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 7

The PERK branch of UPR mediates DCA-inhibited ILC2 function and colitis recovery.

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The PERK branch of UPR mediates DCA-inhibited ILC2 function and colitis ...
(A–G) WT mice received NCD or DCA by gavage for 5 days, starting 5 days after 2.5% DSS administration. One group of NCD- or DCA-fed mice was simultaneously i.p. injected with GSK2606414 or vehicle for 5 days. (A, top) Experimental outline is shown. (A, bottom) Weight course. The red asterisk represents comparison between NCD and DCA groups; green asterisk represents comparison between DCA and DCA+GSK groups; purple asterisk represents comparison between Van and DCA groups. (B) Representative image of colon. (C) Statistical data of colon length. (D) H&E-stained histological sections. Scale bar: 500 μm. (E) Histopathology scores. (F) Representative flow cytometry plots. (G, top) Percentages of Areg+, IL-5+, and IL-13+ ILC2s (CD45.2+Lin–GATA3+) and (G, bottom) absolute numbers of Areg+ ILC2s, IL-5+ ILC2s, and IL-13+ ILC2s in large intestine. n = 5 mice per group. The experiment was repeated twice. (H and I) Human colonic lamina propria mononuclear cells were stimulated with DCA at 100 μM, supplemented with or without GSK2606414 for 16 hours in complete RPMI 1640 media. (H) AREG expression was analyzed after gating on CD45+Lin−CD127+CRTH2+ ILC2s. (I) Percentage of AREG+ ILC2s. Connected lines are samples from the same clinical samples (n = 10). Data are shown as mean ± SD. One-way ANOVA with Tukey’s multiple-comparison test or Kruskal-Wallis test with Dunn’s multiple-comparison test used in A, C, E, G, and I, based on data normality. Statistical methods and exact P values are provided in the Supporting Data Values file.*P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.