Increased Sero-Reactivity To Antigens Of Firmicutes Flagellin Prior To Diagnosis Of Crohn'S Disease

BACKGROUND: Disturbance of symbiosis between host and gut microbiota has been shown to have an important role in the pathogenesis of inflammatory bowel disease (IBD).In particular, fecal and mucosal-associated microbial diversity are significantly changed in patients with Crohn's disease, showing reduced Firmicutes but increased Proteobacteria.However, it is unknown whether immune response to altered microbial diversity predates the diagnosis of IBD.AIM: The aim of this study was to assess for changes in the adaptive immune response to intestinal microbiota in the pre-diagnostic stage of IBD.METHODS: This study used the pre-and peri-diagnoses sera of 300 U.S. military personnel with Crohn's disease (CD), ulcerative colitis (UC), and healthy controls.Three serum samples were obtained for each individual: just before diagnosis, approximately 2 years prior to diagnosis, and at the time of the earliest available serum.The serum IgG response to a panel of intestinal microbiota antigens was assessed using a novel protein microarray previously described (Christmann BS, Abrahamsson TR, Bernstein CN, et al.Human seroreactivity to gut microbiota antigens.J Allergy Clin Immunol.2015 Nov;136(5):1378-1386).Antigens on the array represented the major phylum somatic and flagella antigens of Bacteroidetes, Firmicutes, and Proteobacteria.Nonparametric tests were used to compare the average sero-reactivity to antigens from different phyla prior to diagnosis among patients with CD, UC, and controls. RESULTS:The earliest available serum sample for patients with CD and UC was obtained at a median of 6 years (IQR, 5.6-8.2) before diagnosis and at a median of 7.8 years (IQR, 10.4-6.0)before diagnosis, respectively.Comparing these first available samples, IgG immune reactivity against all tested phyla antigens was significantly higher in patients with CD, compared to patients with UC and controls (Figure).The difference in IgG immune reactivity to phyla antigens among the three groups was decreased as the diagnosis approached, except IgG reactivity to Firmicutes-related antigens.In particular, IgG immune reactivity to Firmicutes Flagellin antigens in all three samples was consistently significantly higher in patients with CD, compared to patients with UC and controls.Interestingly, IgG reactivity to Proteobacteria antigens in patients with CD was significantly reduced approaching diagnosis (P for trend = .02).CONCLUSIONS: The immune system long harbors a potent immune response directed against flagellar antigens derived from Firmicutes that are known to be reduced in active Crohn's disease.These data suggest that an abnormal adaptive immune response to specific microbial antigens could be a key early event in CD pathogenesis.