Colorectal cancer (CRC) is a leading cause of cancer death in the United States. Chronic inflammation has been linked to colorectal neoplasia. More recent studies also implicate imbalances in the gut microbiota (bacteria) CRC. We sought to understand the relationship between the gut microbiota, mucosal inflammation and colorectal adenomas, CRC precursors. We hypothesized that the gut microbiota promotes inflammation via activation of mucosal immune cells to elevate adenoma risk. We examined the relationship between adherent gut bacteria, mucosal immune cells, namely T cells (CD4+ and CD8+), macrophages (CD11b+) and natural killer cells (CD57+) and adenomas in a case control study.
Methods: Participants were consenting screening colonoscopy patients at UNC Hospitals without history or diagnosis of inflammatory bowel disease. Subjects were defined as cases (n=42) or controls (n=35) based on the presence or absence of adenomas. High throughput deep sequencing method was used to assess the microbiota in normal colonic mucosa of cases and controls. Immune cells were assessed by immunohistochemistry and automated image analysis using Aperio software. Differences in microbiota abundance or mucosal immune cell numbers between cases and controls were evaluated by t-tests. Diversity was measured by Shannon diversity. Correlation between bacteria and immune cells was performed using Spearman's correlation.
Results: Cases had higher WHR than controls (p=0.0001). No difference was observed for age, sex, BMI among cases and controls. The abundance of several bacteria taxa differed significantly between cases and controls. We observed a positive relationship between mucosal immune cell density and adenomas. In particular, CD 4+ density and CD4/CD8 ratio were higher in cases than controls (CD4; 1.44 case, 0.69 control p = 0.001; CD4/CD8 1.66 case, 0.56 control, p= 0.002). There were no statistically significant differences in CD 57+, CD11b or CD 8+ cell density between cases and controls. The correlation patterns between the gut microbiota and immune cells differed markedly for cases and controls. There was a positive correlation between Proteobacteria and CD4 or CD4/CD8+ cells among cases but not controls.
Conclusions: our results suggest that the gut bacteria and immune cells are interacting differently depending on adenoma status. These findings suggest activation of mucosal immune cells by bacteria may promote local inflammation and contribute to the etiology of colorectal cancer.
Citation Format: Temitope O. Keku, Romin Bonakdar, Felix Araujo Perez, Amber N. McCoy, Patrick Edmundson, Kevin Smith. Gut microbiota and mucosal inflammation and colorectal neoplasia. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1259. doi:10.1158/1538-7445.AM2014-1259