Potential Impact of Microbial Dysbiosis and Tryptophan Metabolites in Advanced Stages of Colorectal Cancer

<b>Background/Objectives</b>: We conducted an untargeted metabolomic study in serum, urine, and fecal water in colorectal cancer (CRC) patients compared to healthy controls. The aim was to define the interactions between metabolites and microbiota. <b>Methods</b>: Effluents were collected before colonoscopy. Metabolites were analyzed using LC-HRMS. Bioinformatics analyses included Limma test, along with spectral house and public databases for annotations. Whole-genome shotgun sequencing was performed on fecal samples. Species-metabolite interactions were calculated using Spearman correlation. Interleukins and inflammatory proteins were measured. <b>Results</b>: Fifty-three patients (11 stage I, 10 stage II, 10 stage III, and 22 stage IV) and twenty controls were included. Derivatives of deoxycholic acid, cholic acid, and fatty acids were lower in serum, while urinary bile acids were higher in stage IV CRC patients (versus controls). Metabolites related to tryptophan and glutamate were found significantly altered in stage IV: upregulation of kynurenine and downregulation of indole pathways. This was linked to increased inflammatory protein and microbial metabolites and to the imbalance between virulent pro-inflammatory bacteria (<i>Escherichia</i> and <i>Desulfovibrio</i>) and symbiotic (<i>Ruminococcus</i> and <i>Bifidobacterium</i>) bacteria. <b>Conclusions</b>: <i>E. coli</i>-related tryptophan catabolism shift is shown through stage IV CRC as compared to controls. As a consequence, tryptophan/kynurenine metabolite may become a promising marker for detecting the failure to immune response during therapy.