Gut microbial fatty acid isomerization modulates intraepithelial T cells

Xinyang Song (), Haohao Zhang, Yanbo Zhang, Byoungsook Goh, Bin Bao, Suelen S. Mello, Ximei Sun, Wen Zheng, Francesca S. Gazzaniga, Meng Wu, Fangfang Qu, Qiangzong Yin, Michael S. Gilmore, Sungwhan F. Oh and Dennis L. Kasper ()
Additional contact information
Xinyang Song: University of Chinese Academy of Sciences
Haohao Zhang: University of Chinese Academy of Sciences
Yanbo Zhang: Harvard Medical School
Byoungsook Goh: Brigham and Women’s Hospital, Harvard Medical School
Bin Bao: Boston Children’s Hospital, Harvard Medical School
Suelen S. Mello: Harvard Medical School, Massachusetts Eye and Ear Infirmary
Ximei Sun: Harvard Medical School
Wen Zheng: Harvard Medical School
Francesca S. Gazzaniga: Harvard Medical School
Meng Wu: Harvard Medical School
Fangfang Qu: Tufts University
Qiangzong Yin: University of Massachusetts Medical School
Michael S. Gilmore: Harvard Medical School, Massachusetts Eye and Ear Infirmary
Sungwhan F. Oh: Brigham and Women’s Hospital, Harvard Medical School
Dennis L. Kasper: Harvard Medical School

Nature, 2023, vol. 619, issue 7971, 837-843

Abstract: Abstract The human gut microbiome constantly converts natural products derived from the host and diet into numerous bioactive metabolites1–3. Dietary fats are essential micronutrients that undergo lipolysis to release free fatty acids (FAs) for absorption in the small intestine4. Gut commensal bacteria modify some unsaturated FAs—for example, linoleic acid (LA)—into various intestinal FA isomers that regulate host metabolism and have anticarcinogenic properties5. However, little is known about how this diet–microorganism FA isomerization network affects the mucosal immune system of the host. Here we report that both dietary factors and microbial factors influence the level of gut LA isomers (conjugated LAs (CLAs)) and that CLAs in turn modulate a distinct population of CD4+ intraepithelial lymphocytes (IELs) that express CD8αα in the small intestine. Genetic abolition of FA isomerization pathways in individual gut symbionts significantly decreases the number of CD4+CD8αα+ IELs in gnotobiotic mice. Restoration of CLAs increases CD4+CD8αα+ IEL levels in the presence of the transcription factor hepatocyte nuclear factor 4γ (HNF4γ). Mechanistically, HNF4γ facilitates CD4+CD8αα+ IEL development by modulating interleukin-18 signalling. In mice, specific deletion of HNF4γ in T cells leads to early mortality from infection by intestinal pathogens. Our data reveal a new role for bacterial FA metabolic pathways in the control of host intraepithelial immunological homeostasis by modulating the relative number of CD4+ T cells that were CD4+CD8αα+.

Date: 2023
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DOI: 10.1038/s41586-023-06265-4

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