Chronic Low-Dose Phlorizin Intake Is Associated with Gut Microbiota Remodeling and Arachidonic Acid–Related Serum Metabolomic Changes in Healthy Mice

Abstract Phlorizin, a major apple-derived dihydrochalcone glycoside, has been reported to contribute to metabolic and inflammatory regulation and has been linked to alterations in the gut microbiota across various disease models, but its relationship with the gut microbiota under normal physiological conditions remains unclear. This study aimed to characterize gut microbial ecology and serum metabolomic changes associated with chronic, low-dose phlorizin intake in healthy mice. Healthy male C57BL/6J mice received phlorizin orally at 30 mg/kg/day for 28 days. We assessed organ safety and histology, SGLT1/2 protein expression, glucose handling, gut microbiota, and the serum metabolome, and performed integrative correlation analysis.Results showed that phlorizin was generally well tolerated. Serum ALT, AST, and BUN were significantly elevated, although histopathology showed no overt abnormalities; values remained within reference ranges, but safety still requires further evaluation. Neither SGLT1/2 protein expression nor indirect functional assessment (OGTT glucose tolerance and urinary glucose concentration) differed between groups, but total 24-h urinary glucose excretion was modestly higher in the phlorizin group, possibly reflecting a mild residual effect of phlorizin on SGLT-related glucose handling, whose specific basis requires further study. Phlorizin intake was associated with altered gut microbial diversity and composition, including enrichment of Akkermansia, Alistipes, and Ligilactobacillus, and with a distinct serum metabolic signature enriched in arachidonic acid (AA) and other PUFA-derived lipid mediator pathways, with several mediators showing lower relative abundance and correlating with specific microbial taxa.Taken together, chronic low-dose phlorizin intake was associated with changes in gut microbiota and the serum metabolome, particularly within AA- and other PUFA-derived lipid pathways; whether these changes are independent of phlorizin's inhibition of SGLT function requires further exploration. As this was a correlational study, these findings provide a preliminary basis for future mechanistic studies of dietary polyphenol–host–microbiota interactions.