Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

You are viewing this page in draft mode.

Early-onset colorectal cancer: initial clues and current views

A Publisher Correction to this article was published on 29 June 2020

This article has been updated

Abstract

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

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

Change history

References

  1. 1.

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

    PubMed  Google Scholar 

  2. 2.

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

    PubMed  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  Google Scholar 

  5. 5.

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

    PubMed  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  13. 13.

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

    PubMed Central  Google Scholar 

  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).

    PubMed  Google Scholar 

  15. 15.

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

    PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

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

    PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  37. 37.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    Google Scholar 

  40. 40.

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

    Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    PubMed  Google Scholar 

  54. 54.

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

    PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    PubMed  Google Scholar 

  64. 64.

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

    CAS  PubMed  Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  73. 73.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74.

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

    PubMed  Google Scholar 

  75. 75.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76.

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

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  80. 80.

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

    PubMed  Google Scholar 

  81. 81.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  84. 84.

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

    PubMed  Google Scholar 

  85. 85.

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

    PubMed  Google Scholar 

  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).

    Google Scholar 

  87. 87.

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

    PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  98. 98.

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

    PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  100. 100.

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

    CAS  PubMed  Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    PubMed  Google Scholar 

  113. 113.

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

    PubMed  Google Scholar 

  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).

    PubMed  Google Scholar 

  115. 115.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 116.

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

    PubMed  Google Scholar 

  117. 117.

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

    CAS  PubMed  Google Scholar 

  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).

    Google Scholar 

  119. 119.

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

    PubMed  Google Scholar 

  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).

    PubMed  Google Scholar 

  121. 121.

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

    PubMed  PubMed Central  Google Scholar 

  122. 122.

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

    PubMed  Google Scholar 

  123. 123.

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

    PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  139. 139.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  Google Scholar 

  141. 141.

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

    PubMed  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    Google Scholar 

  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).

    PubMed  Google Scholar 

  156. 156.

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

    PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  171. 171.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  172. 172.

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

    PubMed  Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. 175.

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

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  178. 178.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  179. 179.

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

    CAS  Google Scholar 

  180. 180.

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

    Google Scholar 

  181. 181.

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

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed Central  Google Scholar 

  184. 184.

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

    PubMed  PubMed Central  Google Scholar 

  185. 185.

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

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  189. 189.

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

    PubMed  PubMed Central  Google Scholar 

  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).

    Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  202. 202.

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

    CAS  PubMed  Google Scholar 

  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).

    Google Scholar 

  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).

    Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  Google Scholar 

  217. 217.

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

    CAS  PubMed  Google Scholar 

  218. 218.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    Google Scholar 

  222. 222.

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

    PubMed  PubMed Central  Google Scholar 

  223. 223.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  224. 224.

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

    PubMed  PubMed Central  Google Scholar 

  225. 225.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  Google Scholar 

  227. 227.

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

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  229. 229.

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

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    PubMed  Google Scholar 

  235. 235.

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

    CAS  PubMed  Google Scholar 

  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).

    PubMed Central  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  255. 255.

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

    CAS  PubMed  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  257. 257.

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

    PubMed  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  260. 260.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  261. 261.

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

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  265. 265.

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

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

Download references

Author information

Affiliations

Authors

Contributions

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.

Corresponding author

Correspondence to Lorne J. Hofseth.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

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

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Hofseth, L.J., Hebert, J.R., Chanda, A. et al. Early-onset colorectal cancer: initial clues and current views. Nat Rev Gastroenterol Hepatol 17, 352–364 (2020). https://doi.org/10.1038/s41575-019-0253-4

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing