Michael B Burns | bioRxiv Science

bioRxiv2016

Genetic and transcriptional analysis of human host response to healthy gut microbiome

Many studies have demonstrated the importance of the gut microbiome in healthy and disease states. However, establishing the causality of host-microbiome interactions in humans is still challenging. Here, we describe a novel experimental system to define the transcriptional response induced by the microbiome in human cells and to shed light on the molecular mechanisms underlying host-gut microbiome interactions. In primary human colonic epithelial cells, we identified over 6,000 genes that change expression at various time points following co-culturing with the gut microbiome of a healthy individual. The differentially expressed genes are enriched for genes associated with several microbiome-related diseases, such as obesity and colorectal cancer. In addition, our experimental system allowed us to identify 87 host SNPs that show allele-specific expression in 69 genes. Furthermore, for 12 SNPs in 12 different genes, allele-specific expression is conditional on the exposure to the microbiome. Of these 12 genes, eight have been associated with diseases linked to the gut microbiome, specifically colorectal cancer, obesity and type 2 diabetes. Our study demonstrates a scalable approach to study host-gut microbiome interactions and can be used to identify putative mechanisms for the interplay between host genetics and microbiome in health and disease.

Genomics↗

bioRxiv2014

Virulence genes are a signature of the microbiome in the colorectal tumor microenvironment

BackgroundThe human gut microbiome is associated with the development of colon cancer, and recent studies have found changes in the composition of the microbial communities in cancer patients compared to healthy controls. However, host-bacteria interactions are mainly expected to occur in the cancer microenvironment, whereas current studies primarily use stool samples to survey the microbiome. Here, we highlight the major shifts in the colorectal tumor microbiome relative to that of matched normal colon tissue from the same individual, allowing us to survey the microbial communities at the tumor microenvironment, and provides intrinsic control for environmental and host genetic effects on the microbiome.\n\nResultsWe characterized the microbiome in 44 primary tumor and 44 patient-matched normal colon tissues. We find that tumors harbor distinct microbial communities compared to nearby healthy tissue. Our results show increased microbial diversity at the tumor microenvironment, with changes in the abundances of commensal and pathogenic bacterial taxa, including Fusobacterium and Providencia. While Fusobacteria has previously been implicated in CRC, Providencia is a novel tumor-associated agent, and has several features that make it a potential cancer driver, including a strong immunogenic LPS and an ability to damage colorectal tissue. Additionally, we identified a significant enrichment of virulence-associated genes in the colorectal cancer microenvironment.\n\nConclusionsThis work identifies bacterial taxa significantly correlated with colorectal cancer, including a novel finding of an elevated abundance of Providencia in the tumor microenvironment. We also describe several metabolic pathways and enzymes differentially present in the tumor associated microbiome, and show that the bacterial genes in the tumor microenvironment are enriched for virulence associated genes from the aggregate microbial community. This virulence enrichment indicates that the microbiome likely plays an active role in colorectal cancer development and/or progression. These reuslts provide a starting point for future prognostic and therapeutic research with the potential to improve patient outcomes.

Genomics↗