Association Between the Sulfur Microbial Diet and Risk of Colorectal Cancer

Abstract

Importance: Sulfur-metabolizing bacteria that reduce dietary sulfur to hydrogen sulfide have been associated with colorectal cancer (CRC). However, there are limited studies investigating the association between diet and sulfur-metabolizing bacteria in the development of CRC.

Objective: To develop a dietary score that correlates with gut sulfur-metabolizing bacteria and to examine its association with CRC risk.

Design, setting, and participants: This prospective cohort study included data from the Health Professionals Follow-up Study (1986-2014), Nurses' Health Study (1984-2016), and Nurses' Health Study II (1991-2017). Participants were US male health professionals and female registered nurses who were free of inflammatory bowel disease and cancer at baseline, with a subsample of participants who provided stool samples from 2012 to 2014. Statistical analysis was conducted from September 1, 2020, to June 1, 2021.

Exposure: A dietary pattern, assessed by a food-frequency questionnaire, that most correlated with 43 sulfur-metabolizing bacteria identified through taxonomic and functional profiling of gut metagenome data.

Main outcomes and measures: Incident CRC.

Results: Among 214 797 participants comprising 46 550 men (mean [SD] age at baseline, 54.3 [9.7] years) and 168 247 women (mean [SD] age at baseline, 43.0 [9.2] years), 3217 incident cases of CRC (1.5%) were documented during 5 278 048 person-years of follow-up. The sulfur microbial diet, developed in a subsample of 307 men (mean [SD] age, 70.5 [4.3] years) and 212 women (mean [SD] age, 61.0 [3.8] years), was characterized by high intakes of low-calorie beverages, french fries, red meats, and processed meats and low intakes of fruits, yellow vegetables, whole grains, legumes, leafy vegetables, and cruciferous vegetables. After adjustment for other risk factors, greater adherence to the sulfur microbial diet was associated with an increased risk of CRC, with a hazard ratio (HR) of 1.27 (95% CI, 1.12-1.44) comparing the highest vs the lowest quintile of the diet score (linear trend of diet score quintiles; P < .001 for trend). When assessed by anatomical subsites, greater adherence to the sulfur microbial diet was positively associated with distal CRC (HR, 1.25; 95% CI, 1.05-1.50; P = .02 for trend) but not proximal colon cancer (HR, 1.13; 95% CI, 0.93-1.39; P = .19 for trend).

Conclusions and relevance: Adherence to the sulfur microbial diet was associated with an increased risk of CRC, suggesting a potential mediating role of sulfur-metabolizing bacteria in the associaton between diet and CRC. Further research is needed to confirm these findings and to determine the underlying mechanisms.

Figure 1.. Sparse Canonical Correlation Analysis of Dietary Intake and Sulfur-Metabolizing Bacteria

Pairwise Spearman correlations between selected food groups and bacteria. Numbers in parentheses are the weights for food groups and bacteria, whose linear combination maximizes the correlation (0.375). The food group weights were used to create the sulfur microbial diet score. ^aStatistically significant correlations (Benjamini-Hochberg false discovery rate <0.25).

Figure 2.. Stratified Analysis of the Association Between Sulfur Microbial Diet and Risk of Colorectal Cancer (CRC)

Multivariable-adjusted hazard ratios (HRs) and 95% CIs comparing the highest quintile vs the lowest quintile of sulfur microbial diet score were calculated using Cox proportional hazards regression models stratified by age, questionnaire cycle, and cohort and adjusted for the following covariates: race, body mass index (calculated as weight in kilograms divided by height in meters squared), family history of CRC, physical activity, smoking status, smoking pack-years, menopausal hormone use (women only), aspirin use, nonsteroidal anti-inflammatory drug use, prior endoscopy, recent physical examination, and total calorie intake. P value for interaction was estimated using the likelihood ratio test comparing the model with and without the interaction term of the sulfur microbial diet score and the respective stratification variable.