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

Author:

Nissilä E12ORCID,Korpela K1,Lokki A I13,Paakkanen R4,Jokiranta S12,de Vos W M1,Lokki M-L4,Kolho K-L5,Meri S126

Affiliation:

1. Immunobiology, Research Programs Unit, University of Helsinki, Helsinki, Finland

2. Department of Bacteriology and Immunology, University of Helsinki, Helsinki, Finland

3. Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland

4. Transplantation Laboratory, Medicum, University of Helsinki, Helsinki, Finland

5. Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland

6. Helsinki University Hospital Laboratory (HUSLAB), Helsinki, Finland

Abstract

Summary Complement C4 genes are linked to paediatric 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 reverse transcription–polymerase chain reaction (RT-PCR) from 64 patients with PIBD (Crohn's disease or ulcerative colitis). The severity of the disease course was determined from faecal calprotectin levels. Intestinal microbiota was assessed using the HITChip microarray. Complement reactivity in patients was analysed by incubating their sera with Yersinia pseudotuberculosis and Akkermansia muciniphila and determining the levels of C3a and soluble terminal complement complex (SC5b-9) using enzyme immunoassays. The microbiota diversity was wider in patients with no C4B genes than in those with one or two 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 with 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.

Funder

Finnish Foundation for Pediatric Research

Helsinki University Central Hospital Research Funds

Academy of Finland

Sigrid Jusélius Foundation

Publisher

Oxford University Press (OUP)

Subject

Immunology,Immunology and Allergy

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