The gastrointestinal microbiota and colorectal cancer

Abstract

The human gut is home to a complex and diverse microbiota that contributes to the overall homeostasis of the host. Increasingly, the intestinal microbiota is recognized as an important player in human illness such as colorectal cancer (CRC), inflammatory bowel diseases, and obesity. CRC in itself is one of the major causes of cancer mortality in the Western world. The mechanisms by which bacteria contribute to CRC are complex and not fully understood, but increasing evidence suggests a link between the intestinal microbiota and CRC as well as diet and inflammation, which are believed to play a role in carcinogenesis. It is thought that the gut microbiota interact with dietary factors to promote chronic inflammation and CRC through direct influence on host cell physiology, cellular homeostasis, energy regulation, and/or metabolism of xenobiotics. This review provides an overview on the role of commensal gut microbiota in the development of human CRC and explores its association with diet and inflammation.

Keywords: bacterial metabolites; colorectal adenoma; diet; inflammation.

Fig. 1.

Mechanisms of gut microbiome to chronic inflammation, adenoma, and colorectal cancer (CRC). The gut microbiome involves several mechanisms to modulate colorectal carcinogenesis. Bacterial dysbiosis weakens the host defense mechanism of barrier function disruption of epithelial layer tight junctions and the mucus film covering. The action causes increased permeability of the intestinal epithelium and favors bacterial translocation through mucosal epithelium (173). Macrophages on recognition of microorganism-associated molecular patterns (MAMPs) expressed by commensal microbiota, through molecular pattern-recognition receptors (TLR), trigger various signal pathways to produce inflammatory responses (55, 96). Activation of nuclear factor-kB (NF-kB) pathways stimulates the transcription of proinflammatory genes, resulting in increased production of proinflammatory cytokines (TNF, IL-1, IL-23). Proinflammatory cytokines induce signal transducer and activation of transcription 3 (STAT3) and NF-κB signaling, which leads to the suppression of apoptosis and the promotion of cell cycle progression that progress to chronic inflammation and carcinogenic activity (52, 83, 105, 155). During chronic inflammation, there is an overall imbalance in the gut due to production of toxic chemicals or procarcinogens. The production of such chemicals as reactive oxygen species (ROS)/reactive nitrogen species (RNS) from inflammatory cells such as macrophages, as well as bacterial genotoxins (colibactin) and hydrogen sulfide (H₂S) from the bacteria, results in oxidative stress which in the target tissue exhorts DNA damage and upshoots DNA repair (46, 167). TLR, Toll-like receptor; T_H17, T helper 17; Th, T helper. STAT3, signal transducer and activator of transcription 3.

Fig. 2.

A: roles of various components of diet and bacteria in CRC. The principal components of diet intake are carbohydrates, protein, and fat, which undergo colonic bacterial digestion to generate byproducts that are shown to involve in CRC via various mechanism. Some gut bacteria such as Clostridium spp. convert primary bile acids (intermediate product of fat) into a secondary bile acid such as deoxycholic acid (DCA). DCA is widely considered as a carcinogen that is associated with DNA damage via the production of free radicals or ROS and further induce chronic inflammation and CRC (138). B: metabolism of complex carbohydrates and fibers by colonic bacteria produces the metabolites for the involvement of CRC inhibition. A wide variety of fermentable fibers in the diet include nonstarch polysaccharides (cellulose, pectins, gums, arabinoxylans, mucilages, insulin, galacto-oligosaccharides), carbohydrate fibers (resistant starches, dextrins), and lignans (waxes, tannins). Fermentation of these complex carbohydrates and fibers by gut bacteria results in the production of short-chain fatty acids (SCFAs) such as formic acid, acetic acid, propionic acid, butyric acid, and valeric acid. SCFAs promote large-bowel functions modulating colonic motility, promoting visceral blood flow, and preventing potential pathogen overgrowth (153, 158). Butyric acid or butyrate promotes colonic fermentation, lowers the absorption of procarcinogens, protects against inflammation, and reduces CRC risk (162). Butyrate can also act as a histone deactylase (HDAC), inhibiting the function of HDAC thereby favoring an acetylated state of histone in the cell (60). HDAC inhibition via SCFAs results in upregulation of p21, a key regulatory molecule of cell cycle arrest that is also involved in cell proliferation, differentiation, and apoptosis (27, 66). SCFAs enhance the barrier functions promoting epithelial cell attachment to the basement while suppressing type IV collagen activity. All these mechanisms involve maintaining gut homeostasis and CRC inhibition. C: breakdown of protein by colonic bacteria to potential carcinogenic metabolites and CRC. (modified from Ref. 89). The breakdown of proteins and peptides by colonic microorganisms also generate end products that are considered as procarcinogenic, mutagenic, and genotoxic besides health-benefiting SCFAs and energy. A variety of branched-chain fatty acids (BCFAs), such as isobutyrate, 2-methylbutyrate, and isovalerate, are usually one carbon shorter than their respective amino acid precursors valine, isoleucine, and leucine. The BCFAs are mainly produced in the colon via digestion by various gut bacteria; the major contributor is Clostridia (89). BCFAs are not considered to be risk factors for CRC. Ammonia, phenol, and H₂S produced during amino acid fermentation are putrefactive toxic substances. Amines (end product of amino acids via deamination) act as mutagen-precursors, and phenols and indoles act as procarcinogens (89). Thioles and H₂S, also numerously reported as genetoxic, can release ROS, damage host DNA, and induce CRC.