Multi-omics integration reveals a gut microbiota-metabolite-immune axis in PFOA-induced intestinal toxicity.

Abstract

Perfluorooctanoic acid (PFOA) is a persistent environmental contaminant associated with immunometabolic toxicity; however, its effects on the intestinal microenvironment remain incompletely understood. We integrated a murine PFOA exposure model with untargeted serum metabolomics, 16S rRNA gene sequencing, and single-cell RNA sequencing to characterize intestinal injury and explore microbiota-metabolite-immune relationships. PFOA exposure caused dose-dependent body weight loss, colon shortening, histopathological injury, disrupted epithelial junctional staining, and increased proinflammatory cytokine concentrations. It was also associated with restructuring of the gut microbiota and broad alterations in serum tryptophan-related metabolites, including a metabolomic feature putatively annotated as indole-3-propionic acid (IPA), whose normalized relative abundance was reduced. Single-cell analyses indicated remodeling of epithelial, T-cell, and fibroblast states, including enrichment of a T helper 1 (Th1)-like transcriptional program and altered fibroblast-associated inflammatory pathways. IPA supplementation partially ameliorated several PFOA-associated intestinal and inflammatory phenotypes but did not broadly normalize α-diversity, β-diversity, the relative abundance of Clostridium, or the fibroblast-associated markers examined. In polarized murine Th1 cells, IPA reduced JAK2 and STAT3 phosphorylation; this effect was partially attenuated by the AhR antagonist CH-223191, consistent with AhR-dependent restraint of JAK-STAT signaling. CellChat analysis further identified computationally inferred changes in selected CD44-associated ligand-receptor pairs between fibroblasts and Th1 cells. Collectively, these findings support a model in which PFOA-associated perturbation of microbial tryptophan metabolism and IPA-related signaling may contribute to epithelial and immune dysfunction.

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