C4B gene influences intestinal microbiota through complement activation in patients with paediatric‐onset inflammatory bowel disease

Summary Complement C4 genes are linked to pediatric inflammatory bowel disease (PIBD), but the mechanisms have remained unclear. We examined the influence of C4B gene number on intestinal microbiota and in vitro serum complement activation by intestinal microbes in PIBD patients. Complement C4A and C4B gene numbers were determined by genomic RT-PCR from 64 patients with PIBD (Crohn's disease or ulcerative colitis). The severity of the disease course was determined from fecal calprotectin levels. Intestinal microbiota was assessed using the HITChip microarray. Complement reactivity in patients was analyzed by incubating their sera with Yersinia pseudotuberculosis and Akkermansia muciniphila and determining the levels of C3a and SC5b-9 using enzyme immunoassays. The microbiota diversity was wider in patients with no C4B genes than in those with 1 or 2 C4B genes, irrespective of intestinal inflammation. C4B and total C4 gene numbers correlated positively with soluble terminal complement complex (TCC, SC5b-9) levels, when patient serum samples were stimulated with bacteria. Our results suggest that the C4B gene number associates positively to inflammation in patients with PIBD. Multiple copies of the C4B gene may thus aggravate the IBD-associated dysbiosis through escalated complement reactivity towards the microbiota. (Word count 191/250) This article is protected by copyright. All rights reserved.