Gut microbially produced phenolic acids have differential and sex-dependent effects on host metabolic health
- 1Cleveland Clinic Research
Abstract
Gut microbiota-derived metabolites are increasingly recognized as important regulators of host metabolism, but the specific functions of individual metabolites remain poorly understood. We therefore investigated the metabolic effects of two structurally related, phenylalanine-derived microbial metabolites phenylacetic acid (PAA) and phenylpropionic acid (PPA) in a mouse model of diet-induced obesity. Although clinical studies have linked PAA and its downstream product phenylacetylglutamine to metabolic disease, PAA did not alter body mass or adiposity in this model. Instead, it improved glucose tolerance selectively in male mice and markedly remodeled lipid metabolism in both sexes, reducing circulating triglycerides and acylcarnitines and activating hepatic PPAR--associated transcriptional programs associated with fatty acid {omega}-hydroxylation and peroxisomal lipid metabolism. Despite this extensive metabolic remodeling, PAA did not worsen hepatic steatosis, fibrosis, or markers of liver injury. By contrast, PPA had minimal effects on hepatic metabolic pathways but produced pronounced sex-dependent physiological responses, increasing adiposity in female mice and improving glucose tolerance in male mice. These findings show that structurally related microbial metabolites can have distinct, sex-dependent metabolic effects and highlight the need to define the actions of individual microbiome-derived metabolites when developing targeted therapies for metabolic disease.
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BibTeX
@misc{kim2026microbially,
title = {{Gut microbially produced phenolic acids have differential and sex-dependent effects on host metabolic health}},
author = {J. Kim and K. M. Carr and S. Alqudah and K. A. Bacik and H. Park and C. G. Fulmer and M. Awoniyi and J. Claesen and I. Nemet},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.12.757096},
url = {https://www.biorxiv.org/content/10.64898/2026.10.12.757096v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Gut microbially produced phenolic acids have differential and sex-dependent effects on host metabolic health
AU - J. Kim
AU - K. M. Carr
AU - S. Alqudah
AU - K. A. Bacik
AU - H. Park
AU - C. G. Fulmer
AU - M. Awoniyi
AU - J. Claesen
AU - I. Nemet
PY - 2026
DA - 2026/10/12
PB - bioRxiv
DO - 10.64898/2026.10.12.757096
UR - https://www.biorxiv.org/content/10.64898/2026.10.12.757096v1
AB - Gut microbiota-derived metabolites are increasingly recognized as important regulators of host metabolism, but the specific functions of individual metabolites remain poorly understood. We therefore investigated the metabolic effects of two structurally related, phenylalanine-derived microbial metabolites phenylacetic acid (PAA) and phenylpropionic acid (PPA) in a mouse model of diet-induced obesity. Although clinical studies have linked PAA and its downstream product phenylacetylglutamine to metabolic disease, PAA did not alter body mass or adiposity in this model. Instead, it improved glucose tolerance selectively in male mice and markedly remodeled lipid metabolism in both sexes, reducing circulating triglycerides and acylcarnitines and activating hepatic PPAR--associated transcriptional programs associated with fatty acid {omega}-hydroxylation and peroxisomal lipid metabolism. Despite this extensive metabolic remodeling, PAA did not worsen hepatic steatosis, fibrosis, or markers of liver injury. By contrast, PPA had minimal effects on hepatic metabolic pathways but produced pronounced sex-dependent physiological responses, increasing adiposity in female mice and improving glucose tolerance in male mice. These findings show that structurally related microbial metabolites can have distinct, sex-dependent metabolic effects and highlight the need to define the actions of individual microbiome-derived metabolites when developing targeted therapies for metabolic disease.
ER -