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Bile acid–microbiota crosstalk in gastrointestinal inflammation and carcinogenesis

Key Points

  • Bile acids are critical components of the gastrointestinal tract that link the gut microbiota to hepatic and intestinal metabolism and therefore influence gastrointestinal motility, intestinal permeability and carcinogenesis

  • The gut microbiota regulates bile acid production and signalling via the biotransformation of intestinal bile acids to unconjugated and secondary forms that readily activate bile acid receptors

  • Bile acids are ligands for the G protein-coupled bile acid receptor 1 (TGR5) and for the nuclear hormone receptor farnesoid X receptor (FXR)

  • The profiles of bile acids and gut microbiota influence each other; bile acids can modulate microbiota composition, which in turn regulates the size and composition of the bile acid pool

  • Disruption of bile acid–microbiota crosstalk promotes inflammation and a gastrointestinal disease phenotype, which can contribute to the development of gastrointestinal cancers, including colorectal cancer and hepatocellular carcinoma

  • The modulation of gut microbiota and bile acid profiles holds promise as a novel therapeutic approach for the treatment of gastrointestinal cancers and represents the next frontier for gastrointestinal cancer research

Abstract

Emerging evidence points to a strong association between the gut microbiota and the risk, development and progression of gastrointestinal cancers such as colorectal cancer (CRC) and hepatocellular carcinoma (HCC). Bile acids, produced in the liver, are metabolized by enzymes derived from intestinal bacteria and are critically important for maintaining a healthy gut microbiota, balanced lipid and carbohydrate metabolism, insulin sensitivity and innate immunity. Given the complexity of bile acid signalling and the direct biochemical interactions between the gut microbiota and the host, a systems biology perspective is required to understand the liver–bile acid–microbiota axis and its role in gastrointestinal carcinogenesis to reverse the microbiota-mediated alterations in bile acid metabolism that occur in disease states. An examination of recent research progress in this area is urgently needed. In this Review, we discuss the mechanistic links between bile acids and gastrointestinal carcinogenesis in CRC and HCC, which involve two major bile acid-sensing receptors, farnesoid X receptor (FXR) and G protein-coupled bile acid receptor 1 (TGR5). We also highlight the strategies and cutting-edge technologies to target gut-microbiota-dependent alterations in bile acid metabolism in the context of cancer therapy.

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Figure 1: Bile acid biosynthesis, transport and metabolism.
Figure 2: Enterohepatic circulation of bile acids under normal physiological conditions and during dysbiosis and inflammation.
Figure 3: Bile acid-induced hepatic inflammation and carcinogenesis.
Figure 4: Bile-acid-induced TGR5 signalling pathways in macrophages.
Figure 5: Effects of intestinal bile acids on colorectal carcinogenesis.

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Acknowledgements

Wei J. and G.X. are supported by grants from the US NIH (1U01CA188387-01A1).

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Wei J. and G.X. researched data for the article and wrote the article. Wei J., G.X. and Weiping J. made substantial contributions to discussion of content and reviewed/edited the manuscript before submission.

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Glossary

Hypochlorhydria

A deficiency of hydrochloric acid in the stomach.

Enterotoxigenic bacteria

Bacteria that cause disease in humans and domestic animals by producing enterotoxin.

Enterohepatic circulation

The circulation of bile salts, bilirubin, drugs or other substances from the liver to the bile, followed by entry into the small intestine, absorption by enterocytes and return to the liver via the portal circulation.

Bile canaliculus

A thin tube that collects bile secreted by hepatocytes.

Lithogenic diet

A diet designed to increase the likelihood of stone formation, particularly gallstones.

Senescence-associated secretory phenotype

A phenotype in which cells induced to senesce by genotoxic stress secrete pro-inflammatory cytokines, chemokines, and proteases associated with inflammation and malignancy.

Primary biliary cholangitis

A type of liver disease caused by damage to the bile ducts in the liver.

Primary sclerosing cholangitis

A chronic liver disease characterized by a progressive course of cholestasis with inflammation and fibrosis of the intrahepatic and extrahepatic bile ducts.

Hyperammonaemia

A metabolic disturbance characterized by an excess of ammonia in the blood.

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Jia, W., Xie, G. & Jia, W. Bile acid–microbiota crosstalk in gastrointestinal inflammation and carcinogenesis. Nat Rev Gastroenterol Hepatol 15, 111–128 (2018). https://doi.org/10.1038/nrgastro.2017.119

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