e15727 Background: Dietary patterns rich in specific sulfur-containing foods that can be metabolized into hydrogen sulfide by the gut microbiota have been associated with increased risk of colorectal cancer (CRC). Long-term exposure to dietary derived hydrogen sulfide is capable of damaging the intestinal epithelium and promoting carcinogenesis and has been hypothesized to contribute to recent increases in colorectal adenomas and cancers, particularly in younger adults (age < 50). This study evaluated whether sulfur-metabolizing enzymes are differentially enriched in individuals with CRC and whether these associations vary by age using publicly available human microbiome data. Methods: We performed a two-stage individual patient data meta-analysis (IPDMA) of fecal metagenomic sequencing data from 692 CRC patients and 609 healthy controls across eleven studies. Relative abundances of 52 sulfur-metabolizing enzyme-catalyzed reactions, annotated by Enzyme Commission number, were extracted using HUMAnN3. Logistic and mixed-effects regression models adjusted for age, gender, and BMI were used to evaluate associations between enzyme presence and CRC case status. Species-level contributions to sulfur-metabolizing genes were mapped. Results: Across eleven metagenomic cohorts, several sulfur-metabolizing enzymes, such as sulfolactaldehyde reductase, peptide-methionine sulfoxide reductase, dimethylsulfoxide reductase, were enriched in individuals with CRC. In contrast, enzymes involved in cysteine and methionine synthesis were more common in healthy controls. Age-stratified analyses demonstrated minimal effect modification by younger versus older age groups, indicating that sulfur-metabolizing pathways may be consistently associated with CRC across the age spectrum. Species-level profiling revealed that several bacterial species, including F. nucleatum , I. butyriciproducens , and B. wadsworthia , carried a higher prevalence of sulfur-metabolizing genes in CRC samples. Early-onset CRC samples were enriched for sulfur-metabolizing genes in species such as Citrobacter spp. , Klebsiella spp. , and Raoultella spp . Conclusions: Individuals with CRC in these cohorts harbored a higher relative abundance of sulfur-metabolizing enzymes, supporting the concept that microbial metabolism of dietary sulfur to hydrogen sulfide may contribute CRC carcinogenesis. Although specific bacterial species have been linked to CRC, sulfur-metabolizing genes are distributed across many taxa, suggesting that microbial function rather than composition may better explain disease risk. The consistency of these associations across ages suggests that early or prolonged exposure to sulfur-rich dietary patterns may promote a gut microbial environment capable of generating carcinogenic metabolites and support further mechanistic studies examining how diet and microbial function interact to influence CRC development.
Lee et al. (Thu,) studied this question.