Environmental Factors, Gut Microbiota, and Colorectal Cancer Prevention

The substantial burden of colorectal cancer and increasing trend in young adults highlight the importance of lifestyle modification as a complement to screening for colorectal cancer prevention. Several dietary and lifestyle factors have been implicated in the development of colorectal cancer, possibly through the intricate metabolic and inflammatory mechanisms. Likewise, as a key metabolic and immune regulator, the gut microbiota has been recognized to play an important role in colorectal tumorigenesis. Increasing data support that environmental factors are crucial determinants for the gut microbial composition and function, whose alterations induce changes in the host gene expression, metabolic regulation, and local and systemic immune response, thereby influencing cancer development. Here, we review the epidemiologic and mechanistic evidence regarding the links between diet and lifestyle and the gut microbiota in the development of colorectal cancer. We focus on factors for which substantial data support their importance for colorectal cancer and their potential role in the gut microbiota, including overweight and obesity, physical activity, dietary patterns, fiber, red and processed meat, marine omega-3 fatty acid, alcohol, and smoking. We also briefly describe other colorectal cancer-preventive factors for which the links with the gut microbiota have been suggested but remain to be mechanistically characterized, including vitamin D status, dairy consumption, and metformin use. Given limitations in available evidence, we highlight the need for further investigations in the relationship between environmental factors, gut microbiota, and colorectal cancer, which may lead to development and clinical translation of potential microbiota-based strategies for cancer prevention. The substantial burden of colorectal cancer and increasing trend in young adults highlight the importance of lifestyle modification as a complement to screening for colorectal cancer prevention. Several dietary and lifestyle factors have been implicated in the development of colorectal cancer, possibly through the intricate metabolic and inflammatory mechanisms. Likewise, as a key metabolic and immune regulator, the gut microbiota has been recognized to play an important role in colorectal tumorigenesis. Increasing data support that environmental factors are crucial determinants for the gut microbial composition and function, whose alterations induce changes in the host gene expression, metabolic regulation, and local and systemic immune response, thereby influencing cancer development. Here, we review the epidemiologic and mechanistic evidence regarding the links between diet and lifestyle and the gut microbiota in the development of colorectal cancer. We focus on factors for which substantial data support their importance for colorectal cancer and their potential role in the gut microbiota, including overweight and obesity, physical activity, dietary patterns, fiber, red and processed meat, marine omega-3 fatty acid, alcohol, and smoking. We also briefly describe other colorectal cancer-preventive factors for which the links with the gut microbiota have been suggested but remain to be mechanistically characterized, including vitamin D status, dairy consumption, and metformin use. Given limitations in available evidence, we highlight the need for further investigations in the relationship between environmental factors, gut microbiota, and colorectal cancer, which may lead to development and clinical translation of potential microbiota-based strategies for cancer prevention. Over the past 3 decades, the incidence rate of colorectal cancer has dropped by almost 45% in the United States, from a peak of 66.3 in 1985 to 37.5 per 100,000 persons in 2013. This is mirrored by a similar decline for colorectal cancer mortality, dropping from its peak of 28.6 in 1976 to 14.1 per 100,000 in 2014.1Siegel R.L. Miller K.D. Fedewa S.A. et al.Colorectal cancer statistics, 2017.CA Cancer J Clin. 2017; 67: 177-193Crossref PubMed Scopus (1086) Google Scholar These trends are believed to be mainly attributable to increases in screening uptake (mainly colonoscopy) and reductions in certain risk factors (eg, smoking and red meat consumption), with additional contributions from advances in treatment.2Vogelaar I. van Ballegooijen M. Schrag D. et al.How much can current interventions reduce colorectal cancer mortality in the U.S.? Mortality projections for scenarios of risk-factor modification, screening, and treatment.Cancer. 2006; 107: 1624-1633Crossref PubMed Scopus (142) Google Scholar Despite these advances, colorectal cancer remains the third most common cancer and the third leading cause of cancer death in each sex in the country.1Siegel R.L. Miller K.D. Fedewa S.A. et al.Colorectal cancer statistics, 2017.CA Cancer J Clin. 2017; 67: 177-193Crossref PubMed Scopus (1086) Google Scholar In 2018, an estimated total of 140,250 men and women will be diagnosed with colorectal cancer; 50,630 deaths will be attributable to the disease. A particularly alarming trend is the rising incidence of colorectal cancer in adults younger than 50 years old whose incidence has risen by 1.6% and mortality by 13% from 2000 to 2013–2014.3Siegel R.L. Fedewa S.A. Anderson W.F. et al.Colorectal cancer incidence patterns in the United States, 1974-2013.J Natl Cancer Inst. 2017; 109: djw322Crossref PubMed Scopus (84) Google Scholar This increase has motivated the American Cancer Society to revise their recommended age to initiate colorectal cancer screening from 50 to 45 years old.4Wolf A.M.D. Fontham E.T.H. Church T.R. et al.Colorectal cancer screening for average-risk adults: 2018 guideline update from the American Cancer Society.CA Cancer J Clin. 2018; 68: 250-281Crossref PubMed Scopus (93) Google Scholar Although the reasons for the increasing incidence of young-onset colorectal cancer have yet to be elucidated, the obesity epidemic and related changes in lifestyle patterns are thought to have played an important role. Therefore, the continued burden of colorectal cancer, particularly among young adults, highlights the critical need to consider novel prevention strategies beyond screening. A variety of diet and lifestyle factors have been implicated in the development of colorectal cancer. Studies have consistently estimated that approximately 50%–60% of incident colorectal cancer cases in the United States can be prevented by lifestyle modification.5Islami F. Goding Sauer A. Miller K.D. et al.Proportion and number of cancer cases and deaths attributable to potentially modifiable risk factors in the United States.CA Cancer J Clin. 2018; 68: 31-54Crossref PubMed Scopus (89) Google Scholar, 6Song M. Giovannucci E. Preventable incidence and mortality of carcinoma associated with lifestyle factors among white adults in the United States.JAMA Oncol. 2016; 2: 1154-1161Crossref PubMed Scopus (49) Google Scholar Smoking, body fatness, alcohol drinks, and red and processed meat have been established to increase the risk of colorectal cancer, whereas physical activity and intake of dietary fiber, whole grains, dairy products, calcium supplements, vitamin D, and marine omega-3 fatty acid may lower disease risk.7World Cancer Research Fund/American Institute for Cancer Research. Continuous update project report: diet, nutrition, physical activity and colorectal cancer. Available at: wcrf.org/colorectal-cancer-2017. Accessed September 8, 2018.Google Scholar Furthermore, increasing data indicate a potential chemopreventive effect of metformin, an antidiabetic drug, for colorectal cancer.8Gandini S. Puntoni M. Heckman-Stoddard B.M. et al.Metformin and cancer risk and mortality: a systematic review and meta-analysis taking into account biases and confounders.Cancer Prev Res (Phila). 2014; 7: 867-985Crossref PubMed Scopus (168) Google Scholar Although the exact mechanisms through which each of these factors may affect colorectal cancer are likely to differ and largely remain to be elucidated, several lines of evidence suggest that the gut microbiome may represent a congregate mode of action mediating the relationship of environmental factors with colorectal cancer (Figure 1). First, the large intestine represents a vast microbial ecosystem, housing several trillion microbes that encode 100-fold greater unique genes than our own genome. The composition and function of this ecosystem seem to be largely shaped by environmental factors, particularly diet and lifestyle.9Rothschild D. Weissbrod O. Barkan E. et al.Environment dominates over host genetics in shaping human gut microbiota.Nature. 2018; 555: 210-215Crossref PubMed Scopus (193) Google Scholar Second, the gut microbiota plays an important role in nutrient processing and synthesis, and may affect colorectal cancer development through metabolite-mediated changes in the immune and metabolic signals.10Kau A.L. Ahern P.P. Griffin N.W. et al.Human nutrition, the gut microbiome and the immune system.Nature. 2011; 474: 327-336Crossref PubMed Scopus (1142) Google Scholar Finally, increasing data indicate that gut microbes are pivotal in integrating environmental cues with host physiology and metabolism, and may influence several biologic processes critical to carcinogenesis, including the balance of intestinal cell proliferation and death, systemic and local immune homeostasis, and alterations of the host metabolic activities.11Garrett W.S. Cancer and the microbiota.Science. 2015; 348: 80-86Crossref PubMed Scopus (21) Google Scholar Specifically for colorectal cancer, several microbes have been found to be differentially enriched in tumor versus normal tissues from the same host, or in fecal samples from patients with colorectal neoplasia versus healthy control subjects. Although the epidemiologic evidence remains limited and inconsistent, relatively consistent data indicate that Fusobacterium nucleatum and Bacteroides fragilis are enriched in colorectal cancer, whereas butyrate-producing bacteria are depleted in cancer patients. The role of these and other microbes in colorectal cancer has been extensively reviewed elsewhere.12Tilg H. Adolph T.E. Gerner R.R. et al.The intestinal microbiota in colorectal cancer.Cancer Cell. 2018; 33: 954-964Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar, 13Sears C.L. Garrett W.S. Microbes, microbiota, and colon cancer.Cell Host Microbe. 2014; 15: 317-328Abstract Full Text Full Text PDF PubMed Scopus (297) Google Scholar Herein, we review the evidence on how diet and lifestyle factors may influence colorectal cancer through gut microbiota–related mechanisms. We focus on factors for which substantial data support their importance for colorectal cancer and their potential role in the gut microbiota, including overweight and obesity, physical activity, dietary patterns, fiber, red and processed meat, marine omega-3 fatty acids, alcohol, and smoking. We also briefly describe other colorectal cancer–preventive factors for which the links with the gut microbiota have been suggested but remain to be mechanistically characterized, including vitamin D, dairy products, and metformin. For each factor, we review the epidemiologic evidence supporting its relationship with colorectal cancer and then summarize major findings about the interaction with the gut microbiota. Fueled by Western dietary patterns and sedentary lifestyle, the prevalence of obesity in US adults has almost tripled in the past few decades, rising from 13.4% in 1960–1962 to 37.7% in 2013–2014.14Ogden CL, Carroll MD. Prevalence of overweight, obesity, and extreme obesity among adults: United States, trends 1960–1962 through 2007–2008. 2010:1–6.Google Scholar, 15Ogden CL, Carroll MD, Fryar CD, et al. Prevalence of obesity among adults and youth: United States, 2011–2014. In: National Center for Health Statistics, Division of Health and Nutrition Examination Surveys, eds. 2015.Google Scholar Numerous epidemiologic studies have consistently associated higher body fatness in adulthood to increased risk of colorectal cancer (Table 1). Excess body weight has been estimated to contribute to approximately 5% of incident colorectal cancer cases in the United States.5Islami F. Goding Sauer A. Miller K.D. et al.Proportion and number of cancer cases and deaths attributable to potentially modifiable risk factors in the United States.CA Cancer J Clin. 2018; 68: 31-54Crossref PubMed Scopus (89) Google ScholarTable 1Summary of Evidence and Potential Mechanisms Underlying the Relationship Between Environmental Factors, Gut Microbiota, and Colorectal CancerRisk factorEstimated association with colorectal cancer (RR [95% CI])aData are derived from the meta-analysis conducted by the World Cancer Research Fund/American Institute for Cancer Research,7 unless stated otherwise.Associated microbesPotential microbiota-related mechanismsOverweight and obesity1.05 (1.03–1.07) per 5 kg/m2 increase in body mass index↓Bacteroidetes/Firmicutes ratioIncreased LPS levels; epigenetic changes in the colonic epithelial cells; increased production of DNA-damaging bile acidsPhysical activity0.80 (0.72–0.88) comparing the highest with the lowest levels↑Bacteroidetes/Firmicutes ratio;↑SCFAs-producing bacteriaIncreased production of SCFAs; changes in the metabolism of the microbiotaSmoking1.26 (1.11–1.43) for current smokers and 1.18 (1.09–1.27) for former smokers, compared with never smokersbReference 128.↓Diversity↑Firmicutes, Actinobacteria;↓Bacteroidetes, ProteobacteriaAltered mucin composition of the mucus layer and increased inflammatory responseDiet Western dietary pattern1.40 (1.26–1.56) comparing the highest with the lowest category of the Western diet scorecReference 30.↑Bacteroides, Escherichia, and Acinetobacter; ↓PrevotellaLower production of SCFAs from fiber deficiency Fiber0.93 (0.87–1.00) per 10 g/day increase in dietary consumption↑SCFAs-producing bacteriaEpigenetic regulation and immunomodulatory benefits of SCFAs Red and processed meat1.12 (1.04–1.21) per 100 g/day increase in consumption↑Mucin-degrading bacteria (eg, Akkermansia muciniphila)Microbiota-dependent barrier dysfunction induced by heme iron; increased production of secondary bile acids and hydrogen sulfide by microbiota associated with high red meat consumption Marine omega-3 fatty acid0.76 (0.59–0.97) comparing the highest with the lowest category of biospecimen composition of marine omega-3 fatty acidsdReference 84.↑Lactobacillus and Bifidobacterium;↓ Fusobacterium nucleatum and LPS-producing bacteriaPreserved intestinal immune homeostasis caused by increased abundance of immune-protective bacteria and reduced abundance of proinflammatory bacteria, and increased production of SCFAs and lipid mediators Alcohol1.07 (1.05–1.08) per 10 g/day increase in consumptionDysbiosis; ↓Bacteroidetes, Firmicutes, and butyrate-producing bacteria; ↑Proteobacteria and ActinobacteriaIntestinal bacterial overgrowth and hyperpermeability; reduced production of SCFAs; bacterial production of acetaldehyde from ethanol Dairy products0.87 (0.83–0.90) per 400 g/day increase in consumption↓Bilophila wadsworthiaIncreased production of SCFAs and decreased abundance of proinflammatory pathobionts Vitamin D0.92 (0.85–1.00) per 30 nmol/L increase in circulating vitamin DVariants in the vitamin D receptor gene are among the most significant loci associated with gut microbial compositionUnclearMetformin0.80 (0.64–1.00) comparing users to nonuserseReference 8.↑Escherichia and Bifidobacterium;↓IntestinibacterIncreased production of SCFAsCI, confidence interval; LPS, lipopolysaccharides; RR, relative risk; SCFA, short-chain fatty acid.a Data are derived from the meta-analysis conducted by the World Cancer Research Fund/American Institute for Cancer Research,7World Cancer Research Fund/American Institute for Cancer Research. Continuous update project report: diet, nutrition, physical activity and colorectal cancer. Available at: wcrf.org/colorectal-cancer-2017. Accessed September 8, 2018.Google Scholar unless stated otherwise.b Reference 128.c Reference 30.d Reference 84.e Reference 8. Open table in a new tab CI, confidence interval; LPS, lipopolysaccharides; RR, relative risk; SCFA, short-chain fatty acid. Several metabolic and inflammatory factors, including insulin/insulin-like growth factor 1 signaling, sex hormones, adipokines, and systemic inflammation, have been proposed to underlie the relationship between obesity and colorectal cancer. However, the gut microbiota has emerged as an integral factor that modulates host metabolism and has been suggested to play a vital role in obesity-related metabolic alterations, including inflammation and insulin resistance.16Khan M.T. Nieuwdorp M. Backhed F. Microbial modulation of insulin sensitivity.Cell Metab. 2014; 20: 753-760Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar The complex, bidirectional relationship between obesity and the gut microbiota is indicated by the substantial changes in the gut microbial community induced by obesity and weight loss in animal and human studies, and recapitulation of obesity and its phenotypic features by fecal transplantation in gnotobiotic (germ-free) mouse models, and the positive association of antibiotic exposure in early life with childhood obesity. Although obesity-induced changes in the gut microbiota may promote cancer development through modulation of microbe-derived proinflammatory molecules (eg, lipopolysaccharide [LPS]) and metabolites (eg, increased acetate and reduced butyrate) that impair gut barrier function and increase permeability,17Cani P.D. Jordan B.F. Gut microbiota-mediated inflammation in obesity: a link with gastrointestinal cancer.Nat Rev Gastroenterol Hepatol. 2018; ([Epub ahead of print])Crossref PubMed Scopus (0) Google Scholar only recently has direct evidence emerged for the mechanisms through which the gut microbiota may mediate the relationship between obesity and cancer (Figure 2). Studies led by Wade and colleagues uncover a potential role of epigenetic alterations in the link between obesity, gut microbiota, and colorectal cancer.18Li R. Grimm S.A. Mav D. et al.Transcriptome and DNA methylome analysis in a mouse model of diet-induced obesity predicts increased risk of colorectal cancer.Cell Rep. 2018; 22: 624-637Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar, 19Li R. Grimm S.A. Chrysovergis K. et al.Obesity, rather than diet, drives epigenomic alterations in colonic epithelium resembling cancer progression.Cell Metab. 2014; 19: 702-711Abstract Full Text Full Text PDF PubMed Google Scholar, 20Qin Y. Roberts J.D. Grimm S.A. et al.An obesity-associated gut microbiome reprograms the intestinal epigenome and leads to altered colonic gene expression.Genome Biol. 2018; 19: 7Crossref PubMed Scopus (8) Google Scholar They showed that high-fat diet-induced obesity led to widespread remodeling of the acetylation landscape at presumptive cis-regulatory regions that likely influence the transcriptional responses integral to the initiation and progression of colon cancer.19Li R. Grimm S.A. Chrysovergis K. et al.Obesity, rather than diet, drives epigenomic alterations in colonic epithelium resembling cancer progression.Cell Metab. 2014; 19: 702-711Abstract Full Text Full Text PDF PubMed Google Scholar This epigenetic remodeling was found to be dependent on the gut microbiota because animals fed the same diet that received bacteria from nonobese donors did not show similar changes.20Qin Y. Roberts J.D. Grimm S.A. et al.An obesity-associated gut microbiome reprograms the intestinal epigenome and leads to altered colonic gene expression.Genome Biol. 2018; 19: 7Crossref PubMed Scopus (8) Google Scholar Gene expression analysis indicated that the combination of high-fat diet and fecal transplantation induced a gene expression profile that had partial resemblance to that observed in human colorectal cancer.19Li R. Grimm S.A. Chrysovergis K. et al.Obesity, rather than diet, drives epigenomic alterations in colonic epithelium resembling cancer progression.Cell Metab. 2014; 19: 702-711Abstract Full Text Full Text PDF PubMed Google Scholar These findings highlight potential interactions between obesity and microbiome and their effects on the host epigenome, which prime putative enhancers in the host colon epithelium for malignant transformation. In addition to modifications of the enhancer landscape, obesity may also promote colorectal cancer through changes in DNA methylation,18Li R. Grimm S.A. Mav D. et al.Transcriptome and DNA methylome analysis in a mouse model of diet-induced obesity predicts increased risk of colorectal cancer.Cell Rep. 2018; 22: 624-637Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar although the role of the gut microbiota in this process remains to be elucidated. Interestingly, the consequences of obesity-associated epigenetic changes may be different according to age; in young mice, obesity was associated with a colonic cellular switch favoring long-chain fatty acid oxidation that may increase the number of intestinal stem/stem-like cells; whereas in aged mice, obesity was associated with decreased expression of tumor suppressor genes and negative feedback regulators of prosurvival and proproliferation pathways that in turn prime for unrestrained signaling to accelerate the initiation and progression of colon tumorigenesis once oncogenic events occur.18Li R. Grimm S.A. Mav D. et al.Transcriptome and DNA methylome analysis in a mouse model of diet-induced obesity predicts increased risk of colorectal cancer.Cell Rep. 2018; 22: 624-637Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar These findings may have implications for explaining the role of the obesity epidemic in the recent increase in the incidence of young-onset colorectal cancer. In addition to epigenetic mechanisms, changes in the gut microbial metabolites and constituents have also been implicated in the obesity-cancer link. Specifically, obesity enhances production of deoxycholic acid, a secondary bile acid that is produced solely by gram-positive gut bacteria and known to cause DNA damage through reactive oxygen species production. Increased enterohepatic circulation of deoxycholic acid may promote hepatocellular carcinoma development by inducing cellular senescence and the senescence-associated secretory phenotype in hepatic stellate cells in the tumor microenvironment.21Yoshimoto S. Loo T.M. Atarashi K. et al.Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome.Nature. 2013; 499: 97-101Crossref PubMed Scopus (740) Google Scholar, 22Ohtani N. Yoshimoto S. Hara E. Obesity and cancer: a gut microbial connection.Cancer Res. 2014; 74: 1885-1889Crossref PubMed Scopus (0) Google Scholar More recent evidence indicates that this effect requires cooperative induction of another gram-positive gut microbial component, lipoteichoic acid, which upregulates the expression of prostaglandin-endoperoxide synthase 2 (also known as cyclooxygenase-2) in deoxycholic acid–induced senescent hepatic stellate cells to promote cancer development in obese mice.23Loo T.M. Kamachi F. Watanabe Y. et al.Gut microbiota promotes obesity-associated liver cancer through PGE2-mediated suppression of antitumor immunity.Cancer Discov. 2017; 7: 522-538Crossref PubMed Scopus (48) Google Scholar As a critical enzyme in inflammation, prostaglandin-endoperoxide synthase 2 mediates production of prostaglandin E2, which suppresses antitumor immunity.23Loo T.M. Kamachi F. Watanabe Y. et al.Gut microbiota promotes obesity-associated liver cancer through PGE2-mediated suppression of antitumor immunity.Cancer Discov. 2017; 7: 522-538Crossref PubMed Scopus (48) Google Scholar Given the potential role of prostaglandin E2 and secondary bile acid in promoting colorectal cancer, further studies are needed to investigate whether microbial imbalance-induced metabolic change also mediates obesity-related tumor promotion in the colon. Convincing evidence indicates that total and recreational physical activity reduces risk of colon cancer, whereas no benefit is found for rectal cancer. Recent animal evidence suggests that voluntary exercise can alter the composition of the gut microbiota and increase production of short-chain fatty acids (SCFAs).24Matsumoto M. Inoue R. Tsukahara T. et al.Voluntary running exercise alters microbiota composition and increases n-butyrate concentration in the rat cecum.Biosci Biotechnol Biochem. 2008; 72: 572-576Crossref PubMed Scopus (83) Google Scholar, 25Evans C.C. LePard K.J. Kwak J.W. et al.Exercise prevents weight gain and alters the gut microbiota in a mouse model of high fat diet-induced obesity.PLoS One. 2014; 9: e92193Crossref PubMed Scopus (122) Google Scholar, 26Petriz B.A. Castro A.P. Almeida J.A. et al.Exercise induction of gut microbiota modifications in obese, non-obese and hypertensive rats.BMC Genomics. 2014; 15: 511Crossref PubMed Scopus (95) Google Scholar, 27Queipo-Ortuno M.I. Seoane L.M. Murri M. et al.Gut microbiota composition in male rat models under different nutritional status and physical activity and its association with serum leptin and ghrelin levels.PLoS One. 2013; 8: e65465Crossref PubMed Scopus (98) Google Scholar Exercise restored bacterial diversity in obese rats26Petriz B.A. Castro A.P. Almeida J.A. et al.Exercise induction of gut microbiota modifications in obese, non-obese and hypertensive rats.BMC Genomics. 2014; 15: 511Crossref PubMed Scopus (95) Google Scholar and increased the ratio of Bacteroidetes to Firmicutes, which was reduced in obesity in a manner that was proportional to the intensity of exercise in mice.25Evans C.C. LePard K.J. Kwak J.W. et al.Exercise prevents weight gain and alters the gut microbiota in a mouse model of high fat diet-induced obesity.PLoS One. 2014; 9: e92193Crossref PubMed Scopus (122) Google Scholar Exercise also increased the relative proportion of butyrate-producing bacteria and the intestinal concentration of butyrate (Table 1).24Matsumoto M. Inoue R. Tsukahara T. et al.Voluntary running exercise alters microbiota composition and increases n-butyrate concentration in the rat cecum.Biosci Biotechnol Biochem. 2008; 72: 572-576Crossref PubMed Scopus (83) Google Scholar, 25Evans C.C. LePard K.J. Kwak J.W. et al.Exercise prevents weight gain and alters the gut microbiota in a mouse model of high fat diet-induced obesity.PLoS One. 2014; 9: e92193Crossref PubMed Scopus (122) Google Scholar However, whether these effects can be generalized to human remains largely unknown. A study compared the gut microbiome among 40 male elite professional rugby players and 2 control groups; one matched for athlete size with a comparable body mass index (n = 23) and another reflecting the background age- and gender-matched population (n = 23). It found that the athletes had a more diverse gut microbiota than either of the control groups and the increased gut microbiota diversity in athletes was driven by substantially higher exercise and protein intake.28Clarke S.F. Murphy E.F. O'Sullivan O. et al.Exercise and associated dietary extremes impact on gut microbial diversity.Gut. 2014; 63: 1913-1920Crossref PubMed Scopus (287) Google Scholar When the metabolic profile and functional capacity of the gut microbiota were examined, compared with control groups, athletes had relative increase in pathways related to amino acid and antibiotic biosynthesis, and carbohydrate metabolism, as well as increased levels of fecal metabolites (eg, SCFAs) associated with enhanced muscle turnover and overall health.29Barton W. Penney N.C. Cronin O. et al.The microbiome of professional athletes differs from that of more sedentary subjects in composition and particularly at the functional metabolic level.Gut. 2018; 67: 625-633PubMed Google Scholar The hypothesis that a Western dietary pattern increases colorectal cancer risk originates from the observation that Japanese migrants to Hawaii acquire the same risk of colorectal cancer as that experienced by white persons in the United States. This hypothesis is supported by subsequent epidemiologic studies in different countries showing an increased risk of colorectal cancer among individuals consuming a Western-style diet that is high in red and processed meats, refined grains, soda, and sweets, and low in fruits, vegetables, and whole-grain products (Table 1).30Feng Y.L. Shu L. Zheng P.F. et al.Dietary patterns and colorectal cancer risk: a meta-analysis.Eur J Cancer Prev. 2017; 26: 201-211Crossref PubMed Scopus (0) Google Scholar In contrast, a lower risk of colorectal cancer has been observed in individuals adhering to a prudent diet that is high in fruits, vegetables, whole grains, fish, soy, poultry, and low-fat dairy.30Feng Y.L. Shu L. Zheng P.F. et al.Dietary patterns and colorectal cancer risk: a meta-analysis.Eur J Cancer Prev. 2017; 26: 201-211Crossref PubMed Scopus (0) Google Scholar A potential role of the gut microbiota in mediating the associations of dietary patterns with colorectal cancer risk is supported by the dramatic difference in the gut microbial structures and metabolite profiles between populations consuming different diets. The gut microbiota of rural Africans, whose diet is rich in fiber and low in fat, is characterized by a predominance of Prevotella genus that is involved in starch, hemicellulose, and xylan degradation, whereas the American microbiota is predominated by Bacteroides genus with a higher abundance of potentially pathogenic proteobacteria, such as Escherichia and Acinetobacter.31Ou J. Carbonero F. Zoetendal E.G. et al.Diet, microbiota, and microbial metabolites in colon cancer risk in rural Africans and African Americans.Am J Clin Nutr. 2013; 98: 111-120Crossref PubMed Scopus (222) Google Scholar These micro