The gut complement system, primarily composed of complement component 3 (C3), is synthesized locally by stromal cells in the intestinal mucosa and is regulated by the composition of the gut microbiota. This system plays a critical role in defending against pathogens while sparing commensal bacteria. C3 is expressed upon colonization with commensal microbes and is regulated by the host's microbiota, leading to individual-specific luminal C3 levels. The absence of membrane attack complex (MAC) components in the gut prevents C3 from lysing commensals. Pathogen infection triggers immune responses that recruit neutrophils to clear pathogens, with basal C3 levels correlating with protection against enteric infections. The gut complement system functions as an innate immune sentinel, combating pathogens and maintaining tolerance to the microbiota. C3 is produced by stromal cells in the subepithelial compartment of the intestine, which are the primary source of C3 expression during homeostasis. Stromal cells express C3 in response to bacterial stimulation, and their C3 production is influenced by microbial interactions. The gut complement system includes components such as C1q, Cfp, and C4B, which are expressed in different cell populations. The system's ability to opsonize pathogens and facilitate phagocytosis by neutrophils is crucial for clearing infections. C3-deficient mice are more susceptible to infections, highlighting the importance of the gut complement system in host defense. The study demonstrates that the gut complement system is distinct from the systemic complement system and is regulated by the microbiota. The presence of C3 in the gut lumen is influenced by the composition of the microbiota, with certain bacterial species, such as Prevotella spp., contributing to high C3 production. The gut complement system's role in protecting against pathogens like Citrobacter rodentium and E. coli is significant, with C3-dependent phagocytosis by neutrophils playing a key role in pathogen clearance. The findings suggest that the gut complement system is essential for maintaining intestinal homeostasis and protecting against enteric infections. The study also highlights the importance of the microbiota in shaping the host's immune response and susceptibility to infections.The gut complement system, primarily composed of complement component 3 (C3), is synthesized locally by stromal cells in the intestinal mucosa and is regulated by the composition of the gut microbiota. This system plays a critical role in defending against pathogens while sparing commensal bacteria. C3 is expressed upon colonization with commensal microbes and is regulated by the host's microbiota, leading to individual-specific luminal C3 levels. The absence of membrane attack complex (MAC) components in the gut prevents C3 from lysing commensals. Pathogen infection triggers immune responses that recruit neutrophils to clear pathogens, with basal C3 levels correlating with protection against enteric infections. The gut complement system functions as an innate immune sentinel, combating pathogens and maintaining tolerance to the microbiota. C3 is produced by stromal cells in the subepithelial compartment of the intestine, which are the primary source of C3 expression during homeostasis. Stromal cells express C3 in response to bacterial stimulation, and their C3 production is influenced by microbial interactions. The gut complement system includes components such as C1q, Cfp, and C4B, which are expressed in different cell populations. The system's ability to opsonize pathogens and facilitate phagocytosis by neutrophils is crucial for clearing infections. C3-deficient mice are more susceptible to infections, highlighting the importance of the gut complement system in host defense. The study demonstrates that the gut complement system is distinct from the systemic complement system and is regulated by the microbiota. The presence of C3 in the gut lumen is influenced by the composition of the microbiota, with certain bacterial species, such as Prevotella spp., contributing to high C3 production. The gut complement system's role in protecting against pathogens like Citrobacter rodentium and E. coli is significant, with C3-dependent phagocytosis by neutrophils playing a key role in pathogen clearance. The findings suggest that the gut complement system is essential for maintaining intestinal homeostasis and protecting against enteric infections. The study also highlights the importance of the microbiota in shaping the host's immune response and susceptibility to infections.