Gut microbiota-derived metabolites and colorectal cancer: New insights and updates
Introduction
The human gut microbiota is composed of a variety of microorganisms that contribute to the host's health, physiology, and disease by synthesizing unique enzymes and through biochemical pathways relating to their versatile metabolic genes [1]. Several studies showed that diet has predominant role in formation of gut microbiota composition. Host diet impacts the gut microbial community and their metabolites (protective or harmful), making microbes a link between diet and different physiological states of host. It is assumed that colorectal cancer (CRC) may be closely correlated with dietary regime and life style of the patients [2,3].
Scientific evidences suggest that the innate immune cells can translate the signals and metabolites from gut microbiota into physiological responses [4]. Consistent with this finding, the more studies revealed that the gut microbiota and their metabolites strongly influence the host's immune system [5]. Multiple studies have shown that metabolites such as butyrate, propionate, acetate, and niacin contribute to protection of host against CRC, compared to metabolites like secondary bile acids, lactate, trimethylamine N-oxide (TMAO), N-nitroso compounds (NOC), Acetaldehyde, 4-hydroxyphenylacetic acid (HO-PAA), Phenylacetic acid (PAA), phenol, and bacterial toxin, which are correlated with CRC development (Fig. 1). Our current knowledge supports the idea that cross talk between the host, gut microbiota, and their metabolites can offer an innovative strategy for prevention and control of several diseases and cancers [6]. In this review, we will discuss about the current understanding of the role of specialized gut microbiota-derived metabolites on various aspects of immunity and cancer with a special focus on CRC.
Section snippets
Search strategy
We conducted a comprehensive search strategy of the literatures to review best available evidence and identify studies relevant to this review. We searched PubMed, Web of Science, Scopus, and Google Scholar for available papers on this subject with the following search terms: gut microbiota, metabolites, short-chain fatty acids (SCFAs), butyrate, propionate, acetate, bile acid, lactate, succinate, protein-derived metabolites, TMAO, NOC, bacterial toxin, niacin, diet, CRC, and the results were
Short-chain fatty acids (SCFAs)
The most important fermentative products of microbial activity in the gut are SCFAs containing butyrate, propionate, and acetate [7]. It was shown that bacterial fermentation of complex non-digestible polysaccharide can produce SCFAs through distinct pathways [8]. Also, it is reported that the number of SCFA-producing bacteria in mice treated with a high-fiber was higher than that in mice treated with low-fiber [9]. G protein-coupled receptors (GPR) such as GPR40, GPR41, GPR43, and GPR109A are
Butyrate
Butyrate is undeniably the most important SCFA. Butyrate activates GPR109A and inhibits the protein kinase B or Akt (PKB/Akt) and nuclear transcription factor-kappa beta p65 (NF-κB) signaling pathways to improve the intestinal epithelium barrier dysfunction and inflammatory response [18]. Growing evidence has demonstrated the positive role of butyrate in suppressing the expression of the essential molecules for gut homeostasis such as indoleamine 2, 3-dioxygenase-1 (IDO-1) by two separate
Propionate
Propionate can show an equivalent influence as butyrate as an anti-inflammatory agent in the gut and in colon cancer [30]. Accumulating in-vitro and in-vivo evidence has indicated that propionate as well as butyrate could directly increase the expression of gene related to Tc17 cells and CD8+ CTLs and promote antitumor effects [20]. Remarkably, Furusawa et al. showed that butyrate and propionate play critical roles in controlling intestinal inflammation by stimulating the differentiation of
Acetate
Acetate is one of the most abundant produced SCFA, followed by propionate and butyrate. There are few studies on acetate regarding its implication in CRC as compared to butyrate and propionate. Therefore, the exact mechanism of anti-inflammatory effect of acetate on CRC development is poorly understood. One study demonstrated that by increasing the expression of anti-inflammatory cytokine and reducing the generation of pro-inflammatory factors and NF-κB pathway in CRC cells, acetate can inhibit
Bile acid
Another important metabolite of gut microbiota is bile acids, which can be classified into two groups: i-primary bile acids; ii-secondary bile acids. The interaction between primary bile acid like cholic acid (CA) and gut microbiota can transform it into secondary bile acids like lithocholic acid (LCA) and deoxycholic acid (DCA). Secondary bile acids are increase due to intake of high-fat diets and can prompt the development of CRC. The association between bile acids and gut microbiota was
Lactate
Lactate is an intermediate and/or terminal metabolite produced by the gut microbiota. Based on the angiogenic effect of lactate, the delivery of nutrients and growth factors to the tumor microenvironment (TME) can be related to the functions of glycolytic tumor cells [52]. In this way, lactate can promote tumor invasion by providing environmental conditions through acidification of TME [53]. Moreover, it can stimulate angiogenic responses for transferring oxygen, glucose, and other nutrients to
Succinate
Another intermediate metabolite of the gut microbiota is succinate, which can be significantly produced by gut microbiota during fermentation of dietary fiber. At present, there is both supporting and conflicting literature focused on the role of succinate in the regulation of cancerous cell and CRC. The in-vitro and ex-vivo results have shown that polyphenols can result in high amounts of succinate production in the cecum and impact CRC by inhibiting the growth and proliferation of colon
Protein-derived metabolites
Fermentation of protein by the gut microbiota produces numerous amino acid metabolites. Hydrogen sulfide (H2S) is one of the amino acid derived metabolites which has usually been used as an energy source for colonic epithelial metabolism. The evidence outlining the effects of H2S on CRC has been summarized in a few studies. Interestingly, high concentration of H2S in the colon due to consumption of high protein diet (HPD) can form the adaptive response in colonocytes by stimulating the
Trimethylamine-N-oxide (TMAO)
Another intestinal microbiota-dependent metabolite is TMAO that can play an important role in the development of CRC by reacting with flavin monooxygenase (FMO) [70]. In accordance with the results obtained by Xu et al. the relationship between CRC risk and plasma factors of choline metabolism showed that TMAO is a potential indicator of CRC [71]. Although its molecular function still remains to be identified.
N-nitroso compounds (NOC)
Consumptions of high red meats and/or processed meats diet as primary source of protein and other nitrogenous residues have been previously shown as a risk factor for development of CRC. It is well known that host diet with high-protein content can increase the production of NOC by gut microbiota. Taken together, NOC by G—>A transitions in K-ras gene could mediate the progression of CRC [72]. It is generally accepted notion that activated human neutrophils could produce NOC during chronic
Bacterial toxin
Microbes can promote cancer by producing toxic metabolites or carcinogenic products that increase disease incidences and susceptibility. Bacterial toxin is another type of CRC-related metabolite which can be produced by gut microbiota such as Bacteroides fragilis (B. fragilis) and Escherichia coli (E. coli). The B. fragilis toxin plays an important role in the development of CRC through several mechanisms such as activation of β-catenin signaling and E-cadherin cleavage, induction of NF-κB
Niacin
Niacin is another bacterial product that can inhibit inflammation and tumorigenesis by connecting to the GPR109A. The valuable effect of niacin was discovered by Singh et al. in an in-vivo study, showing its role in the induction of anti-inflammatory activities in macrophages and dendritic cells and also in differentiation of Treg and IL-10-producing T cells is possible through GPR109A signaling. The end result is suppression of inflammation and tumor progression [87]. Confirming these results,
Correlation between gut microbiota-derived metabolites, diet, and CRC
Over recent years, it is generally accepted that there is an obvious relationship between the gut microbiota composition and their metabolites, diet, and the risk of CRC (Table 1). Dietary fibers are commonly indigestible complex carbohydrates for the host, which can be fermented by gut bacteria into SCFA [89]. In recent years, studies have aimed to address how fibers or fat alone or combined with each other can affect CRC risk. In this respect, an elegant clinical trial has found that higher
Potential role of the gut microbiota-derived metabolites in the early screening of CRC
Apart from mechanistic evaluation of the gut microbiota-derived metabolites, in terms of CRC detection, several metabolomics studies strongly supported the association between the levels of metabolites present in the gut and progression of CRC. Data proved that suitable CRC screening through identification and elimination of precancerous lesions can potentially result in early detection and reduction of incidence and mortality rates of CRC. Based on the recommendations from the American Cancer
Perspectives and future directions
It is now becoming apparent that the gut microbiota-derived metabolites have a significant role in host physiology and CRC. Over the past decades, elegant experiments exploiting the effect of the gut microbiota-derived metabolites on the intestine found that changing the eating habits could result in the progression or reduction of CRC. Metabolically, SCFAs as well as niacin cause opposing effects compared to secondary BAs, lactate, TMAO, and NOC on the course of colonic inflammation and CRC,
Conclusion
Recent researches have begun to focus attention on the role of gut microbiota-derived metabolites in the development, prevention, and screening of CRC. Dysbiosis is characterized by starvation of the gut microbiota which can be caused by dietary imbalance. This leads to increased incidences of CRC as a consequence of secondary bile acid and/or bacterial toxin production by gut microbiota. Contrastingly, gut microbiota-derived SCFAs have been shown to have inhibitory impacts on colonic
Funding/support
This work was supported by the National Science Foundation of China (grant number 81972315).
Authors' contributions
All the authors equally contributed to this work. Also, all authors read and approved the final manuscript.
Declaration of competing interest
The authors declare no conflicts of interest with respect to authorship and publication of this article.
Acknowledgements
We apologize to researchers whose work was not cited because of limitations for publication.
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