Intestinal cGAS-STING-IFN signalling promotes obesity by downregulating microbiota-derived IAA in male mice.

Authors

Jiangming Deng, Wen Meng, Yuanqin Yang, Ting Xiao, Zhangliu Jin, Jing Wang, Qing-Xin Li, Lingxiang Xie, Jingyi Hu, Rong Song, Yibo Hu, Yi Chu, Qing Li, Ping Jin, Zheng Wang, Irene Xy Wu, Feng Liu, Yang Xiao

Published in

Nature metabolism. Volume 8. Issue 8. Pages 1713-1729. Epub Aug 19, 2026.

Abstract

The gut constantly interacts with both pathogens and dietary signals, but how it balances immune and metabolic responses remains unclear. Here we show that intestinal cGAS, a key DNA sensor, acts as a regulator linking gut immunity to whole-body metabolism. We show that cGAS signalling is activated in the intestines of humans and male mice with obesity, leading to increased type I interferon production and heightened immune activity in intestinal cells. Strikingly, deleting cGAS specifically in intestinal epithelial cells enhances energy expenditure, protects against diet-induced obesity and improves metabolic health. These effects depend on the gut microbiota, particularly Lactobacillus murinus and its metabolite indole-3-acetic acid (IAA), which promotes adipose thermogenesis. Our findings position intestinal cGAS as a key driver of obesity through gut-to-fat signalling and suggest that targeting the intestinal cGAS-microbiota IAA axis could offer promising strategies to combat obesity and related metabolic diseases.

PMID:
42618739
Bibliographic data and abstract were imported from PubMed on 20 Aug 2026.

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