The complement system is involved in human IBD and interacts with commensal bacteria

Introduction:

While its key impact as major effector arm of the humoral immune system is well established, the role of the complement system in gut immune homeostasis remains obscure. A recent genome wide association study associates variants of the complement protein C4 with Crohn's disease.

Methods:

This study aims to investigate interactions of the complement system with the intestinal microbiota and its impact on mucosal immunity in health and inflammation. Intestinal complement components were analyzed by quantitative real-time PCR from biopsy specimens of IBD patients and healthy controls. Fecal complement proteins were further assayed by ELISA. Complement opsonization of the microbiota was quantified by flow cytometry (FC) on fecal bacterial single cell suspensions. Complement C3b,c and/or Immunoglobulin A positive events were quantified and statistically linked to the level of inflammation and other clinical metadata. The individual FC populations were separated by fluorescence-activated cell sorting (FACS) and populations characterized by metagenomic 16S rDNA analysis.

Results:

Expression of complement proteins in ileal and colonic biopsies was generally increased during inflammation, but notably some targets also showed downregulation. Complement proteins in the feces were hardly detectable and only certain complement proteins surpassed the detection limit. In contrast, C3b was readily detectable on fecal bacteria and its abundance correlated significantly with fecal calprotectin (p = 0.003), while the proportion of opsonized bacteria (0% to 4%) did not. IgA opsonization increased significantly with inflammation. Using FACS and metagenomics analysis, differentially abundant taxa between sorting groups could be found. For these species, prediction of their metabolic potential and common traits was performed.

Conclusion:

The complement system is involved in mucosal and luminal immunity in patients with IBD. This study indicates a certain degree of specificity of complement towards commensal bacteria, which is distinct from IgA.