Postbiotic <i>Parabacteroides Distasonis</i> Supplementation Enhances Intestinal and Skeletal Muscle Function in Aged Mice

Parabacteroides distasonis (Pd), a core member of the human gut microbiota, is enriched in centenarians, suggesting a potential role in promoting organismal resilience. While Pd supplementation has been shown to alleviate cancer and inflammatory diseases, its ability to mitigate the decline associated with aging remains unexplored. Here, we demonstrate that postbiotic Pd supplementation induces multiple beneficial effects in 18- and 26-month-old mice following three months of treatment. Pd-treated mice exhibit lower blood glucose levels and increased ketone body production. In the gut, Pd reduces colon shortening observed in aged control mice and decreases the inflammatory mediator NFκB, in the colonic mucosa. Microbiome analysis further reveals enhanced gut microbiota diversity in Pd-supplemented mice. Additionally, FITC-dextran permeability assays indicate improved intestinal barrier function. Cell culture experiments in HCT116 colon cell line show that Pd reduces oxygen consumption and promotes mitochondrial networking, accompanied by upregulation of PGC1α and CHOP, suggesting a mitohormetic response. Beyond metabolic and gut-related benefits, Pd supplementation enhances skeletal muscle strength in both 18- and 26-month-old mice. Proteomic analysis of gastrocnemius muscle reveals that Pd increases the expression of mitochondrial proteins associated with mitochondrial fitness and survival. Notably, Pd-supplemented mice challenged with a high-fat diet gain weight at a slower rate, while maintaining better skeletal muscle coordination and strength. In summary, our findings suggest that postbiotic Pd supplementation enhances metabolic health, reduces inflammation, improves mitochondrial function, and preserves muscle strength in aged mice. These results position Pd as a promising therapeutic tool for promoting healthy aging and combating aging-related diseases.