The gut microbiota-produced vitamin B6 mitigates alcohol-associated liver disease by attenuating hepatic oxidative stress damage

Alcohol-associated liver disease (ALD) is a major clinical issue characterized by progressive stages, including hepatic steatosis, liver fibrosis, cirrhosis, and HCC. Patients with long-term chronic alcoholism often present with gut microbiota dysbiosis and reduced plasma levels of vitamin B6. This study aimed to verify that gut microbiota disruption in ALD significantly contributes to reduced in vivo production of vitamin B6 and to investigate the role of this reduction in the pathogenesis of ALD.

The ALD was investigated utilizing the Gao-binge mouse model. Fecal microbial composition was analyzed in pair-fed mice and ALD mice to identify alcohol-induced functional changes in the microbiota. Additionally, liver protein expression profiles and liver and plasma metabolomic profiles were characterized to elucidate the role of vitamin B6 in ALD pathogenesis through integrated proteomic and metabolomic analyses. The findings were further validated using animal models and clinical patient samples.

Alcohol consumption disrupted the gut microbiota in the mice, impairing the vitamin B6 synthesis by intestinal microorganisms. Vitamin B6 deficiency aggravated the disorder of amino acid metabolism in the liver and inhibited ornithine aminotransferase expression, thereby worsening oxidative stress damage. In patients with ALD, significant disturbances of gut microbiota were observed, along with decreased intestinal vitamin B6 levels, which were negatively correlated with serum biochemical markers.

The imbalance of gut microbiota in ALD mice reduces vitamin B6 synthesis, which affects amino acid metabolism and glutathione synthesis in the liver, thereby exacerbating ALD. These findings suggest that vitamin B6 may play a critical protective role in ALD progression by regulating amino acid metabolism.