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. Author manuscript; available in PMC: 2023 Sep 1.
Published in final edited form as: Clin Gastroenterol Hepatol. 2021 Nov 17;20(9):1986–1996.e11. doi: 10.1016/j.cgh.2021.11.016

Gluten intake and risk of digestive system cancers in three large prospective cohort studies

Yiqing Wang 1,2, Yin Cao 3,4,5, Benjamin Lebwohl 6,7, Mingyang Song 1,2,8,9, Qi Sun 8,9,10, Peter HR Green 6, Edward L Giovannucci 8,9,10, Walter C Willett 8,9,10, Andrew T Chan 1,2,9,10
PMCID: PMC9110553  NIHMSID: NIHMS1758185  PMID: 34800737

Abstract

Background & Aims:

In patients with celiac disease, gluten triggers an immune reaction that damages small intestinal villi and may increase long-term risk of gastrointestinal cancer. However, the health impacts of gluten in the general population are understudied. We aimed to examine the association between gluten intake and risk of digestive system cancers among individuals without celiac disease.

Methods:

We leveraged longitudinal data from three prospective cohorts, Nurses’ Health Study (1984-2018, 73,166 women aged 65.1±10.8 years), Nurses’ Health Study II (1991-2017, 90,423 women aged 49.1±8.2 years), and Health Professionals Follow-Up Study (1986-2016, 42,617 men aged 64.8±10.8 years). Using Cox proportional hazards regression, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) of digestive system cancers according to quintiles of gluten intake assessed from food frequency questionnaires.

Results:

During 4,801,513 person-years of follow-up, we documented 6,231 incident digestive system cancer cases among three cohorts. After adjusting for a wide-range of risk factors, including body mass index, physical activity, diet quality, gluten intake was not associated with an increased risk of digestive system cancer, with a HR (95% CI) of 0.94 (0.87, 1.02) comparing the highest to the lowest quintile of gluten intake (p-trend=0.05). Similar null associations were found for individual digestive system cancers: oral cavity and oropharyngeal cancer, esophageal cancer, stomach cancer, small intestine cancer, colorectal cancer, pancreatic cancer, gallbladder cancer, and liver cancer.

Conclusions:

Gluten intake was not associated with risk of digestive system cancers in adults without celiac disease. Restricting dietary gluten is unlikely to be beneficial to the prevention of digestive system cancers in the general population.

Keywords: diet, gastrointestinal carcinogenesis, celiac disease, epidemiology

INTRODUCTION

Cancers of the gastrointestinal tract and accessory organs of digestion, colloquially known as digestive system cancers, contribute substantially to the global cancer burden. According to the GLOBOCAN 2020 database, digestive system cancers accounted for about 30% of new cancer cases and 39% of deaths for all cancers.1

Diet is one of the major modifiable risk factors for digestive system cancers.2 For example, numerous epidemiological studies have demonstrated that whole-grain intake and cereal fiber intake are inversely associated with risk of digestive system cancers,3–6 including gastric cancer and colorectal cancer. In contrast, gluten, a protein component of certain grains like wheat, barley and rye, causes abnormal immune reactions and inflammation in the small intestine of patients with celiac disease (CD),7 a serious autoimmune disease that affects about 1% of Western populations. Many cohort studies have shown that CD patients may at higher risk of esophageal cancer and small intestinal cancer compared with the general population.8–10 Potential mechanisms underlying the development of digestive system cancers involve chronic inflammation, oxidative stress, and alterations in oncogenic signaling pathways.11 Although a gluten-free diet can alleviate intestinal damage and reduce oxidative stress in CD patients,12 it is unclear whether dietary gluten intake affects digestive system cancer risk, especially among individuals without CD. Nevertheless, the consumption of gluten-free products has risen rapidly over the past three decades due to perceived health benefits popularized by media and marketing.13

Therefore, In the present study, we prospectively examined the association between gluten intake and risk of digestive system cancers in US adults free of CD, using high-quality dietary data acquired through a validated food frequency questionnaires (FFQ) and detailed disease outcome information from three large population-based cohort studies.

METHODS

Study population

We used longitudinal data from the Nurses’ Health Study (NHS), the Nurses’ Health Study II (NHSII), and the Health Professionals Follow-Up Study (HPFS). Launched in 1976 and 1989, the NHS and NHSII recruited 121,700 (30-55 years old, from 11 states) and 116,429 female registered nurses (25-42 years old, from 14 states), respectivley. The HPFS enrolled 51,529 male health professionals (40-75 years old, from 50 states) when initiated in 1986. In each cohort, detailed questionnaires on demographics, lifestyle risk factors, and diseases were mailed every two years, with a response rate of >90%.14–16 Informed consent was implied by the completion of questionnaires. These studies have been approved by the institutional review boards of the Brigham and Women’s Hospital and the Harvard T.H. Chan School of Public Health and those of participating registries as required.

Among participants who completed the baseline dietary assessments in 1984 NHS (n=81,704), and 1991 NHSII (n=95,233), and 1986 HPFS (n=49,915), we excluded those who had been diagnosed with cancer, heart disease, or inflammatory bowel disease before or at baseline (NHS: n=7,452; NHSII: n=3,787; HPFS: n=6,091), had subsequently been diagnosed with CD during follow-ups (NHS: n=286; NHSII: n=473; HPFS: n=155), or only returned the baseline questionnaires (NHS: n=800; NHSII: n=550; HPFS: n=1,052). The final analytic cohort included 73,166 NHS participants, 90,423 NHSII participants, and 42,617 HPFS participants.

Assessment of gluten intake

In every four years, participants self-administered a validated semi-quantitative FFQ,.17 to indicate how frequently (9 options from “never, or less than once per month” to “6+ per day”) they consumed each food item in common portion size (e.g., 1 cup cooked oatmeal, 1 slice bread) during the past year.

We estimated gluten intake by first identifying food items with gluten-containing ingredients, including wheat, rye, barley, cereal, couscous, and beer, and quantifying these ingredients using year-specific product labels and ingredient lists from manufacturers or recipes from cookbooks. Following prior studies,18, 19 we then calculated gluten contents in these foods as 75% of the protein contents and adjusted for total energy intake using the residual method.20 In a subset of 650 HPFS participants, consumption of gluten (Spearman correlation coefficient r: 0.58) and gluten-rich foods (median r: 0.60) estimated from FFQs were highly correlated with those assessed from 7-day dietary records.21 To reduce interindividual variation and capture long-term intake, we calculated cumulative averages of gluten intake across follow-up and updated at each questionnaire cycle.

Ascertainment of digestive system cancers

Incident physician-diagnosed cancer cases were reported by participants in biennial questionnaires or by next of kin. Study physicians confirmed cancer diagnoses by reviewing medical records, pathology reports, state cancer registries, death certificates, or National Death Index.

Statistical analysis

We calculated person-years from the return of baseline FFQ until cancer diagnosis, death, or the end of follow-up (NHS: June 30, 2018; NHSII: June 30, 2017; HPFS: January 31, 2016), whichever occurred first. We performed Cox proportional hazards regression models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations between cohort-specific quintiles of gluten intake and risk of all (primary outcome) and individual types of digestive system cancers (secondary outcomes): oral cavity and oropharyngeal cancer, esophageal cancer, stomach cancer, small intestine cancer, colorectal cancer, pancreatic cancer, gallbladder cancer, and liver cancer. We tested linear trends by modeling the median values of gluten quintiles as a continuous variable, consistent with prior analyses.18, 19 The heterogeneity across cohorts was tested using Cochran’s Q test.

In the age-adjusted model (Model 1), we stratified by age (months), calendar years, and cohort. In Model 2, we additionally controlled for the following potential confounders selected a priori: race (white/others), BMI (kg/m2), family history of cancer (yes/no), personal history of diabetes (yes/no), physical examination in the past 2 years (yes/no), smoking status (never smokers/past and current smokers: <14, 15-24, or ≥25 cigarettes/d), smoking (pack-years), physical activity (metabolic equivalent task-hours/week), current multivitamin use (yes/no), regular aspirin use (yes/no), regular non-steroid anti-inflammatory drug (NSAID) use (yes/no), and menopausal status (in women; pre-/post-menopausal: never/past/current hormone users). For colorectal cancer, we adjusted for family history of colorectal cancer (yes/no) and endoscopy in the past 2 years (yes/no) instead of family history of cancer. In the fully-adjusted Model 3, we additionally adjusted for the following continuous dietary confounders: alcohol intake (g/d), total calorie intake (kcal), calcium intake (mg/d), folic acid intake (mcg/d), coffee intake (servings/d), and diet quality assessed by Alternative Healthy Eating Index score (AHEI-2010, excluding alcohol and whole grains).22 More detailed description for covariates is in the Supplementary Methods. We added a 2-year lag period between exposures and outcomes to address the concern of potential reverse causation, which is consistent with prior research.23 For example, in the NHS, we used the cumulative average intake of gluten in 1990 for cancer cases ascertained during 1992-1996, and so forth.

In sensitivity analyses, we suspended updating dietary data if participants reported having diabetes, hypertension, hypercholesterolemia, myocardial infarction, stroke, or cancer, to account for the possibility that participants’ usual diet changed due to the diagnosis of these chronic diseases.24 Additionally, we individually adjusted for the consumption of refined grains (e.g., white bread, white rice, and pasta), whole grains (e.g., whole wheat bread, oat bran, brown rice), and cereal fiber in Model 3, and assessed the interactions of gluten with these carbohydrate sources (in tertiles) to test for potential modification by these correlated carbohydrate intakes. We also calculated whole grain-adjusted and refined grain-adjusted gluten intake using the residual method,20 so that gluten intake was uncorrelated with one of these two major dietary sources of gluten, to examine whether gluten from different sources associated with digestive system cancer risk differently. Lastly, we repeated the analysis using percentage of total energy from gluten. As an exploratory analysis, we conducted stratified analyses by age (<65 years, ≥65 years), BMI (<25 kg/m2, ≥25 kg/m2), smoking status (never, ever), physical activity (<18 METs/week, ≥18 METs/week), alcohol intake (<5 g/d, ≥5 g/d), and aspirin use (no, yes) to examined potential modification by these risk factors. Interaction between gluten intake and each stratification variable was tested using the log-likelihood ratio test. In addition, to explore whether the association between gluten intake and digestive system cancer risk varied over time, we stratified the follow-up period by year 2000 and tested heterogeniety in results using Cochran’s Q test.

Analyses were performed using SAS version 9.4 (Cary, NC). All tests were two-sided and a p-value<0.05 indicated statistical significance.

RESULTS

The mean gluten intake ranged from 3.2 (SD: 0.7) g/day to 7.1 (1.0) g/day (from the highest to the lowest quintile) in the NHS, from 4.0 (0.8) g/day to 9.1 (1.3) g/day in the NHSII, and from 3.9 (0.9) g/day to 9.7 (1.6) g/day in the HPFS (Table 1). Participants with higher gluten intake were more likely to be white and nonsmokers, and tended to consume less alcohol but more whole grains, refined grains, and cereal fibers. Age, BMI, physical activity, total calorie intake, and diet quality did not materially differ across gluten quintiles.

Table 1.

Participant characteristics (weighted by person-years) by quintiles of gluten intake across the entire follow-up perioda

NHS (1984-2018) NHS II (1991-2017) HPFS (1986-2016)
Q1 Q3 Q5 Q1 Q3 Q5 Q1 Q3 Q5
Gluten intakeb, g/d 3.2 (0.7) 4.9 (0.3) 7.1 (1.0) 4.0 (0.8) 6.2 (0.3) 9.1 (1.3) 3.9 (0.9) 6.4 (0.4) 9.7 (1.6)
Age, year 65.7 (10.4) 64.9 (10.8) 65.1 (11.1) 49.5 (8.4) 49.1 (8.2) 48.9 (8.0) 65.6 (10.7) 64.6 (10.8) 64.2(10.8)
White, % 94.9 98.3 98.9 87.2 95.3 96.6 86.0 90.9 91.7
BMI, kg/m2 25.2 (4.5) 25.2 (4.4) 24.8 (4.3) 26.1 (5.9) 25.6 (5.5) 24.7 (5.0) 26.3 (3.7) 25.9 (3.3) 25.2 (3.1)
Family history of cancer, % 56.6 59.3 59.6 71.1 77.6 78.46 35.5 39.6 38.9
Personal history of diabetes, % 7.9 7.6 7.9 4.6 3.8 3.0 7.7 6.5 5.8
Menopausal hormone use among postmenopausal women
   Never, % 31.6 29.0 29.3 12.9 12.4 12.0 - - -
   Past, % 28.5 29.2 29.2 8.7 8.3 7.0 - - -
   Current, % 29.5 28.6 28.0 12.1 10.8 9.5 - - -
Smoking status
   Never, % 41.1 45.9 48.9 62.3 66.1 67.8 44.0 48.5 53.1
   Past, % 41.7 41.8 41.9 23.9 25.4 26.1 43.4 42.4 40.0
   Current, % 17.2 12.3 9.6 13.9 8.5 6.1 12.6 9.2 6.9
Pack-years among ever smokersc 22.8 (17.9) 19.7 (16.7) 18.8 (16.7) 14.6 (10.7) 12.2 (9.3) 11.1 (8.8) 24.8 (17.8) 22.2 (16.3) 20.4 (15.5)
Physical activity METS/wk 17.5 (19.4) 16.5 (17.2) 16 (16.5) 22.3 (25.2) 21.5 (22.5) 22.7 (23.7) 27.4 (24.6) 28.8 (24.2) 30.3 (25.4)
Physical exam in past 2 years, % 65.5 70.1 69.6 90.1 90.8 89.8 55.5 62.7 63.1
Endoscopy in past 2 years, % 19.1 21.0 21.1 13.9 14.9 14.6 24.8 27.2 29.1
Multivitamin use, % 48.3 51.2 51.7 52.4 54.2 53.2 43.7 48.0 49.9
Regular aspirin use, % 54.5 56.3 55.5 22.7 21.9 19.7 43.6 46.8 46.3
Regular non-aspirin NSAID use, % 30.7 33.4 30.3 42.4 44.3 41.1 21.8 22.5 20.6
Total energy intake, kcal/d 1732 (482) 1783 (450) 1663 (426) 1795 (518) 1834 (485) 1746 (474) 1970 (587) 2026 (558) 1900 (524)
Folateb, mcg/d 453 (214) 448 (191) 467 (202) 500 (257) 525 (232) 557 (242) 517 (271) 531 (242) 580 (259)
Calciumb, mg/d 1056 (444) 1035 (395) 1047 (402) 1092 (467) 1117 (406) 1125 (401) 926 (426) 919 (350) 956 (362)
Alcohol intake, g/d 8.0 (12.0) 6.0 (9.0) 4.2 (7.0) 3.7 (7.1) 3.8 (6.1) 3.4 (5.4) 12.7 (16.2) 11.3 (13.7) 8.5 (11.1)
Coffee, servings/d 15.4 (11.3) 15.8 (10.8) 15.2 (10.9) 10.2 (10.8) 10.8 (10.4) 10.8 (10.5) 10.5 (10.6) 11.9 (10.6) 11.0 (10.5)
AHEI-10 score 45.2 (9.2) 43.8 (8.4) 43.9 (8.3) 42.1 (9.6) 42.2 (8.8) 43.3 (8.6) 45.4 (9.8) 44.6 (9.1) 46.1 (9.1)
Whole grains intakeb, g/d 13.6 (10.7) 17.3 (10.5) 25.3 (14.4) 17.9 (12.6) 23.2 (12.3) 31 (16.4) 18.4 (15.9) 24.5 (14.8) 37.9 (21.1)
Refined grains intakeb, g/d 35.7 (11.7) 48.1 (9) 60.5 (14.3) 46.4 (17.0) 62.1 (10.7) 82.2 (17.4) 43.8 (18.2) 59.6 (13.5) 77.8 (20.8)
Cereal fiber intakeb, g/d 3.3 (1.5) 4.7 (1.6) 6.9 (2.6) 4.1 (1.6) 5.9 (1.8) 8.4 (3.1) 4.1 (2.0) 6.2 (2.3) 9.7 (4.4)
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Abbreviations: NSAID, non-steroidal anti-inflammatory drug; AHEI-10, alternative healthy eating index 2010

a

Weighted by the follow-up time (person-years) accrued by each participant. Values are means (SD) unless noted as percentages (%) for categorical variables.

b

Adjusted for total energy intake using the residual method.

During a median follow-up of 31.0 (interquartile range: 20.2-31.9) years in NHS, 24.0 (23.6-24.0) years in NHSII, and 25.8 (15.3-27.8) years in HPFS, we documented 6,231 incident digestive system cancer cases over 4,801,513 person-years of follow-ups (Table 2). In the pooled analytic cohort, Model 1 (age-adjusted) and Model 2 (additionally adjusted for non-dietary risk factors including BMI, smoking status, and physical activity) showed inverse associations between gluten intake and digestive system cancer risk, with HRs (95% CI) of 0.87 (0.80, 0.94) and 0.91 (0.84, 0.99), respectively, comparing the highest to the lowest gluten quintile. However, after additionally adjusting for dietary risk factors in Model 3, including total energy intake and diet quality, the association between gluten intake and digestive system cancer risk was no longer statistically significant (HR [95% CI] comparing the highest to the lowest quintile of gluten intake: 0.94 [0.87, 1.02]; p-trend=0.05). Null associations were also observed for cancers of the gastrointestinal tract and accessory organs of digestion. There were likewise no multivariable-adjusted associations between gluten intake and risk of digestive system cancers in individual cohorts (Supplementary Table 1), with no evidence of heterogeneity across cohorts.

Table 2.

Hazard ratios (HRs) and 95% CIs of digestive system cancers by quintiles of gluten intake in the pooled analytic cohort

HR (95% CI) by quintiles of gluten intake
Model Q1 Q2 Q3 Q4 Q5 p-trenda
Person-years 955,985 959,831 961,569 961,893 962,235
All digestive system cancers
Cases 1,375 1,313 1,221 1,193 1,129
Crude incidence/100,000 person-years 144 137 127 124 117
Model 1b 1 [ref.] 0.99 (0.92, 1.07) 0.94 (0.87, 1.02) 0.91 (0.85, 0.99) 0.87 (0.80, 0.94) <0.0001
Model 2c 1 [ref.] 1.01 (0.93, 1.09) 0.97 (0.89, 1.04) 0.95 (0.88, 1.03) 0.91 (0.84, 0.99) 0.006
Model 3d 1 [ref.] 1.02 (0.94, 1.10) 0.98 (0.90, 1.06) 0.97 (0.90, 1.05) 0.94 (0.87, 1.02) 0.05
Gastrointestinal tract cancers
Cases 1,040 1,018 942 916 867
Crude incidence/100,000 person-years 109 106 98 95 90
Model 1b 1 [ref.] 1.01 (0.93, 1.10) 0.95 (0.87, 1.04) 0.92 (0.84, 1.01) 0.88 (0.80, 0.96) <0.0001
Model 2c 1 [ref.] 1.03 (0.94, 1.12) 0.98 (0.90, 1.07) 0.96 (0.88, 1.05) 0.92 (0.84, 1.01) 0.02
Model 3d 1 [ref.] 1.04 (0.95, 1.13) 0.99 (0.91, 1.09) 0.98 (0.89, 1.07) 0.95 (0.87, 1.04) 0.11
   Oral cavity and oropharyngeal cancer
   Cases 110 98 101 75 90
   Crude incidence/100,000 person-years 12 10 11 8 9
   Model 1b 1 [ref.] 0.90 (0.68, 1.18) 0.95 (0.72, 1.24) 0.71 (0.52, 0.95) 0.86 (0.65, 1.14) 0.23
   Model 2c 1 [ref.] 0.91 (0.69, 1.20) 0.98 (0.75, 1.30) 0.74 (0.55, 1.00) 0.93 (0.70, 1.23) 0.51
   Model 3d 1 [ref.] 0.94 (0.72, 1.25) 1.04 (0.79, 1.38) 0.78 (0.58, 1.06) 0.99 (0.74, 1.32) 0.85
   Esophageal cancer
   Cases 76 62 50 47 46
   Crude incidence/100,000 person-years 8 6 5 5 5
   Model 1b 1 [ref.] 0.85 (0.60, 1.19) 0.68 (0.47, 0.98) 0.64 (0.44, 0.92) 0.63 (0.43, 0.91) 0.01
   Model 2c 1 [ref.] 0.92 (0.65, 1.30) 0.77 (0.53, 1.11) 0.73 (0.50, 1.05) 0.75 (0.51, 1.09) 0.09
   Model 3d 1 [ref.] 0.94 (0.67, 1.33) 0.79 (0.55, 1.15) 0.76 (0.52, 1.10) 0.79 (0.54, 1.15) 0.16
   Stomach cancer
   Cases 74 53 62 59 53
   Crude incidence/100,000 person-years 8 6 6 6 6
   Model 1b 1 [ref.] 0.71 (0.50, 1.01) 0.85 (0.61, 1.20) 0.83 (0.59, 1.18) 0.74 (0.52, 1.06) 0.22
   Model 2c 1 [ref.] 0.75 (0.53, 1.07) 0.92 (0.65, 1.30) 0.92 (0.65, 1.30) 0.83 (0.58, 1.19) 0.59
   Model 3d 1 [ref.] 0.74 (0.52, 1.06) 0.90 (0.64, 1.28) 0.90 (0.63, 1.28) 0.81 (0.56, 1.16) 0.47
   Small intestine cancer
   Cases 31 26 23 21 22
   Crude incidence/100,000 person-years 3 3 2 2 2
   Model 1b 1 [ref.] 0.87 (0.51, 1.47) 0.76 (0.44, 1.30) 0.68 (0.39, 1.18) 0.76 (0.44, 1.33) 0.14
   Model 2c 1 [ref.] 0.86 (0.51, 1.46) 0.76 (0.44, 1.31) 0.68 (0.38, 1.19) 0.78 (0.45, 1.36) 0.16
   Model 3d 1 [ref.] 0.84 (0.50, 1.43) 0.75 (0.43, 1.29) 0.67 (0.38, 1.18) 0.79 (0.45, 1.39) 0.19
   Colorectal cancer
   Cases 755 786 714 719 660
   Crude incidence/100,000 person-years 79 82 74 75 69
   Model 1b 1 [ref.] 1.08 (0.98, 1.20) 1.00 (0.91, 1.11) 1.00 (0.91, 1.11) 0.92 (0.83, 1.02) 0.02
   Model 2c 1 [ref.] 1.10 (0.99, 1.22) 1.03 (0.93, 1.14) 1.04 (0.94, 1.16) 0.97 (0.87, 1.07) 0.19
   Model 3d 1 [ref.] 1.11 (1.00, 1.22) 1.04 (0.94, 1.15) 1.06 (0.96, 1.18) 1.00 (0.89, 1.11) 0.50
Cancers of accessory organs of digestion
Cases 337 296 284 279 264
Crude incidence/100,000 person-years 35 31 30 29 27
Model 1b 1 [ref.] 0.93 (0.79, 1.08) 0.91 (0.77, 1.06) 0.88 (0.75, 1.03) 0.84 (0.71, 0.99) 0.03
Model 2c 1 [ref.] 0.94 (0.80, 1.10) 0.93 (0.79, 1.09) 0.92 (0.78, 1.08) 0.88 (0.75, 1.04) 0.14
Model 3d 1 [ref.] 0.95 (0.81, 1.12) 0.95 (0.81, 1.11) 0.94 (0.80, 1.10) 0.91 (0.77, 1.07) 0.27
   Pancreatic cancer
   Cases 245 226 215 211 190
   Crude incidence/100,000 person-years 26 24 22 22 20
   Model 1b 1 [ref.] 0.97 (0.81, 1.16) 0.94 (0.78, 1.13) 0.92 (0.76, 1.11) 0.83 (0.69, 1.01) 0.06
   Model 2c 1 [ref.] 0.98 (0.81, 1.17) 0.95 (0.79, 1.15) 0.95 (0.78, 1.14) 0.86 (0.71, 1.05) 0.16
   Model 3d 1 [ref.] 0.99 (0.83, 1.19) 0.97 (0.81, 1.17) 0.96 (0.80, 1.16) 0.88 (0.72, 1.07) 0.23
   Gallbladder cancer
   Cases 47 38 42 39 41
   Crude incidence/100,000 person-years 5 4 4 4 4
   Model 1b 1 [ref.] 0.85 (0.55, 1.31) 0.98 (0.64, 1.49) 0.88 (0.57, 1.35) 0.95 (0.62, 1.45) 0.90
   Model 2c 1 [ref.] 0.87 (0.57, 1.34) 1.01 (0.66, 1.53) 0.93 (0.60, 1.43) 1.01 (0.66, 1.54) 0.84
   Model 3d 1 [ref.] 0.87 (0.57, 1.35) 1.02 (0.67, 1.56) 0.96 (0.62, 1.48) 1.06 (0.69, 1.64) 0.65
   Liver cancer
   Cases 46 33 27 29 33
   Crude incidence/100,000 person-years 5 3 3 3 3
   Model 1b 1 [ref.] 0.78 (0.50, 1.22) 0.64 (0.40, 1.04) 0.66 (0.41, 1.05) 0.76 (0.49, 1.20) 0.11
   Model 2c 1 [ref.] 0.80 (0.51, 1.26) 0.69 (0.43, 1.12) 0.73 (0.45, 1.17) 0.81 (0.51, 1.27) 0.23
   Model 3d 1 [ref.] 0.80 (0.50, 1.26) 0.71 (0.43, 1.15) 0.76 (0.47, 1.22) 0.89 (0.56, 1.42) 0.45
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a

The median value of gluten intake for each quintile was modeled as a continuous variable to test for linear trend.

b

Cox proportional hazards regression was stratified by age in months, calendar year, and cohort, with a 2-year lag period between exposures and outcomes to minimize potential reverse causation.

c

In addition to covariates in Model 1, Model 2 was adjusted for the following non-dietary covariates: race, BMI, family history of cancer, personal history of diabetes, physical examination, smoking status and cigarettes per day, pack-years of smoking, physical activity, current multivitamin use, regular aspirin use, regular non-aspirin non-steroid anti-inflammatory drug use, menopausal status and menopausal hormone use. For colorectal cancer, instead of adjusting for family history of cancer, we adjusted for family history of colorectal cancer and endoscopy.

d

In addition to covariates in Model 2, Model 3 was adjusted for the following dietary covariates: calorie intake, 2010 alternative healthy eating index score excluding alcohol and whole grains, alcohol intake, calcium intake, folic acid intake, and coffee intake.

In the sensitivity analysis, in which we suspended updating dietary variables upon diagnosis of chronic conditions, including diabetes, hypertension, and stroke, we did not observe any material alterations in the associations between gluten intake and risk of digestive system cancers (Supplemental Table 2). After additional adjustment for whole-grain intake in the fully-adjusted Model 3 (Table 3), thus leaving the variance of gluten intake explained by refined grain intake, the association between gluten intake and digestive system cancer risk was further attenuated (HR [95% CI] comparing the highest to the lowest quintile of gluten intake: 0.97 [0.89-1.06]; p-trend=0.31). The null association also persisted after additional adjustment for refined grain intake or cereal fiber intake. Results for refined grain-adjusted gluten intake and whole grain-adjusted gluten intake calculated using the residual model, as well as the percentage of total energy intake from gluten were likewise not statistically significant (Supplementary Table 3). Subsequent stratified analysis by tertiles of cereal fiber intake, whole grain intake, and refined grain intake yielded similar null associations between gluten intake and digestive system cancer risk across strata (Supplementary Figure 1).

Table 3.

Multivariable (MV)-adjusted hazard ratios (HRs) and 95% CIs of digestive system cancers by quintiles of gluten intake in the pooled analytic cohort, with additional adjustment for carbohydrate sourcesa

HR (95% CI) by quintiles of gluten intake
Model Q1 Q2 Q3 Q4 Q5 p-trendb
All digestive system cancers
MV-adjusted HR + refined grain intakec 1 [ref.] 1.02 (0.94, 1.10) 0.98 (0.90, 1.06) 0.97 (0.89, 1.06) 0.94 (0.85, 1.04) 0.12
MV-adjusted HR + whole grain intaked 1 [ref.] 1.02 (0.95, 1.11) 0.99 (0.91, 1.07) 0.99 (0.91, 1.07) 0.97 (0.89, 1.06) 0.31
MV-adjusted HR + cereal fiber intakee 1 [ref.] 1.03 (0.95, 1.11) 1.00 (0.92, 1.08) 1.00 (0.91, 1.08) 0.98 (0.89, 1.08) 0.50
Gastrointestinal tract cancer
MV-adjusted HR + refined grain intakec 1 [ref.] 1.04 (0.95, 1.14) 1.00 (0.91, 1.10) 0.98 (0.89, 1.09) 0.96 (0.86, 1.07) 0.22
MV-adjusted HR + whole grain intaked 1 [ref.] 1.04 (0.96, 1.14) 1.00 (0.92, 1.10) 1.00 (0.91, 1.09) 0.98 (0.89, 1.08) 0.42
MV-adjusted HR + cereal fiber intakee 1 [ref.] 1.05 (0.96, 1.15) 1.01 (0.92, 1.11) 1.01 (0.92, 1.11) 1.00 (0.90, 1.12) 0.71
   Oral cavity and oropharyngeal cancer
   MV-adjusted HR + refined grain intakec 1 [ref.] 0.93 (0.70, 1.24) 1.02 (0.76, 1.38) 0.76 (0.55, 1.06) 0.95 (0.67, 1.36) 0.80
   MV-adjusted HR + whole grain intaked 1 [ref.] 0.96 (0.73, 1.27) 1.08 (0.82, 1.43) 0.83 (0.61, 1.12) 1.09 (0.80, 1.48) 0.64
   MV-adjusted HR + cereal fiber intakee 1 [ref.] 1.00 (0.75, 1.32) 1.14 (0.86, 1.53) 0.90 (0.65, 1.24) 1.23 (0.87, 1.76) 0.22
   Esophageal cancer
   MV-adjusted HR + refined grain intakec 1 [ref.] 0.91 (0.64, 1.29) 0.75 (0.51, 1.10) 0.70 (0.46, 1.05) 0.69 (0.43, 1.10) 0.10
   MV-adjusted HR + whole grain intaked 1 [ref.] 0.94 (0.67, 1.33) 0.78 (0.54, 1.14) 0.74 (0.51, 1.09) 0.76 (0.51, 1.14) 0.14
   MV-adjusted HR + cereal fiber intakee 1 [ref.] 0.94 (0.66, 1.32) 0.78 (0.54, 1.14) 0.74 (0.51, 1.09) 0.76 (0.50, 1.15) 0.15
   Stomach cancer
   MV-adjusted HR + refined grain intakec 1 [ref.] 0.73 (0.51, 1.05) 0.87 (0.61, 1.25) 0.85 (0.58, 1.25) 0.74 (0.48, 1.15) 0.34
   MV-adjusted HR + whole grain intaked 1 [ref.] 0.75 (0.53, 1.08) 0.92 (0.65, 1.31) 0.93 (0.65, 1.33) 0.85 (0.58, 1.26) 0.71
   MV-adjusted HR + cereal fiber intakee 1 [ref.] 0.78 (0.54, 1.12) 0.98 (0.68, 1.40) 1.00 (0.68, 1.47) 0.96 (0.62, 1.48) 0.81
   Small intestine cancer
   MV-adjusted HR + refined grain intakec 1 [ref.] 0.91 (0.52, 1.56) 0.84 (0.46, 1.51) 0.78 (0.41, 1.49) 1.00 (0.49, 2.04) 0.62
   MV-adjusted HR + whole grain intaked 1 [ref.] 0.87 (0.51, 1.48) 0.78 (0.45, 1.37) 0.72 (0.40, 1.29) 0.88 (0.48, 1.62) 0.37
   MV-adjusted HR + cereal fiber intakee 1 [ref.] 0.85 (0.50, 1.46) 0.76 (0.43, 1.34) 0.69 (0.37, 1.26) 0.82 (0.42, 1.60) 0.27
   Colorectal cancer
   MV-adjusted HR + refined grain intakec 1 [ref.] 1.12 (1.01, 1.24) 1.06 (0.95, 1.18) 1.08 (0.97, 1.22) 1.03 (0.90, 1.17) 0.85
   MV-adjusted HR + whole grain intaked 1 [ref.] 1.11 (1.00, 1.23) 1.05 (0.94, 1.16) 1.07 (0.97, 1.19) 1.02 (0.91, 1.14) 0.81
   MV-adjusted HR + cereal fiber intakee 1 [ref.] 1.11 (1.00, 1.22) 1.04 (0.94, 1.15) 1.06 (0.96, 1.18) 0.99 (0.89, 1.11) 0.50
Cancer of accessory organs of digestion
MV-adjusted HR + refined grain intakec 1 [ref.] 0.95 (0.81, 1.11) 0.94 (0.79, 1.11) 0.93 (0.78, 1.11) 0.89 (0.73, 1.09) 0.31
MV-adjusted HR + whole grain intaked 1 [ref.] 0.96 (0.82, 1.13) 0.96 (0.82, 1.13) 0.96 (0.81, 1.13) 0.94 (0.79, 1.12) 0.56
MV-adjusted HR + cereal fiber intakee 1 [ref.] 0.96 (0.81, 1.12) 0.96 (0.81, 1.13) 0.95 (0.80, 1.13) 0.93 (0.76, 1.13) 0.49
   Pancreatic cancer
   MV-adjusted HR + refined grain intakec 1 [ref.] 1.01 (0.83, 1.22) 1.00 (0.82, 1.21) 1.00 (0.81, 1.23) 0.93 (0.73, 1.17) 0.64
   MV-adjusted HR + whole grain intaked 1 [ref.] 1.00 (0.83, 1.20) 0.98 (0.81, 1.19) 0.98 (0.81, 1.19) 0.91 (0.74, 1.12) 0.44
   MV-adjusted HR + cereal fiber intakee 1 [ref.] 0.99 (0.82, 1.19) 0.97 (0.80, 1.17) 0.95 (0.78, 1.17) 0.86 (0.69, 1.08) 0.27
   Gallbladder cancer
   MV-adjusted HR + refined grain intakec 1 [ref.] 0.83 (0.53, 1.29) 0.94 (0.60, 1.47) 0.86 (0.53, 1.38) 0.90 (0.53, 1.51) 0.80
   MV-adjusted HR + whole grain intaked 1 [ref.] 0.88 (0.57, 1.36) 1.03 (0.67, 1.58) 0.97 (0.62, 1.52) 1.09 (0.69, 1.73) 0.58
   MV-adjusted HR + cereal fiber intakee 1 [ref.] 0.89 (0.57, 1.38) 1.05 (0.67, 1.63) 0.99 (0.62, 1.59) 1.12 (0.67, 1.89) 0.53
   Liver cancer
   MV-adjusted HR + refined grain intakec 1 [ref.] 0.76 (0.48, 1.21) 0.65 (0.40, 1.08) 0.67 (0.40, 1.12) 0.74 (0.43, 1.27) 0.16
   MV-adjusted HR + whole grain intaked 1 [ref.] 0.81 (0.51, 1.29) 0.73 (0.45, 1.19) 0.79 (0.48, 1.29) 0.97 (0.59, 1.60) 0.67
   MV-adjusted HR + cereal fiber intakee 1 [ref.] 0.86 (0.54, 1.37) 0.79 (0.48, 1.33) 0.89 (0.53, 1.52) 1.17 (0.65, 2.10) 0.83
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a

Cox proportional hazards regression was stratified by age in months, calendar year, and cohort, and adjusted for the following covariates: race, BMI, family history of cancer, personal history of diabetes, physical examination, smoking status and cigarettes per day, pack-years of smoking, physical activity, alcohol intake, current multivitamin use, regular aspirin use, regular non-aspirin non-steroid anti-inflammatory drug use, calorie intake, calcium intake, folic acid intake, coffee intake, 2010 alternative healthy eating index score excluding alcohol and whole grains, menopausal status and menopausal hormone use.

b

The median value of gluten intake for each quintile was modeled as a continuous variable to test for linear trend.

c

Additionally adjusted for refined grain intake.

d

Additionally adjusted for whole grain intake.

e

Additionally adjusted for cereal fiber grain intake.

In exploratory analysis (Supplementary Table 4–5), we did not found any evidence that the association between gluten intake and digestive system cancer risk varied by age, BMI, smoking status, physical activity, alcohol intake, regular aspirin use, or follow-up period.

DISCUSSION

Among 206,206 US men and women without CD from three large prospective cohorts, dietary gluten intake was not associated with the overall risk of digestive system cancer and risk of major individual cancers of gastrointestinal tract and accessory organs of digestion, after controlling for various risk factors. The null association was independent of primary dietary sources of gluten, refined grains and whole grains, and was consistent across subgroups of cancer risk factors, including age, BMI, and smoking status. This study, to our knowledge, is the first to comprehensively investigate the association of gluten intake with digestive system cancer risk in a population without a history of CD diagnosis.

Gluten, a protein component of wheat, rye, and barley, is commonly consumed in Western diets and has been suggested to play a role in the development of certain gastrointestinal malignancies among patients with CD. Because of its high proline content, gluten cannot be completely digested by human proteases. In consequence, as illustrated by in vitro and in vivo studies,25, 26 toxic proline-rich 33-mer peptides incite immune response and promote inflammation in individuals genetically susceptible to CD, which has been linked to an increased risk of certain digestive system cancers, including small intestinal cancer and esophageal cancer.8–10 In turn, a gluten-free diet can resolve symptoms and normalize intestinal mucosa in CD.27 A study of 210 patients with CD showed that, compared with the general population, patients who followed a gluten-free diet for at least five years did not have increased cancer risk, whereas those who followed a usual gluten-containing diet had an excess risk of cancers of the mouth, pharynx, and esophagus.28 A reverse association between adherence to a gluten-free diet and excess morbidity rate was also observed in these patients.28

In contrast, there is scarce evidence supporting the gluten-cancer relationship in the general population. A recent study of 159,265 adults without CD from the UK Biobank demonstrated that gluten intake was not associated with cancer mortality and all-cause mortality.29 In another recent study of 112,149 US men and women from the Cancer Prevention Study-II Nutrition Cohort, Um et al. found that there was no statistically significant association between gluten intake and the overall colorectal cancer risk, though gluten intake was potentially associated with an increased risk of proximal colon cancer.4 Similarly, our analysis suggested a null association between gluten intake and colorectal cancer risk. In addition, rather than focusing on colorectal cancer risk only, our study showed that gluten intake was not associated with the risk of other major types of digestive system cancers as well, including esophageal cancer, small intestinal cancer, and liver cancer. Compared to Um et al.,4 the present study specifically excluded participants with CD, had longer follow-up (24-31 years versus 9.8 years), and more frequent dietary assessment (every four years versus only collected in 1999 and 2003) to capture long-term interindividual variation in diet. Together, these findings do not support the hypothesis that dietary gluten intake contributes to the development of digestive system cancers in individuals without CD.

Despite the lack of evidence regarding the perceived harmful influence of dietary gluten on the development of digestive system cancers in the general population, the popularity of a gluten-free diet has grown considerably in the US.30 According to the 2009-2014 National Health and Nutrition Examination Survey,30 while the prevalence of CD remained around 0.7%, the prevalence of people without CD but avoiding gluten had increased from 0.5% to 1.7%. The belief that restricting dietary gluten may have nutritional benefits for cognition, weight loss, and intestinal symptoms may contribute to the increasing popularity of a gluten-free diet.31–33 However, several studies have indicated that avoiding gluten may worsen the already low diet quality of the Western population.34–36 Individuals adhering to a strict gluten-free diet have been shown to have inadequate intakes of minerals and vitamins, including calcium, zinc, folate, and vitamin B-12,34, 35 and gluten-free products tended to have less protein and more saturated fat, sodium, and cholesterol than equivalent products with gluten.36 Additionally, recent studies have reported that individuals on a gluten-free diet had higher blood and urine levels of heavy metals and toxins like lead, mercury, cadmium, and arsenic, than individuals not avoiding gluten.37, 38 This was likely due to the large proportion of rice, which tends to accumulate more of these toxins than other food crops, in gluten-free products.39 Therefore, given the poor nutritional profiles of gluten-free products and gluten-free diet,34–36 limiting gluten intake among individuals without CD for putative health benefits is not warranted.

Our study has several strengths, including large sample size, prospective design, validated dietary assessment tools,17, 21 long follow-up period with high retention rate, and repeated measures of lifestyles and health outcomes, thus limiting measurement errors, recall bias, and selection bias. The detailed assessments of lifestyle risk factors allowed us to comprehensively control for potential confounders, though we acknowedlege that residual confounding was still possible. After adjustment for dietary risk factors such as overall diet quality, the weak non-significant inverse association between gluten and incident digestive system cancers disappeared, indicating that other dietary risk factors are the major confounders. This weak inverse association could also be explained by the correlated intake of whole grains, a major source of gluten, and cereal fibers, which have been shown to be protective for digestive system cancers.3–6 Moreover, we performed latency analyses to minimize bias from reverse causation and conducted numerous secondary analyses to verify the robustness of our findings.

There are also some limitations of this study. First, our participants were predominantly white US health professionals, which may limit the generalizability of our results to other populations, though the biological mechanism underlying the diet-cancer relationship is unlikely to be substantially different between different populations. Besides, the relatively homogenous population minimized socioeconomic confounding. Furthermore, our questionnaires did not specifically ask about dietary preference to gluten-free products and we estimated gluten primarily based on foods containing wheat, rye, and barley. Because we could not distinguish participants avoiding gluten and our method did not capture trace amounts of gluten from sources like soy sauce, our results may not apply to individuals on a strict gluten-free diet.

In summary, gluten intake was not associated with risk of the overall and major types of digestive system cancers in three large population-based, prospective cohorts of US adults free of CD, after controlling for a wide range of risk factors. Our findings suggest that reducing dietary gluten intake is unlikely to help prevent digestive system cancers in the general population. Further mechanistic studies and cohort studies are needed to confirm our findings.

Supplementary Material

1

What You Need to Know.

  1. Background:

    Among patients with celiac disease, dietary gluten can damage intestinal mucosa and is potentially associated with increased risk of certain types of digestive system cancers, yet whether it is a risk factor for digestive system cancers in the general population remains unknown.

  2. Findings:

    Long-term dietary consumption of gluten was not associated with an increased risk of digestive system cancers in US men and women without celiac disease.

  3. Implications for patient care:

    For individuals free of celiac disease, following a gluten-restricted diet is unlikely to be beneficial for reducing the risk of digestive system cancers.

Acknowledgments:

We thank the participants and staff of the Health Professionals Follow-Up Study, Nurses’ Health Study, and Nurses’ Health Study II for their valuable contributions, as well as the following state cancer registries for their help: Alabama, Arizona, Arkansas, California, Colorado, Connecticut, Delaware, Florida, Georgia, Idaho, Illinois, Indiana, Iowa, Kentucky, Louisiana, Maine, Maryland, Massachusetts, Michigan, Nebraska, New Hampshire, New Jersey, New York, North Carolina, North Dakota, Ohio, Oklahoma, Oregon, Pennsylvania, Rhode Island, South Carolina, Tennessee, Texas, Virginia, Washington, and Wyoming. The authors assume full responsibility for analyses and interpretation of these data.

Grant support:

This work was supported by the National Institutes of Health (U01 CA167552 to Health Professionals Follow-Up Study, UM1 CA186107 and P01 CA87969 to the Nurses’ Health Study, U01 CA176726 to the Nurses’ Health Study II, R37 CA246175, R21 AA027608, and K07 CA218377 to YC, R00 CA215314 to MS, UM1 CA167552 to WCW, R35 CA253185 to ATC), World Cancer Research Fund (to ELG), the Louis and Gloria Flanzer Philanthropic Trust (to BL), the American Gastroenterological Association (Research Scholar Award to BL), the American Cancer Society (Mentored Research Scholar Grant in Applied and Clinical Research to MS), the Crohn’s and Colitis Foundation (Senior Investigator Award to ATC), and Massachusetts General Hospital (Stuart and Suzanne Steele Research Scholar Award to ATC). The funders had no role in the study design; in the collection, analysis, and interpretation of data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Abbreviations:

AHEI-10

Alternative Healthy Eating Index 2010

BMI

body mass index

CD

celiac disease

CI

confidence interval

HPFS

Health Professionals Follow-Up study

MET

metabolic equivalent

NHS

Nurses’ Health Study

NSAID

non-steroid anti-inflammatory drug

SD

standard deviation

Q

quintile

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Disclosures: Yin Cao previously served as a consultant for Geneoscopy for work unrelated to the topic. Andrew T. Chan served as a consultant for Bayer Pharma AG, Pfizer Inc., and Boehringer Ingelheim. No other disclosures were reported.

Transcript Profiling: Not applicable.

Writing Assistance: None.

Data Transparency Statement: Data, analytic methods, and study materials are available to all researchers with access to Channing Division of Network Medicine (CDNM) and can be made available to other researchers upon request. Although the research was not preregistered in an independent, institutional registry, the analysis plan of this study has been presented on the CDNM cohort meeting prior to initiating the analysis, reviewed by the investigator board, and published on the CDNM intranet, which is available to all collaborators or by request.

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