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“Colorectal cancer (CRC) is the second leading cause of cancer death in the Western world.”

Colorectal cancer (CRC) is the second leading cause of cancer death in the Western world. It afflicts 150,000 Americans, 250,000 Europeans and 1 million people worldwide annually, and nearly one third of affected individuals will die.¹ The global burden of CRC is expected to increase to more than 2.2 million new cases and 1.1 million annual cancer deaths by 2030.²  Rather than taking a closer look at the root cause of this problem and implement interventions to reverse this trend, the response of the medical system has been the promotion of colon cancer screening without paying much attention to the role of life style factors that have dramatically changed in the past 75 years, in particular dietary changes.  There is no question that screening colonoscopy has permitted early detection and recent studies have clearly shown that this early detection is associated with a reduction in mortality rates. Screening colonoscopy has also given a dramatic boost to the income of hospital systems and gastroenterologists charged with performing these additional procedures.  However, the overall impact of colon cancer screening has been small, particularly among African Americans who shoulder the greatest burden of the disease in the United States.  When I recently asked an expert on colon cancer screening if individual dietary habits are considered as a risk factor to determine how closely individuals with a positive finding on a screening colonoscopy have to be followed, the surprising answer was “this would be a great idea”.

“CRC incidence has been on the rise among young adults aged 20 to 39 years since the mid-1980s”

Despite the success of colon cancer screening in older patients, in many industrialized countries, the burden of CRC is rapidly shifting to younger individuals, a trend seen for several other non-communicable chronic diseases as well.^{3, 4, 5} In the United States, despite declines in older individuals, the incidence has been increasing in young and middle-aged adults with 22% of CRC cases occurring in those younger than 55 years in 2013 to 2017.⁶ CRC incidence has been on the rise among young adults aged 20 to 39 years since the mid-1980s, and this elevated risk in generations born in the US after 1950 strongly indicates that widespread changes in early-life exposures, such as diet and lifestyle factors, may explain the upward trend in early-onset CRC.^7,8

“Colon cancer shows all the hallmarks of a number of diseases that make up the current epidemic of non-communicable chronic diseases  affecting all organs…”

As I have explained in The Gut Immune Connection, colon cancer shows all the hallmarks of a number of diseases that make up the current epidemic of non-communicable chronic diseases  affecting all organs in our body and presenting as such different medical problems as cardiovascular disorders, non-alcoholic fatty liver disease, type 2 diabetes, metabolic syndrome, obesity, autism spectrum disorder and depression, and neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease. These various diseases are not only connected with each other (e.g. the presence of one diagnosis often increases the risk for another), but they share the disease mechanism of low grade systemic immune system activation, occur at increasingly younger age groups, and in developing countries, and are strongly related to dietary habits and other lifestyle factors, including increased exposure to chemicals and certain medications. For example, studies in Japanese Hawaiians, have demonstrated that it only takes one generation for the immigrant population to assume the colon cancer incidence of the host country (e.g., the US), with adoption of the Western diet playing a major role.⁹

“…diet-induced changes in the interactions between the gut microbiome and the gut-associated immune system are a key mechanism in the current disease epidemic.”

Reviewing the current evidence, I have concluded that diet-induced changes in the interactions between the gut microbiome and the gut-associated immune system are a key mechanism in the current disease epidemic.  It is becoming increasingly clear that one dietary pattern in particular, the Standard American Diet (SAD) contains many of the components responsible for the negative health effects:  High consumption of ultra-processed foods, refined sugars, and animal products (red meat and animal fats), greatly reduced consumption of variable fruits and vegetables containing fiber and polyphenols, and a low consumption of naturally fermented foods.

A body of evidence suggests that the relationship between the SAD and colon cancer risk is multifactorial, in other words different dietary components play a role, in addition to genetic predisposition and exposure to environmental toxin. A study published by Stephen J.D. O’Keefe and colleagues in the journal Nature Communications in 2015 compared the effect of diet on colon cancer risk in African Americans and rural South Africans to explore the hypothesis that colon cancer risk is determined by dietary influences on the production of microbial metabolites which can decrease (anti-neoplastic) or increase (pro-neoplastic) colon cancer risk.

“…two potential mechanisms for diet-associated CRC risk: the protective effect of dietary fiber in increasing the production of the anti-inflammatory and anti-neoplastic short chain fatty and the cancer promoting effect of animal fat.”

As expected and confirming previous studies, the diets eaten by the two groups were fundamentally different in preparation, cooking and composition. Animal protein and fat intake was two to three times higher in Americans, whereas carbohydrate and fiber, chiefly in the form of resistant starch, were higher in Africans. On colonoscopy, African Americans had more polyps and higher rates of mucosal growth, considered precursors of colon cancer. These differences were shown to be associated with profound differences in the prevalence of microbial taxa: In Americans the microbial group Bacteroides dominated while in Africans Prevotella was the predominant taxa.  Notable differences included higher levels of microbial taxa that are able to break down starch, ferment carbohydrates and produce the short chain fatty acid butyrate in Africans, and higher levels of microbes able to produce potentially harmful metabolites, including secondary bile acids in Americans. These findings suggested two potential mechanisms for diet-associated cancer risk: the protective effect of dietary fiber in increasing the production of the anti-inflammatory and anti-neoplastic short chain fatty acid butyrate, and the cancer promoting effect of animal fat on stimulating bile acid synthesis by the liver, thereby increasing gut microbial production of carcinogenic secondary bile acids.

“Between 1965 and 1996, SSB intake among US adolescents more than doubled”

But a high consumption of animal products (red meat, animal fat, dairy and eggs), and a reduction in the intake of dietary fiber are not the only dietary factors that play a role in colon cancer risk as pointed out by a recent study led by Jinhee Hur and published in the journal Gut. This study focused on the high consumption of sugar in the form of sugar-sweetened beverages (SSB), particularly amongst adolescents and young adults. Incidence of early-onset colorectal cancer diagnosed under age 50 years has been on the rise in the US and many high-income countries over the past two decades.

Simple sugar, especially added fructose intake has steeply increased in recent decades largely due to the marked increase in SSB intake.^{10, 11} SBs (carbonated and noncarbonated soft drinks, fruit drinks, and sports drinks) are mostly sweetened with high-fructose corn syrup (usually 55% fructose and 45% glucose) or sucrose (half fructose and half glucose).¹² In the United States, hidden sugar availability has risen dramatically since the 1950s – in beverages, sauces, salad dressings, baked beans, canned foods teriyaki and ketchup – paralleled by the rise of industrial agriculture with federally subsidized production of corn.

Between 1965 and 1996, SSB intake among US adolescents more than doubled (per capita g/d: boys 364 to 1046, girls 303 to 678).¹³ Compared with other age groups, adolescents had the highest SSB intake with approximately 10% of daily calories from SSBs in 2011 to 2014.  SSB consumption is also rapidly increasing worldwide, particularly in developing countries. In 53 low- and middle-income countries, 54% of adolescents consumed carbonated soft drinks at least once per day in 2009 to 2013.^{14, 15,16} A Mexican colleague told me at a medical conference that former president of Mexico and CEO of Coca Cola Mexico recommended Coke as a calming remedy for infants!

It had previously been known that the consumption of sugar-sweetened beverages can exert adverse metabolic repercussions throughout the course of life, including childhood and adulthood obesity and type 2 diabetes.  However, despite the highest level of sugary drink consumption being characterized among adolescents and young adults, the association between sugar consumption by this age group and early onset colon cancer had not been investigated.

The authors of the Gut manuscript used data from the Nurses’ Health Study II (1991–2015), to prospectively study the association of SSB intake in adulthood and adolescence with early onset CRC risk among 95,464 women who had reported adulthood beverage intake using validated food frequency questionnaires every 4 years. A subset of 41,272 participants reported beverage intake at age 13–18 years using a validated high school-FFQ in 1998.

“…each serving/day increment of SSB intake at age 13–18 years was associated with a 32% higher risk of early onset CRC.”

The authors identified 109 cases of early onset CRC in their study population.  Compared with <1 serving/week of SSB consumption, higher intake (i.e., ≥2 servings/day) in adulthood was associated with a 2.2-fold higher risk of EO-CRC. Amazingly, each serving/day increment of SSB intake at age 13–18 years was associated with a 32%

higher risk of early onset-CRC!

The take home message from these two studies is pretty clear.  CRC, in particular CRC in younger age groups is significantly related to key features of the Standard American diet, making it another striking example of the non-communicable chronic disease epidemic.   Policy makers might consider a reevaluation of subsidies to sugar producing agrobusinesses (e.g., heavily subsidized corn production), while intensifying public education of children and pregnant mothers about the negative health consequences of sugar consumption (as well as other aspects of the Standard American diet).  Such major policy changes may prevent that in 10 years from now, another lowering of the threshold for colon cancer screening to individuals in their 30s may be required.

References

1. Arnold M, Sierra MS, Laversanne M, et al. Global patterns and trends in colorectal cancer incidence and mortality. Gut 2017;66:683–691
2. Arnold M, Sierra MS, Laversanne M, et al. Global patterns and trends in colorectal cancer incidence and mortality. Gut 2017;66:683–691
3. Siegel RL, Jakubowski CD, Fedewa SA, et al. Colorectal cancer in the young: epidemiology, prevention, management. Am Soc Clin Oncol Educ Book 2020;40:1–14.
4. Keum N, Giovannucci E. Global burden of colorectal cancer: emerging trends, risk factors and prevention strategies. Nat Rev Gastroenterol Hepatol 2019;16:713–732.
5. Siegel RL, Miller KD, Goding Sauer A, et al. Colorectal cancer statistics, 2020. CA Cancer J Clin 2020;70:145– 164.
6. SEER Cancer Stat Facts: CRC. Bethesda, MD: National Cancer Institute. Available at seer.cancer.gov/statfacts/ html/colorect.html.
7. Siegel RL, Jakubowski CD, Fedewa SA, et al. Colorectal cancer in the young: epidemiology, prevention, management. Am Soc Clin Oncol Educ Book 2020;40:1–14.
8. Siegel RL, Miller KD, Goding Sauer A, et al. Colorectal cancer statistics, 2020. CA Cancer J Clin 2020;70:145– 164.
9. Siegel RL, Jakubowski CD, Fedewa SA, et al. Colorectal cancer in the young: epidemiology, prevention, management. Am Soc Clin Oncol Educ Book 2020;40:1–14.
10. Bray GA, Nielsen SJ, Popkin BM. Consumption of high fructose corn syrup in beverages may play a role in theepidemic of obesity. Am J Clin Nutr 2004;79:537–543.
11. Marriott BP, Cole N, Lee E. National estimates of dietary fructose intake increased from 1977 to 2004 in the United States. J Nutr 2009;139:1228s–1235s.
12. Bray GA, Nielsen SJ, Popkin BM. Consumption of high fructose corn syrup in beverages may play a role in theepidemic of obesity. Am J Clin Nutr 2004;79:537–543.
13. Cavadini C, Siega-Riz AM, Popkin BM. US adolescent food intake trends from 1965 to 1996. West J Med 2000; 173:378–383.
14. Rosinger A, Herrick K, Gahche J, et al. Sugar-sweetened beverage consumption among U.S. youth, 2011–2014. NCHS Data Brief 2017;271:1–8.
15. Malik VS, Hu FB. Sugar-sweetened beverages and cardiometabolic health: an update of the evidence. Nutrients 2019;11:1840.
16. Yang L, Bovet P, Liu Y, et al. Consumption of carbonated soft drinks among young adolescents aged 12 to 15 years in 53 low- and middle-income countries. Am J Public Health 2017;107:1095–1100.