Abstract IA06: Changes in the composition and activity of the colonic microbiome that may explain the extreme risk of colon cancer in Alaskan Native People
Authors: O'Keefe Stephen , Wilson Annette , Koller Kathryn , Flanagan Christie , Sapp Flora , Day Gretchen , Holck Peter , Methe Barbara , Morris Alison , Li Jia , Kinross James , Thomas Timothy 
Published: February 2019

Abstract
Alaska Native People (AN) suffer the highest recorded incidence of CRC globally (100:100,000) and thus have the greatest risk of dying from this disease. Diet drives genetic susceptibility risk factors, and there is convincing evidence that high consumption rates of red and processed meats and fat increase risk, while a diet rich in fiber suppresses risk. We have shown that the high risk of colon cancer in African Americans (~65:100,000) is suppressed by increasing the consumption of high-fiber foods, in part driven by the health-promoting and antineoplastic influence of colonic microbiome cometabolites (e.g., short chain fatty acids [SCFA] and butyrate) and the suppression of inflammatory and procarcinogenic cometabolites (e.g., conjugated bile acids, nitrogenous end products). This study aimed to determine if dietary-microbiome metabolism explains the extreme risk of colon cancer in AN. 20 adults living in Anchorage and 9 in Barrow (age range 40-65 years) were prospectively recruited and dietary data were recorded. This cohort was compared to 25 native Africans who consume a high-fiber diet (&gt;50g/day) and have an extremely low risk of colon cancer (&lt;5:100,000). Meta-taxonomic analysis of stool was performed by 16s rRNA sequencing and by 1H NMR (nuclear magnetic spectroscopy) for analysis of the metabolome. Results confirmed the AN diet was rich in protein and fat, but low in fiber-rich foods. Measurements of the microbiome composition showed clear separation between AN and Africans on PCA and MDS plots (p=0.0001). The microbiotas were dominated at the genus level by Blautia, Bacteroides, and Lachnospiraceae, which characterize Western populations (enterotype I) while the Africans overexpressed Prevotella, Ruminococcus, and Succinovibria, organisms that play a key role in fiber breakdown and butyrogenesis (enterotype II). The fecal metabolome showed clear separation on OPLS-DA cross-validated scores plot (p=4x10-11) driven in part by higher levels of SCFA and butyrate in Africans. Subgroup analysis showed that these differences were exaggerated in the Barrow cohort. In conclusion, these findings are consistent with our hypothesis that the extreme risk of colon cancer in AN is related to insufficient intake of fiber-rich foods and that fiber supplementation of their current diet may reduce the development of cancer.
Citation Format: Stephen O'Keefe, Annette Wilson, Kathryn Koller, Christie Flanagan, Flora Sapp, Gretchen Day, Peter Holck, Barbara Methe, Alison Morris, Jia Li, James Kinross, Timothy Thomas. Changes in the composition and activity of the colonic microbiome that may explain the extreme risk of colon cancer in Alaskan Native People [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr IA06.