The Colorectal Cancer Microbiota Alter Their Transcriptome To Adapt to the Acidity, Reactive Oxygen Species, and Metabolite Availability of Gut Microenvironments

The gut microbiome is implicated in the pathology of colorectal cancer (CRC). However, the mechanisms by which the microbiota actively contribute to disease onset and progression remain elusive. In this pilot study, we sequenced fecal metatranscriptomes of 10 non-CRC and 10 CRC patient gut microbiomes and conducted differential gene expression analyses to assess any changed functionality in disease. We report that oxidative stress responses were the dominant activity across cohorts, an overlooked protective housekeeping role of the human gut microbiome. However, expression of hydrogen peroxide and nitric oxide-scavenging genes was diminished and augmented, respectively, positing that these regulated microbial responses have implications for CRC pathology. CRC microbes enhanced expression of genes for host colonization, biofilm formation, genetic exchange, virulence determinants, antibiotic, and acid resistances. Moreover, microbes promoted transcription of genes involved in metabolism of several beneficial metabolites, suggesting their contribution to patient metabolite deficiencies previously solely attributed to tumor cells. We showed in vitro that expression of genes involved in amino acid-dependent acid resistance mechanisms of meta-gut Escherichia coli responded differently to acid, salt, and oxidative pressures under aerobic conditions. These responses were mostly dictated by the host health status of origin of the microbiota, suggesting their exposure to fundamentally different gut conditions. These findings for the first time highlight mechanisms by which the gut microbiota can either protect against or drive colorectal cancer and provide insights into the cancerous gut environment that drives functional characteristics of the microbiome.