Open Access
REVIEW
Microbial-Derived Metabolites as Modulators of Hepatic and Systemic Oxidative Stress: Mechanistic Insights and Clinical Implications
Carlo Acierno1,*, Flavia Carriero2, Alfredo Caturano3, Ferdinando Carlo Sasso4, Salvatore D’Angelo5,6, Luca Rinaldi7, Giuseppe Terrazzano2
1 Department of Infectious Diseases, San Carlo Hospital, Potenza, Italy
2 Dipartimento di Scienze della Salute, Università degli Studi della Basilicata, Potenza, Italy
3 Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma University, Rome, Italy
4 Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, Napoli, Italy
5 Department of Health Sciences, University of Basilicata, Potenza, Italy
6 Rheumatology Department of Basilicata, San Carlo Hospital, Potenza, Italy
7 Department of Medicine and Health Sciences “Vincenzo Tiberio”, Università degli Studi del Molise, Campobasso, Italy
* Corresponding Author: Carlo Acierno. Email: 
(This article belongs to the Special Issue: Cellular and Molecular Mechanisms of Gut Microbiota, Oxidative Stress, and Inflammation in Health and Disease)
BIOCELL https://doi.org/10.32604/biocell.2026.084065
Received 16 April 2026; Accepted 25 June 2026; Published online 10 July 2026
Abstract
Microbiota-derived metabolites have emerged as modulators of hepatic redox biology, because the liver is the first organ to receive and biotransform gut-derived signals through the portal circulation. Oxidative stress is best viewed as a dynamic, compartmentalized redox network rather than a static excess of reactive species. This review provides a liver-centered, mechanistic synthesis of how microbiota-derived products influence hepatic redox balance through receptor sensing, first-pass biotransformation, immunometabolic remodeling, and subcellular stress responses. Particular attention is given to direct microbial metabolites (short-chain fatty acids, indoles, and aromatic derivatives), the trimethylamine/trimethylamine N-oxide axis, bile acid pool remodeling, and lipopolysaccharide. These signals converge on a restricted set of master regulators, namely nuclear factor erythroid 2–related factor 2 (Nrf2), nuclear factor-κB (NF-κB), farnesoid X receptor (FXR), Takeda G protein-coupled receptor 5 (TGR5), aryl hydrocarbon receptor (AhR), AMP-activated protein kinase (AMPK), and mechanistic target of rapamycin (mTOR), thereby modulating mitochondrial, endoplasmic reticulum, peroxisomal, and lysosomal function across the major hepatic cell types. Across major liver diseases, microbiota-derived metabolites may support redox resilience under homeostatic conditions or promote oxidative injury when barrier dysfunction, metabolic vulnerability, or inflammatory priming are present, supporting a shift from a taxonomy-based to a metabolite-centered, function-oriented view of the gut–liver axis.
Keywords
Gut–liver axis; microbiota-derived metabolites; hepatic oxidative stress; redox signaling; bile acids; short-chain fatty acids; indoles; trimethylamine N-oxide
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