Gut microbial phenylalanine metabolism contributes to MASLD in a dietary protein-dependent manner
- 1Nanyang Technological University
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) affects nearly a third of adults worldwide, yet how diet shapes the microbiota's contribution remains unclear. In a diet-induced mouse model varying protein content independently of caloric intake, microbiota depletion ameliorated hepatic steatosis and liver injury under protein- sufficient but not protein-restricted conditions. Caecal and plasma metabolomics implicated microbial phenylalanine catabolism and its host conjugates phenylacetylglutamine (PAGln) and phenylacetylglycine (PAGly). PAGln supplementation exacerbated steatosis and liver injury without altering body weight, adiposity or glucose homeostasis. Individual-antibiotic perturbation with metagenomics linked bacterial phenylalanine catabolic capacity to disease severity, and in gnotobiotic mice, genetic disruption of bacterial phenylalanine-to-phenylacetic acid conversion lowered circulating conjugates and attenuated steatosis and fibrosis. In a human cohort, circulating PAGln was selectively elevated in cardiometabolic MASLD. These findings identify dietary protein availability as a modifier of the contribution of microbial phenylalanine metabolism to MASLD and highlight PAGln as a microbiota-derived metabolite that exacerbates hepatic disease.
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BibTeX
@misc{bah2026microbial,
title = {{Gut microbial phenylalanine metabolism contributes to MASLD in a dietary protein-dependent manner}},
author = {Y. R. Bah and D. Nurul Asyiqin Binte Mustafa and F. E. Saputri and T. Emoto and S. H. Wong and R. Dalan and W.-K. Wu and N. S. Tan and T. Wuestefeld and K. Kasahara},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.28.754936},
url = {https://www.biorxiv.org/content/10.64898/2026.09.28.754936v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Gut microbial phenylalanine metabolism contributes to MASLD in a dietary protein-dependent manner
AU - Y. R. Bah
AU - D. Nurul Asyiqin Binte Mustafa
AU - F. E. Saputri
AU - T. Emoto
AU - S. H. Wong
AU - R. Dalan
AU - W.-K. Wu
AU - N. S. Tan
AU - T. Wuestefeld
AU - K. Kasahara
PY - 2026
DA - 2026/09/28
PB - bioRxiv
DO - 10.64898/2026.09.28.754936
UR - https://www.biorxiv.org/content/10.64898/2026.09.28.754936v1
AB - Metabolic dysfunction-associated steatotic liver disease (MASLD) affects nearly a third of adults worldwide, yet how diet shapes the microbiota's contribution remains unclear. In a diet-induced mouse model varying protein content independently of caloric intake, microbiota depletion ameliorated hepatic steatosis and liver injury under protein- sufficient but not protein-restricted conditions. Caecal and plasma metabolomics implicated microbial phenylalanine catabolism and its host conjugates phenylacetylglutamine (PAGln) and phenylacetylglycine (PAGly). PAGln supplementation exacerbated steatosis and liver injury without altering body weight, adiposity or glucose homeostasis. Individual-antibiotic perturbation with metagenomics linked bacterial phenylalanine catabolic capacity to disease severity, and in gnotobiotic mice, genetic disruption of bacterial phenylalanine-to-phenylacetic acid conversion lowered circulating conjugates and attenuated steatosis and fibrosis. In a human cohort, circulating PAGln was selectively elevated in cardiometabolic MASLD. These findings identify dietary protein availability as a modifier of the contribution of microbial phenylalanine metabolism to MASLD and highlight PAGln as a microbiota-derived metabolite that exacerbates hepatic disease.
ER -