Team:NRP-UEA-Norwich/Modeling/Glyco2D
Project Background
Colon (colorectal) cancer is the second most common cause of cancer death in the UK. 30,000 new cases are diagnosed every year (1). Epidemiological studies have determined that 90% of the risk factors for colorectal cancer are environmental, with diet have the biggest effect. According to the US Food and Drug Administration (US-FDA), diets that are high in red meat and fat correlate to an increased risk of colorectal cancer while the consumption of dietary fibre reduces risk (2).
Resistant starches are carbohydrate molecules that, because of their structure, are not able to be fully digested by the carbohydrate degradation enzymes produced by the upper digestive system (3). These starches pass through the small intestine and are fermented by the colonic microbiome.
Certain species of colonic bacteria produce short chain fatty acids (SCFAs) such as butyric acid during fermentation.
Butyrate, the conjugate base of butyric acid, has been shown to have many beneficial effects in health (4). For example:
At the intestinal level butyrate is known to
• Be the major metabolic substrate for colonocytes. Without butyrate for energy, colon cells undergo autophagy
• Maintain an acidic luminal pH, which prevents the production and absorption of carcinogenic factors
• Boost the mucosa of the gut and the immune system
At the extra-intestinal level butyrate may
• Induce expression of fetal globin genes preventing β-heamoglobinopathies
• Inhibit cholesterol production, preventing hypercholesterolemia
• Reduce insulin resistance, preventing type II diabetes
We are particularly interested in the relationship between butyrate and colorectal cancers.
Butyrate has been shown to inhibit cell proliferation and induce apoptosis in carcinoma cell lines by hyper-acetylating histones through inhibition of histone deacetylase (HDAC) and inducing gene silencing leading to apoptosis (5). Additionally, studies in rats have shown that increasing the amount of butyrate in the gut resulted in significant reduction in smooth muscle cell contractility, which lowers the risk of colon cancer (6). Another study confirmed the direct correlation of increased butyrate in the colon with a reduced tumor mass formation (7).
People consuming typical Western diets do not consume enough dietary fibre. For example, the average American only consumes 8 g a day; far less than the recommended 20 to 30 g per day (8). In addition, the microbiome differs between individuals. Some individuals have fewer bacteria that contain the butyrate biosynthetic pathway. The most abundant strains of butyrate producing bacteria in the gut was demonstrated to be Eubacterium rectum and E. halliii (9). The overall quantity of SCFAs produced in the colon is dependent on two factors: the amount of resistant carbohydrate molecules that pass to the colon for fermentation by colonic bacteria and bacteria with SCFA biosynthetic pathways being present in the microbiome.
House of Carbs is taking two approaches to increase the levels of butyrate in the colon.
References
1. Haggar F, Boushey R. Colorectal Cancer Epidemiology: Incidence, Mortality, Survival, and Risk Factors. Clinics in Colon and Rectal Surgery. 2009; 22(4): p. 191-197.
2. Food and Drug Adminstration. Food and Drug Administration. [Online].; 2015 [cited 2015 August 24.] Available from: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=101.76
3. Elmståhl HL. Resistant starch content in a selection of starchy foods on the Swedish market. European Journal Of Clinical Nutrition. 2002 June; 56(6): p. 500-505
4. Zeng H, Lazarova DL, Bordonaro M. Mechanisms linking dietary fiber, gut microbiota and colon cancer prevention. World Journal of Gastrointestinal Oncology. 2014; 6(2): p. 41-51.
5. Canani RB, Di Costanzo M, Leone L, Pedata M, Meli R, Calignano A. Potential beneficial effects of butyrate in intestinal and extraintestinal diseases. World Journal of Gastroenterology. 2011 March 28; 17(12): p. 1519-1528.
6. Bajkaa BH, Clarkea JM, Toppinga DL, Cobiacc L, Abeywardenaa MY, Patten GS. Butyrylated starch increases large bowel butyrate levels and lowers colonic smooth muscle contractility in rats. Nutrition Research. 2010; 30: p. 427-424.
7. McIntyre A, Gibson PR, Young GP. Butyrate production from dietary fibre and protection against large bowel cancer in a rat model. Gut. 1993; 34: p. 386-391.
8. Murphy MM, Douglass JS, Birkett A. Resistant starch intakes in the United States. J Am Diet Assoc. 2008 Jan;108(1):67–78.
9. Louis P, Young P, Holtrop G, Flint HJ. Diversity of human colonic butyrate-producing bacteria revealed by analysis of the butyryl-CoA:acetate CoA-transferase gene. Environ Microbiol. 2010 Feb;12(2):304–14.
