Intestinal Complement Modulates Colitis by Targeting the Gut Microbiota
AbstractThe proteins that make up the immune effector system known as complement are synthesized by hepatocytes and are present at high levels in the bloodstream. Serum complement not only displays antimicrobial activities such as bacteriolysis and opsonization, but is also involved in boosting adaptive immune responses to foreign antigens. However, little is known about the presence or activity of complement on mucosal surfaces, including the gastrointestinal mucosa.
The studies described here provide new insights into complement function within the mouse intestinal mucosa. Specifically, we show that the level of complement component C3 in intestinal contents is dependent upon the presence of the gut commensal microbiota. Germ-free animals are deficient in intestinal complement compared to conventionally raised animals. C3 is synthesized and secreted by epithelial cell lines when stimulated by bacteria. In situ hybridization detects C3 mRNA in intestinal cells, and C3 protein can be found in the intestinal lumen, where it coats bacterial cells. Using fluorescence-activated cell sorting (FACS) and next-generation sequencing (a method we call C3-SEQ), we showed that many, but not all, bacterial types in the colon are coated with C3 under normal homeostatic conditions. We collected C3-coated and non-coated bacterial cells by FACS, implanted the bacteria into germ-free mice, and challenged the animals with dextran sodium sulfate. Compared to mice challenged with non-coated bacteria, the mice harboring C3-coated bacteria developed more severe colitis, with significant weight loss and histologic damage. In addition, C3 was found to be important in the control of the non-invasive enteric pathogen Citrobacter rodentium, opsonizing this organism within the intestine. Overall, our studies show that the complement system is active in intestinal mucosal secretions, where it modulates the gut microbiota and plays a critical role in maintaining intestinal homeostasis and health.
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