Molecular Hydrogen Metabolism: a Widespread Trait of Pathogenic Bacteria and Protists

Pathogenic microorganisms use various mechanisms to conserve energy in host tissues and environmental reservoirs. One widespread but often overlooked means of energy conservation is through the consumption or production of molecular hydrogen (H₂). Here, we comprehensively review the distribution, biochemistry, and physiology of H₂ metabolism in pathogens. Over 200 pathogens and pathobionts carry genes for hydrogenases, the enzymes responsible for H₂ oxidation and/or production. Furthermore, at least 46 of these species have been experimentally shown to consume or produce H₂ Several major human pathogens use the large amounts of H₂ produced by colonic microbiota as an energy source for aerobic or anaerobic respiration. This process has been shown to be critical for growth and virulence of the gastrointestinal bacteria Salmonella enterica serovar Typhimurium, Campylobacter jejuni, Campylobacter concisus, and Helicobacter pylori (including carcinogenic strains). H₂ oxidation is generally a facultative trait controlled by central regulators in response to energy and oxidant availability. Other bacterial and protist pathogens produce H₂ as a diffusible end product of fermentation processes. These include facultative anaerobes such as Escherichia coli, S Typhimurium, and Giardia intestinalis, which persist by fermentation when limited for respiratory electron acceptors, as well as obligate anaerobes, such as Clostridium perfringens, Clostridioides difficile, and Trichomonas vaginalis, that produce large amounts of H₂ during growth. Overall, there is a rich literature on hydrogenases in growth, survival, and virulence in some pathogens. However, we lack a detailed understanding of H₂ metabolism in most pathogens, especially obligately anaerobic bacteria, as well as a holistic understanding of gastrointestinal H₂ transactions overall. Based on these findings, we also evaluate H₂ metabolism as a possible target for drug development or other therapies.