The Relationship of Host Genetics and the Microbiome in Colon Cancer

Colorectal cancer (CRC) ranks as the third most deadly cancer with approximately ~50,000 deaths in the U.S. alone. Chronic intestinal inflammation plays a key role in CRC development given that patients with inflammatory bowel disease, ulcerative colitis or Crohn’s disease, have an increased risk of CRC. At the same time, the microbiome may also contribute to inflammation in the gut. One crucial area of research is studying the interaction between host genetics and the microbiome. Here, we untangle the relationship between TGF-beta, a gene involved in immune system control, H. hepaticus, a known inflammatory bacteria, and the microbiome. Using a TGFb-signaling-deficient mouse model of human colorectal cancer (CRC), we show that the disruptions host-TGFb-signaling produce changes within the microbiome, suggesting a causative role in the development of colon cancer. We reveal specific bacterial species that contribute to 4 major pathways known to affect human CRC: LPS production leading to inflammatory bowel, butyrate metabolism invoking the Warburg effect, polyamine biosynthesis, and oxidative phosphorylation leading to reactive oxygen and nitrogen species. With the exception of LPS production, surprisingly the gut microbiome is a major contributor to pathway dysregulation heretofore thought to originate entirely from the colon mucosal epithelium. Studies that integrate host-genetics in model systems with changes in the microbiome have the potential to identify bacterial contributions to human disease. This information can then be used to test the efficacy of anti/probiotics in disease treatment, and identify new targets based on the cross-talk between the host and microbiome.