Soeren Ocvirk1,2, Annette S Wilson1, Joram M Posma3, Jia V Li4,5, Kathryn R Koller6, Gretchen M Day6, Christie A Flanagan6, Jill Evon Otto6, Pam E Sacco6, Frank D Sacco6, Flora R Sapp6, Amy S Wilson6, Keith Newton7, Faye Brouard8, James P DeLany9,10, Marissa Behnning1, Corynn N Appolonia1, Devavrata Soni1, Faheem Bhatti1, Barbara Methé11, Adam Fitch11, Alison Morris11, H Rex Gaskins12, James Kinross13, Jeremy K Nicholson5,13, Timothy K Thomas6, Stephen J D O'Keefe1. 1. Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. 2. Department of Gastrointestinal Microbiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany. 3. Section of Bioinformatics, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College, London, United Kingdom. 4. Section of Nutritional Research, Division of Digestive Diseases, Department of Metabolism, Digestion, and Reproduction, Imperial College, London, United Kingdom. 5. Centre for Digestive and Gut Health, Institution of Global Health Innovation, Imperial College, London, United Kingdom. 6. Clinical & Research Services, Community Health Services, Alaska Native Tribal Health Consortium, Anchorage, AK, USA. 7. Division of Gastroenterology, University of KwaZulu-Natal, Durban, South Africa. 8. Manguzi Hospital, Manguzi, KwaZulu-Natal, South Africa. 9. Division of Endocrinology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. 10. Translational Research Institute for Metabolism and Diabetes, Advent Health, Orlando, FL, USA. 11. Center for Medicine and the Microbiome, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. 12. Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, USA. 13. Department of Surgery and Cancer, Faculty of Medicine, Imperial College, London, United Kingdom.
Abstract
BACKGROUND: Alaska Native (AN) people have the world's highest recorded incidence of sporadic colorectal cancer (CRC) (∼91:100,000), whereas rural African (RA) people have the lowest risk (<5:100,000). Previous data supported the hypothesis that diet affected CRC risk through its effects on the colonic microbiota that produce tumor-suppressive or -promoting metabolites. OBJECTIVES: We investigated whether differences in these metabolites may contribute to the high risk of CRC in AN people. METHODS: A cross-sectional observational study assessed dietary intake from 32 AN and 21 RA healthy middle-aged volunteers before screening colonoscopy. Analysis of fecal microbiota composition by 16S ribosomal RNA gene sequencing and fecal/urinary metabolites by 1H-NMR spectroscopy was complemented with targeted quantification of fecal SCFAs, bile acids, and functional microbial genes. RESULTS: Adenomatous polyps were detected in 16 of 32 AN participants, but not found in RA participants. The AN diet contained higher proportions of fat and animal protein and less fiber. AN fecal microbiota showed a compositional predominance of Blautia and Lachnoclostridium, higher microbial capacity for bile acid conversion, and low abundance of some species involved in saccharolytic fermentation (e.g., Prevotellaceae, Ruminococcaceae), but no significant lack of butyrogenic bacteria. Significantly lower concentrations of tumor-suppressive butyrate (22.5 ± 3.1 compared with 47.2 ± 7.3 SEM µmol/g) coincided with significantly higher concentrations of tumor-promoting deoxycholic acid (26.7 ± 4.2 compared with 11 ± 1.9 µmol/g) in AN fecal samples. AN participants had lower quantities of fecal/urinary metabolites than RA participants and metabolite profiles correlated with the abundance of distinct microbial genera in feces. The main microbial and metabolic CRC-associated markers were not significantly altered in AN participants with adenomatous polyps. CONCLUSIONS: The low-fiber, high-fat diet of AN people and exposure to carcinogens derived from diet or environment are associated with a tumor-promoting colonic milieu as reflected by the high rates of adenomatous polyps in AN participants.
BACKGROUND: Alaska Native (AN) people have the world's highest recorded incidence of sporadic colorectal cancer (CRC) (∼91:100,000), whereas rural African (RA) people have the lowest risk (<5:100,000). Previous data supported the hypothesis that diet affected CRC risk through its effects on the colonic microbiota that produce tumor-suppressive or -promoting metabolites. OBJECTIVES: We investigated whether differences in these metabolites may contribute to the high risk of CRC in AN people. METHODS: A cross-sectional observational study assessed dietary intake from 32 AN and 21 RA healthy middle-aged volunteers before screening colonoscopy. Analysis of fecal microbiota composition by 16S ribosomal RNA gene sequencing and fecal/urinary metabolites by 1H-NMR spectroscopy was complemented with targeted quantification of fecal SCFAs, bile acids, and functional microbial genes. RESULTS:Adenomatous polyps were detected in 16 of 32 AN participants, but not found in RAparticipants. The AN diet contained higher proportions of fat and animal protein and less fiber. AN fecal microbiota showed a compositional predominance of Blautia and Lachnoclostridium, higher microbial capacity for bile acid conversion, and low abundance of some species involved in saccharolytic fermentation (e.g., Prevotellaceae, Ruminococcaceae), but no significant lack of butyrogenic bacteria. Significantly lower concentrations of tumor-suppressive butyrate (22.5 ± 3.1 compared with 47.2 ± 7.3 SEM µmol/g) coincided with significantly higher concentrations of tumor-promoting deoxycholic acid (26.7 ± 4.2 compared with 11 ± 1.9 µmol/g) in AN fecal samples. AN participants had lower quantities of fecal/urinary metabolites than RAparticipants and metabolite profiles correlated with the abundance of distinct microbial genera in feces. The main microbial and metabolic CRC-associated markers were not significantly altered in AN participants with adenomatous polyps. CONCLUSIONS: The low-fiber, high-fat diet of AN people and exposure to carcinogens derived from diet or environment are associated with a tumor-promoting colonic milieu as reflected by the high rates of adenomatous polyps in AN participants.
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