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. 2021 Aug 1;12(8):e00338.
doi: 10.14309/ctg.0000000000000338.

The Sulfur Microbial Diet and Risk of Colorectal Cancer by Molecular Subtypes and Intratumoral Microbial Species in Adult Men

Daniel R Sikavi  1   2 , Long H Nguyen  2   3   4 , Koichiro Haruki  5 , Tomotaka Ugai  5   6 , Wenjie Ma  2   3   4 , Dong D Wang  4   7 , Kelsey N Thompson  4   8 , Yan Yan  4 , Tobyn Branck  4 , Jeremy E Wilkinson  4 , Naohiko Akimoto  5 , Rong Zhong  5 , Mai Chan Lau  5 , Kosuke Mima  5 , Keisuke Kosumi  5 , Teppei Morikawa  5 , Eric B Rimm  7 , Wendy S Garrett  8   9 , Jacques Izard  10   11 , Yin Cao  12   13 , Mingyang Song  2   3   6   7 , Curtis Huttenhower  4   8   14 , Shuji Ogino  5   6   8   15 , Andrew T Chan  2   3   8   14
Affiliations

The Sulfur Microbial Diet and Risk of Colorectal Cancer by Molecular Subtypes and Intratumoral Microbial Species in Adult Men

Daniel R Sikavi et al. Clin Transl Gastroenterol. .

Abstract

Introduction: We recently described the sulfur microbial diet, a pattern of intake associated with increased gut sulfur-metabolizing bacteria and incidence of distal colorectal cancer (CRC). We assessed whether this risk differed by CRC molecular subtypes or presence of intratumoral microbes involved in CRC pathogenesis (Fusobacterium nucleatum and Bifidobacterium spp.).

Methods: We performed Cox proportional hazards modeling to examine the association between the sulfur microbial diet and incidence of overall and distal CRC by molecular and microbial subtype in the Health Professionals Follow-Up Study (1986-2012).

Results: We documented 1,264 incident CRC cases among 48,246 men, approximately 40% of whom had available tissue data. After accounting for multiple hypothesis testing, the relationship between the sulfur microbial diet and CRC incidence did not differ by subtype. However, there was a suggestion of an association by prostaglandin synthase 2 (PTGS2) status with a multivariable adjusted hazard ratio for highest vs lowest tertile of sulfur microbial diet scores of 1.31 (95% confidence interval: 0.99-1.74, Ptrend = 0.07, Pheterogeneity = 0.04) for PTGS2-high CRC. The association of the sulfur microbial diet with distal CRC seemed to differ by the presence of intratumoral Bifidobacterium spp. with an adjusted hazard ratio for highest vs lowest tertile of sulfur microbial diet scores of 1.65 (95% confidence interval: 1.14-2.39, Ptrend = 0.01, Pheterogeneity = 0.03) for Bifidobacterium-negative distal CRC. We observed no apparent heterogeneity by other tested molecular markers.

Discussion: Greater long-term adherence to the sulfur microbial diet could be associated with PTGS2-high and Bifidobacterium-negative distal CRC in men. Additional studies are needed to further characterize the role of gut microbial sulfur metabolism and CRC.

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Conflict of interest statement

Guarantors of the article: Daniel R. Sikavi, MD, Long H. Nguyen, MD, MS, Koichiro Haruki, MD, PhD, Tomotaka Ugai, MD, PhD, Shuji Ogino, MS, MD, PhD, Curtis Huttenhower, PhD, and Andrew T. Chan, MD, MPH.

Specific author contributions: All authors contributed to analysis and interpretation of data and critical revision of the manuscript. Daniel R. Sikavi, MD, Long H. Nguyen, MD, MS, Koichiro Haruki, MD, PhD, Tomotaka Ugai, MD, PhD share co-first authorship. Curtis Huttenhower, PhD, Shuji Ogino, MS, MD, PhD, Andrew T. Chan, MD, MPH share co-PI. D.R.S., L.H.N., W.S.G., E.B.R., J.I., C.H., S.O., and A.T.C.: contributed to study concept and design. D.R.S., L.H.N., C.H., S.O., and A.T.C.: acquired data. D.R.S., L.H.N., C.H., S.O., and A.T.C.: drafted the manuscript. D.R.S., L.H.N., K.H., T.U., C.H., S.O., and A.T.C.: performed statistical analyses. W.S.G., E.B.R., J.I., C.H., S.O., and A.T.C.: obtained funding. C.H., S.O., and A.T.C.: provided administrative, technical, or material support. C.H., S.O., and A.T.C.: provided study supervision.

Financial support: National Institutes of Health (NIH) grants U54DE023798, U01CA167552, P01CA055075, U01CA152904, and K23 DK125838 (to L.H.N.), Loan Repayment Program (to L.H.N.), and K99DK119412 (to D.W.), R21AA027608 (to Y.C.), R00CA215314 (to M.S.), and R01CA202704 (to W.S.G., J.I., C.H., and A.T.C.), R35 CA253185 (to A.T.C.), R35CA197735 (to S.O.), R01CA151993 (to S.O.), and R01 CA248857 (to S.O.); American Gastroenterological Association Research Scholars Award (to L.H.N.), Crohn's and Colitis Foundation Research Fellowship Award and Career Development Award (to L.H.N.), and Senior Investigator Award (to A.T.C.); American Cancer Society Mentored Research Scholar Grant (to M.S.); the USDA National Institute of Food and Agriculture Hatch Multistate Research Capacity Funding Program grant W4122 (to J.I.); Cancer Research UK Grand Challenge Award (C10674/A27140; to W.S.G., S.O., and C.H.); Dana-Farber Harvard Cancer Center Nodal Award (to S.O.); STARR Cancer Consortium; the Massachusetts General Hospital Stuart and Suzanne Steel Research Scholars Award (to A.T.C.); Overseas Research Fellowship (201960541) from the Japan Society for the Promotion of Science (to T.U.); Uehara Memorial Foundation fellowship grants (to K.H. and T.U.); Yasuda Medical Foundation fellowship grant (to T.U.); and Mitsukoshi Health and Welfare Foundation grant to K.H.

Potential competing interests: None to report.

Use of standardized official symbols: We use Human Genome Organization (HUGO)-approved official symbols (or root symbols) for genes and gene products, including BRAF, CACNA1G, CDKN2A, CRABP1, CTNNB1, IGF2, KRAS, MLH1, NEUROG1, PIK3CA, PTGS2, RUNX3, SOCS1, and WNT, all of which are described at www.genenames.org. Gene symbols are italicized, whereas symbols for gene products are not italicized.

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