Background: The gut microbiome is increasingly recognized as an important factor modulating intestinal inflammation, tumorigenesis, and immunological functions. We recently developed a dietary pattern based on the gut microbial signature of colorectal cancer (CRC) (CRC Microbial Dietary Score [CMDS], Fig1). Characterized by a high consumption of processed foods and low consumption of fiber-rich foods, CMDS showed an association with higher risk of CRC, particular tumors with detectable F. nucleatum and pks⁺ E. coli in tissue. To further examine the potential of CMDS for CRC prevention, we assessed the association of CMDS with risk of conventional adenomas and serrated polyps (SPs), the two major precursor lesions of CRC.
Methods: We used data that were collected in the Nurses’ Health Study (NHS) (1990-2016), the NHSII (1991-2017), and the Health Professionals Follow-up Study (1990-2010) of 158,394 participants who had undergone a lower gastrointestinal endoscopy, provided updated diet and lifestyle data every 2-4 years, and were followed until diagnosis of any colorectal polyp. If a participant had more than one endoscopy during the study period, multiple records from the same participant were included. To capture long-term exposure, we calculated the cumulative average of CMDS from preceding questionnaires up to the current cycle. Multivariable-adjusted logistic regressions for clustered data (PROC GENMOD) were used to account for multiple endoscopies and to calculate odds ratios (ORs) and 95% confidence intervals (CIs).
Results: We documented 13,763 conventional adenomas and 11,540 SPs during 20-26 years of follow-up. CMDS was associated with higher risk of both conventional adenomas (OR_Q5vs.Q1, 1.14; 95% CI, 1.07-1.21; P_trend<0.001) and SPs (OR_Q5vs.Q1, 1.08; 95% CI, 1.01-1.15; P_trend<0.001). For conventional adenomas, the associations were found to be stronger for advanced (sized ≥10mm and in types of tubular, tubulo-villous, villous, or CIS/high grade dyplasia) than non-advanced adenomas (OR_Q5vs.Q1, 1.25 vs. 1.07) (P_{heterogeneity}=0.026). For SPs, the associations were stronger for lesions in the distal colon (OR_Q5vs.Q1, 1.20; 95% CI, 1.09-1.32; P_trend<0.001) and rectum (OR_Q5vs.Q1, 1.09; 95% CI, 0.98-1.21; P_trend=0.002) than proximal colon (OR_Q5vs.Q1, 0.90; 95% CI, 0.80-1.00; P_trend=0.051) (P_{heterogeneity}<0.001). For both conventional adenomas and SPs, the associations were stronger for the lesions occurring at age >50 years than those occurring at age £50 years (P_{heterogeneity}=0.021 and 0.009, respectively).
Conclusions: CMDS was associated with increased risk of both conventional adenomas and SPs, especially for advanced adenomas, distal/rectal SPs, and late-onset lesions. Our findings suggest a potential role of diet in early stage of colorectal carcinogenesis through modulating the gut microbial community.

<b>Figure 1. Study design for the development of the colorectal cancer (CRC) Microbial Dietary Score (CMDS) in the Men’s Lifestyle Validation Study (MLVS) and Mind-Body Study (MBS). a, </b>To associate the gut microbiome with dietary intake, we profiled stool metagenomes from the MLVS and MBS. The MLVS is a sub-study of the Health Professionals Follow-up Study (HPFS) and MBS is a sub-study of the Nurses’ Health Study II (NHSII). <b>b,</b> The 37 species associated with colorectal cancer (CRC) as reported by Thomas <i>et al</i> (PMID: 30936548)<i> </i>were used to define the CRC microbial score and then linked with 37 food groups to create the CMDS.

Figure 1. Study design for the development of the colorectal cancer (CRC) Microbial Dietary Score (CMDS) in the Men’s Lifestyle Validation Study (MLVS) and Mind-Body Study (MBS). a, To associate the gut microbiome with dietary intake, we profiled stool metagenomes from the MLVS and MBS. The MLVS is a sub-study of the Health Professionals Follow-up Study (HPFS) and MBS is a sub-study of the Nurses’ Health Study II (NHSII). b, The 37 species associated with colorectal cancer (CRC) as reported by Thomas et al (PMID: 30936548) were used to define the CRC microbial score and then linked with 37 food groups to create the CMDS.

<b>Figure 2. Associations of CRC microbial dietary score (CMDS) with risk of conventional adenomas and serrated polyps according to polyp features in the 3 cohorts (NHS, NHSII, and HPFS).</b>

Figure 2. Associations of CRC microbial dietary score (CMDS) with risk of conventional adenomas and serrated polyps according to polyp features in the 3 cohorts (NHS, NHSII, and HPFS).

Tomotaka Ugai

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