The study reveals the presence of a gut complement system, distinct from the systemic complement system, which is primarily synthesized by stromal cells in the intestinal lumen. This system is regulated by the composition of the gut microbiota and plays a crucial role in combatting pathogens while preserving commensal bacteria. Key findings include: 1. **Local Synthesis of C3**: C3, a central component of the complement system, is synthesized locally in the gut by stromal cells and regulated by the gut microbiota. This synthesis is not observed in the liver or plasma. 2. **Microbiota-Dependent C3 Levels**: C3 levels in the gut lumen are influenced by the composition of the gut microbiota, leading to individual-specific levels. High-C3-producing microbiota, such as *Prevotella*, are associated with increased C3 levels. 3. **Stromal Cells as Major C3 Sources**: Stromal cells in the subepithelial compartment of the colon are the primary source of C3 during homeostasis. They express C3 and can produce C3 upon bacterial stimulation. 4. **Function of Gut Complement System**: The gut complement system operates as an independent entity, distinct from the circulatory system. It uses complement-mediated phagocytosis to clear pathogens without causing lysis of commensals, ensuring a balance between pathogen defense and gut health. 5. **Protection Against Infection**: C3-deficient mice are more susceptible to *Citrobacter rodentium* infection, highlighting the critical role of luminal C3 in protecting against enteric pathogens. The level of luminal C3 driven by the gut microbiota modulates susceptibility to infection. 6. **C3 Production During Infection**: C3 production increases significantly during enteropathogenic infections, with stromal cells, myeloid cells, and epithelial cells contributing to C3 expression. Neutrophils, recruited during infection, are the major source of high-C3-expressing myeloid cells. 7. **Microbiota and Disease Susceptibility**: The composition of the gut microbiota can influence host susceptibility to infectious diseases, suggesting that changes in the microbiota due to malnutrition may contribute to increased vulnerability to enteric pathogens. This study provides new insights into the role of the gut complement system in maintaining gut homeostasis and protecting against infections, highlighting the importance of the gut microbiota in shaping immune responses.The study reveals the presence of a gut complement system, distinct from the systemic complement system, which is primarily synthesized by stromal cells in the intestinal lumen. This system is regulated by the composition of the gut microbiota and plays a crucial role in combatting pathogens while preserving commensal bacteria. Key findings include: 1. **Local Synthesis of C3**: C3, a central component of the complement system, is synthesized locally in the gut by stromal cells and regulated by the gut microbiota. This synthesis is not observed in the liver or plasma. 2. **Microbiota-Dependent C3 Levels**: C3 levels in the gut lumen are influenced by the composition of the gut microbiota, leading to individual-specific levels. High-C3-producing microbiota, such as *Prevotella*, are associated with increased C3 levels. 3. **Stromal Cells as Major C3 Sources**: Stromal cells in the subepithelial compartment of the colon are the primary source of C3 during homeostasis. They express C3 and can produce C3 upon bacterial stimulation. 4. **Function of Gut Complement System**: The gut complement system operates as an independent entity, distinct from the circulatory system. It uses complement-mediated phagocytosis to clear pathogens without causing lysis of commensals, ensuring a balance between pathogen defense and gut health. 5. **Protection Against Infection**: C3-deficient mice are more susceptible to *Citrobacter rodentium* infection, highlighting the critical role of luminal C3 in protecting against enteric pathogens. The level of luminal C3 driven by the gut microbiota modulates susceptibility to infection. 6. **C3 Production During Infection**: C3 production increases significantly during enteropathogenic infections, with stromal cells, myeloid cells, and epithelial cells contributing to C3 expression. Neutrophils, recruited during infection, are the major source of high-C3-expressing myeloid cells. 7. **Microbiota and Disease Susceptibility**: The composition of the gut microbiota can influence host susceptibility to infectious diseases, suggesting that changes in the microbiota due to malnutrition may contribute to increased vulnerability to enteric pathogens. This study provides new insights into the role of the gut complement system in maintaining gut homeostasis and protecting against infections, highlighting the importance of the gut microbiota in shaping immune responses.