Oxidative stress and chronic inflammation have been implicated in the pathophysiology of metabolic diseases, including diabetes mellitus (DM), metabolic syndrome (MS), fatty liver (FL), atherosclerosis (AS), and obesity. Molecular hydrogen (H₂) has long been considered a physiologically inert gas. In the last two decades, accumulating evidence from pre-clinical and clinical studies has indicated that H₂ may act as an antioxidant to exert therapeutic and preventive effects on various disorders, including metabolic diseases. However, the mechanisms underlying the action of H₂ remain unclear. The purpose of this review was to (1) provide an overview of the current research on the potential effects of H₂ on metabolic diseases; (2) discuss the possible mechanisms underlying these effects, including the canonical anti-oxidative, anti-inflammatory, and anti-apoptotic effects, as well as suppression of ER stress, activation of autophagy, improvement of mitochondrial function, regulation of gut microbiota, and other possible mechanisms. The potential target molecules of H₂ will also be discussed. With more high-quality clinical trials and in-depth mechanism research, it is believed that H₂ will eventually be applied to clinical practice in the future, to benefit more patients with metabolic disease.

The potential for preventive and therapeutic applications of H2 have now been confirmed in various disease. However, the effects of H2 on health status have not been fully elucidated. Our previous study reported changes in the body weight and 13 serum biochemical parameters during the six-month hydrogen intervention. To obtain a more comprehensive understanding of the effects of long-term hydrogen consumption, the plasma metabolome and gut microbiota were investigated in this study. Compared with the control group, 14 and 10 differential metabolites (DMs) were identified in hydrogen-rich water (HRW) and hydrogen inhalation (HI) group, respectively. Pathway enrichment analysis showed that HRW intake mainly affected starch and sucrose metabolism, and DMs in HI group were mainly enriched in arginine biosynthesis. 16S rRNA gene sequencing showed that HRW intake induced significant changes in the structure of gut microbiota, while no marked bacterial community differences was observed in HI group. HRW intake mainly induced significant increase in the abundance of Lactobacillus, Ruminococcus, Clostridium XI, and decrease in Bacteroides. HI mainly induced decreased abundances of Blautia and Paraprevotella. The results of this study provide basic data for further research on hydrogen medicine. Determination of the effects of hydrogen intervention on microbiota profiles could also shed light on identification of mechanism underlying the biological effects of molecular hydrogen.