With the rapid development and high therapeutic efficiency and biosafety of gas-involving theranostics, hydrogen medicine has been particularly outstanding because hydrogen gas (H₂), a microbial-derived gas, has potent anti-oxidative, anti-apoptotic, and anti-inflammatory activities in many disease models. Studies have suggested that H₂-enriched saline/water alleviates colitis in murine models; however, the underlying mechanism remains poorly understood. Despite evidence demonstrating the importance of the microbial hydrogen economy, which reflects the balance between H₂-producing (hydrogenogenic) and H₂-utilizing (hydrogenotrophic) microbes in maintaining colonic mucosal ecosystems, minimal efforts have been exerted to manipulate relevant H₂-microbe interactions for colonic health. Consistent with previous studies, we found that administration of hydrogen-rich saline (HS) ameliorated dextran sulfate sodium-induced acute colitis in a mouse model. Furthermore, we demonstrated that HS administration can increase the abundance of intestinal-specific short-chain fatty acid (SCFA)-producing bacteria and SCFA production, thereby activating the intracellular butyrate sensor peroxisome proliferator-activated receptor γ signaling and decreasing the epithelial expression of Nos2, consequently promoting the recovery of the colonic anaerobic environment. Our results also indicated that HS administration ameliorated disrupted intestinal barrier functions by modulating specific mucosa-associated mucolytic bacteria, leading to substantial inhibition of opportunistic pathogenic Escherichia coli expansion as well as a significant increase in the expression of interepithelial tight junction proteins and a decrease in intestinal barrier permeability in mice with colitis. Exogenous H₂ reprograms colonocyte metabolism by regulating the H₂-gut microbiota-SCFAs axis and strengthens the intestinal barrier by modulating specific mucosa-associated mucolytic bacteria, wherein improved microbial hydrogen economy alleviates colitis.

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