Research Article: Promotion and induction of liver cancer by gut microbiome-mediated modulation of bile acids

Date Published: September 5, 2019

Publisher: Public Library of Science

Author(s): Baolei Jia, Che Ok Jeon, June L. Round.

http://doi.org/10.1371/journal.ppat.1007954

Abstract

Partial Text

The human gastrointestinal tract is colonized by a complex and dynamic range of symbiotic microorganisms, collectively termed the gut microbiome, which defends the human host against pathogens and maintains metabolic homeostasis and immune balance [1]. However, although the gut microbiome directly benefits the host, it is also involved in the development of diseases [2], and there is mounting evidence of its contribution to both local and distant carcinogenesis in humans and animal models [3]. Local bacterial–induced carcinogenesis (i.e., gastrointestinal carcinogenesis) is exemplified by the induction of gastric cancer by Helicobacter pylori through its secretion of the virulence factor cytotoxin-associated gene A (CagA) [4]. Another example is that gut commensal Escherichia coli (pks+) and other Proteobacteria that produce colibactin promote colon cancer development [5]. In contrast, distal bacterial–induced carcinogenesis affects extraintestinal organs such as the liver, heart, adipose tissue, pancreas, lungs, brain, and cardiovascular system [6]. The liver, being closely connected to the gut via the hepatic portal vein, is the first recipient of gut microbiome metabolites and antigens, including bile acids (BAs), lipopolysaccharide (LPS), choline, indole derivatives, and short-chain fatty acids [7].

Recent studies have demonstrated direct associations between the gut microbiome, secondary BAs, immune system, and liver cancer [10, 11, 13]. Two pathways through which the gut microbiome regulates liver cancer via secondary BAs have been described, as shown in Fig 1. To elucidate the pathway of secondary BA-mediated tumor progression through suppression of antitumor immunity, the obesity-associated HCC model was used [11]. The population of Clostridium cluster XI was strikingly increased in the mice model [13]. Further, Ma and colleagues used WT mice induced by tumor cell injection or spontaneously HCC-induced MYC transgenic mice to study the regulation of live cancer by BAs via NKT cells [10]. The study showed that C. scindens colonization in the gut reduced the amount of hepatic NKT cells and promoted liver tumor growth in the mice injected with tumor cells [10]. Furthermore, Singh and colleagues recently demonstrated that clostridia, including Clostridium cluster XIVa, were enriched in the gut of T5KO mice with pre-existing microbiota dysbiosis fed fermentable fiber-enriched compositionally defined diets [12]. These studies imply that the liver cancer–promoting effect of clostridia is conditioned and may be related to the specific mouse model or presence of gut dysbiosis. Further, cohousing of the dysbiotic T5KO mice with WT mice demonstrated that the oncogenic bacteria could be transmitted to susceptible mice [12]. On the basis of these findings, we propose that Clostridium species harboring the bai operon and other related strains should be considered oncogenic microbiota capable of promoting and/or inducing liver cancer.

 

Source:

http://doi.org/10.1371/journal.ppat.1007954

 

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