The metabolic pathways encoded by the human gut microbiome constantly interact with host gene products through numerous bioactive molecules 1. Primary bile acids (BAs) are synthesized within hepatocytes and released into the duodenum to facilitate absorption of lipids or fat-soluble vitamins 2. Some BAs (~5%) escape into the colon, where gut commensal bacteria convert them into a variety of intestinal BAs 2 that are important hormones regulating host cholesterol metabolism and energy balance via several nuclear receptors and/or G protein-coupled receptors 3,4. These receptors play pivotal roles in shaping host innate immune responses 1,5. However, the impact of this host-microbe biliary network on the adaptive immune system remains poorly characterized. Here we report that both dietary and microbial factors influence the composition of the gut BA pool and modulate an important population of colonic Foxp3 + regulatory T cells (Tregs) expressing the transcriptional factor RORγ. Genetic abolition of BA metabolic pathways in individual gut symbionts significantly decreases this Treg population. Restoration of the intestinal BA pool increases colonic RORγ + Treg levels and ameliorates host susceptibility to inflammatory colitis via BA nuclear receptors. Thus, a pan-genomic biliary network interaction between hosts and their bacterial symbionts can control host immunologic homeostasis via the resulting metabolites.

Toll-like receptors (TLRs) are critical in mediating innate immune responses against infections. However, uncontrolled TLR-triggered inflammation is associated with endotoxin shock. To better understand the homeostatic mechanisms induced by TLR4 signaling, we screened a group of key cytokines, chemokines, growth factors, and their receptors for bacteria- or LPS-induced expression. The surface vascular endothelial growth factor receptor-3 (VEGFR-3) and its ligand VEGF-C were upregulated in macrophages. VEGFR-3 ligation by VEGF-C significantly attenuated proinflammatory cytokine production. Notably, ablation of the ligand-binding domain or tyrosine kinase activity of VEGFR-3 rendered mice more sensitive to septic shock. VEGFR-3 restrained TLR4-NF-κB activation by regulating the PI3-kinase-Akt signaling pathway and SOCS1 expression. Aside from targeting lymphatic vessels, we suggest a key role of VEGFR-3 on macrophages to prevent infections that is complicated with lymphoedema. Thus, VEGFR-3-VEGF-C signaling represents a "self-control" mechanism during antibacterial innate immunity.