Lactobacillus rhamnosus GG induces STING-dependent IL-10 in intestinal monocytes and alleviates inflammatory colitis in mice
Wei Si, Xin Zhao, Ruitong Li, Yaopeng Li, Cui Ma, Xiaohan Zhao, Jason Bugno, Yuchang Qin, Junmin Zhang, Hongwei Liu, Liangliang Wang
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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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 7

Oral administration of live LGG prevents immune checkpoint blockade–associated colitis.

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Oral administration of live LGG prevents immune checkpoint blockade–asso...
(A) Body weight assessment of WT mice treated with 3% DSS (for 7 days), ICB (ICB: 100 μg anti–CTLA-4 mAb and 250 μg anti–PD-1 mAb), and/or oral administration of live LGG (n = 5 per group). (B) Colon length of mice as indicated in A (n = 5 per group). (C) The protein levels of IL-10, TNF-α, and IL-6 in colon tissues from the mice, as indicated in A, assessed using a LEGENDplex cytokine kit (n = 5 per group). (D) Schematic image illustrating FMT experimental design. WT mice were treated with broad-spectrum antibiotics for 10 days followed by regular water for 2 days. FMT was performed with fresh feces from non-LGG or LGG-training mice into ABX-treated WT mice donor mice via oral gavage every other day for 7 days with or without ICB+DSS treatment. (E and F) Body weight change (E) and colon length (F) of the indicated mice and treatments (n = 5 per group). (G) The protein levels of TNF-α and IL-6 in colon tissues from the indicated mice, assessed using a LEGENDplex cytokine kit (n = 6 per group). Data are expressed as mean ± SEM. One of 2 representative experiments is shown. Statistical analysis was performed using 2-way ANOVA test with corrections for multiple variables (A and E), 1-way ANOVA with Bonferroni’s multiple comparison tests (B and F), and unpaired 2-tailed Student’s t tests (C and G). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.