Fiber to Reduce Colon Cancer in Alaska Native People

Alaska native people (AN) have the highest recorded incidence and death rate from colon cancer in the world (\>90:100,000). We hypothesize that the AN, despite their high consumption of anti-inflammatory and antineoplastic n-3 fish oils, are at increased risk of colon cancer because of colonic butyrate deficiency resulting from their remarkably low consumption of fiber-containing foods. We hypothesize that fiber supplementation of their usual diet will result in a bloom of butyrate producing microbes in the colon, resulting in increased butyrate production, which will suppress their high microbial secondary bile acid production, antagonize the actions of other food (smoked fish) and environmental carcinogens (tobacco, alcohol), and interact with the high circulating levels of n-3 fish oils to suppress colonic inflammation and cancer risk. In order to investigate this, we will conduct a randomized double-blinded 4-week clinical trial in up to 100 randomizable healthy, middle-aged AN undergoing screening colonoscopy, with the objective of obtaining 60 completed interventions. The interventions will consist of either a high-dose soluble fiber supplement given as a drink, together with their usual diet which currently contains about 15g total fiber/d, or to a control digestible starch drink plus their usual diet. The primary endpoint will be a clinically significant reduction in Ki67 proliferative colonic mucosal biomarkers of cancer risk. Microbiome and metabolome mechanisms responsible for the anticipated changes in mucosal biomarkers will also be investigated. Our results in extreme risk AN will be further evaluated by comparison to similar measurements previously made in minimal risk rural Africans and intermediate risk African Americans. Our results will be used to provide the scientific basis for a definitive large-scale high-fiber supplementation study (to achieve \>50g total fiber/d) to suppress adenomatous polyp recurrence following colonoscopy.

Sex

All

Minimum age

40 Years

Maximum age

70 Years

Inclusion Criteria: Healthy AN volunteers (from GI standpoint) between 40-70 years (age at which colon cancer screening colonoscopy is recommended in this population) and BMI between 18-40 Kg/m2. It should be noted that in our previous study, we found no difference in the responses of the key parameters (mucosal biomarkers, butyrate and secondary bile acid producers, fecal SCFA and bile acids) to increased fiber diets between those with normal body weight, those overweight, and those who were obese (Nature Comm Supplement). Patients who have, or have had noncancerous polyps removed previously by colonoscopy will be eligible. Alaska Native race will be defined as those eligible to receive health care through the Alaska Tribal Health System. Exclusion criteria: These are detailed under Human Subjects. Participants will be ineligible if they have a history of familial adenomatous polyposis or hereditary non-polyposis colorectal cancer, or have previous colonoscopic evidence of inflammatory bowel disease or colon cancer. Also ineligible will be individuals with known renal, hepatic, or bleeding disorders; previous GI surgery resulting in disturbed gut function due to of loss of bowel or altered anatomy; or any form of chronic GI disease resulting in disturbed gut function, diarrhea, and malabsorption. Individuals with antibiotic use within the past 12 weeks, current steroids use, or on medical treatment for diabetes, will also be excluded.

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• RESULTO'Keefe SJ, Li JV, Lahti L, Ou J, Carbonero F, Mohammed K, Posma JM, Kinross J, Wahl E, Ruder E, Vipperla K, Naidoo V, Mtshali L, Tims S, Puylaert PG, DeLany J, Krasinskas A, Benefiel AC, Kaseb HO, Newton K, Nicholson JK, de Vos WM, Gaskins HR, Zoetendal EG. Fat, fibre and cancer risk in African Americans and rural Africans. Nat Commun. 2015 Apr 28;6:6342. doi: 10.1038/ncomms7342. PMID 25919227
• RESULTOu J, Carbonero F, Zoetendal EG, DeLany JP, Wang M, Newton K, Gaskins HR, O'Keefe SJ. Diet, microbiota, and microbial metabolites in colon cancer risk in rural Africans and African Americans. Am J Clin Nutr. 2013 Jul;98(1):111-20. doi: 10.3945/ajcn.112.056689. Epub 2013 May 29. PMID 23719549
• RESULTKoller KR, Wilson A, Normolle DP, Nicholson JK, Li JV, Kinross J, Lee FR, Flanagan CA, Merculieff ZT, Iyer P, Lammers DL, Thomas TK, O'Keefe SJD. Dietary fibre to reduce colon cancer risk in Alaska Native people: the Alaska FIRST randomised clinical trial protocol. BMJ Open. 2021 Aug 27;11(8):e047162. doi: 10.1136/bmjopen-2020-047162. PMID 34452959
• DERIVEDKoller KR, Wilson AS, Eberhart BL 2nd, Day GM, Lee FR, Perez MR, Thomas TK, O'Keefe SJD. Tolerance of high fibre supplementation among participants in a randomised trial to reduce cancer risk among Alaska Native peoples: Alaska FIRST. Int J Circumpolar Health. 2025 Dec;84(1):2561283. doi: 10.1080/22423982.2025.2561283. Epub 2025 Sep 26. PMID 40999949