Gut microbial dysbiosis activates the classical complement pathway in a short-term morphine treatment model

Antibodies play an essential role in preserving intestinal homeostasis in healthy and dysbiotic states. Recent studies demonstrate that a microbiome-dependent intestine-specific complement system maintains intestinal homeostasis. Morphine induces microbial dysbiosis within hours of administration characterized by the expansion of pathogenic bacteria with a concurrent decrease in commensal bacteria. A murine model of short-term morphine treatment was used to provide insights into the early immune processes during microbial dysbiosis. Within 24 h, morphine treatment upregulates the expression of classical complement pathway genes in intestinal tissue, with a concurrent increase in the complement proteins C1q and C3 in the ileal luminal content. Importantly, a parallel increase in the concentration of complement-activating antibodies IgM and IgG is observed in the ileal luminal content at 24 h. The increased concentration of complement proteins and antibodies are dependent on the microbiome, as microbial depletion prior to morphine treatment abolishes this increase. Finally, intestinal infiltration and activation of neutrophils is observed concurrent with microbial dysbiosis. This study demonstrates rapid microbiome-dependent intestinal recruitment of complement machinery during microbial dysbiosis. Together, these data confirm the relationship between intestinal complement and the microbiome and shows that the classical complement system is activated to protect the host during microbial dysbiosis.