Gut complement induced by the microbiota combats pathogens and spares commensals

Canonically, the complement system is known for its rapid response to remove microbes in the bloodstream. However, relatively little is known about a functioning complement system on intestinal mucosal surfaces. Herein we report the local synthesis of complement component 3 (C3) in the gut, primarily by stromal cells. C3 is expressed upon commensal colonization, is regulated by the composition of the microbiota in healthy humans and mice, leading to an individual host's specific luminal C3 levels. The absence of membrane attack complex (MAC) components in the gut ensures that C3 deposition does not result in the lysis of commensals. Pathogen infection triggers the immune system to recruit neutrophils to the infection site for pathogen clearance. Basal C3 levels directly correlate with protection against enteric infection. Our study reveals the gut complement system as a novel innate immune mechanism acting as a vigilant sentinel that combats pathogens and spares commensals. Overall design: To examine the C3 transcriptional levles and other complement gene expression levels in the colon, we used fluorescence-activated cell sorting (FACS) to isolate stromal (EpCAM-CD45-CD31-PDPN+ cells), CD45+, and IEC (EpCAM+) populations from the subepithelial compartment of the colon of WT C57BL/6 mice, then performed bulk RNASeq.