The Sulfur Microbial Diet Is Associated With Increased Risk of Early-Onset Colorectal Cancer Precursors

  • Author Footnotes
    ∗ Authors share co-first authorship.
    Long H. Nguyen
    Footnotes
    ∗ Authors share co-first authorship.
    Affiliations
    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
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  • Author Footnotes
    ∗ Authors share co-first authorship.
    Yin Cao
    Footnotes
    ∗ Authors share co-first authorship.
    Affiliations
    Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine in St. Louis, St Louis, Missouri

    Alvin J. Siteman Cancer Center, Washington University School of Medicine in St. Louis, St Louis, Missouri

    Division of Gastroenterology, Washington University School of Medicine in St. Louis, St Louis, Missouri
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  • Jinhee Hur
    Affiliations
    Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
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  • Raaj S. Mehta
    Affiliations
    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
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  • Daniel R. Sikavi
    Affiliations
    Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts

    Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
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  • Yiqing Wang
    Affiliations
    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
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  • Wenjie Ma
    Affiliations
    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
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  • Kana Wu
    Affiliations
    Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
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  • Mingyang Song
    Affiliations
    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
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  • Edward L. Giovannucci
    Affiliations
    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

    Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
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  • Eric B. Rimm
    Affiliations
    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

    Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
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  • Walter C. Willett
    Affiliations
    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

    Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
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  • Wendy S. Garrett
    Affiliations
    Broad Institute of MIT and Harvard, Cambridge, Massachusetts

    Department of Medicine, Dana-Farber Cancer Institute, Boston, Massachusetts
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  • Jacques Izard
    Affiliations
    Department of Food Science and Technology, University of Nebraska, Lincoln, Nebraska

    Nebraska Food for Health Center, University of Nebraska, Lincoln, Nebraska

    Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska
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  • Author Footnotes
    § Authors share co-senior authorship.
    Curtis Huttenhower
    Correspondence
    Curtis Huttenhower, PhD, Department of Biostatistics, Harvard T.H. Chan School of Public Health, 677 Huntington Avenue, Boston, Massachusetts 02115.
    Footnotes
    § Authors share co-senior authorship.
    Affiliations
    Department of Biostatistics, Harvard T.H. Chan School of Public Health, 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
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  • Author Footnotes
    § Authors share co-senior authorship.
    Andrew T. Chan
    Correspondence
    Correspondence Address correspondence to: Andrew T. Chan, MD, MPH, Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School 55 Fruit Street, GRJ-825C, Boston, Massachusetts 02114.
    Footnotes
    § Authors share co-senior authorship.
    Affiliations
    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
    Search for articles by this author
  • Author Footnotes
    ∗ Authors share co-first authorship.
    § Authors share co-senior authorship.

      Background & Aims

      Diet may contribute to the increasing incidence of colorectal cancer (CRC) before age 50 (early-onset CRC). Microbial metabolism of dietary sulfur produces hydrogen sulfide (H2S), a gastrointestinal carcinogen that cannot be easily measured at scale. As a result, evidence supporting its role in early neoplasia is lacking.

      Methods

      We evaluated long-term adherence to the sulfur microbial diet, a dietary index defined a priori based on increased abundance of 43 bacterial species involved with sulfur metabolism, with risk of CRC precursors among 59,013 individuals who underwent lower endoscopy in the Nurses’ Health Study II (1991–2015), a prospective cohort study with dietary assessment every 4 years through validated food frequency questionnaires and an assessment of dietary intake during adolescence in 1998. The sulfur microbial diet was characterized by intake high in processed meats, foods previously linked to CRC development, and low in mixed vegetables and legumes. Multivariable logistic regression for clustered data was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs).

      Results

      We documented 2911 cases of early-onset adenoma. After adjusting for established risk factors, higher sulfur microbial diet scores were associated with increased risk for early-onset adenomas (ORquartile [Q]4 vs Q1, 1.31; 95% CI, 1.10–1.56, Ptrend = .02), but not serrated lesions. Compared with the lowest, women in the highest quartile of sulfur microbial diet scores had significantly increased risk of early-onset adenomas with greater malignant potential (ORQ4 vs Q1, 1.65 for villous/tubulovillous histology; 95% CI, 1.12–2.43; Ptrend = .04). Similar trends for early-onset adenoma were observed based on diet consumed during adolescence. In contrast, no clear association for adenomas was identified after age 50.

      Conclusions

      Our findings in a cohort of young women support a role for dietary interactions with gut sulfur-metabolizing bacteria in early-onset colorectal carcinogenesis, possibly beginning in adolescence.

      Keywords

      Abbreviations used in this paper:

      BMI (body mass index), CI (confidence interval), CRC (colorectal cancer), FFQ (food frequency questionnaire), H2S (hydrogen sulfide), NSAIDs (nonsteroidal anti-inflammatory drugs), NHSII (Nurses’ Health Study II), OR (odds ratio), Q (quartile)
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