Unraveling the Influence of Gut Microbiome on the Efficacy of Colorectal Cancer Therapeutics

Abstract

Colorectal cancer (CRC) remains a leading cause of cancer-related deaths, with chemoresistance significantly hindering treatment efficacy. This study explores the influence of the gut microbiome on chemoresistance in CRC patients, aiming to identify microbial genes and species associated with treatment outcomes. The study analyzed metagenomic data from CRC patients categorized into groups with progressive disease and partial response. Validation was conducted using a separate dataset with untreated and treated CRC samples. In this analysis key microbial genes were identified, such as butyrate, ABC family, deoxy uridine triphosphatase, histone deacetylase, glutathione s-transferase, cytidine deaminase, cystine desulfurase, ribonucleotide reductase, and thymidylate synthase, which were significantly associated with chemoresistance. The high abundance of these genes correlated with poor treatment responses, suggesting their roles in modulating drug efficacy. Taxa association analysis revealed species Akkermansia muciniphila, Escherichia coli, Ruminococcus albus, Clostridium saccharolyticum, and Ethanoligenens harbinense to be prevalent in non-responders, indicating their potential involvement in CRC progression and therapeutic response. Machine learning models, particularly Gradient Boosting, demonstrated high accuracy in classifying chemoresistance-associated genes and species. These findings provide novel insights into the microbial mechanisms underlying chemoresistance in CRC, identifying potential biomarkers and therapeutic targets to enhance treatment efficacy. This study highlights the critical role of the gut microbiome in CRC treatment response, offering avenues for xv developing microbiome-based interventions to overcome chemoresistance and improve patient outcomes.