Gut microbial fatty acid isomerization modulates intraepithelial T cells

The human gut microbiome constantly converts natural products derived from the host and diet into numerous bioactive metabolites^1–3. 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⁺.