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. 2024 Jan-Dec;16(1):2363020.
doi: 10.1080/19490976.2024.2363020. Epub 2024 Jun 6.

Microbial metabolite butyrate modulates granzyme B in tolerogenic IL-10 producing Th1 cells to regulate intestinal inflammation

Wenjing Yang  1   2   3 , Tianming Yu  1   2   3 , Xia Liu  3 , Suxia Yao  1   2   3 , Kamil Khanipov  4 , George Golovko  4 , Danyvid Olivares-Villagómez  5 , Yingzi Cong  1   2   3
Affiliations

Microbial metabolite butyrate modulates granzyme B in tolerogenic IL-10 producing Th1 cells to regulate intestinal inflammation

Wenjing Yang et al. Gut Microbes. 2024 Jan-Dec.

Abstract

CD4+ T cells play a critical role in regulating autoimmune diseases, and intestinal microbial metabolites control various immune responses. Granzyme B (GzmB)-producing CD4+ T cells have been recently reported to participate in the pathogenesis of autoimmune diseases. Here, we found that GzmbB-deficient CD4+ T cells induced more severe colitis in Rag1-/- mice than wild-type (WT) CD4+ T cells. Germ-free (GF) mice exhibited a lower expression of GzmB in intestinal CD4+ T cells compared to specific pathogen-free (SPF) mice. Intestinal microbial metabolite butyrate increased GzmB expression in CD4+ T cells, especially in IL-10-producing Th1 cells, through HDAC inhibition and GPR43, but not GPR41 and GPR109a. Butyrate-treated GzmB-deficient CD4+ T cells demonstrated more severe colitis compared to butyrate-treated WT CD4+ T cells in the T cell transfer model. Butyrate altered intestinal microbiota composition, but altered microbiota did not mediate butyrate induction of intestinal CD4+ T cell expression of GzmB in mice. Blimp1 was involved in the butyrate induction of GzmB in IL-10-producing Th1 cells. Glucose metabolism, including glycolysis and pyruvate oxidation, mediated butyrate induction of GzmB in Th1 cells. In addition, we found that IKZF3 and NR2F6 regulated GzmB expression induced by butyrate. Together, our studies underscored the critical role of GzmB in mediating gut bacterial metabolite butyrate regulation of T cell tolerance at the mucosal surface.

Keywords: GzmB; Microbiota; colitis; glucose metabolism.

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Conflict of interest statement

No potential conflict of interest was reported by the author(s).

Figures

Figure 1.
Figure 1.
Butyrate increases GzmB expression in Th1 cells.
Figure 2.
Figure 2.
Butyrate-pretreated Th1 cells induced less severe colitis partially through GzmB.
Figure 3.
Figure 3.
Fecal microbiota from butyrate-pretreated mice does not increase intestinal T-cell production of GzmB.
Figure 4.
Figure 4.
GPR43 and HDAC inhibitor mediate butyrate induction of GzmB in Th1 cells.
Figure 5.
Figure 5.
Blimp1 mediates butyrate induction of GzmB in Th1 cells.
Figure 6.
Figure 6.
Glucose metabolism mediates butyrate induction of GzmB in Th1 cells.
Figure 7.
Figure 7.
IKZF3 and NR2F6 regulate butyrate induction of GzmB in Th1 cells.
See this image and copyright information in PMC

References

    1. Hou K, Wu Z-X, Chen X-Y, Wang J-Q, Zhang D, Xiao C, Zhu D, Koya JB, Wei L, Li J, et al. Microbiota in health and diseases. Signal Transduct Target Ther. 2022;7(1):135. doi:10.1038/s41392-022-00974-4. - DOI - PMC - PubMed
    1. Yang W, Cong Y.. Gut microbiota-derived metabolites in the regulation of host immune responses and immune-related inflammatory diseases. Cell Mol Immunol. 2021;18(4):866–17. doi:10.1038/s41423-021-00661-4. - DOI - PMC - PubMed
    1. Bilotta AJ, Ma C, Yang W, Yu Y, Yu Y, Zhao X, Zhou Z, Yao S, Dann SM, Cong Y, et al. Propionate enhances cell speed and persistence to promote intestinal epithelial turnover and repair. Cell Mol Gastroenterol Hepatol. 2021;11(4):1023–1044. doi:10.1016/j.jcmgh.2020.11.011. - DOI - PMC - PubMed
    1. Wu W, Sun M, Chen F, Cao AT, Liu H, Zhao Y, Huang X, Xiao Y, Yao S, Zhao Q, et al. Microbiota metabolite short-chain fatty acid acetate promotes intestinal IgA response to microbiota which is mediated by GPR43. Mucosal Immunol. 2017;10(4):946–956. doi:10.1038/mi.2016.114. - DOI - PMC - PubMed
    1. Yang W, Xiao Y, Huang X, Chen F, Sun M, Bilotta AJ, Xu L, Lu Y, Yao S, Zhao Q, et al. Microbiota metabolite short-chain fatty acids facilitate mucosal adjuvant activity of cholera toxin through GPR43. J Immunol. 2019;203(1):282–292. doi:10.4049/jimmunol.1801068. - DOI - PMC - PubMed

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