Microbial Metabolite Dysbiosis and Colorectal Cancer

Abstract

The global burden of colorectal cancer (CRC) is expected to continuously increase. Through research performed in the past decades, the effects of various environmental factors on CRC development have been well identified. Diet, the gut microbiota and their metabolites are key environmental factors that profoundly affect CRC development. Major microbial metabolites with a relevance for CRC prevention and pathogenesis include dietary fiber-derived short-chain fatty acids, bile acid derivatives, indole metabolites, polyamines, trimethylamine-N-oxide, formate, and hydrogen sulfide. These metabolites regulate various cell types in the intestine, leading to an altered intestinal barrier, immunity, chronic inflammation, and tumorigenesis. The physical, chemical, and metabolic properties of these metabolites along with their distinct functions to trigger host receptors appear to largely determine their effects in regulating CRC development. In this review, we will discuss the current advances in our understanding of the major CRC-regulating microbial metabolites, focusing on their production and interactive effects on immune responses and tumorigenesis in the colon.

Keywords: Colonic neoplasms; Inflammation; Intestine; Microbial metabolites; Microbiome.

Fig. 1

Major metabolites produced by the gut microbiota. (A) Non-digestible carbohydrates are metabolized to the short-chain fatty acids, acetate, propionate, and butyrate. (B) Primary bile acids are conjugated in several different forms and secreted into the intestine. Gut bacteria deconjugate and further modify primary bile acids by 7α-dehydroxylation to produce secondary bile acids, such as deoxycholic acid and lithocholic acid. (C) Arginine is converted to polyamines by host and bacterial enzymes. Polyamines are also present in diets. (D) Tryptophan metabolites are produced via four different pathways: The serotonin pathway, the tryptamine pathway, the kynurenine pathway, and the bacterial indole pathway. (E) Degradation of cysteine to pyruvate produces hydrogen sulfate (H₂S). (F) The animal meat-derived metabolites carnitine, choline, or phosphocholine (PC) are degraded by gut bacteria to trimethylamine (TMA), which is further metabolized in the liver to trimethylamine N-oxide (TMAO).

Fig. 2

Basic functions and host receptors of microbial metabolites. Dietary or host-derived molecules are converted by the gut microbiota to microbial metabolites that act on host receptors or are utilized by the host. Thereby, microbial metabolites regulate host metabolism, gene expression and signaling pathways. G-protein coupled receptors (GPRs) that sense short-chain fatty acids (SCFAs) include GPR43, GPR41, GPR109A, and Olfr78. The solute carriers that transport SCFAs across the cell membrane include SLC16A1, SLC16A3, SLC5A8, and SLC5A12. The receptors for the microbial metabolites are distinctively expressed depending on cell their types (i.e., epithelial cells, macrophages, endothelial cells, T cells etc.), and the effects of the metabolites on different cell types can be distinct. SLC, solute carrier family proteins; PPARγ, peroxisome proliferator-activated receptor γ; HDACs, histone deacetylases; TGR5, G protein-coupled bile acid receptor 1; PXR, pregnane X receptor; FXR, farnesoid X receptor; VDR, vitamin D receptor; AhR, aryl hydrocarbon receptor; PC, phosphocholine; TMA, trimethylamine; TMAO, trimethylamine-N-oxide; NLRP3, NLR family pyrin domain containing 3; ROS, reactive oxygen species.

Fig. 3

Impact of microbial balance and dysbiosis on cell functions and colorectal cancer development. The risk for developing colorectal cancer is influenced by the concentrations and relative balance between the protective (butyrate, indoles, and UDCA) and potentially harmful (DCA, formate, TMAO, polyamines, and H₂S) metabolites produced by the gut microbiota. The absolute and relative levels of these metabolites in the gut and tissues are determined by diet, microbial composition, other lifestyle factors and underlying health conditions. Metabolite dysbiosis undermines tissue and immune cell homeostasis and barrier immunity and affects cell growth, leading to microbial invasion, inflammation, and tumorigenesis. UDCA, ursodeoxycholic acid; DCA, deoxycholic acid; TMAO, trimethylamine-N-oxide; H₂S, hydrogen sulfate.