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

Background/Objectives: 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. Methods: Ef-fluents were collected before colonoscopy. Metabolites were analyzed using LC-HRMS. Bioinformatics analyses included Limma test, along with spectral house and public da-tabases for annotations. Whole-genome shotgun sequencing was performed on fecal sam-ples. Species-metabolite interactions were calculated using Spearman correlation. Inter-leukins and inflammatory proteins were measured. Results: 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 pro-tein and microbial metabolites and to the imbalance between virulent pro-inflammatory bacteria (Escherichia, Desulfovibrio) and symbiotic (Ruminococcus, Bifidobacterium) bacteria. Conclusions: E. coli-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.