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Pentachlorophenol (PCP), a ubiquitous environmental pollutant, has been reported as a possible contributor to diabetes. However, evidence for general population is scarce while related mechanisms are largely unknown. Using a representative population-based case-control study in Beijing (n = 1796), we found a positive association between PCP exposure and diabetes risk with the odds ratio reaching 1.68 (95 % confidence interval: 1.30 to 2.18). A further rat experiment revealed that low-dose PCP mimicking real-world human exposure can significantly impair glycemic homeostasis by inducing pancreatic β-cell dysfunction, with non-linear dose-response relationships. Subsequent multi-omics analysis suggested that low-dose PCP led to notable gut microbiota dysbiosis (especially the species from genus Prevotella , such as intermedia, dentalis, ruminicola, denticola, melaninogenica, and oris), decreased serum amino acids (L-phenylalanine, L-tyrosine, and L-tryptophan) and increased serum fatty acids (oleic and palmitic acid) in rats, while strong correlations were observed among alterations of gut microbes, serum metabolites and glycemic-related biomarkers (e.g., fasting blood glucose and insulin). Collectively, these results imply PCP may increase diabetes risk by disrupting gut microbial-related amino acids and fatty acids biosynthesis. This will help guide future in-depth studies on the roles of PCP in the development of human diabetes. [Display omitted] • Epidemiological study reveals a positive correlation between PCP and diabetes risk. • Human exposure doses of PCP significantly impair glycemic homeostasis in rats. • Impairment of β-cell secretory function may underlie PCP-induced hyperglycemia. • PCP destroys gut microbiota balance and perturbs amino/fatty acids metabolism. [ABSTRACT FROM AUTHOR]