A probiotic Bifidobacterium pseudocatenulatum converts hesperidin to bioactive hesperetin and improves metabolic dysfunction in aging mice.

Dietary flavonoids often require microbial metabolism to generate bioactive metabolites that influence host physiology. Hesperidin, a citrus flavanone glycoside, exhibits limited intestinal absorption and depends on gut microbial biotransformation to yield its active aglycone, hesperetin. Hesperetin activates CDGSH iron-sulfur domain 2 (CISD2), a pro-longevity gene whose expression declines with age, and its pharmacological activation has emerged as a strategy to promote healthy aging. Here, we identified a probiotic strain, Bifidobacterium pseudocatenulatum CL256B, that efficiently converts hesperidin to hesperetin via coordinated α-L-rhamnosidase and β-glucosidase activities, achieving ~90% bioconversion efficiency. In naturally aging mice challenged with a Western diet, six-month treatment with probiotic-derived hesperetin significantly improved age-associated metabolic phenotypes, including reduced body weight and adiposity, increased lean mass, enhanced muscle integrity and grip strength, and attenuation of hepatic steatosis. In addition, glucose tolerance, insulin sensitivity, and whole-body energy metabolism were improved. Transcriptomic analyses revealed activation of SIRT1 and HNF4α signaling in the liver and restoration of ribosome homeostasis in skeletal muscle. These findings support a microbiome-enabled strategy in which probiotic-assisted hesperetin bioconversion activates the CISD2 longevity pathway to improve metabolic health during aging.