Diet, microorganisms and their metabolites, and colon cancer

Abstract

Colorectal cancer is one of the so-called westernized diseases and the second leading cause of cancer death worldwide. On the basis of global epidemiological and scientific studies, evidence suggests that the risk of colorectal cancer is increased by processed and unprocessed meat consumption but suppressed by fibre, and that food composition affects colonic health and cancer risk via its effects on colonic microbial metabolism. The gut microbiota can ferment complex dietary residues that are resistant to digestion by enteric enzymes. This process provides energy for the microbiota but culminates in the release of short-chain fatty acids including butyrate, which are utilized for the metabolic needs of the colon and the body. Butyrate has a remarkable array of colonic health-promoting and antineoplastic properties: it is the preferred energy source for colonocytes, it maintains mucosal integrity and it suppresses inflammation and carcinogenesis through effects on immunity, gene expression and epigenetic modulation. Protein residues and fat-stimulated bile acids are also metabolized by the microbiota to inflammatory and/or carcinogenic metabolites, which increase the risk of neoplastic progression. This Review will discuss the mechanisms behind these microbial metabolite effects, which could be modified by diet to achieve the objective of preventing colorectal cancer in Western societies.

Figure 1 |. Geographical variation in colorectal cancer rates.

Data from the WHO demonstrating the high incidence of colorectal cancer (CRC) in westernized countries in a | men and b | women. Reprinted from GLOBOCAN 2012, v1.0, Ferlay, J. et al., Cancer incidence and mortality worldwide: International Agency for Research on Cancer CancerBase No. 11 http://globocan.iarc.fr/Pages/factsheetscancer.aspx?cancer=colorectal (2013).

Figure 2 |. Importance of dietary residues and the colonic microbiota in determining colon cancer risk.

In health, >90% of a normal diet is absorbed in the small intestine and nutrients are distributed to maintain general body health. Residues entering the colon are chiefly complex carbohydrates (fibre), but also contain protein residues and primary bile acids secreted by the liver in response to fat ingestion. These residues have a critical role in the maintenance of colonic health as they determine the composition and metabolic activity of the colonic microbiota which, through fermentation, maintain mucosal and colonic health. With a balanced diet, saccharolytic fermentation of carbohydrates is dominant, producing short-chain fatty acids, particularly butyrate, which is the preferred energy source for colonocytes and has anti-inflammatory and antineoplastic properties through actions shown. With an imbalanced high-fat, high-meat, low-fibre diet, the proinflammatory and proneoplastic properties of protein fermentation and bile acid deconjugated residues predominate, leading to increased colon cancer risk.

Figure 3 |. Key metabolic pathways of the colonic microbiota.

Through the process of fermentation, these metabolic pathways culminate with the production and release of the major short-chain fatty acids (acetate, propionate and butyrate) and phytochemicals from plant cell walls. Note that there are two microbial enzymes that are responsible for the final synthesis of butyrate, namely butyryl-CoA transferase (dominant, formed by a variety of genera and species) and butyrate kinase (favoured in proteolytic fermentation). Also shown is the pathway for converting the amino acid lysine into butyrate, which also generates ammonia. The main propionate production pathway is the succinate pathway. Bacterial species found to use certain pathways are shown but are not exhaustive. The asterix indicates species shown to use lactate to form butyrate.