Lactobacillus rhamnosus GG induces STING-dependent IL-10 in intestinal monocytes and alleviates inflammatory colitis in mice
Wei Si, … , Hongwei Liu, Liangliang Wang
Wei Si, … , Hongwei Liu, Liangliang Wang
Published February 3, 2025
Citation Information: J Clin Invest. 2025;135(3):e174910. https://doi.org/10.1172/JCI174910.
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Research Article Immunology Inflammation

Lactobacillus rhamnosus GG induces STING-dependent IL-10 in intestinal monocytes and alleviates inflammatory colitis in mice

Abstract

Preclinical and clinical observations indicate that the probiotic Lactobacillus rhamnosus GG (LGG) can modulate colonic inflammation. However, the underlying mechanisms have not been explored in depth. Here, we demonstrate that oral administration of live LGG alleviated inflammatory colitis by increasing IL-10 expression in intestinal Ly6C+ monocytes. Mechanistically, LGG induced IL-10 production via the stimulator of IFN genes (STING)/TBK1/NF-κB (RELA) signaling pathway in intestinal Ly6C+ monocytes, enhancing their immune-suppressive function. Elevated IL-10 subsequently activated IL-10 signaling in Ly6C+ monocytes, resulting in an IL-10–based autocrine regulatory loop and inhibition of proinflammatory cytokine production. Furthermore, LGG shifted the gut microbial community and its metabolic functions, leading to intestinal immune responses against colitis. Fecal microbiota transplantation from LGG-colonized mice alleviated immune checkpoint blockade–associated colitis. Our findings highlight the importance of STING signaling in IL-10–dependent antiinflammatory immunity and establish an empirical basis for developing oral administration of live LGG as an efficient and safe therapeutic strategy against inflammatory colitis.

Authors

Wei Si, Xin Zhao, Ruitong Li, Yaopeng Li, Cui Ma, Xiaohan Zhao, Jason Bugno, Yuchang Qin, Junmin Zhang, Hongwei Liu, Liangliang Wang

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Figure 1

Oral administration of live LGG alleviates inflammatory colitis in a manner dependent on IL-10.

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Oral administration of live LGG alleviates inflammatory colitis in a man...
(A) Body weight assessment of WT SPF mice receiving 3% of dextran sodium sulfate (DSS) in drinking water for 7 days. WT mice were orally administered LGG (2 × 109 CFU) daily for 2 weeks (starting 1 week before DSS administration). The body weight of mice was measured every day. The percentage weight change is shown (n = 5 per group). (B) Colon length on day 7 of each group, as indicated in A (n = 5 per group). (C–E) Representative images of H&E-stained colon tissues (C) and the matching histological grade (D) and inflammation score (E) in mice with different treatments as indicated (day 7) (n = 5 per group). Scale bar: 100 μm. (F) Heatmap showing the mRNA expression of proinflammatory cytokines and antiinflammatory cytokine genes (identified by qPCR analysis) in colon tissues of each group, as indicated in A (n = 3 per group). (G) Heatmap showing the protein levels of the matching proinflammatory cytokines and antiinflammatory cytokines (identified by qPCR analysis) as in F (n = 3 per group). (H) Body weight assessment of WT SPF mice receiving the indicated treatment (n = 5). One hundred micrograms of anti–IL-10 antibody was administered i.p. every other day during DSS treatment (n = 5 per group). Data are expressed as mean ± SEM. One of 2 or 3 representative experiments is shown. Statistical analysis was performed using 2-way ANOVA test with corrections for multiple variables (A and H) and 1-way ANOVA with Bonferroni’s multiple comparison tests (B, D, and E). *P < 0.05, ***P < 0.001, ****P < 0.0001.