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As one of the three mammalian gasotransmitters, hydrogen sulfide (H 2 S) plays a major role in maintaining physiological homeostasis. Endogenously produced H 2 S plays numerous beneficial roles including mediating vasodilation and conferring neuroprotection. Due to its high membrane permeability, exogenously produced H 2 S originating from the gut microbiota can also influence human physiology and is implicated in reducing intestinal mucosal integrity and potentiating genotoxicity and is therefore a potential target for therapeutic interventions. Gut microbial H 2 S production is often attributed to dissimilatory sulfate reducers such as  Desulfovibrio  and  Bilophila  species. However, an alternative source for H 2 S production, cysteine degradation, is present in some gut microbes, but the genes responsible for cysteine degradation have not been systematically annotated in all known gut microbes. We classify mechanisms of cysteine degradation into primary, secondary, and erroneous levels of H 2 S production and perform a comprehensive search for primary, secondary, and erroneous cysteine-degrading enzymes in 4,644 non-redundant bacterial genomes from the Unified Human Gastrointestinal Genome (UHGG) catalog. Of the 4,644 genomes we have putatively identified 2,046 primary, 1,951 secondary, and 5 erroneous cysteine-degrading species. We identified the presence of at least one putative cysteine-degrading bacteria in metagenomic data of 100% of 6,623 healthy subjects and the expression of cysteine-degrading genes in metatranscriptomic data of 100% of 736 samples taken from 318 individuals. Additionally, putative cysteine-degrading bacteria are more abundant than sulfate-reducing bacteria across healthy controls, IBD patients and CRC patients ( p  < 2.2e-16, Wilcoxon rank sum test). Although we have linked many taxa with the potential for cysteine degradation, experimental validation is required to establish the H 2 S production potential of the gut microbiome. Overall, this study improves our understanding of the capacity for H 2 S production by the human gut microbiome and may help to inform interventions to therapeutically modulate gut microbial H 2 S production.

The Capacity to Produce Hydrogen Sulfide (H2S) via Cysteine Degradation Is Ubiquitous in the Human Gut Microbiome