Structure of gut microbial glycolipid modulates host inflammatory response

Commensals are constantly shaping the host’s immunological landscape. Lipopolysaccharides found in gram-negative microbes have a terminal lipid A in their outer membrane. Here, we report that structural variations in symbiotic lipid A lead to divergent immune responses with each lipid A structure, eliciting effects distinct from those induced by classical lipid A. Certain lipid A structures can induce a sustained interferon (IFN)-β response orchestrated by Cdc42-facilitated Toll-like receptor 4 (TLR4) endocytosis and lipid droplet (LD) formation. This lipid A-directed IFN-β response is paramount for colon RORγt⁺ regulatory T cell (Treg) induction while simultaneously suppressing colonic T_H17 cells and controlling gut inflammation. Intriguingly, the quantitatively dominant penta-acylated lipid A species in Bacteroidetes fails to elicit an IFN-β response. Instead, a less abundant tetra-acylated lipid A species sustainably induces IFN-β, thereby contributing to RORγt⁺ Treg homeostasis. Nuances in symbiont lipid A structure contribute to maintaining potent regulation of Tregs to maintain a healthy endobiotic balance.