”

Síndrome de intestino irritable y autoinmunidad

“…Del total de 153 artículos se descartaron 141 artícu-los que no cumplieron con los criterios predeterminados de asociación epidemiológica o fisiopatológica entre SII y autoinmunidad y/o autoanticuerpos, y finalmente se seleccionaron 12 artículos para la revisión que cumplieron con dichos criterios. Estos se complementaron con otras 3 referencias citadas en otros artículos o por conocimiento de los autores [11][12][13] .…”

“…Esto condujo al desarrollo de dos nuevos biomarcadores para el diagnóstico del SII, el antiCdtB y el anti-vinculina. El estudio de validación realizado por Pimentel, et al, y publicado en 2015, se llevó a cabo en 2,375 pacientes con SII-D (SII con diarrea) según los criterios de Roma III que participaron en el estudio de TARGET 3 para evaluar la efectividad del retratamiento de rifaximina y 306 controles con EII (73 con enfermedad de Crohn y 69 con colitis ulcerativa crónica idiopática), 121 con enfermedad celíaca y 43 controles sanos 12 . En todos ellos se determinaron las concentraciones plasmáticas de anti-CdtB y anti-vinculina por medio de la técnica ELISA (ensayo por inmunoabsorción ligado a enzimas).…”

“…El área bajo la curva para el diagnóstico de SII-D frente a EII para el antiCdtB y el anti-vinculina fue de 0.81 y 0.62, respectivamente. Sin embargo, estas pruebas mostraron una menor especificidad para la diferenciación del SII-D y la enfermedad celíaca 12 .…”