Article | Published:

Dietary Gluten Intake and Risk of Microscopic Colitis Among US Women without Celiac Disease: A Prospective Cohort Study

The American Journal of Gastroenterology (2018) | Download Citation




Microscopic colitis is a common cause of chronic watery diarrhea among the elderly. Although the prevalence of celiac disease appears to be higher in patients with microscopic colitis, the relationship between dietary gluten intake and risk of microscopic colitis among individuals without celiac disease has not been explored.


We conducted a prospective study of 160,744 US women without celiac disease enrolled in the Nurses’ Health Study (NHS) and the NHSII. Dietary gluten intake was estimated using validated food frequency questionnaires every 4 years. Microscopic colitis was confirmed through medical records review. We used Cox proportional hazard modeling to estimate the multivariable-adjusted hazard ratio (HR) and 95% confidence interval (CI).


We documented 219 incident cases of microscopic colitis over more than 20 years of follow-up encompassing 3,716,718 person-years (crude incidence rate: 5.9/100,000 person-years) in NHS and NHSII. Dietary gluten intake was not associated with risk of microscopic colitis (Ptrend = 0.88). Compared to individuals in the lowest quintile of energy-adjusted gluten intake, the adjusted HR of microscopic colitis was 1.18 (95% CI: 0.77–1.78) for the middle quintile and 1.03 (95% CI: 0.67–1.58) for the highest quintile. Additional adjustment for primary dietary sources of gluten including refined and whole grains did not materially alter the effect estimates (All Ptrend ≥ 0.69). The null association did not differ according to lymphocytic or collagenous subtypes (Pheterogeneity = 0.72) and was not modified by age, smoking status, or body mass index (All Pinteraction ≥ 0.17).


Dietary gluten intake during adulthood was not associated with risk of microscopic colitis among women without celiac disease.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    Pardi DS, Kelly CP. Microscopic colitis. Gastroenterology . 2011;140:1155–65.

  2. 2.

    Munch A, Langner C. Microscopic colitis: clinical and pathologic perspectives. Clin Gastroenterol Hepatol. 2015;13:228–36.

  3. 3.

    Munch A, Aust D, Bohr J, et al. Microscopic colitis: Current status, present and future challenges: statements of the European Microscopic Colitis Group. J Crohns Colitis. 2012;6:932–45.

  4. 4.

    Matteoni CA, Goldblum JR, Wang N, Brzezinski A, Achkar E, Soffer EE. Celiac disease is highly prevalent in lymphocytic colitis. J Clin Gastroenterol. 2001;32:225–7.

  5. 5.

    Wolber R, Owen D, Freeman H. Colonic lymphocytosis in patients with celiac sprue. Hum Pathol. 1990;21:1092–6.

  6. 6.

    Green PH, Yang J, Cheng J, Lee AR, Harper JW, Bhagat G. An association between microscopic colitis and celiac disease. Clin Gastroenterol Hepatol. 2009;7:1210–6.

  7. 7.

    Lebwohl B, Ludvigsson JF, Green PH. Celiac disease and non-celiac gluten sensitivity. BMJ . 2015;351:h4347.

  8. 8.

    Lebwohl B, Cao Y, Zong G, et al. Long term gluten consumption in adults without celiac disease and risk of coronary heart disease: prospective cohort study. BMJ . 2017;357:j1892.

  9. 9.

    History of The Nurses’ Health Study (NHS). Accessed 12/05/2017.

  10. 10.

    Nimptsch K, Bernstein AM, Giovannucci E, Fuchs CS, Willett WC, Wu K. Dietary intakes of red meat, poultry, and fish during high school and risk of colorectal adenomas in women. Am J Epidemiol. 2013;178:172–83.

  11. 11.

    Burke KE, Ananthakrishnan AN, Lochhead P, et al. Smoking is associated with an increased risk of microscopic colitis: results from two large prospective cohort studies of US women. J Crohns Colitis. 2018;12:559–67.

  12. 12.

    Willett WC, Sampson L, Stampfer MJ, et al. Reproducibility and validity of a semiquantitative food frequency questionnaire. Am J Epidemiol. 1985;122:51–65.

  13. 13.

    Harvard TH Chan School of Public Health. Nutrition Department. (2017).

  14. 14.

    Andren Aronsson C, Lee HS, Koletzko S, et al. Effects of gluten intake on risk of celiac disease: a case-control study on a Swedish birth cohort. Clin Gastroenterol Hepatol. 2016;14:403–9 e403.

  15. 15.

    See JA, Kaukinen K, Makharia GK, Gibson PR, Murray JA. Practical insights into gluten-free diets. Nat Rev Gastroenterol Hepatol. 2015;12:580–91.

  16. 16.

    Yuan C, Spiegelman D, Rimm EB, et al. Validity of a dietary questionnaire assessed by comparison with multiple weighed dietary records or 24-hour recalls. Am J Epidemiol. 2017;185:570–84.

  17. 17.

    Willett W, Stampfer MJ. Total energy intake: implications for epidemiologic analyses. Am J Epidemiol. 1986;124:17–27.

  18. 18.

    Willett W. Nutritional epidemiology. Oxford: Oxford University Press; 2012.

  19. 19.

    Nishihara R, Morikawa T, Kuchiba A, et al. A prospective study of duration of smoking cessation and colorectal cancer risk by epigenetics-related tumor classification. Am J Epidemiol. 2013;178:84–100.

  20. 20.

    Higuchi LM, Khalili H, Chan AT, Richter JM, Bousvaros A, Fuchs CS. A prospective study of cigarette smoking and the risk of inflammatory bowel disease in women. Am J Gastroenterol. 2012;107:1399–406.

  21. 21.

    Wolf AM, Hunter DJ, Colditz GA, et al. Reproducibility and validity of a self-administered physical activity questionnaire. Int J Epidemiol. 1994;23:991–9.

  22. 22.

    Ainsworth BE, Haskell WL, Leon AS, et al. Compendium of physical activities: classification of energy costs of human physical activities. Med Sci Sports Exerc. 1993;25:71–80.

  23. 23.

    Chiuve SE, Fung TT, Rimm EB, et al. Alternative dietary indices both strongly predict risk of chronic disease. J Nutr. 2012;142:1009–18.

  24. 24.

    Colditz GA, Stampfer MJ, Willett WC, et al. Reproducibility and validity of self-reported menopausal status in a prospective cohort study. Am J Epidemiol. 1987;126:319–25.

  25. 25.

    Fernandez-Banares F, de Sousa MR, Salas A, et al. Epidemiological risk factors in microscopic colitis: a prospective case-control study. Inflamm Bowel Dis. 2013;19:411–7.

  26. 26.

    Beaugerie L, Pardi DS. Review article: drug-induced microscopic colitis—proposal for a scoring system and review of the literature. Aliment Pharmacol Ther. 2005;22:277–84.

  27. 27.

    Wang M, Spiegelman D, Kuchiba A, et al. Statistical methods for studying disease subtype heterogeneity. Stat Med. 2016;35:782–800.

  28. 28.

    Westerlind H, Mellander MR, Bresso F, et al. Dense genotyping of immune-related loci identifies HLA variants associated with increased risk of collagenous colitis. Gut . 2017;66:421–8.

  29. 29.

    Westerlind H, Bonfiglio F, Mellander MR, et al. HLA associations distinguish collagenous from lymphocytic colitis. Am J Gastroenterol. 2016;111:1211–3.

  30. 30.

    Fernandez-Banares F, de Sousa MR, Salas A, et al. Impact of current smoking on the clinical course of microscopic colitis. Inflamm Bowel Dis. 2013;19:1470–6.

  31. 31.

    Masclee GM, Coloma PM, Kuipers EJ, Sturkenboom MC. Increased risk of microscopic colitis with use of proton pump inhibitors and non-steroidal anti-inflammatory drugs. Am J Gastroenterol. 2015;110:749–59.

  32. 32.

    Dobbins WO 3rd, Rubin CE. Studies of the rectal mucosa in celiac sprue. Gastroenterology . 1964;47:471–9.

  33. 33.

    Fernandez-Banares F, Esteve M, Farre C, et al. Predisposing HLA-DQ2 and HLA-DQ8 haplotypes of coeliac disease and associated enteropathy in microscopic colitis. Eur J Gastroenterol Hepatol. 2005;17:1333–8.

  34. 34.

    Kim HS, Patel KG, Orosz E, et al. Time trends in the prevalence of celiac disease and gluten-free diet in the US population: results from the national health and nutrition examination surveys 2009-2014. JAMA Intern Med. 2016;176:1716–7.

  35. 35.

    Fasano A, Sapone A, Zevallos V, Schuppan D. Nonceliac gluten sensitivity. Gastroenterology. 2015;148:1195–204.

  36. 36.

    Freeman HJ. Failure of added dietary gluten to induce small intestinal histopathological changes in patients with watery diarrhea and lymphocytic colitis. Can J Gastroenterol. 1996;10:436–9.

  37. 37.

    Williams JJ, Kaplan GG, Makhija S, et al. Microscopic colitis-defining incidence rates and risk factors: a population-based study. Clin Gastroenterol Hepatol. 2008;6:35–40.

  38. 38.

    Pardi DS. Diagnosis and management of microscopic colitis. Am J Gastroenterol. 2017;112:78–85.

Download references


We would like to thank the participants and staff of the NHS and NHS2 for their valuable contributions.

Author information


  1. Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    • Po-Hong Liu MD, MPH
    • , Kristin E. Burke MD
    • , Ashwin N. Ananthakrishnan MBBS, MPH
    • , Paul Lochhead MBChB, PhD
    • , Andrew T. Chan MD, MPH
    •  & Hamed Khalili MD, MPH
  2. Celiac Disease Center, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA

    • Benjamin Lebwohl MD, MS
  3. Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA

    • Benjamin Lebwohl MD, MS
  4. Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    • Kristin E. Burke MD
    • , Ashwin N. Ananthakrishnan MBBS, MPH
    • , Paul Lochhead MBChB, PhD
    • , James M. Richter MD
    • , Andrew T. Chan MD, MPH
    •  & Hamed Khalili MD, MPH
  5. Harvard Medical School, Boston, MA, USA

    • Kristin E. Burke MD
    • , Ashwin N. Ananthakrishnan MBBS, MPH
    • , Paul Lochhead MBChB, PhD
    •  & Hamed Khalili MD, MPH
  6. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    • Kerry L. Ivey PhD
    •  & Andrew T. Chan MD, MPH
  7. Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    • Kerry L. Ivey PhD
  8. South Australian Health and Medical Research Institute, Infection and Immunity Theme, School of Medicine, Flinders University, Adelaide, SA, Australia

    • Kerry L. Ivey PhD
  9. Department of Medicine, Clinical Epidemiology Unit, Karolinska Institutet, Stockholm, Sweden

    • Ola Olen MD, PhD
    •  & Hamed Khalili MD, MPH
  10. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

    • Jonas F. Ludvigsson MD, PhD
  11. Department of Pediatrics, Örebro University Hospital, Örebro University, Örebro, Sweden

    • Jonas F. Ludvigsson MD, PhD
  12. Broad Institute of MIT and Harvard, Cambridge, MA, USA

    • Andrew T. Chan MD, MPH
  13. Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    • Andrew T. Chan MD, MPH
  14. Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    • Andrew T. Chan MD, MPH


  1. Search for Po-Hong Liu MD, MPH in:

  2. Search for Benjamin Lebwohl MD, MS in:

  3. Search for Kristin E. Burke MD in:

  4. Search for Kerry L. Ivey PhD in:

  5. Search for Ashwin N. Ananthakrishnan MBBS, MPH in:

  6. Search for Paul Lochhead MBChB, PhD in:

  7. Search for Ola Olen MD, PhD in:

  8. Search for Jonas F. Ludvigsson MD, PhD in:

  9. Search for James M. Richter MD in:

  10. Search for Andrew T. Chan MD, MPH in:

  11. Search for Hamed Khalili MD, MPH in:

Guarantor of the article

Dr. Hamed Khalili, MD, MPH.

Specific author contributions

P-HL and HK have full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: P-HL, OO, JFL, ATC, HK. Acquisition of data: BL, KEB, ANA, PL, ATC, HK. Analysis and interpretation of data: all coauthors. Drafting of the manuscript: P-HL, HK. Critical revision of the manuscript for important intellectual content: all coauthors. Obtained funding: ATC, HK. Administrative, technical, or material support: ATC, HK. Study supervision: ATC, HK.

Financial support

KEB is supported by F32 DK115134. HK is supported by K23 DK099681. PL is supported by a career development award from the Crohn’s and Colitis Foundation. ATC is supported by K24 DK098311, a Crohn’s and Colitis Foundation Senior Investigator Award, and a Stuart and Suzanne Steele MGH Research Scholars Award. The Nurses’ Health Study and Nurses’ Health Study II are supported by UM1 CA186107 and UM1 CA176726, respectively. The salary of KLI is supported by a National Health and Medical Research Council early career fellowship.

Potential competing interests

HK receives consulting fees from Abbvie, Takeda, and Samsung Bioepis. HK also receives funding from Takeda. BL receives consulting fees from Takeda. ANA serves on the scientific advisory board of Abbvie, Takeda, and Merck. ATC receives consulting fees from Pfizer Inc., and Bayer A.G. The remaining authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Hamed Khalili MD, MPH.

About this article

Publication history