Gut microbiota modulate CD8⁺ T cell immunity in gastric cancer through Butyrate/GPR109A/HOPX

ABSTRACT

The gut microbiota and Short-chain fatty acids (SCFAs) can influence the progression of diseases, yet the role of these factors on gastric cancer (GC) remains uncertain. In this work, the analysis of the gut microbiota composition and SCFA content in the blood and feces of both healthy individuals and GC patients indicated that significant reductions in the abundance of intestinal bacteria involved in SCFA production were observed in GC patients compared with the controls. ABX mice transplanted with fecal microbiota from GC patients developed more tumors during the induction of GC and had lower levels of butyric acid. Supplementation of butyrate during the induction of gastric cancer along with H. pylori and N-methyl-N-nitrosourea (MNU) in WT in GPR109A^−/−mice resulted in fewer tumors and more IFN-γ⁺ CD8⁺ T cells, but this effect was significantly weakened after knockout of GPR109A. Furthermore, In vitro GC cells and co-cultured CD8⁺ T cells or CAR-Claudin 18.2⁺ CD8⁺ T cells, as well as in vivo tumor-bearing studies, have indicated that butyrate enhanced the killing function of CD8⁺ T cells or CAR-Claudin 18.2⁺ CD8⁺ T cells against GC cells through G protein-coupled receptor 109A (GPR109A) and homologous domain protein homologous box (HOPX). Together, these data highlighted that the restoration of gut microbial butyrate enhanced CD8⁺ T cell cytotoxicity via GPR109A/HOPX, thus inhibiting GC carcinogenesis, which suggests a novel theoretical foundation for GC management against GC.

KEYWORDS:

• Gut microbiota
• butyrate
• CD8⁺ T cell immunity
• gastric cancer

Acknowledgments

We appreciate the GPR109A^−/− mice provided by Professor Guo-Qiang CHEN at School of Life Sciences, Tsinghua University.

Disclosure statement

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

Authors’ contributions

XY, GXL and YFH designed the studies. XY, JZO, LZW, ZYL and LX performed the research and analyzed the animal data. XY and YFH wrote the manuscript. All authors read and checked this manuscript.

Data availability statement

The 16S rRNA sequencing data have been deposited in the NCBI BioProject database (https://www.ncbi.nlm.nih.gov/bioproject/) under accession numbers PRJNA976526 and PRJNA976543.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2024.2307542

Additional information

Funding

This work was supported by grants from National Natural Science Foundation of China (Nos. 82272062, 81971746, 81901987), Key-Area Research and Development Program of Guangdong Province (2021B0101420005), Guangdong Basic and Applied Basic Research Foundation (2022A1515220014), Guangdong Provincial Major Talents Project (2019JC05Y361), Funding by Science and Technology projects in Guangzhou (2023B03J0277), Clinical Research Program of Nanfang Hospital, Southern Medical University (2022CR002).