Diet, microbiota, and dysbiosis: a 'recipe' for colorectal cancer

Abstract

The food we consume feeds not only us, but also a vast and diverse community of microbiota within our gastrointestinal tract. In a process of symbiotic co-evolution, the gut microbiota became essential for the maintenance of the health and integrity of our colon. The advent of next-generation DNA sequencing technology and metabolic profiling have, in the recent years, revealed the remarkable complexity of microbial diversity and function, and that the microbiota produce a wide variety of bioactive products that are not only active at the mucosal surface, but also absorbed and circulated throughout the body, influencing distant organ health and function. As a result, several microbiota compositional patterns and their associations with both health and disease states have been identified. Importantly, a disturbed microbiota-host relationship, termed dysbiosis, is now recognized to be the root cause for a growing list of diseases, including colorectal cancer (CRC). There is mounting in vitro and in vivo evidence to suggest that diet selects for the microbiota composition and several health promoting and deleterious effects of diet are, in fact, mediated by the microbiota. Recent findings of the feasibility of dietary fiber to boost the colonic microbial synthesis of anti-proliferative and counter carcinogenic metabolites, particularly butyrate, underscores the prerequisite of dietary modification as a key measure to curb the pandemic of CRC in westernized countries. Better understanding of the diet-microbiota interplay and large-scale studies to evaluate the efficacy of dietary modification and gut microbiota modulation in reversing dysbiosis and restoring health could offer novel preventative and/or therapeutic strategies against westernized diseases, which are now considered the chief threat to public health.

Fig. 1

Distinct colonic microbial composition of African Americans (high CRC risk group) and native rural South Africans (low CRC risk group). Microbial composition was dominated by Bacteroides in the African Americans, which indicated that they belonged to enterotype 1, and was dominated by Prevotella in the native rural South Africans, which categorized them as enterotype 2 (10). AA, African American; CRC, colorectalcancer; NA, native African. Adapted with permission from “Junhai Ou, et al. Am. J. Clin. Nutr., 2013, 98, 111–120, American Society for Nutrition.”

Fig. 2

Dietary risk of CRC is mediated by dysbiosis of gut microbiota and their metabolites. Dietary fiber/complex carbohydrates promote saccharolytic fermentation yielding anti-inflammatory and antiproliferative SCFAs, such as butyrate, whereas, red meat generates inflammatory and genotoxic metabolites by promoting proteolytic fermentation, H₂S production from its sulfur-rich amino acid content, and exposing colonic mucosa to other carcinogenic constituents such as heme, nitrosamines, HCA, and PAH. High dietary fat promotes excess primary BA secretion and their conversion to pro-carcinogenic secondary bile acids (LCA, DCA). Dysbiosis, an imbalance between the ‘protective’ and ‘detrimental’ microbiota composition and their metabolic end-products results determines the risk of CRC. BA (bile acids), BCFA (branched-chain fatty acids), CH₄ (methane), DCA (deoxycholic acid), HCA (heterocyclic amines), H₂ (hydrogen), H₂S (hydrogen sulfide), LCA (lithocholic acid), PAH (polyaromatic hydrocarbons), short-chain fatty acids (SCFAs). (Original work).

Fig. 3

Colonic mucosal immunohistochemistry of proliferative and inflammatory biomarkers. Immunohistochemical analysis of colonic mucosal biopsies taken at colonoscopy with their associated quantitative analysis on the right panel. Decreased expression of the cancer biomarker – Ki67 staining of epithelial crypt cells (a) and inflammatory biomarkers – CD3⁺ staining (b) and CD68⁺ macrophages in the lamina propria (c) in an African American (the first and second panels) and reciprocal changes in a native/rural African (the third and 4th panels left to right) before and after dietary switch. The bar graphs on the far right summarize the group mean ± S.E. results in 20 African Americans and 12 rural Africans. The two-tailed Mann–Whitney U-test was used for comparisons for non-paired samples and the Wilcoxon rank sum test for paired samples, with Bonferroni correction for multivariate comparisons. Triangles indicate significant (P < 0.05) baseline differences and stars indicate significant changes induced by diet switch. Adapted with permission from Nat. Commun., 20156(Apr 28), 6342, DOI: 10.1038/ncomms7342”.