Microbiome alterations in mismatch-repair deficient metastatic colorectal cancer patients

Abstract

Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide. Many efforts have been made to stratify CRC cases, from investigating the genomic characteristics of the tumor to – more recently – considering the gut microbiome. Differences in the composition of the gut microbiome occur along CRC stages and according to primary tumor location. The microbiome links with other tumor characteristics remain underinvestigated, including those related to microsatellite instability, that have been so far assessed only with respect to intratumoral bacterial presence and not to the whole gut or oral microbiome. Here we study associations between tumor microsatellite instability and the microbiome by collecting oral and gut microbiome samples from two clinical trials, ARETHUSA and AtezoTRIBE, enrolling metastatic CRC (mCRC) patients with microsatellite stable (MSS) tumors and with high microsatellite instability (MSI-H) tumors. We identified a significant reduction in microbial diversity in oral and gut microbiomes of CRC patients with MSI-H compared to patients with MSS (Wilcoxon rank-sum test P  = 0.001 and 0.005, respectively). In addition, the MSI-H condition could be predicted by machine learning algorithms (AUC of 0.7 for both stool and oral microbiome) and the microbial signature for this condition comprises fewer microbial species compared to MSS with Ligilactobacillus salivarius and Rothia mucilaginosa detected as the strongest MSI-H associated intestinal and oral species, respectively. Our work provides evidence of human microbiome connections with tumor genetic stability, and poses the basis for larger validating investigations and mechanistic studies.