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. 2024 Dec;167(7):1371-1383.e4.
doi: 10.1053/j.gastro.2024.07.040. Epub 2024 Aug 6.

An Empirical Dietary Pattern Associated With the Gut Microbial Features in Relation to Colorectal Cancer Risk

Kai Wang  1 , Chun-Han Lo  2 , Raaj S Mehta  3 , Long H Nguyen  4 , Yiqing Wang  3 , Wenjie Ma  3 , Tomotaka Ugai  5 , Hidetaka Kawamura  5 , Satoko Ugai  5 , Yasutoshi Takashima  5 , Kosuke Mima  5 , Kota Arima  5 , Kazuo Okadome  5 , Marios Giannakis  6 , Cynthia L Sears  7 , Jeffrey A Meyerhardt  6 , Kimmie Ng  6 , Nicola Segata  8 , Jacques Izard  9 , Eric B Rimm  10 , Wendy S Garrett  11 , Curtis Huttenhower  12 , Edward L Giovannucci  13 , Andrew T Chan  14 , Shuji Ogino  15 , Mingyang Song  16
Affiliations

An Empirical Dietary Pattern Associated With the Gut Microbial Features in Relation to Colorectal Cancer Risk

Kai Wang et al. Gastroenterology. 2024 Dec.

Abstract

Background & aims: Epidemiologic evidence for dietary influence on colorectal cancer (CRC) risk through the gut microbiome remains limited.

Methods: Leveraging 307 men and 212 women with stool metagenomes and dietary data, we characterized and validated a sex-specific dietary pattern associated with the CRC-related gut microbial signature (CRC Microbial Dietary Score [CMDS]). We evaluated the associations of CMDS with CRC risk according to Fusobacterium nucleatum, pks+Escherichia coli, and enterotoxigenic Bacteroides fragilis status in tumor tissue using Cox proportional hazards regression in the Health Professionals Follow-Up Study (1986-2018), Nurses' Health Study (1984-2020), and Nurses' Health Study II (1991-2019).

Results: The CMDS was characterized by high industrially processed food and low unprocessed fiber-rich food intakes. In 259,200 participants, we documented 3854 incident CRC cases over 6,467,378 person-years of follow-up. CMDS was associated with a higher risk of CRC (Ptrend < .001), with a multivariable hazard ratio (HRQ5 vs Q1) of 1.25 (95% CI, 1.13-1.39). The association remained after adjusting for previously established dietary patterns, for example, the Western and prudent diets. Notably, the association was stronger for tumoral F nucleatum-positive (HRQ5 vs Q1, 2.51; 95% CI, 1.68-3.75; Ptrend < .001; Pheterogeneity = .03, positivity vs negativity), pks+E coli-positive (HRQ5 vs Q1, 1.68; 95% CI, 0.84-3.38; Ptrend = .005; Pheterogeneity = .01, positivity vs negativity), and enterotoxigenic Bacteroides fragilis-positive CRC (HRQ5 vs Q1, 2.06; 95% CI, 1.10-3.88; Ptrend = .016; Pheterogeneity = .06, positivity vs negativity), compared with their negative counterparts.

Conclusions: CMDS was associated with increased CRC risk, especially for tumors with detectable F nucleatum, pks+E coli, and enterotoxigenic Bacteroides fragilis in tissue. Our findings support a potential role of the gut microbiome underlying the dietary effects on CRC.

Keywords: Cohort Study; Colorectal Cancer; Dietary Pattern; Gut Microbiome.

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Conflict of interest statement

Competing interests

All authors have completed the ICMJE uniform disclosure form at http://www.icmje.org/coi_disclosure.pdf. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Andrew T. Chan previously served as a consultant for Bayer Pharma AG, Pfizer Inc., and Boeheringer Ingelheim for work unrelated to the topic of this manuscript. Cynthia L. Sears has grant funding from Bristol Myers Squibb and Janssen for work unrelated to the topic of this manuscript. This study was not funded by Bayer Pharma AG, Pfizer Inc., Boeheringer Ingelheim, Bristol Myers Squibb, or Janssen. No other conflict of interest exists.

Figures

Figure 1.
Figure 1.. Experimental design.
A) Study population and sampling details in the development of colorectal cancer (CRC) Microbial Dietary Score (CMDS). Participants in the Men’s Lifestyle Validation Study (MLVS) and Mind-Body Study (MBS) provided up to 4 stool samples over a 6-month study period with measurement of dietary intake via FFQ, identical to the FFQ given to participants in the Health Professionals Follow-up Study (HPFS), Nurses’ Health Study (NHS), and NHSII. Stool samples underwent metagenomic sequencing. Using the CRC-related microbial signature reported by Thomas et al. (reference #18) as outcome in reduced rank regression, loadings of 37 food groups were derived to comprise the CMDS in men and women, separately. The CMDS was then validated in the Microbiome Among Nurses study (Micro-N). B) Study population for the assessment of the association between CMDS and risk of CRC. We calculated CMDS in every FFQ assessment that was administered every four years among a total of 289,658 participants in the overall HPFS, NHS, and NHSII cohorts, while adjusting for relevant medical and lifestyle information that was collected every two years. During up to 36 years of follow-up, 3,854 incident CRC cases were documented, among which 1,672, 1,096, and 1,119 cases were measured for Fusobacterium nucleatum (F. nucleatum), pks+ Escherichia coli (pks+ E. coli), and enterotoxigenic Bacteroides fragilis (ETBF) in tumor tissue.
Figure 2.
Figure 2.. Loadings of food groups comprising the colorectal cancer (CRC) Microbial Dietary Score (CMDS) and validation results of the CMDS in men and women.
A) Food group loadings in CMDS in men derived from the Men’s Lifestyle Validation Study (MLVS). B) Food group loadings in CMDS in women derived from the Mind-Body Study (MBS). C) Spearman correlation between the CMDS that was used for the primary analysis in MLVS and the CMDS that was defined using the food group loadings derived in MBS. D) Spearman correlation between the CMDS that was used for the primary analysis in MBS and the CMDS that was defined using the food group loadings derived in MLVS. E) Spearman correlation between the CMDS that was defined using the food group loadings derived in MLVS and MBS in the validation cohort from the Microbiome Among Nurses study (Micro-N). F) Spearman correlation between the CMDS that was defined using the food group loadings derived in MLVS and the CRC microbial signature in MLVS and Micro-N. G) Spearman correlation between the CMDS that was defined using the food group loadings derived in MBS and the CRC microbial signature in MBS and Micro-N.
Figure 3.
Figure 3.. Spearman correlations between individual food groups and colorectal cancer (CRC)-related microbes used for the development of the CRC Microbial Dietary Score (CMDS) in men (A) and women (B).
Bar plots above the heatmaps show the associations between each of the microbes and CRC risk reported by Thomas et al.
See this image and copyright information in PMC

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