A microbiota dependent CLA PPARgamma axis reprograms intestinal CD8 T cell metabolism to enhance mucosal defense against Salmonella

Conjugated linoleic acid (CLA) is a bioactive fatty acid with recognized immunomodulatory and metabolic benefits. This study investigated how dietary CLA supplementation influences intestinal microbiota composition, metabolic profiles, and mucosal immune responses during Salmonella Typhimurium infection in mice. Integrated multi omics analyses including 16S rRNA gene sequencing, untargeted metabolomics (LC MS), bulk RNA sequencing, and ATAC seq were performed on ileal tissues and intraepithelial lymphocytes (IELs) to elucidate host microbe metabolite interactions. CLA supplementation reshaped the gut microbial community, enriching beneficial taxa such as Lactobacillus and Dubosiella, and altered the luminal metabolite landscape toward enhanced lipid and energy metabolism. Functionally, CLA promoted mitochondrial oxidative phosphorylation and effector function in intestinal CD8 T cells through PPARgamma dependent transcriptional remodeling. Fecal microbiota transplantation confirmed that the CLA conditioned microbiota conferred protection against Salmonella infection by reinforcing epithelial barrier integrity and limiting pathogen colonization. These findings reveal a previously unrecognized microbiota metabolite immunity axis through which CLA enhances mucosal defense and metabolic resilience, providing mechanistic insights into how dietary fatty acids modulate host immunity to enteric pathogens.