Structure of gut microbial glycolipid modulates host inflammatory response

  • Cell. 2025 Jul 18:S0092-8674(25)00566-5. doi: 10.1016/j.cell.2025.05.016.
Hyoung-Soo Cho  1 ,  Ji-Sun Yoo  2 ,  Xinyang Song  3 ,  Byoungsook Goh  2 ,  Alos Diallo  3 ,  Jesang Lee  4 ,  Sumin Son  4 ,  Yoon Soo Hwang  4 ,  Seung Bum Park  4 ,  Sungwhan F Oh  5 ,  Dennis L Kasper  6
Affiliations
  • 1. Department of Immunology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: [email protected].
  • 2. Department of Anesthesiology, Perioperative and Pain Medicine, Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital, Boston, MA 02115, USA.
  • 3. Department of Immunology, Harvard Medical School, Boston, MA 02115, USA.
  • 4. Department of Chemistry, CRI Center for Chemical Proteomics, Seoul National University, Seoul, Republic of Korea.
  • 5. Department of Anesthesiology, Perioperative and Pain Medicine, Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital, Boston, MA 02115, USA; Program in Immunology, Division of Medical Sciences, Harvard Medical School, Boston, MA 02115, USA.
  • 6. Department of Immunology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: [email protected].
PMID: 40701150 DOI: 10.1016/j.cell.2025.05.016
Abstract

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 TH17 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.

Keywords
Cdc42; IFNAR signaling; RORγt(+) Tregs; TLR4 endocytosis; colonic inflammation; endobiotic balance; lipid droplet; microbiome; symbiotic lipid A; type I IFNs.
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