Structure of gut microbial glycolipid modulates host inflammatory response

Commensals are constantly shaping the host’s immunological landscape. Lipopolysaccharide (LPS) 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 between the symbiont’s various lipid A structures, each distinct from the responses elicited by classical lipid A. Certain lipid A structures can induce a sustained IFN-β response orchestrated by Cdc42-facilitated TLR4 endocytosis and lipid droplet formation. This lipid A-directed IFN-β response is paramount for colon RORγt+ Treg induction while simultaneously suppressing colonic TH17 and controlling gut inflammation. Intriguingly, the quantitatively dominant penta-acylated lipid A species in Bacteroidetes fails to elicit IFN-β response. Instead, a less abundant tetra-acylated lipid A species sustainably induces IFN-β, thereby contributing to RORγt+ Treg homeostasis. These structural nuances in symbiotic lipid A contribute to maintaining potent regulation of Treg to maintain a healthy endobiotic balance.