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 2

Monocytic IL-10 is predominantly responsible for the LGG protective activity against colitis.

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Monocytic IL-10 is predominantly responsible for the LGG protective acti...
(A and B) Mean fluorescence intensity (MFI) of IL-10 in different myeloid cells (CD45+CD11b+F4/80+, CD45+CD11b+Ly6C+, and CD45+CD11b+Ly6G+) from MLNs of GF mice (A) or SPF mice (B) with the indicated treatment (n = 5 per group). (C and D) WT or Il10-knockdown (Il10-KD) bone marrow–derived monocytes with or without LGG treatment were used for adoptive transfer into 3% DSS–treated mice. Body weight was monitored (C). Colon length on day 6 of each group, as indicated in C. (D) (n = 5 per group). (E) Representative images of H&E-stained colon tissues and the matching histological grade score (n = 5 per group) in DSS-treated mice with adoptive transfer with LGG-training WT or Il10-KD monocytes. Scale bar: 50 μm. (F) Ly6C+ monocytes were isolated from MLNs in mice following the indicated treatment and subjected to qPCR analysis of the mRNA level of Il10 (n = 3 per group). (G) IL-10 levels produced by Ly6C+ monocytes, as shown in F (n = 4 per group). (H) 2 × 105 Ly6C+ monocytes were isolated from untreated or DSS-treated mice and cocultured with live LGG (2 × 106 CFU) in vitro. The Il10 mRNA levels were measured by qPCR (n = 5 per group). Data are expressed as mean ± SEM. One of 2 or 3 representative experiments is shown. Statistical analysis was performed using 1-way ANOVA with Bonferroni’s multiple comparison tests (A, B, D, F, and G), 2-way ANOVA test with corrections for multiple variables (C), and unpaired 2-tailed Student’s t tests (E and H). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001