Diversity and Distribution of Sulfur Metabolism 1 in the Human Gut Microbiome and its Association with Colorectal Cancer

Abstract Background: Microbial sulfidogenesis produces genotoxic hydrogen sulfide (H2S) in the human gut using inorganic (sulfate) and organic (taurine/cysteine/methionine) substrates, however the majority of studies have focused on sulfate reduction using dissimilatory sulfite reductases (Dsr). Recent evidence implicates microbial sulfidogenesis as a potential trigger of colorectal cancer (CRC), highlighting the need for comprehensive knowledge of sulfur metabolism within the human gut.Results: Here we show that microbial sulfur metabolism is more abundant and diverse than previously studied and is statistically associated with CRC. Using ~17,000 bacterial genomes from publicly available stool metagenomes, we studied the diversity of sulfur metabolic genes in 667 participants across different health statuses: healthy, adenoma, and carcinoma. Sulfidogenic genes were harbored by 142 bacterial genera and both organic and inorganic sulfidogenic genes were associated with carcinoma. Significantly, anaerobic sulfite reductases were twice as abundant as dsr, demonstrating that this enzyme is likely a more important contributor to sulfate reduction in the human gut. We identified twelve potential pathways for reductive taurine metabolism and discovered novel genera harboring these pathways. Finally, prevalence of metabolic genes for organic sulfur indicate that these understudied substrates may be the most abundant source of microbially derived H2S.Conclusions: Our findings significantly expand knowledge of microbial sulfur metabolism in the human gut. We show that microbial sulfur metabolism in the human gut is more prevalent than previously known, irrespective of health status (i.e., in both healthy and diseased states). Our results significantly increase the diversity of pathways and bacteria that are associated with microbial sulfur metabolism in the human gut. Overall, our results have implications for understanding the role of the human gut microbiome and its potential contributions to the pathogenesis of CRC.