Gut microbial phenol impairs energy metabolism and promotes sarcopenic obesity-like phenotypes in mice

Abstract Gut microbial phenol has been recognized as a uremic toxin associated with chronic kidney disease; however, its effects under preclinical conditions remain unclear. In this study, we established a mouse model with increased endogenous phenol production using a tyrosine-rich diet. High-tyrosine feeding markedly increased fecal phenol and circulating phenyl sulfate (PhS) levels without affecting body weight, food intake, or glucose tolerance. In contrast, respiratory gas analysis revealed reduced energy expenditure and carbohydrate oxidation during the dark phase. CT and histological analyses demonstrated increased adiposity, adipocyte hypertrophy, and reduced skeletal muscle fiber size in the tyrosine-fed group. Inflammatory cytokines in adipose tissue and liver were also elevated. These alterations were largely suppressed by administration of the tyrosine phenol-lyase inhibitor 3,5-dihydroxybenzoic acid (35DHBA), accompanied by a marked reduction in phenol production. Although plasma PhS levels were elevated, no apparent renal dysfunction was observed in the current experimental conditions. These results suggest that gut microbial phenol production may contribute to alterations in energy metabolism and body composition before the onset of overt kidney dysfunction. Our findings indicate that microbial phenol production is potentially involved in metabolic abnormalities associated with excess dietary tyrosine.