Lee, D.; Ollberding, N. J.; Duan, Q.; Kharofa, J.

Background: Sulfur-rich dietary patterns have been associated with colorectal cancer risk. Certain gut bacteria metabolize dietary sulfur compounds into hydrogen sulfide, which can damage the intestinal epithelium and promote carcinogenesis. We evaluated whether sulfur-metabolizing enzymes are enriched in colorectal cancer and whether associations differ by age. Results: Across eleven metagenomic cohorts, several sulfur-metabolizing enzymes were more prevalent in individuals with colorectal cancer than in healthy controls. Enzymes involved in sulfur reduction and detoxification, including sulfolactaldehyde reductase, peptide-methionine sulfoxide reductase, dimethylsulfoxide reductase, glutathione transferase, hydroxyacylglutathione hydrolase, and arylsulfatase, were consistently enriched in colorectal cancer. In contrast, enzymes involved in cysteine and methionine synthesis were more common in healthy controls. Age-stratified analyses showed minimal effect modification. Fusobacterium nucleatum, Intestinimonas butyriciproducens, and Bilophila wadsworthia carried more sulfur-metabolizing genes in colorectal cancer samples. Early-onset colorectal cancer samples were enriched for these genes in Citrobacter, Klebsiella, and Raoultella, whereas healthy controls showed greater representation of detoxification-associated genes in Bifidobacterium species. Conclusions: Individuals with colorectal cancer harbor a greater abundance of sulfur-metabolizing enzymes, supporting a potential role for microbial conversion of dietary sulfur into hydrogen sulfide in colorectal carcinogenesis. Because these genes are distributed across many taxa, microbial function may better explain disease risk than individual species. Associations were consistent across age groups, suggesting that prolonged sulfur-rich dietary exposure may foster a microbial environment capable of generating carcinogenic metabolites. Microbial sulfur metabolism may therefore represent a modifiable pathway for prevention and further mechanistic study.