The biological activities of postbiotics have garnered significant attention, with anti-inflammatory properties being the most frequently documented. However, the functional components and mechanisms underlying the anti-inflammatory activity of postbiotics remain inadequately understood due to the diversity and complexity. In this study, we investigated the chemical composition of the postbiotic derived from Lacticaseibacillus paracasei K56 (K56) using non-targeted metabolomics. Our analysis revealed that the K56 cell-free supernatant (CFS) predominantly consists of lipids, amino acids and peptides, organic acids, nucleotides, and carbohydrates. Among the top 30 organic acids present in the CFS, malic acid (MA) and decanedioic acid (DA) have been demonstrated to effectively inhibit LPS-induced inflammation in RAW264.7 cells. In zebrafish subjected to a high-fat diet (HFD), we observed that the HFD induced inflammation in both the liver and intestine. The intervention with K56 CFS was found to mitigate hepatic and intestinal inflammation. When compared to CFS, both MA and DA similarly suppressed the mRNA levels of pro-inflammatory cytokines and significantly increased the mRNA levels of anti-inflammatory cytokines and ZO-1. 16S rRNA gene sequencing indicated that treatments with K56 CFS, MA, and DA altered the gut microbiota composition of zebrafish. Specifically, K56 CFS increased the abundance of the beneficial bacterium Cetobacterium, while reducing the prevalence of the pathogenic bacteria Shewanella and Vibrio. Additionally, this study identified that MA and DA were not only constituents of the postbiotics produced by Lacticaseibacillus paracasei but were also widespread among various probiotic strains. Collectively, these findings suggested that MA and DA may play a crucial role in the anti-inflammatory properties of the postbiotic.
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