Intestinal dysbiosis exacerbates skin inflammation via microbial metabolite-driven Th2 cell differentiation

作者：Yu L, Peng S, Chen X, Wu T, Dong L, Luo J, Xu S, Zhou J, Zhao X, Zheng L, Shu G, Wang X, Huang L, Chen Q, Jiang D, Sun LD, Hylemon P, Wang XY, Sun L, Ma L, Zuo D · 发表于：Immunity · 年份：2026 · DOI：10.1016/j.immuni.2026.03.019 · 研究领域：Th2 response、Toll-like receptor 4、atopic dermatitis、choline、gut microbiome、microbial metabolite、peroxisome proliferator-activated receptor γ、trimethylamine oxide

The interplay between gut microbiota and the mucosal immune system critically regulates systemic immunity and disease susceptibility. Here, we demonstrate that intestinal epithelial Toll-like receptor (TLR)4 deficiency reshaped the gut microbiome and subsequently exacerbated atopic dermatitis (AD) in mice. Mechanistically, TLR4 deficiency reduced Akkermansia muciniphila abundance and enriched choline trimethylamine-lyase (CutC)-expressing bacteria. This enhanced microbial choline-to-trimethylamine conversion and elevated circulating trimethylamine oxide (TMAO) levels. Clinically, AD patients exhibited increased plasma TMAO levels that positively correlated with disease severity and immunoglobulin E (IgE) levels. UK Biobank data also showed that higher dietary choline intake was associated with increased AD risk. TMAO promoted T helper (Th)2 differentiation by directly interacting with protein phosphatase 5 (PPP5) and enhancing PPP5-mediated dephosphorylation of PPARγ. CD4+ T cell-specific PPARγ deletion abolished TMAO-driven skin pathology in AD mice. Our results reveal intestinal dysbiosis, as a result of innate immune deficiency, as a driver of inflammatory Th2 cells and AD pathology, highlighting a link among the gut immune environment, microbial metabolites, and skin disease.