Long H Nguyen1, Wenjie Ma2, Dong D Wang3, Yin Cao4, Himel Mallick5, Teklu K Gerbaba6, Jason Lloyd-Price5, Galeb Abu-Ali7, A Brantley Hall8, Daniel Sikavi9, David A Drew10, Raaj S Mehta2, Cesar Arze7, Amit D Joshi2, Yan Yan7, Tobyn Branck7, Casey DuLong7, Kerry L Ivey11, Shuji Ogino12, Eric B Rimm13, Mingyang Song14, Wendy S Garrett15, Jacques Izard16, Curtis Huttenhower17, Andrew T Chan18. 1. Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. 2. Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. 3. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. 4. Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St Louis, Missouri; Siteman Cancer Center, Washington University School of Medicine, St Louis, Missouri. 5. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; Broad Institute of MIT and Harvard, Cambridge, Massachusetts. 6. Department of Food Science & Technology, University of Nebraska, Lincoln, Nebraska. 7. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. 8. Broad Institute of MIT and Harvard, Cambridge, Massachusetts. 9. Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. 10. Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. 11. Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; South Australian Health and Medical Research Institute, Microbiome & Host Health Programme, Precision Medicine Theme, South Australia, Australia. 12. Broad Institute of MIT and Harvard, Cambridge, Massachusetts; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; Cancer Immunology and Cancer Epidemiology Programs, Dana-Farber Harvard Cancer Center, Boston, Massachusetts; Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. 13. Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. 14. Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. 15. Broad Institute of MIT and Harvard, Cambridge, Massachusetts; Department of Medicine, Dana-Farber Cancer Institute, Boston, Massachusetts; Department of Immunology and Infectious Disease, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. 16. Department of Food Science & Technology, University of Nebraska, Lincoln, Nebraska; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska. 17. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; Broad Institute of MIT and Harvard, Cambridge, Massachusetts. Electronic address: chuttenh@hsph.harvard.edu. 18. Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Broad Institute of MIT and Harvard, Cambridge, Massachusetts; Department of Immunology and Infectious Disease, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. Electronic address: achan@partners.org.
Abstract
BACKGROUND & AIMS: Sulfur-metabolizing microbes, which convert dietary sources of sulfur into genotoxic hydrogen sulfide (H2S), have been associated with development of colorectal cancer (CRC). We identified a dietary pattern associated with sulfur-metabolizing bacteria in stool and then investigated its association with risk of incident CRC using data from a large prospective study of men. METHODS: We collected data from 51,529 men enrolled in the Health Professionals Follow-up Study since 1986 to determine the association between sulfur-metabolizing bacteria in stool and risk of CRC over 26 years of follow-up. First, in a subcohort of 307 healthy men, we profiled serial stool metagenomes and metatranscriptomes and assessed diet using semiquantitative food frequency questionnaires to identify food groups associated with 43 bacterial species involved in sulfur metabolism. We used these data to develop a sulfur microbial dietary score. We then used Cox proportional hazards modeling to evaluate adherence to this pattern among eligible individuals (n = 48,246) from 1986 through 2012 with risk for incident CRC. RESULTS: Foods associated with higher sulfur microbial diet scores included increased consumption of processed meats and low-calorie drinks and lower consumption of vegetables and legumes. Increased sulfur microbial diet scores were associated with risk of distal colon and rectal cancers, after adjusting for other risk factors (multivariable relative risk, highest vs lowest quartile, 1.43; 95% confidence interval 1.14-1.81; P-trend = .002). In contrast, sulfur microbial diet scores were not associated with risk of proximal colon cancer (multivariable relative risk 0.86; 95% CI 0.65-1.14; P-trend = .31). CONCLUSIONS: In an analysis of participants in the Health Professionals Follow-up Study, we found that long-term adherence to a dietary pattern associated with sulfur-metabolizing bacteria in stool was associated with an increased risk of distal CRC. Further studies are needed to determine how sulfur-metabolizing bacteria might contribute to CRC pathogenesis.
BACKGROUND & AIMS:Sulfur-metabolizing microbes, which convert dietary sources of sulfur into genotoxic hydrogen sulfide (H2S), have been associated with development of colorectal cancer (CRC). We identified a dietary pattern associated with sulfur-metabolizing bacteria in stool and then investigated its association with risk of incident CRC using data from a large prospective study of men. METHODS: We collected data from 51,529 men enrolled in the Health Professionals Follow-up Study since 1986 to determine the association between sulfur-metabolizing bacteria in stool and risk of CRC over 26 years of follow-up. First, in a subcohort of 307 healthy men, we profiled serial stool metagenomes and metatranscriptomes and assessed diet using semiquantitative food frequency questionnaires to identify food groups associated with 43 bacterial species involved in sulfur metabolism. We used these data to develop a sulfur microbial dietary score. We then used Cox proportional hazards modeling to evaluate adherence to this pattern among eligible individuals (n = 48,246) from 1986 through 2012 with risk for incident CRC. RESULTS: Foods associated with higher sulfur microbial diet scores included increased consumption of processed meats and low-calorie drinks and lower consumption of vegetables and legumes. Increased sulfur microbial diet scores were associated with risk of distal colon and rectal cancers, after adjusting for other risk factors (multivariable relative risk, highest vs lowest quartile, 1.43; 95% confidence interval 1.14-1.81; P-trend = .002). In contrast, sulfur microbial diet scores were not associated with risk of proximal colon cancer (multivariable relative risk 0.86; 95% CI 0.65-1.14; P-trend = .31). CONCLUSIONS: In an analysis of participants in the Health Professionals Follow-up Study, we found that long-term adherence to a dietary pattern associated with sulfur-metabolizing bacteria in stool was associated with an increased risk of distal CRC. Further studies are needed to determine how sulfur-metabolizing bacteria might contribute to CRC pathogenesis.
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