Early-onset colorectal cancer: initial clues and current views


Over the past several decades, the incidence of early-onset colorectal cancer (EOCRC; in patients <50 years old) has increased at an alarming rate. Although robust and scientifically rigorous epidemiological studies have sifted out environmental elements linked to EOCRC, our knowledge of the causes and mechanisms of this disease is far from complete. Here, we highlight potential risk factors and putative mechanisms that drive EOCRC and suggest likely areas for fruitful research. In addition, we identify inconsistencies in the evidence implicating a strong effect of increased adiposity and suggest that certain behaviours (such as diet and stress) might place nonobese and otherwise healthy people at risk of this disease. Key risk factors are reviewed, including the global westernization of diets (usually involving a high intake of red and processed meats, high-fructose corn syrup and unhealthy cooking methods), stress, antibiotics, synthetic food dyes, monosodium glutamate, titanium dioxide, and physical inactivity and/or sedentary behaviour. The gut microbiota is probably at the crossroads of these risk factors and EOCRC. The time course of the disease and the fact that relevant exposures probably occur in childhood raise important methodological issues that are also discussed.

Key points

  • The alarming rise in early-onset colorectal cancer (EOCRC) over the past four decades described by epidemiological studies and cancer registry data requires coordination and follow-up with mechanistic in vitro testing, animal experimentation and human intervention studies.

  • EOCRC occurs in both people who are obese and those who are nonobese, and the rising incidence is global.

  • Some solutions to EOCRC can be deployed now (for example, awareness campaigns); some can be deployed with additional work to overcome barriers (such as identifying surrogate end points); and some can deployed with money, time, ingenuity and scientific rigour (for example, uncovering mechanisms and gene–environment interactions).

  • Key elements driving EOCRC are exposed when four metrics are fulfilled: one, a temporal relationship exists that follows that of EOCRC; two, exposure is global, as with EOCRC; three, evidence exists of inflammatory or microbiome-modifying properties or evidence of an effect on the distal colon or rectum; and four, exposure occurs during development from conception to adulthood.

  • The following elements reach all four of the above metrics: a westernized diet including red and processed meats; consumption of monosodium glutamate, titanium dioxide, high-fructose corn syrup and synthetic dyes; obesity; stress; and widespread use of antibiotics.

  • Delineation of exposomal elements attacking the rectum versus colon and their interactions with genetics is a critical step to understanding this disease for purposes of chemoprevention and treatment.

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Fig. 1: The effect of the exposome and early-life environmental exposures on microbiome health.
Fig. 2: Solutions for EOCRC.


  1. 1.

    Patel, S. G. & Ahnen, D. J. Colorectal cancer in the young. Curr. Gastroenterol. Rep. 20, 15 (2018).

  2. 2.

    Mauri, G. et al. Early-onset colorectal cancer in young individuals. Mol. Oncol. 13, 109–131 (2019).

  3. 3.

    Bailey, C. E. et al. Increasing disparities in the age-related incidences of colon and rectal cancers in the United States, 1975–2010. JAMA Surg. 150, 17–22 (2015).

  4. 4.

    Murphy, C. C., Singal, A. G., Baron, J. A. & Sandler, R. S. Decrease in incidence of young-onset colorectal cancer before recent increase. Gastroenterology 155, 1716–1719 (2018).

  5. 5.

    Siegel, R. L. et al. Global patterns and trends in colorectal cancer incidence in young adults. Gut 68, 2179–2185 (2019).

  6. 6.

    Vuik, F. E. et al. Increasing incidence of colorectal cancer in young adults in Europe over the last 25 years. Gut 68, 1820–1826 (2019).

  7. 7.

    Patel, P. & De, P. Trends in colorectal cancer incidence and related lifestyle risk factors in 15–49-year-olds in Canada, 1969–2010. Cancer Epidemiol. 42, 90–100 (2016).

  8. 8.

    Siegel, R. L., Miller, K. D. & Jemal, A. Colorectal cancer mortality rates in adults aged 20 to 54 years in the United States, 1970–2014. JAMA 318, 572–574 (2017).

  9. 9.

    Nguyen, L. H. et al. Sedentary behaviors, TV viewing time, and risk of young-onset colorectal cancer. JNCI Cancer Spectr. 2, pky073 (2018).

  10. 10.

    Stoffel, E. M. & Murphy, C. C. Epidemiology and mechanisms of the increasing incidence of colon and rectal cancers in young adults. Gastroenterology 158, 341–353 (2020).

  11. 11.

    Wild, C. P., Scalbert, A. & Herceg, Z. Measuring the exposome: a powerful basis for evaluating environmental exposures and cancer risk. Env. Mol. Mutagen. 54, 480–499 (2013).

  12. 12.

    Wild, C. P. Complementing the genome with an “exposome”: the outstanding challenge of environmental exposure measurement in molecular epidemiology. Cancer Epidemiol. Biomarkers Prev. 14, 1847–1850 (2005).

  13. 13.

    Lucas, C., Barnich, N. & Nguyen, H. T. T. Microbiota, inflammation and colorectal cancer. Int. J. Mol. Sci. 18, 1310 (2017).

  14. 14.

    Connell, L. C., Mota, J. M., Braghiroli, M. I. & Hoff, P. M. The rising incidence of younger patients with colorectal cancer: questions about screening, biology, and treatment. Curr. Treat. Options Oncol. 18, 23 (2017).

  15. 15.

    Yeo, H. et al. Early-onset colorectal cancer is distinct from traditional colorectal cancer. Clin. Colorectal Cancer 16, 293–299.e6 (2017).

  16. 16.

    Yeo, S. A., Chew, M. H., Koh, P. K. & Tang, C. L. Young colorectal carcinoma patients do not have a poorer prognosis: a comparative review of 2,426 cases. Tech. Coloproctol. 17, 653–661 (2013).

  17. 17.

    Modest, D. P. et al. Exploring the effect of primary tumor sidedness on therapeutic efficacy across treatment lines in patients with metastatic colorectal cancer: analysis of FIRE-3 (AIOKRK0306). Oncotarget 8, 105749–105760 (2017).

  18. 18.

    Lim, D. R., Kuk, J. K., Kim, T. & Shin, E. J. Comparison of oncological outcomes of right-sided colon cancer versus left-sided colon cancer after curative resection: which side is better outcome? Medicine 96, e8241 (2017).

  19. 19.

    Norat, T. et al. Meat, fish, and colorectal cancer risk: the European prospective investigation into cancer and nutrition. J. Natl Cancer Inst. 97, 906–916 (2005).

  20. 20.

    Bernstein, A. M. et al. Processed and unprocessed red meat and risk of colorectal cancer: analysis by tumor location and modification by time. PLoS One 10, e0135959 (2015).

  21. 21.

    Nimptsch, K. et al. Dietary intakes of red meat, poultry, and fish during high school and risk of colorectal adenomas in women. Am. J. Epidemiol. 178, 172–183 (2013).

  22. 22.

    Akhter, M. et al. Alcohol consumption is associated with an increased risk of distal colon and rectal cancer in Japanese men: the Miyagi cohort study. Eur. J. Cancer 43, 383–390 (2007).

  23. 23.

    Bongaerts, B. W., van den Brandt, P. A., Goldbohm, R. A., de Goeij, A. F. & Weijenberg, M. P. Alcohol consumption, type of alcoholic beverage and risk of colorectal cancer at specific subsites. Int. J. Cancer 123, 2411–2417 (2008).

  24. 24.

    Annema, N., Heyworth, J. S., McNaughton, S. A., Iacopetta, B. & Fritschi, L. Fruit and vegetable consumption and the risk of proximal colon, distal colon, and rectal cancers in a case-control study in Western Australia. J. Am. Dietetic Assoc. 111, 1479–1490 (2011).

  25. 25.

    Zhang, X. et al. Calcium intake and colorectal cancer risk: results from the nurses’ health study and health professionals follow-up study. Int. J. Cancer 139, 2232–2242 (2016).

  26. 26.

    Hjartaker, A. et al. Subsite-specific dietary risk factors for colorectal cancer: a review of cohort studies. J. Oncol. 2013, 703854 (2013).

  27. 27.

    Wu, K., Willett, W. C., Fuchs, C. S., Colditz, G. A. & Giovannucci, E. L. Calcium intake and risk of colon cancer in women and men. J. Natl Cancer Inst. 94, 437–446 (2002).

  28. 28.

    Oh, K., Willett, W. C., Wu, K., Fuchs, C. S. & Giovannucci, E. L. Calcium and vitamin D intakes in relation to risk of distal colorectal adenoma in women. Am. J. Epidemiol. 165, 1178–1186 (2007).

  29. 29.

    Larsson, S. C., Bergkvist, L., Rutegard, J., Giovannucci, E. & Wolk, A. Calcium and dairy food intakes are inversely associated with colorectal cancer risk in the cohort of Swedish men. Am. J. Clin. Nutr. 83, 667–673 (2006).

  30. 30.

    Cho, E. et al. Dietary choline and betaine and the risk of distal colorectal adenoma in women. J. Natl Cancer Inst. 99, 1224–1231 (2007).

  31. 31.

    Wang, Z. J. et al. Dietary polyphenols and colorectal cancer risk: the Fukuoka colorectal cancer study. World J. Gastroenterol. 19, 2683–2690 (2013).

  32. 32.

    Zhang, X. et al. A prospective study of intakes of zinc and heme iron and colorectal cancer risk in men and women. Cancer Causes Control. 22, 1627–1637 (2011).

  33. 33.

    Higuchi, T. et al. A randomized, double-blind, placebo-controlled trial of the effects of rofecoxib, a selective cyclooxygenase-2 inhibitor, on rectal polyps in familial adenomatous polyposis patients. Clin. Cancer Res. 9, 4756–4760 (2003).

  34. 34.

    Steinbach, G. et al. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N. Engl. J. Med. 342, 1946–1952 (2000).

  35. 35.

    Paschke, S. et al. Are colon and rectal cancer two different tumor entities? A proposal to abandon the term colorectal cancer. Int. J. Mol. Sci. 19, 2577 (2018).

  36. 36.

    Rothwell, P. M. et al. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet 376, 1741–1750 (2010).

  37. 37.

    Ma, Y. et al. Obesity and risk of colorectal cancer: a systematic review of prospective studies. PLoS One 8, e53916 (2013).

  38. 38.

    Movahedi, M. et al. Obesity, aspirin, and risk of colorectal cancer in carriers of hereditary colorectal cancer: a prospective investigation in the CAPP2 study. J. Clin. Oncol. 33, 3591–3597 (2015).

  39. 39.

    Siegel, R. L. et al. Colorectal cancer incidence patterns in the United States, 1974–2013. J. Natl Cancer Inst. 108, 1–6 (2017).

  40. 40.

    The Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature 487, 330–337 (2012).

  41. 41.

    Imperial, R. et al. Comparative proteogenomic analysis of right-sided colon cancer, left-sided colon cancer and rectal cancer reveals distinct mutational profiles. Mol. Cancer 17, 177 (2018).

  42. 42.

    Strum, W. B. & Boland, C. R. Clinical and genetic characteristics of colorectal cancer in persons under 50 years of age: a review. Dig. Dis. Sci. 64, 3059–3065 (2019).

  43. 43.

    Pearlman, R. et al. Prevalence and spectrum of germline cancer susceptibility gene mutations among patients with early-onset colorectal cancer. JAMA Oncol. 3, 464–471 (2017).

  44. 44.

    Stigliano, V., Sanchez-Mete, L., Martayan, A. & Anti, M. Early-onset colorectal cancer: a sporadic or inherited disease? World J. Gastroenterol. 20, 12420–12430 (2014).

  45. 45.

    Lynch, K. L., Ahnen, D. J., Byers, T., Weiss, D. G. & Lieberman, D. A. First-degree relatives of patients with advanced colorectal adenomas have an increased prevalence of colorectal cancer. Clin. Gastroenterol. Hepatol. 1, 96–102 (2003).

  46. 46.

    Lieberman, D. A., Prindiville, S., Weiss, D. G. & Willett, W. Risk factors for advanced colonic neoplasia and hyperplastic polyps in asymptomatic individuals. JAMA 290, 2959–2967 (2003).

  47. 47.

    Rex, D. K. et al. Colorectal cancer screening: recommendations for physicians and patients from the US multi-society task force on colorectal cancer. Am. J. Gastroenterol. 112, 1016–1030 (2017).

  48. 48.

    Tsai, M. H., Xirasagar, S., Li, Y. J. & de Groen, P. C. Colonoscopy screening among US adults aged 40 or older with a family history of colorectal cancer. Prev. Chronic Dis. 12, E80 (2015).

  49. 49.

    Hogan, N. M. et al. Awareness and uptake of family screening in patients diagnosed with colorectal cancer at a young age. Gastroenterol. Res. Pract. 2015, 194931 (2015).

  50. 50.

    Wang, K. et al. Dissecting cancer heterogeneity based on dimension reduction of transcriptomic profiles using extreme learning machines. PLoS One 13, e0203824 (2018).

  51. 51.

    Pi, S., Nap-Hill, E., Telford, J. & Enns, R. Recognition of Lynch syndrome amongst newly diagnosed colorectal cancers at St. Paul’s hospital. Can. J. Gastroenterol. Hepatol. 2017, 9625638 (2017).

  52. 52.

    Claes, E. et al. Predictive testing for hereditary nonpolyposis colorectal cancer: subjective perception regarding colorectal and endometrial cancer, distress, and health-related behavior at one year post-test. Genet. Test. 9, 54–65 (2005).

  53. 53.

    Halbert, C. H. et al. Colon cancer screening practices following genetic testing for hereditary nonpolyposis colon cancer (HNPCC) mutations. Arch. Intern. Med. 164, 1881–1887 (2004).

  54. 54.

    Wu, H. C. et al. Developing screening services for colorectal cancer on Android smartphones. Telemed. J. E. Health 20, 687–695 (2014).

  55. 55.

    Schultz, M., Seo, S. B., Holt, A. & Regenbrecht, H. Family history assessment for colorectal cancer (CRC) risk analysis — comparison of diagram- and questionnaire-based web interfaces. BMC Med. Inform. Decis. Mak. 15, 95 (2015).

  56. 56.

    Giardiello, F. M. et al. Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US multi-society task force on colorectal cancer. Am. J. Gastroenterol. 109, 1159–1179 (2014).

  57. 57.

    Syngal, S. et al. ACG clinical guideline: genetic testing and management of hereditary gastrointestinal cancer syndromes. Am. J. Gastroenterol. 110, 223–2623 (2015).

  58. 58.

    Gupta, S. et al. NCCN guidelines insights: genetic/familial high-risk assessment: colorectal, version 3.2017. J. Natl Compr. Canc Netw. 15, 1465–1475 (2017).

  59. 59.

    Stoffel, E. M., Mangu, P. B. & Limburg, P. J. Hereditary colorectal cancer syndromes: American Society of Clinical Oncology clinical practice guideline endorsement of the familial risk-colorectal cancer: European Society for Medical Oncology clinical practice guidelines. J. Oncol. Pract. 11, e437–e441 (2015).

  60. 60.

    Hippisley-Cox, J. & Coupland, C. Identifying patients with suspected colorectal cancer in primary care: derivation and validation of an algorithm. Br. J. Gen. Pract. 62, e29–e37 (2012).

  61. 61.

    Tao, S., Hoffmeister, M. & Brenner, H. Development and validation of a scoring system to identify individuals at high risk for advanced colorectal neoplasms who should undergo colonoscopy screening. Clin. Gastroenterol. Hepatol. 12, 478–485 (2014).

  62. 62.

    Chiu, H. M. et al. A risk-scoring system combined with a fecal immunochemical test is effective in screening high-risk subjects for early colonoscopy to detect advanced colorectal neoplasms. Gastroenterology 150, 617–625.e13 (2016).

  63. 63.

    Koning, N. R. et al. Identification of patients at risk for colorectal cancer in primary care: an explorative study with routine healthcare data. Eur. J. Gastroenterol. Hepatol. 27, 1443–1448 (2015).

  64. 64.

    Schneider, R. et al. Colorectal carcinoma with suspected Lynch syndrome: a multidisciplinary algorithm. Zentralbl. Chir. 140, 591–599 (2015).

  65. 65.

    Choi, Y. H., Briollais, L., Green, J., Parfrey, P. & Kopciuk, K. Estimating successive cancer risks in Lynch syndrome families using a progressive three-state model. Stat. Med. 33, 618–638 (2014).

  66. 66.

    Pilozzi, E. et al. Left-sided early-onset vs late-onset colorectal carcinoma: histologic, clinical, and molecular differences. Am. J. Clin. Pathol. 143, 374–384 (2015).

  67. 67.

    Liang, J. T. et al. Clinicopathological and molecular biological features of colorectal cancer in patients less than 40 years of age. Br. J. Surg. 90, 205–214 (2003).

  68. 68.

    Boardman, L. A. et al. A search for germline APC mutations in early onset colorectal cancer or familial colorectal cancer with normal DNA mismatch repair. Genes. Chromosomes Cancer 30, 181–186 (2001).

  69. 69.

    Antelo, M. et al. A high degree of LINE-1 hypomethylation is a unique feature of early-onset colorectal cancer. PLoS One 7, e45357 (2012).

  70. 70.

    Watson, R., Liu, T. C. & Ruzinova, M. B. High frequency of KRAS mutation in early onset colorectal adenocarcinoma: implications for pathogenesis. Hum. Pathol. 56, 163–170 (2016).

  71. 71.

    Arriba, M. et al. Unsupervised analysis of array comparative genomic hybridization data from early-onset colorectal cancer reveals equivalence with molecular classification and phenotypes. Neoplasia 19, 28–34 (2017).

  72. 72.

    Boland, P. M., Yurgelun, M. B. & Boland, C. R. Recent progress in Lynch syndrome and other familial colorectal cancer syndromes. CA Cancer J. Clin. 68, 217–231 (2018).

  73. 73.

    Lieu, C. H. et al. Comprehensive genomic landscapes in early and later onset colorectal cancer. Clin. Cancer Res. 25, 5852–5858 (2019).

  74. 74.

    Liang, J., Kalady, M. F. & Church, J. Young age of onset colorectal cancers. Int. J. Colorectal Dis. 30, 1653–1657 (2015).

  75. 75.

    Ballester, V., Rashtak, S. & Boardman, L. Clinical and molecular features of young-onset colorectal cancer. World J. Gastroenterol. 22, 1736–1744 (2016).

  76. 76.

    Willauer, A. N. et al. Clinical and molecular characterization of early-onset colorectal cancer. Cancer 125, 2002–2010 (2019).

  77. 77.

    Yeh, C. C., Hsieh, L. L., Tang, R., Chang-Chieh, C. R. & Sung, F. C. MS-920: DNA repair gene polymorphisms, diet and colorectal cancer risk in Taiwan. Cancer Lett. 224, 279–288 (2005).

  78. 78.

    Khan, N. A. et al. Dietary practices, addictive behavior and bowel habits and risk of early onset colorectal cancer: a case control study. Asian Pac. J. Cancer Prev. 16, 7967–7973 (2015).

  79. 79.

    Nimptsch, K. & Wu, K. Is timing important? The role of diet and lifestyle during early life on colorectal neoplasia. Curr. Colorectal Cancer Rep. 14, 1–11 (2018).

  80. 80.

    Rosato, V. et al. Risk factors for young-onset colorectal cancer. Cancer Causes Control. 24, 335–341 (2013).

  81. 81.

    Kim, J. Y. et al. Different risk factors for advanced colorectal neoplasm in young adults. World J. Gastroenterol. 22, 3611–3620 (2016).

  82. 82.

    Boyle, T. et al. Timing and intensity of recreational physical activity and the risk of subsite-specific colorectal cancer. Cancer Causes Control. 22, 1647–1658 (2011).

  83. 83.

    Zhang, Q. L. et al. The joint effects of major lifestyle factors on colorectal cancer risk among Chinese men: a prospective cohort study. Int. J. Cancer 142, 1093–1101 (2018).

  84. 84.

    Siegel, R. L. & Jemal, A. Percentage of colorectal cancer diagnosed in adults aged younger than 50 years. Cancer 122, 1462–1463 (2016).

  85. 85.

    Siegel, R. L. et al. Colorectal cancer statistics, 2017. CA Cancer J. Clin. 67, 177–193 (2017).

  86. 86.

    Dulai, P. S., Sandborn, W. J. & Gupta, S. Colorectal cancer and dysplasia in inflammatory bowel disease: a review of disease epidemiology, pathophysiology, and management. Cancer Prev. Res. 9, 887–894 (2016).

  87. 87.

    Gao, Z., Guo, B., Gao, R., Zhu, Q. & Qin, H. Microbiota disbiosis is associated with colorectal cancer. Front. Microbiol. 6, 20 (2015).

  88. 88.

    Keinan-Boker, L., Vin-Raviv, N., Liphshitz, I., Linn, S. & Barchana, M. Cancer incidence in Israeli Jewish survivors of World War II. J. Natl Cancer Inst. 101, 1489–1500 (2009).

  89. 89.

    Hughes, L. A. et al. Childhood and adolescent energy restriction and subsequent colorectal cancer risk: results from the Netherlands cohort study. Int. J. Epidemiol. 39, 1333–1344 (2010).

  90. 90.

    Liu, P. H. et al. Association of obesity with risk of early-onset colorectal cancer among women. JAMA Oncol. 5, 37–44 (2019).

  91. 91.

    Ruder, E. H. et al. Adolescent and mid-life diet: risk of colorectal cancer in the NIH-AARP diet and health study. Am. J. Clin. Nutr. 94, 1607–1619 (2011).

  92. 92.

    Jensen, B. W. et al. Childhood body mass index and height in relation to site-specific risks of colorectal cancers in adult life. Eur. J. Epidemiol. 32, 1097–1106 (2017).

  93. 93.

    Hidayat, K., Yang, C. M. & Shi, B. M. Body fatness at an early age and risk of colorectal cancer. Int. J. Cancer 142, 729–740 (2018).

  94. 94.

    Koo, J. E. et al. Prevalence and risk factors of advanced colorectal neoplasms in asymptomatic Korean people between 40 and 49 years of age. J. Gastroenterol. Hepatol. 32, 98–105 (2017).

  95. 95.

    Boyle, T., Keegel, T., Bull, F., Heyworth, J. & Fritschi, L. Physical activity and risks of proximal and distal colon cancers: a systematic review and meta-analysis. J. Natl Cancer Inst. 104, 1548–1561 (2012).

  96. 96.

    Nunez, C., Nair-Shalliker, V., Egger, S., Sitas, F. & Bauman, A. Physical activity, obesity and sedentary behaviour and the risks of colon and rectal cancers in the 45 and up study. BMC Public Health 18, 325 (2018).

  97. 97.

    Longnecker, M. P., Gerhardsson le Verdier, M., Frumkin, H. & Carpenter, C. A case-control study of physical activity in relation to risk of cancer of the right colon and rectum in men. Int. J. Epidemiol. 24, 42–50 (1995).

  98. 98.

    Halle, M. & Schoenberg, M. H. Physical activity in the prevention and treatment of colorectal carcinoma. Dtsch. Arztebl. Int. 106, 722–727 (2009).

  99. 99.

    Moradi, T. et al. Occupational physical activity and risk for cancer of the colon and rectum in Sweden among men and women by anatomic subsite. Eur. J. Cancer Prev. 17, 201–208 (2008).

  100. 100.

    Hill, A. B. Observation and experiment. N. Engl. J. Med. 248, 995–1001 (1953).

  101. 101.

    Malik, V. S., Willett, W. C. & Hu, F. B. Global obesity: trends, risk factors and policy implications. Nat. Rev. Endocrinol. 9, 13–27 (2013).

  102. 102.

    Sung, H. et al. Global patterns in excess body weight and the associated cancer burden. CA Cancer J. Clin. 69, 88–112 (2018).

  103. 103.

    Stokes, A., Ni, Y. & Preston, S. H. Prevalence and trends in lifetime obesity in the US, 1988–2014. Am. J. Prev. Med. 53, 567–575 (2017).

  104. 104.

    Alati, R. et al. Generational increase in obesity among young women: a prospective analysis of mother–daughter dyads. Int. J. Obes. 40, 176–180 (2016).

  105. 105.

    Kantor, E. D. et al. Adolescent body mass index and erythrocyte sedimentation rate in relation to colorectal cancer risk. Gut 65, 1289–1295 (2016).

  106. 106.

    Renehan, A. G. et al. Body mass index at different adult ages, weight change, and colorectal cancer risk in the National Institutes of Health-AARP cohort. Am. J. Epidemiol. 176, 1130–1140 (2012).

  107. 107.

    Levi, Z. et al. Adolescent body mass index and risk of colon and rectal cancer in a cohort of 1.79 million Israeli men and women: a population-based study. Cancer 123, 4022–4030 (2017).

  108. 108.

    Ziccardi, P. et al. Reduction of inflammatory cytokine concentrations and improvement of endothelial functions in obese women after weight loss over one year. Circulation 105, 804–809 (2002).

  109. 109.

    Kasai, C. et al. Comparison of the gut microbiota composition between obese and non-obese individuals in a Japanese population, as analyzed by terminal restriction fragment length polymorphism and next-generation sequencing. BMC Gastroenterol. 15, 100 (2015).

  110. 110.

    Wang, W. et al. Lipidomic profiling reveals soluble epoxide hydrolase as a therapeutic target of obesity-induced colonic inflammation. Proc. Natl Acad. Sci. USA 115, 5283–5288 (2018).

  111. 111.

    Larsson, S. C. & Wolk, A. Obesity and colon and rectal cancer risk: a meta-analysis of prospective studies. Am. J. Clin. Nutr. 86, 556–565 (2007).

  112. 112.

    Segev, L., Kalady, M. F. & Church, J. M. Left-sided dominance of early-onset colorectal cancers: a rationale for screening flexible sigmoidoscopy in the young. Dis. Colon Rectum 61, 897–902 (2018).

  113. 113.

    Sjoblom, T. et al. The consensus coding sequences of human breast and colorectal cancers. Science 314, 268–274 (2006).

  114. 114.

    Brand, M. P., Peeters, P. H., van Gils, C. H. & Elias, S. G. Pre-adult famine exposure and subsequent colorectal cancer risk in women. Int. J. Epidemiol. 46, 612–621 (2017).

  115. 115.

    Kikuchi, N. et al. Perceived stress and colorectal cancer incidence: the Japan collaborative cohort study. Sci. Rep. 7, 40363 (2017).

  116. 116.

    Zhang, Q. et al. Maternal stress and early-onset colorectal cancer. Med. Hypotheses 121, 152–159 (2018).

  117. 117.

    Cohen, S., Janicki-Deverts, D. & Miller, G. E. Psychological stress and disease. JAMA 298, 1685–1687 (2007).

  118. 118.

    Twenge, J. M. et al. Birth cohort increases in psychopathology among young Americans, 1938–2007: a cross-temporal meta-analysis of the MMPI. Clin. Pyschol. Rev. 30, 145–154 (2010).

  119. 119.

    Xin, Z., Niu, J. & Chi, L. Birth cohort changes in Chinese adolescents’ mental health. Int. J. Psychol. 47, 287–295 (2012).

  120. 120.

    Sluggett, L., Wagner, S. L. & Harris, R. L. Sleep duration and obesity in children and adolescents. Can J. Diabetes 43, 146–152 (2019).

  121. 121.

    Jiao, L. et al. Sleep duration and incidence of colorectal cancer in postmenopausal women. Br. J. Cancer 108, 213–221 (2013).

  122. 122.

    Thompson, C. L. et al. Short duration of sleep increases risk of colorectal adenoma. Cancer 117, 841–847 (2011).

  123. 123.

    Vu, H. T. et al. Diabetes mellitus increases risk for colorectal adenomas in younger patients. World J. Gastroenterol. 20, 6946–6952 (2014).

  124. 124.

    Hebert, J. R. et al. Considering the role of stress in populations of high-risk, underserved community networks program centers. Prog. Community Health Partnersh. 9, 71–82 (2015).

  125. 125.

    Tilg, H., Adolph, T. E., Gerner, R. R. & Moschen, A. R. The intestinal microbiota in colorectal cancer. Cancer Cell 33, 954–964 (2018).

  126. 126.

    Tse, J. W. T., Jenkins, L. J., Chionh, F. & Mariadason, J. M. Aberrant DNA methylation in colorectal cancer: what should we target? Trends Cancer 3, 698–712 (2017).

  127. 127.

    Carson, T. L. et al. Associations between race, perceived psychological stress, and the gut microbiota in a sample of generally healthy black and white women: a pilot study on the role of race and perceived psychological stress. Psychosom. Med. 80, 640–648 (2018).

  128. 128.

    Louis, P., Hold, G. L. & Flint, H. J. The gut microbiota, bacterial metabolites and colorectal cancer. Nat. Rev. Microbiol. 12, 661–672 (2014).

  129. 129.

    Castello, A. et al. Low adherence to the western and high adherence to the Mediterranean dietary patterns could prevent colorectal cancer. Eur. J. Nutr. 58, 1495–1505 (2018).

  130. 130.

    Mehta, R. S. et al. Dietary patterns and risk of colorectal cancer: analysis by tumor location and molecular subtypes. Gastroenterology 152, 1944–1953.e1 (2017).

  131. 131.

    Chang, D. T. et al. Clinicopathologic and molecular features of sporadic early-onset colorectal adenocarcinoma: an adenocarcinoma with frequent signet ring cell differentiation, rectal and sigmoid involvement, and adverse morphologic features. Mod. Pathol. 25, 1128–1139 (2012).

  132. 132.

    Kirzin, S. et al. Sporadic early-onset colorectal cancer is a specific sub-type of cancer: a morphological, molecular and genetics study. PLoS One 9, e103159 (2014).

  133. 133.

    Khan, S. A. et al. Colorectal cancer in the very young: a comparative study of tumor markers, pathology and survival in early onset and adult onset patients. J. Pediatr. Surg. 51, 1812–1817 (2016).

  134. 134.

    van Roon, E. H. et al. Early onset MSI-H colon cancer with MLH1 promoter methylation, is there a genetic predisposition? BMC Cancer 10, 180 (2010).

  135. 135.

    Tapial, S. et al. Cimp-positive status is more representative in multiple colorectal cancers than in unique primary colorectal cancers. Sci. Rep. 9, 10516 (2019).

  136. 136.

    Perea, J. et al. Classifying early-onset colorectal cancer according to tumor location: new potential subcategories to explore. Am. J. Cancer Res. 5, 2308–2313 (2015).

  137. 137.

    Kim, H. C. et al. Aberrant CpG island methylation in early-onset sporadic gastric carcinoma. J. Cancer Res. Clin. Oncol. 131, 733–740 (2005).

  138. 138.

    Statovci, D., Aguilera, M., MacSharry, J. & Melgar, S. The impact of western diet and nutrients on the microbiota and immune response at mucosal interfaces. Front. Immunol. 8, 838 (2017).

  139. 139.

    O’Keefe, S. J. Diet, microorganisms and their metabolites, and colon cancer. Nat. Rev. Gastroenterol. Hepatol. 13, 691–706 (2016).

  140. 140.

    Popkin, B. M., Adair, L. S. & Ng, S. W. Global nutrition transition and the pandemic of obesity in developing countries. Nutr. Rev. 70, 3–21 (2012).

  141. 141.

    Brenner, D. R. et al. Increasing colorectal cancer incidence trends among younger adults in Canada. Prev. Med. 105, 345–349 (2017).

  142. 142.

    Veruttipong, D. et al. Age distribution, polyps and rectal cancer in the Egyptian population-based cancer registry. World J. Gastroenterol. 18, 3997–4003 (2012).

  143. 143.

    Khoury, C. K. et al. Increasing homogeneity in global food supplies and the implications for food security. Proc. Natl Acad. Sci. USA 111, 4001–4006 (2014).

  144. 144.

    Musaiger, A. O. Overweight and obesity in the eastern Mediterranean region: can we control it? East. Mediterr. Health J. 10, 789–793 (2004).

  145. 145.

    Odegaard, A. O., Koh, W. P., Yuan, J. M., Gross, M. D. & Pereira, M. A. Western-style fast food intake and cardiometabolic risk in an Eastern country. Circulation 126, 182–188 (2012).

  146. 146.

    Danaei, G. et al. The global cardiovascular risk transition: associations of four metabolic risk factors with national income, urbanization, and western diet in 1980 and 2008. Circulation 127, 1493–1502, 1502e1-8 (2013).

  147. 147.

    Uribarri, J. et al. Advanced glycation end products in foods and a practical guide to their reduction in the diet. J. Am. Dietetic Assoc. 110, 911–916.e12 (2010).

  148. 148.

    Yacoub, R. et al. Advanced glycation end products dietary restriction effects on bacterial gut microbiota in peritoneal dialysis patients; a randomized open label controlled trial. PLoS One 12, e0184789 (2017).

  149. 149.

    Gupta, A. & Uribarri, J. Dietary advanced glycation end products and their potential role in cardiometabolic disease in children. Horm. Res. Paediatr. 85, 291–300 (2016).

  150. 150.

    Rodriguez, J. M. et al. Reduction of serum advanced glycation end-products with a low calorie Mediterranean diet. Nutr. Hops. 31, 2511–2517 (2015).

  151. 151.

    Mayr, H. L. et al. Randomization to 6-month Mediterranean diet compared with a low-fat diet leads to improvement in dietary inflammatory index scores in patients with coronary heart disease: the AUSMED heart trial. Nutr. Red. 55, 94–107 (2018).

  152. 152.

    Harmon, B. E. et al. The dietary inflammatory index is associated with colorectal cancer risk in the multiethnic cohort. J. Nutr. 147, 430–438 (2017).

  153. 153.

    Ramallal, R. et al. Inflammatory potential of diet, weight gain, and incidence of overweight/obesity: the SUN cohort. Obesity 25, 997–1005 (2017).

  154. 154.

    Alipoor, E. et al. Dietary inflammatory index and parameters of diet quality in normal weight and obese patients undergoing hemodialysis. Nutr. 61, 32–37 (2019).

  155. 155.

    Park, Y. M. et al. Dietary inflammatory potential and risk of mortality in metabolically healthy and unhealthy phenotypes among overweight and obese adults. Clin. Nutr. 38, 682–688 (2019).

  156. 156.

    Shivappa, N. et al. Dietary inflammatory index and colorectal cancer risk — a meta-analysis. Nutrients 9, 1043 (2017).

  157. 157.

    Martin, C. A., Milinsk, M. C., Visentainer, J. V., Matsushita, M. & de-Souza, N. E. Trans fatty acid-forming processes in foods: a review. An. Acad. Bras. Cienc. 79, 343–350 (2007).

  158. 158.

    Zhao, Z. et al. Red and processed meat consumption and colorectal cancer risk: a systematic review and meta-analysis. Oncotarget 8, 83306–83314 (2017).

  159. 159.

    Ritchie, H. & Roser, M. Meat and dairy production. Our World in Data https://ourworldindata.org/meat-production (2019).

  160. 160.

    Chai, W. et al. Dietary red and processed meat intake and markers of adiposity and inflammation: the multiethnic cohort study. J. Am. Coll. Nutr. 36, 378–385 (2017).

  161. 161.

    Thogersen, R. et al. Ingestion of an inulin-enriched pork sausage product positively modulates the gut microbiome and metabolome of healthy rats. Mol. Nutr. Food Res. 62, e1800608 (2018).

  162. 162.

    Esaiassen, E. et al. Antibiotic exposure in neonates and early adverse outcomes: a systematic review and meta-analysis. J. Antimicrob. Chemother. 72, 1858–1870 (2017).

  163. 163.

    Azad, M. B. et al. Impact of maternal intrapartum antibiotics, method of birth and breastfeeding on gut microbiota during the first year of life: a prospective cohort study. BJOG 123, 983–993 (2016).

  164. 164.

    Wang, J. L. et al. Infection, antibiotic therapy and risk of colorectal cancer: a nationwide nested case-control study in patients with type 2 diabetes mellitus. Int. J. Cancer 135, 956–967 (2014).

  165. 165.

    Scott, F. I. et al. Administration of antibiotics to children before age 2 years increases risk for childhood obesity. Gastroenterology 151, 120–129.e5 (2016).

  166. 166.

    Dik, V. K., van Oijen, M. G., Smeets, H. M. & Siersema, P. D. Frequent use of antibiotics is associated with colorectal cancer risk: results of a nested case–control study. Dig. Dis. Sci. 61, 255–264 (2016).

  167. 167.

    Boursi, B., Haynes, K., Mamtani, R. & Yang, Y. X. Impact of antibiotic exposure on the risk of colorectal cancer. Pharmacoepidemiol. Drug Saf. 24, 534–542 (2015).

  168. 168.

    Klein, E. Y. et al. Global increase and geographic convergence in antibiotic consumption between 2000 and 2015. Proc. Natl Acad. Sci. USA 115, E3463–E3470 (2018).

  169. 169.

    Ananthakrishnan, A. N. et al. Environmental triggers in IBD: a review of progress and evidence. Nat. Rev. Gastroenterol. Hepatol. 15, 39–49 (2018).

  170. 170.

    Knoop, K. A., McDonald, K. G., Kulkarni, D. H. & Newberry, R. D. Antibiotics promote inflammation through the translocation of native commensal colonic bacteria. Gut 65, 1100–1109 (2016).

  171. 171.

    Rigoni, R. et al. Intestinal microbiota sustains inflammation and autoimmunity induced by hypomorphic RAG defects. J. Exp. Med. 213, 355–375 (2016).

  172. 172.

    Bailey, L. C. et al. Association of antibiotics in infancy with early childhood obesity. JAMA Pediatrics 168, 1063–1069 (2014).

  173. 173.

    Rasmussen, S. H. et al. Antibiotic exposure in early life and childhood overweight and obesity: a systematic review and meta-analysis. Diabetes Obes. Metab. 20, 1508–1514 (2018).

  174. 174.

    Kaur, K. et al. Antibiotic-mediated bacteriome depletion in Apcmin/+ mice is associated with reduction in mucus-producing goblet cells and increased colorectal cancer progression. Cancer Med. 7, 2003–2012 (2018).

  175. 175.

    Zhang, C. et al. Salinomycin inhibits the growth of colorectal carcinoma by targeting tumor stem cells. Oncol. Rep. 34, 2469–2476 (2015).

  176. 176.

    Hattori, N. et al. Antibiotics suppress colon tumorigenesis through inhibition of aberrant DNA methylation in an azoxymethane and dextran sulfate sodium colitis model. Cancer Sci. 110, 147–156 (2019).

  177. 177.

    Hardiman, K. M., Liu, J., Feng, Y., Greenson, J. K. & Fearon, E. R. Rapamycin inhibition of polyposis and progression to dysplasia in a mouse model. PLoS One 9, e96023 (2014).

  178. 178.

    Bullman, S. et al. Analysis of fusobacterium persistence and antibiotic response in colorectal cancer. Science 358, 1443–1448 (2017).

  179. 179.

    Imhann, F. et al. Proton pump inhibitors affect the gut microbiome. Gut 65, 740–748 (2016).

  180. 180.

    Kearney, J. Food consumption trends and drivers. Phil. Trans. R. Soc. Lond. B Biol. Sci. 365, 2793–2807 (2010).

  181. 181.

    Ferguson, L. R. Natural and man-made mutagens and carcinogens in the human diet. Mutat. Res. 443, 1–10 (1999).

  182. 182.

    Espejo-Herrera, N. et al. Colorectal cancer risk and nitrate exposure through drinking water and diet. Int. J. Cancer 139, 334–346 (2016).

  183. 183.

    Crowe, W., Elliott, C. T. & Green, B. D. A review of the in vivo evidence investigating the role of nitrite exposure from processed meat consumption in the development of colorectal cancer. Nutrients 11, 2673 (2019).

  184. 184.

    Nicole, W. Secret ingredients: who knows what’s in your food? Environ. Health Perspect. 121, A126–A133 (2013).

  185. 185.

    Kobylewski, S. & Jacobson, M. F. Toxicology of food dyes. Int. J. Occup. Environ. Health 18, 220–246 (2012).

  186. 186.

    Oplatowska-Stachowiak, M. & Elliott, C. T. Food colors: existing and emerging food safety concerns. Crit. Rev. Food Sci. Nutr. 57, 524–548 (2017).

  187. 187.

    FAO/WHO. Evaluation of certain food additives: eighty-second report of the joint FAO/WHO expert committee on food additives world health organ. Tech. Rep. Ser. 82, 1–162 (2016).

  188. 188.

    Ijssennagger, N., van der Meer, R. & van Mil, S. W. C. Sulfide as a mucus barrier-breaker in inflammatory bowel disease? Trends Mol. Med. 22, 190–199 (2016).

  189. 189.

    Potera, C. The artificial food dye blues. Environ. Health Perspect. 118, A428 (2010).

  190. 190.

    Feng, J., Cerniglia, C. E. & Chen, H. Toxicological significance of azo dye metabolism by human intestinal microbiota. Front. Biosci. 4, 568–586 (2012).

  191. 191.

    Shimada, C., Kano, K., Sasaki, Y. F., Sato, I. & Tsudua, S. Differential colon DNA damage induced by azo food additives between rats and mice. J. Toxicol. Sci. 35, 547–554 (2010).

  192. 192.

    Khayyat, L. I., Essawy, A. E., Sorour, J. M. & Soffar, A. Sunset yellow and allura red modulate Bcl2 and COX2 expression levels and confer oxidative stress-mediated renal and hepatic toxicity in male rats. PeerJ 6, e5689 (2018).

  193. 193.

    Meyer, S. K. et al. Hepatic effects of tartrazine (E102) after systemic exposure are independent of oestrogen receptor interactions in the mouse. Toxicol. Lett. 273, 55–68 (2017).

  194. 194.

    World Health Organization. Evaluation of certain food additives (twenty-third report of the joint FAO/WHO expert committee on food additives). Tech. Rep. Ser. 648, 13 (1980).

  195. 195.

    Bastaki, M., Farrell, T., Bhusari, S., Pant, K. & Kulkarni, R. Lack of genotoxicity in vivo for food color additive allura red AC. Food Chem. Toxicol. 105, 308–314 (2017).

  196. 196.

    Bastaki, M., Farrell, T., Bhusari, S., Pant, K. & Kulkarni, R. Lack of genotoxicity in vivo for food color additive tartrazine. Food Chem. Toxicol. 105, 278–284 (2017).

  197. 197.

    Tsuda, S. et al. DNA damage induced by red food dyes orally administered to pregnant and male mice. Toxicol. Sci. 61, 92–99 (2001).

  198. 198.

    Sasaki, Y. F. et al. The comet assay with 8 mouse organs: results with 39 currently used food additives. Mutat. Res. 519, 103–119 (2002).

  199. 199.

    Nair, A., Morsy, M. A. & Jacob, S. Dose translation between laboratory animals and human in preclinical and clinical phases of drug development. Drug. Dev. Res. 79, 373–382 (2018).

  200. 200.

    Stevens, L. J., Burgess, J. R., Stochelski, M. A. & Kuczek, T. Amounts of artificial food colors in commonly consumed beverages and potential behavioral implications for consumption in children: revisited. Clin. Pediatr. 54, 1228–1230 (2015).

  201. 201.

    Sasaki, Y. et al. Dose dependent development of diabetes mellitus and non-alcoholic steatohepatitis in monosodium glutamate-induced obese mice. Life Sci. 85, 490–498 (2009).

  202. 202.

    Hata, K. et al. Monosodium glutamate-induced diabetic mice are susceptible to azoxymethane-induced colon tumorigenesis. Carcinogenesis 33, 702–707 (2012).

  203. 203.

    Talbot, P. et al. Food-grade TiO2 is trapped by intestinal mucus in vitro but does not impair mucin O-glycosylation and short-chain fatty acid synthesis in vivo: implications for gut barrier protection. J. Nanobiotechnol. 16, 53 (2018).

  204. 204.

    Winkler, H. C., Notter, T., Meyer, U. & Naegeli, H. Critical review of the safety assessment of titanium dioxide additives in food. J. Nanobiotechnol. 16, 51 (2018).

  205. 205.

    Baranowska-Wojcik, E., Szwajgier, D., Oleszczuk, P. & Winiarska-Mieczan, A. Effects of titanium dioxide nanoparticles exposure on human health-a review. Biol. Trace Elem. Res. 193, 118–129 (2019).

  206. 206.

    Urrutia-Ortega, I. M. et al. Food-grade titanium dioxide exposure exacerbates tumor formation in colitis associated cancer model. Food Chem. Toxicol. 93, 20–31 (2016).

  207. 207.

    Bettini, S. et al. Food-grade TiO2 impairs intestinal and systemic immune homeostasis, initiates preneoplastic lesions and promotes aberrant crypt development in the rat colon. Sci. Rep. 7, 40373 (2017).

  208. 208.

    Proquin, H. et al. Gene expression profiling in colon of mice exposed to food additive titanium dioxide (E171). Food Chem. Toxicol. 111, 153–165 (2018).

  209. 209.

    Proquin, H. et al. Transcriptomics analysis reveals new insights in E171-induced molecular alterations in a mouse model of colon cancer. Sci. Rep. 8, 9738 (2018).

  210. 210.

    White, J. S. in Beverage Impacts on Health and Nutrition 2nd edn (eds Wilson, T. & Temple, N. J.) 285–301 (Humana Press, 2016).

  211. 211.

    Tappy, L. Fructose-containing caloric sweeteners as a cause of obesity and metabolic disorders. J. Exp. Biol. 221, jeb164202 (2018).

  212. 212.

    Alexander Bentley, R., Ruck, D. J. & Fouts, H. N. U.S. obesity as delayed effect of excess sugar. Econ. Hum. Biol. 36, 100818 (2019).

  213. 213.

    Jin, R. et al. Dietary fructose reduction improves markers of cardiovascular disease risk in Hispanic-American adolescents with NAFLD. Nutrients 6, 3187–3201 (2014).

  214. 214.

    Zheng, J., Feng, Q., Zhang, Q., Wang, T. & Xiao, X. Early life fructose exposure and its implications for long-term cardiometabolic health in offspring. Nutrients 8, 685 (2016).

  215. 215.

    Bray, G. A., Nielsen, S. J. & Popkin, B. M. Consumption of high-fructose corn syrup in beverages may play a role in the epidemic of obesity. Am. J. Clin. Nutr. 79, 537–543 (2004).

  216. 216.

    Panasevich, M. R. et al. High-fat, high-fructose, high-cholesterol feeding causes severe NASH and cecal microbiota dysbiosis in juvenile Ossabaw swine. Am. J. Phys. Endocrinol. Metab. 314, E78–E92 (2018).

  217. 217.

    Morgan, R. E. Does consumption of high-fructose corn syrup beverages cause obesity in children? Pediatr. Obes. 8, 249–254 (2013).

  218. 218.

    Goncalves, M. D. et al. High-fructose corn syrup enhances intestinal tumor growth in mice. Science 363, 1345–1349 (2019).

  219. 219.

    Toop, C. R. & Gentili, S. Fructose beverage consumption induces a metabolic syndrome phenotype in the rat: a systematic review and meta-analysis. Nutrients 8, 577 (2016).

  220. 220.

    Chassaing, B., Vijay-Kumar, M. & Gewirtz, A. T. How diet can impact gut microbiota to promote or endanger health. Curr. Opin. Gastroenterol. 33, 417–421 (2017).

  221. 221.

    Guinane, C. M. & Cotter, P. D. Role of the gut microbiota in health and chronic gastrointestinal disease: understanding a hidden metabolic organ. Ther. Adv. Gastroenterol. 6, 295–308 (2013).

  222. 222.

    Hernandez-Luna, M. A., Lopez-Briones, S. & Luria-Perez, R. The four horsemen in colon cancer. J. Oncol. 2019, 5636272 (2019).

  223. 223.

    Sobhani, I. et al. Colorectal cancer-associated microbiota contributes to oncogenic epigenetic signatures. Proc. Natl Acad. Sci. USA 116, 24285–24295 (2019).

  224. 224.

    Huang, P. & Liu, Y. A reasonable diet promotes balance of intestinal microbiota: prevention of precolorectal cancer. Biomed Res. Int. 2019, 3405278 (2019).

  225. 225.

    Chassaing, B. et al. Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome. Nature 519, 92–96 (2015).

  226. 226.

    Levi, Z. et al. Measured body mass index in adolescence and the incidence of colorectal cancer in a cohort of 1.1 million males. Cancer Epidemiol. Biomarkers Prev. 20, 2524–2531 (2011).

  227. 227.

    Stidham, R. W. & Higgins, P. D. R. Colorectal cancer in inflammatory bowel disease. Clin. Colon. Rectal Surg. 31, 168–178 (2018).

  228. 228.

    Viennois, E., Merlin, D., Gewirtz, A. T. & Chassaing, B. Dietary emulsifier-induced low-grade inflammation promotes colon carcinogenesis. Cancer Res. 77, 27–40 (2017).

  229. 229.

    Akagawa, S. et al. Effect of delivery mode and nutrition on gut microbiota in neonates. Ann. Nutr. Metab. 74, 132–139 (2019).

  230. 230.

    Tamburini, S., Shen, N., Wu, H. C. & Clemente, J. C. The microbiome in early life: implications for health outcomes. Nat. Med. 22, 713 (2016).

  231. 231.

    Dwyer, A. J. et al. A summary of the fight colorectal cancer working meeting: exploring risk factors and etiology of sporadic early-age onset colorectal cancer. Gastroenterology 157, 280–288 (2019).

  232. 232.

    Chassaing, B., Van de Wiele, T., De Bodt, J., Marzorati, M. & Gewirtz, A. T. Dietary emulsifiers directly alter human microbiota composition and gene expression ex vivo potentiating intestinal inflammation. Gut 66, 1414–1427 (2017).

  233. 233.

    Roberts, C. L. et al. Translocation of Crohn’s disease Escherichia coli across M-cells: contrasting effects of soluble plant fibres and emulsifiers. Gut 59, 1331–1339 (2010).

  234. 234.

    Roberts, C. L., Rushworth, S. L., Richman, E. & Rhodes, J. M. Hypothesis: increased consumption of emulsifiers as an explanation for the rising incidence of Crohn’s disease. J. Crohns Colitis 7, 338–341 (2013).

  235. 235.

    Lewis, J. D. & Abreu, M. T. Diet as a trigger or therapy for inflammatory bowel diseases. Gastroenterology 152, 398–414.e6 (2017).

  236. 236.

    Aguayo-Patron, S. V. & Calderon de la Barca, A. M. Old fashioned vs. ultra-processed-based current diets: possible implication in the increased susceptibility to type 1 diabetes and celiac disease in childhood. Foods 6, 100 (2017).

  237. 237.

    Bel, S. et al. Dietary exposure of the Belgian population to emulsifiers E481 (sodium stearoyl-2-lactylate) and E482 (calcium stearoyl-2-lactylate). Food Addit. Contam. 35, 828–837 (2018).

  238. 238.

    Mozaffarian, D. et al. Dietary intake of trans fatty acids and systemic inflammation in women. Am. J. Clin. Nutr. 79, 606–612 (2004).

  239. 239.

    Dhaka, V., Gulia, N., Ahlawat, K. S. & Khatkar, B. S. Trans fats-sources, health risks and alternative approach — a review. J. Food Sci. Technol. 48, 534–541 (2011).

  240. 240.

    McKelvey, W., Greenland, S. & Sandler, R. S. A second look at the relation between colorectal adenomas and consumption of foods containing partially hydrogenated oils. Epidemiology 11, 469–473 (2000).

  241. 241.

    Slattery, M. L., Benson, J., Ma, K. N., Schaffer, D. & Potter, J. D. Trans-fatty acids and colon cancer. Nutr. Cancer 39, 170–175 (2001).

  242. 242.

    Vinikoor, L. C. et al. Consumption of trans-fatty acid and its association with colorectal adenomas. Am. J. Epidemiol. 168, 289–297 (2008).

  243. 243.

    Hsu, H. T. et al. Kinetics for the distribution of acrylamide in French fries, fried oil and vapour during frying of potatoes. Food Chem. 211, 669–678 (2016).

  244. 244.

    Kumar, J., Das, S. & Teoh, S. L. Dietary acrylamide and the risks of developing cancer: facts to ponder. Front. Nutr. 5, 14 (2018).

  245. 245.

    Raju, J. et al. Negligible colon cancer risk from food-borne acrylamide exposure in male F344 rats and nude (nu/nu) mice-bearing human colon tumor xenografts. PLoS One 8, e73916 (2013).

  246. 246.

    Hogervorst, J. G. et al. Dietary acrylamide intake and the risk of colorectal cancer with specific mutations in KRAS and APC. Carcinogenesis 35, 1032–1038 (2014).

  247. 247.

    Esposito, F., Nardone, A., Fasano, E., Triassi, M. & Cirillo, T. Determination of acrylamide levels in potato crisps and other snacks and exposure risk assessment through a margin of exposure approach. Food Chem. Toxicol. 108, 249–256 (2017).

  248. 248.

    Kadawathagedara, M. et al. Dietary acrylamide intake during pregnancy and anthropometry at birth in the French EDEN mother–child cohort study. Environ. Res. 149, 189–196 (2016).

  249. 249.

    Luopajarvi, K. et al. Enhanced levels of cow’s milk antibodies in infancy in children who develop type 1 diabetes later in childhood. Pediatr. Diabetes 9, 434–441 (2008).

  250. 250.

    Llewellyn, S. R. et al. Interactions between diet and the intestinal microbiota alter intestinal permeability and colitis severity in mice. Gastroenterology 154, 1037–1046.e2 (2018).

  251. 251.

    Bajka, B. H., Clarke, J. M., Cobiac, L. & Topping, D. L. Butyrylated starch protects colonocyte DNA against dietary protein-induced damage in rats. Carcinogenesis 29, 2169–2174 (2008).

  252. 252.

    Toden, S., Bird, A. R., Topping, D. L. & Conlon, M. A. Resistant starch attenuates colonic DNA damage induced by higher dietary protein in rats. Nutr. Cancer 51, 45–51 (2005).

  253. 253.

    Ley, S. H. et al. Associations between red meat intake and biomarkers of inflammation and glucose metabolism in women. Am. J. Clin. Nutr. 99, 352–360 (2014).

  254. 254.

    Shen, Q., Chen, Y. A. & Tuohy, K. M. A comparative in vitro investigation into the effects of cooked meats on the human faecal microbiota. Anaerobe 16, 572–577 (2010).

  255. 255.

    Merlot, E., Couret, D. & Otten, W. Prenatal stress, fetal imprinting and immunity. Brain Behav. Immun. 22, 42–51 (2008).

  256. 256.

    Foster, J. A., Rinaman, L. & Cryan, J. F. Stress & the gut-brain axis: regulation by the microbiome. Neurobiol. Stress 7, 124–136 (2017).

  257. 257.

    Jacob, T., Itzchak, E. B. & Raz, O. Stress among healthcare students — a cross disciplinary perspective. Physiother. Theory Pract. 29, 401–412 (2013).

  258. 258.

    Sharland, M. et al. Antibiotic prescribing in general practice and hospital admissions for peritonsillar abscess, mastoiditis, and rheumatic fever in children: time trend analysis. Br. Med. J. 331, 328–329 (2005).

  259. 259.

    Raposa, B. et al. Food additives: sodium benzoate, potassium sorbate, azorubine, and tartrazine modify the expression of NFkappaB, GADD45alpha, and MAPK8 genes. Physiol. Int. 103, 334–343 (2016).

  260. 260.

    Brown, J. P. Reduction of polymeric azo and nitro dyes by intestinal bacteria. Appl. Environ. Microbiol. 41, 1283–1286 (1981).

  261. 261.

    Sano, C. History of glutamate production. Am. J. Clin. Nutr. 90, 728s–732s (2009).

  262. 262.

    Tennant, D. R. Review of glutamate intake from both food additive and non-additive sources in the European Union. Ann. Nutr. Metab. 73, 21–28 (2018).

  263. 263.

    Zanfirescu, A., Cristea, A. N., Nitulescu, G. M., Velescu, B. S. & Gradinaru, D. Chronic monosodium glutamate administration induced hyperalgesia in mice. Nutrients 10, E1 (2017).

  264. 264.

    Feng, Z. et al. Monosodium L-glutamate and dietary fat exert opposite effects on the proximal and distal intestinal health in growing pigs. Appl. Physiol. Nutr. Metab. 40, 353–363 (2015).

  265. 265.

    Nagata, M. et al. Type 2 diabetes mellitus in obese mouse model induced by monosodium glutamate. Exp. Anim. 55, 109–115 (2006).

  266. 266.

    Weir, A., Westerhoff, P., Fabricius, L., Hristovski, K. & von Goetz, N. Titanium dioxide nanoparticles in food and personal care products. Environ. Sci. Technol. 46, 2242–2250 (2012).

  267. 267.

    Gholinejad, Z., Khadem Ansari, M. H. & Rasmi, Y. Titanium dioxide nanoparticles induce endothelial cell apoptosis via cell membrane oxidative damage and p38, PI3K/Akt, NF-κB signaling pathways modulation. J. Trace Elem. Med. Biol. 54, 27–35 (2019).

  268. 268.

    Klurfeld, D. M., Foreyt, J., Angelopoulos, T. J. & Rippe, J. M. Lack of evidence for high fructose corn syrup as the cause of the obesity epidemic. Int. J. Obes. 37, 771–773 (2013).

  269. 269.

    Charrez, B., Qiao, L. & Hebbard, L. The role of fructose in metabolism and cancer. Horm. Mol. Biol. Clin. Invest. 22, 79–89 (2015).

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L.J.H. researched data for the article, made a substantial contribution to discussion of content and wrote and reviewed/edited the manuscript before submission. J.R.H., E.A.M., M.S., P.J.B. and F.G.B. made a substantial contribution to discussion of content and wrote and reviewed/edited the manuscript before submission. A.S. made a substantial contribution to discussion of content and reviewed/edited the manuscript before submission. A.C., H.C., B.L.L. and M.M.P. wrote the article.

Correspondence to Lorne J. Hofseth.

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Nature Reviews Gastroenterology & Hepatology thanks S. Kahn and other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Hofseth, L.J., Hebert, J.R., Chanda, A. et al. Early-onset colorectal cancer: initial clues and current views. Nat Rev Gastroenterol Hepatol (2020). https://doi.org/10.1038/s41575-019-0253-4

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