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Published on: December 16, 2021
C4B gene influences intestinal microbiota through complement activation in patients with paediatric-onset
E Nissilä1,2, K Korpela1, A I Lokki1,3
1Immunobiology, Research Programs Unit, University of Helsinki, Helsinki, Finland.
Insights
The number of C4B genes influences gut bacteria diversity in children with inflammatory bowel disease (IBD). More C4B genes correlate with increased complement system activation, potentially worsening IBD-associated dysbiosis.
Area of Science:
- Immunology
- Genetics
- Microbiology
Background:
- Complement C4 genes are associated with pediatric inflammatory bowel disease (PIBD).
- The specific mechanisms linking C4 gene variations to PIBD pathogenesis remain unclear.
- Understanding this link is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the impact of C4B gene copy number on intestinal microbiota composition in PIBD patients.
- To assess the effect of C4B gene number on in-vitro serum complement activation by intestinal microbes.
- To explore the relationship between C4B gene number, disease severity, and gut microbiome.
Main Methods:
- Genomic RT-PCR was used to determine C4A and C4B gene copy numbers in 64 PIBD patients.
- Intestinal microbiota was analyzed using the HITChip microarray.
- Serum complement activation was measured by incubating patient sera with bacteria (Yersinia pseudotuberculosis, Akkermansia muciniphila) and quantifying C3a and SC5b-9 levels.
Main Results:
- Microbiota diversity was greater in patients lacking C4B genes compared to those with one or two copies, irrespective of inflammation.
- C4B and total C4 gene copy numbers positively correlated with soluble terminal complement complex (TCC) levels upon bacterial stimulation.
- A positive association was found between C4B gene number and inflammation severity in PIBD patients.
Conclusions:
- C4B gene copy number is linked to inflammation in PIBD.
- Increased C4B gene copies may exacerbate IBD-associated dysbiosis via heightened complement reactivity to gut microbes.
- This suggests a potential role for complement dysregulation in PIBD development and progression.
Abstract:
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.
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