Gut microbially produced phenolic acids have differential and sex-dependent effects on host metabolic health

Gut microbiota-derived metabolites, such as phenylacetic acid (PAA) and phenylpropionic acid (PPA), are increasingly recognized as important regulators of host metabolism. However, the specific functions of individual metabolites remain poorly understood. To investigate this, researchers conducted a study using a mouse model of diet-induced obesity. The study focused on two structurally related metabolites, PAA and PPA, to understand their metabolic effects.

PAA, although previously linked to metabolic diseases in clinical studies, did not alter body mass or adiposity in the mouse model. Surprisingly, PAA improved glucose tolerance selectively in male mice and significantly reshaped lipid metabolism in both sexes. This remodeling included reducing circulating triglycerides and acylcarnitines, and activating hepatic PPAR- mediated transcriptional programs involved in fatty acid omega-hydroxylation and peroxisomal lipid metabolism.

Despite these extensive metabolic changes, PAA did not worsen liver steatosis, fibrosis, or liver injury markers.

In contrast, PPA had minimal effects on hepatic metabolic pathways but induced pronounced sex-dependent physiological responses. It increased adiposity in female mice and improved glucose tolerance in male mice. These findings highlight the distinct, sex-dependent metabolic effects of structurally related microbial metabolites. The study emphasizes the need to define the individual actions of microbiome-derived metabolites when developing targeted therapies for metabolic disease.