Long-lasting gut microbiome and fecal metabolome alterations after colorectal adenoma removal and their relationship to colorectal cancer

Although the gut microbiome is implicated in colorectal cancer (CRC), microbiome and metabolome alterations along the adenoma-carcinoma sequence remain unclear. Here, we profile stool metagenomes obtained from 354 women 12.1 ± 4.8 years following adenoma resection and from their 1:1-matched controls, as well as stool metabolomes from 184 pairs. Metagenomic profiles are compared with those from 14 independent CRC case-control studies. Microbial composition differs between adenoma cases and controls and agrees with CRC-associated alterations (Pearson's rho = 0.26, p < 0.0001). Thirty-one microbes, including Faecalibacterium prausnitzii and Flavonifractor plautii, are altered in both conditions and correlate with lifestyle factors. Thirty metabolites and 7 sub-pathways, particularly sphingolipids, are associated with adenomas. Adenomas also exhibit disease-specific microbe-metabolite associations, including those between Bilophila wadsworthia and alanine-containing dipeptides. These findings reveal gut microbial and metabolomic alterations detectable years after adenoma resection, supporting the presence of an altered microbiome along the adenoma-CRC continuum.