Redox Imbalance and Antioxidants in Gut–Liver Axis Dysfunction: A Focus on Dysbiosis and Microbial Metabolites

Dear Colleagues,

The liver maintains systemic metabolic homeostasis, while reactive oxygen species (ROS) and reactive nitrogen species (RNS) support physiological signaling and host defense. Oxidative stress arises when these species overwhelm hepatic antioxidant capacity, becoming a central driver of cellular injury and liver disease progression. Factors such as chronic alcohol consumption, drug toxicity, environmental pollutants, and metabolic dysregulation contribute to oxidative stress, exacerbating liver diseases like alcohol-associated liver disease (ALD) and metabolic dysfunction-associated liver disease (MASLD). In conditions like metabolic dysfunction-associated steatohepatitis (MASH), lipotoxicity drives the overproduction of free radicals that exacerbate the inflammation, activate the hepatic stellate cells, and promote fibrosis and cirrhosis. Furthermore, the increase in systemic oxidative stress that arises during liver disease can act as a damage driver for extra-hepatic organs, such as brain impairment and kidney failure.

This Special Issue focuses on the gut–liver axis as a critical regulator of hepatic redox balance. The gut microbiota profoundly influences liver redox status through the gut–liver axis. Under healthy conditions, a balanced microbiome preserves intestinal barrier integrity and supplies beneficial antioxidants. Conversely, dysbiosis increases gut permeability ("leaky gut"), facilitating the translocation of lipopolysaccharides (LPS) and microbiota-derived metabolites such as trimethylamine N-oxide (TMAO) into the portal circulation. Elevated TMAO is strongly associated with lipid peroxidation, mitochondrial dysfunction, and hepatic inflammation. LPS activates Kupffer cells via TLR4 signaling, amplifying ROS/RNS production and depleting local antioxidant reserves. These interconnected events establish a cycle where gut-derived pro-oxidant signals perpetuate liver injury.

This Special Issue invites original research and reviews that advance mechanistic understanding of the gut–liver axis in oxidative stress-driven liver diseases. Topics of interest include, but are not limited to:

• Molecular mechanisms of dysbiosis-induced redox imbalance, including LPS/TLR4 signaling and mitochondrial dysfunction.
• Microbiota-derived metabolites (e.g., TMAO, short-chain fatty acids) as regulators or biomarkers of hepatic oxidative stress.
• Gut permeability and bacterial translocation as drivers of hepatic inflammation and fibrosis.
• Antioxidant strategies targeting the gut–liver axis (e.g., probiotics, prebiotics, dietary polyphenols).
• Translational and clinical studies linking gut microbiota profiles to oxidative stress markers in human liver diseases.

Dr. Agostino Di Ciaula
Guest Editor

Dr. Laura Mahdi
Guest Editor Assistant

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• gut–liver axis
• oxidative stress
• dysbiosis
• microbial metabolites