Dietary Prevention of Colon Cancer and Other Noncommunicable Westernized Diseases
This research was conducted by Stephen J.D. O’Keefe, MBBS, MSc, MD, from the Division of Gastroenterology, Hepatology and Nutrition.
Westernized diseases, including colorectal cancer, diabetes, and cardiovascular disease, are a major threat to health care in the United States. The diet consumed by people living in high-income countries is a common underlying factor of these vastly different pathologies. The Westernized diet is low in fiber and high in meats, polyunsaturated fats, and simple carbohydrates. We have made key strides in understanding why the lack of fiber in the Westernized diet is deleterious and why consuming at least 50 grams of fiber daily is beneficial.
A healthy diet has long been lauded as an essential part of a healthy lifestyle conducive to disease prevention. While the nutrients and healthy fats digested in the stomach and small intestine are essential, the nondigestible fiber from plant foods that passes through the colon is crucial for good health as well.
Colon cancer is the second leading cause of cancer-related deaths worldwide. The American Cancer Society predicted that in 2020, approximately 148,000 individuals would be diagnosed with colorectal cancer and approximately 53,000 would die from the disease. Environmental pressures in genetically susceptible individuals promote colon cancer. A low-fiber diet places environmental pressure on the colonic epithelium, as well as on the stomach, esophagus, breast, prostate, pancreas, and liver. Moreover, the obesity that can result from a Westernized diet is associated with 17 different types of cancer. A high-fiber diet is associated with a lower risk of all cancers, a lower risk of cardiovascular and respiratory diseases, and a reduction in all-cause mortality.
A major way that diet is either protective against colon cancer or promotes malignancy is through the bacteria in the colon, the microbiota. Dietary fiber feeds the colonic microbiota, which are highly active metabolically. When presented with sufficient fiber, the microbiota catalyze saccharolytic fermentation and produce biotin, polyphenols, and short-chain fatty acids, including acetate, propionate, and butyrate. These metabolites promote mucosal health and reduce inflammation. When the diet is high in meat and fat and low in fiber, the microbiota produce a different set of metabolites that include hydrogen sulfide, ammonium products, and bile acid. This promotes mucosal inflammation and increases cancer risk. A minimum of 50 grams of fiber a day is needed to promote good health and minimize colon cancer risk.
The production of butyrate by the gut microbiota through the fermentation of dietary fiber is particularly important. Butyrate is the primary energy source of the colonocytes, the epithelial cells of the colon. Butyrate is also immunomodulatory and anti-inflammatory. It stimulates Treg activation and exerts epigenetic regulation of the inflammatory response through its metabolism into a histone deacetylase inhibitor. Additionally, butyrate plays important roles in mucosal defense by stimulating the production of mucus and the formation of tight junctions. Taken together, these actions stimulated by the production of butyrate are anticarcinogenic. Dietary studies support that a high-fiber diet allows an individual to eat increased quantities of meat, which promotes carcinogenesis, without increasing the risk of colon cancer.
Dietary Switch Studies
In 1970, Denis Burkitt, MD, a British surgeon working in Uganda, proposed that individuals should ingest at least 50 grams of fiber daily to reduce the incidence of Westernized diseases. Substantial evidence gathered over the last 50 years supports this recommendation.
To better understand the effects of dietary fiber on the colonic microbiota and colon cancer risk, Dr. O’Keefe started with the observation that colon cancer is not common in rural Africa, where its incidence is less than five per 100,000 people. In contrast, it is prevalent in African Americans, with an incidence from 2012 to 2016 of 45.7 per 100,000 people, despite similar genetics between these populations. Additionally, studies have shown that within one generation of immigrating to a Westernized country, colon cancer risk mirrors that of the new country, indicating that this increased risk of colon cancer comes from the environment rather than from genetic factors. The diet of rural Africans differs markedly from that of Americans. Most notably, the American diet is high in meat, fats, and simple carbohydrates, and the African diet is very high in fiber. The average American eats approximately 15 grams of fiber a day; the average rural African eats 50 to 120 grams.
Dr. O’Keefe and his colleagues at UPMC, in South Africa, and elsewhere conducted a dietary switch study during which a group of 20 African Americans increased fiber consumption to 55 grams per day and decreased fat intake, and a group of 20 rural Africans decreased fiber consumption to 12 grams per day and tripled their fat intake for two weeks. Participants were between the ages of 50 and 65 years and were age-matched and sex-matched between the groups of healthy volunteers. Meals for all participants were provided and served in-house at a nutrition coordinating center to promote adherence to the study diet and accurate records of ingestion. A colonoscopy was performed before and after the dietary switch to look for markers of colorectal cancer risk.
After only two weeks of the dietary switch, there was decreased proliferation in the colonic epithelium of Americans given an Africanized, high-fiber diet and increased proliferation in the colonic epithelium of rural Africans fed a Westernized diet.
Figure 1. Proliferation in epithelial crypt cells, as indicated by Ki67 staining, in colonic mucosal biopsies from dietary-switch–study participants.
Additionally, markers of inflammation increased in Africans and decreased in Americans after the dietary switch. Dr. O’Keefe and his colleagues performed extensive profiling of the microbial metabolites present before and after the dietary switch in each group. The high-fiber dietary switch resulted in increased saccharolytic fermentation and increased production of butyrate and other short-chain fatty acids and suppressed synthesis of secondary bile acids, which are inflammatory, in the colon of African American participants. The inverse was observed in rural African participants. The study strongly suggested that the level of dietary fiber consumed can convert the colon from a cancer-promoting environment to a cancer-preventing environment in as little as two weeks.
Dr. O’Keefe is now expanding his dietary studies to Alaskan Natives, a population with the highest incidence of colorectal cancer (89 per 100,000 population) and mortality from colorectal cancer (40 per 100,000 population) worldwide. The Alaskan Native diet consists almost exclusively of meat and fat. When the colonic microbiota and microbial metabolites in Alaskan Native individuals vs. rural African individuals were compared, the profiles were completely different. In Dr. O’Keefe’s NIH-funded study (NCT03028831), Alaskan Native participants are supplementing their traditional diet with 50 grams of resistant starch fiber per day, which is soluble and easy to drink, as one arm of a four-week randomized controlled trial.
Fiber Consumption to Combat Obesity and Type 2 Diabetes
With African urbanization, there has been an increase in obesity, colon cancer, and other Westernized, noncommunicable diseases. Not surprisingly, the gut microbiota is different between individuals living in urban Africa and in rural Africa. The best solution to this problem is to restore traditional foods, education, and exercise. Enhanced understanding of why this is happening and how to counteract it will have implications for managing similar, long-standing problems in developed countries.
These studies in rural and urban Africans and Alaskan Natives have important implications for all Americans and others living in Westernized societies. High-fiber diets can be used to treat obesity and may provide a novel way to manage type 2 diabetes by promoting intestinal microbiota that produce short-chain fatty acids. Dr. O’Keefe is exploring this at UPMC in an NIH-funded clinical study in collaboration with Terry Hartman, MD, at Emory University. The Pitt-Emory Legume Study will test the ability of high-fiber diets to reduce obesity, diabetes, and colon cancer (NCT04780477).
Participants in this randomized controlled trial will consume either a high-fiber diet with 25-30 grams of dietary fiber per day from legumes or a healthy American control diet. The participants will be between 40 and 75 years of age and at high risk for colon cancer due to being overweight or obese and having a history of a colon polyp in the past three years. The primary endpoints of the study are body weight and proliferation of the colonic epithelium as a biomarker of colon cancer risk. Insulin resistance, biomarkers of systemic inflammation, the microbiome, and gut transit time will also be assessed. Moreover, this important study will assess the long-term effects of the dietary intervention, with a follow-up in approximately three years, when participants undergo their next scheduled surveillance colonoscopy. Dr. O’Keefe is hopeful that the study will provide a scientific framework for a dietary modification program to promote weight control and reduce mortality from colorectal cancer and other Westernized diseases.
Figure 2. High-fiber foods readily available in the United States.
Colon cancer and other Westernized diseases can be attributed to microbiota-diet interactions, and there is increasing evidence that consuming at least 50 grams of fiber per day may prevent these diseases. High-fiber diets have the potential to resolve major public health concerns and allow Americans to live longer and have a better quality of life as they age.
References and Further Reading
Siegel RL, Miller KD, Goding Sauer A, et al. Colorectal cancer statistics, 2020. CA Cancer J Clin. 2020;70(3):145-64.
Aune D, Keum N, Giovannucci E, et al. Whole grain consumption and risk of cardiovascular disease, cancer, and all cause and cause specific mortality: systematic review and dose-response meta-analysis of prospective studies. BMJ. 2016;353:i2716.
Donohoe DR, Garge N, Zhang X, et al. The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon. Cell Metab. 2011;13(5):517-26.
O’Keefe SJ. The association between dietary fibre deficiency and high-income lifestyle-associated diseases: Burkitt’s hypothesis revisited. Lancet Gastroenterol Hepatol. 2019;4(12):984-96.
O’Keefe SJ, Li JV, Lahti L, et al. Fat, fibre and cancer risk in African Americans and rural Africans. Nat Commun. 2015;6:6342.
Ocvirk S, Wilson AS, Posma JM, et al. A prospective cohort analysis of gut microbial co-metabolism in Alaska Native and rural African people at high and low risk of colorectal cancer. Am J Clin Nutr. 2020;111(2):406-19.
Katsidzira L, Ocvirk S, Wilson A, et al. Differences in fecal gut microbiota, short-chain fatty acids and bile acids link colorectal cancer risk to dietary changes associated with urbanization among Zimbabweans. Nutr Cancer. 2019;71(8):1313-24.
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