Vancomycin eliminates gut deoxycholic acid, restoring ER proteostasis in ILC2s and relieving colitis
Qiuheng Tian, Han Liu, Xiang Gu, Jing Shen, Xi Yuan, Mengqi Zheng, Yunjiao Zhai, Yatai Chen, Penghu Han, Yangchun Ma, Wei Xin, Hongyue Ma, Yu Li, Sihan Wang, Lei Guo, Detian Yuan, Yanbo Yu, Shiyang Li
Qiuheng Tian, Han Liu, Xiang Gu, Jing Shen, Xi Yuan, Mengqi Zheng, Yunjiao Zhai, Yatai Chen, Penghu Han, Yangchun Ma, Wei Xin, Hongyue Ma, Yu Li, Sihan Wang, Lei Guo, Detian Yuan, Yanbo Yu, Shiyang Li
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Research Article Gastroenterology Immunology

Vancomycin eliminates gut deoxycholic acid, restoring ER proteostasis in ILC2s and relieving colitis

Abstract

Ulcerative colitis (UC) remission is marked by gut microbiota restructuring, but how microbial metabolites influence immune-mediated tissue repair is unclear. Here, we demonstrate that oral vancomycin alleviates colitis symptoms in murine models, mirroring its clinical efficacy in inducing remission in patients with UC. Mechanistically, vancomycin’s therapeutic effect is achieved by reducing deoxycholic acid (DCA). We reveal that DCA impairs mucosal repair driven by group 2 innate lymphoid cells (ILC2s) by inducing ER stress through direct binding to thioredoxin-related transmembrane protein 2 (TMX2). This interaction disrupts TMX2’s role in protein folding, triggering unresolved unfolded protein response via hyperactivation of PERK/eIF2α signaling, which suppresses the production of pro-healing molecules by ILC2s. Pharmacological inhibition of PERK phosphorylation restores ILC2 function and accelerates colitis resolution. Our work uncovers a pathogenic microbiota/DCA/ILC2 axis that obstructs mucosal healing and positions vancomycin as a targeted strategy to eliminate DCA, thereby promoting UC remission.

Authors

Qiuheng Tian, Han Liu, Xiang Gu, Jing Shen, Xi Yuan, Mengqi Zheng, Yunjiao Zhai, Yatai Chen, Penghu Han, Yangchun Ma, Wei Xin, Hongyue Ma, Yu Li, Sihan Wang, Lei Guo, Detian Yuan, Yanbo Yu, Shiyang Li

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Figure 1

Vancomycin promotes colitis remission by eliminating DCA.

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Vancomycin promotes colitis remission by eliminating DCA. (A–E) WT mice ...
(A–E) WT mice received 5 days of H2O or vancomycin by gavage after 5 days of 5% DSS. (A, top) Experimental outline. (A, bottom) Weight course. (B) Representative image of colon. (C) Statistical data of colon length. (D) H&E-stained histological sections. Scale bar: 500 μm. (E) Histopathology scores. n = 6 mice per group; experiment repeated 3 times. (F) Metabolite profiles in vancomycin-treated compared with H2O-treated mice. (G) DCA in feces. (H) Colon tissue after vancomycin gavage. n = 6 mice per group; experiment repeated 3 times. (I–M) WT mice received 5 days of H2O or vancomycin after 5 days of 2.5% DSS. One group of vancomycin-treated mice was simultaneously fed 2% DCA diet on days 5 to 10. (I, top) Experimental outline. (I, bottom) Weight course. Green asterisk: comparison between NCD and Van groups; red asterisk: comparison between Van and Van+DCA groups. (J) Representative image of colon. (K) Statistical data of colon length. (L) H&E-stained histological sections. Scale bar: 500 μm. (M) Histopathology scores. n = 6 mice per group; experiment repeated 3 times. (N) Within-patient comparison of Truelove-Witts scores before and after vancomycin therapy. n = 4 patients per group. (O) Heatmap represents fecal bile acid (BA) profiling and concentration of 6 BAs of patients receiving vancomycin therapy. n = 4 patients per group. Data shown as mean ± SD (A–O). Two-sided unpaired t test or 2-sided Mann-Whitney U test used in A, C, E, G, and H, depending on data normality. One-way ANOVA with Tukey’s multiple-comparison test or Kruskal-Wallis test with Dunn’s multiple-comparison test used in I, K, and M, based on data normality. Two-sided paired t test according to normal distribution in N and O. Statistical methods and exact P values are in Supporting Data Values file. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.