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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Bile acid-microbiota crosstalk in gastrointestinal inflammation and carcinogenesis.

Bacteria and ætiology of cancer of large bowel

Several studies have characterized the cellular and molecular mechanisms of hepatocyte injury caused by the retention of hydrophobic bile acids (BAs) in cholestatic diseases. BAs may disrupt cell membranes through their detergent action on lipid components and can promote the generation of reactive oxygen species that, in turn, oxidatively modify lipids, proteins, and nucleic acids, and eventually cause hepatocyte necrosis and apoptosis. Several pathways are involved in triggering hepatocyte apoptosis. Toxic BAs can activate hepatocyte death receptors directly and induce oxidative damage, thereby causing mitochondrial dysfunction, and induce endoplasmic reticulum stress. When these compounds are taken up and accumulate inside biliary cells, they can also cause apoptosis. Regarding extrahepatic tissues, the accumulation of BAs in the systemic circulation may contribute to endothelial injury in the kidney and lungs. In gastrointestinal cells, BAs may behave as cancer promoters through an indirect mechanism involving oxidative stress and DNA damage, as well as acting as selection agents for apoptosis-resistant cells. The accumulation of BAs may have also deleterious effects on placental and fetal cells. However, other BAs, such as ursodeoxycholic acid, have been shown to modulate BA-induced injury in hepatocytes. The major beneficial effects of treatment with ursodeoxycholic acid are protection against cytotoxicity due to more toxic BAs; the stimulation of hepatobiliary secretion; antioxidant activity, due in part to an enhancement in glutathione levels; and the inhibition of liver cell apoptosis. Other natural BAs or their derivatives, such as cholyl-N-methylglycine or cholylsarcosine, have also aroused pharmacological interest owing to their protective properties.

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Bile-acid-induced cell injury and protection

Bile acids were first proposed to be carcinogens in 1939 and 1940. On the basis of later work with rodent models, bile acids came to be regarded as cancer promoters rather than carcinogens. However, considerable indirect evidence, obtained more recently, supports the view that bile acids are carcinogens in humans. At least 15 reports, from 1980 through 2003, indicate that bile acids cause DNA damage. The mechanism is probably indirect, involving induction of oxidative stress and production of reactive oxygen species that then damage DNA. Repeated DNA damage likely increases the mutation rate, including the mutation rate of tumor suppressor genes and oncogenes. Additional reports, from 1994 through 2002, indicate that bile acids, at the increased concentrations accompanying a high fat diet, induce frequent apoptosis. Those cells within the exposed population with reduced apoptosis capability tend to survive and selectively proliferate. That bile acids cause DNA damage and may select for apoptosis-resistant cells (both leading to increased mutation), indicates that bile acids are likely carcinogens. In humans, an increased incidence of cancer of the laryngopharyngeal tract, esophagus, stomach, pancreas, the small intestine (near the Ampulla of Vater) and the colon are associated with high levels of bile acids. The much larger number of cell generations in the colonic (and, likely, other gastrointestinal) epithelia of humans compared to rodents may allow time for induction and selection of mutations leading to cancer in humans, although not in rodents.

Bile acids as carcinogens in human gastrointestinal cancers.

The promoting effect of sodium cholate or sodium chenodeoxycholate on colon carcinogenesis was studied in female F344 germ-free and conventional rats. Both germ-free and conventional rats received intrarectal instillations of N -methyl- N ′-nitro- N -nitrosoguanidine (MNNG) for 2 weeks (total dose, 8 mg/rat) and then intrarectal doses of sodium cholate or sodium chenodeoxycholate (20 mg/rat/dose) three times a week for 46 weeks; other groups received MNNG for 2 weeks and vehicle thereafter for 46 weeks or bile acids alone for 48 weeks. Sodium cholate or sodium chenodeoxycholate increased MNNG-induced adenocarcinomas and adenomas in germ-free rats, whereas in conventional rats these bile acids induced more adenomas. Conventional rats treated with MNNG + sodium cholate or MNNG + sodium chenodeoxycholate had a higher incidence ( p 0.05) frequency of colon tumors than did those given MNNG alone. No tumors were detected in the colons of germ-free and conventional rats given sodium cholate or sodium chenodeoxycholate alone. It is concluded that sodium cholate or sodium chenodeoxycholate had a promoting effect in colon carcinogenesis in rats evoked by MNNG.

https://cancerres.aacrjournals.org/content/canres/37/9/3238.full.pdf

Promoting Effect of Bile Acids in Colon Carcinogenesis in Germ-free and Conventional F344 Rats

J. W. COOK1 pointed out that the sterols and bile acids contain in their molecules condensed carbon-ring systems to which are attached a side-chain in such a position that a new 6-membered ring can be formed so as to give the 1: 2-benzanthracene ring system without molecular rearrangement or group migration. The bile acids of the higher vertebrates are all mono-, di-, or tri-hydroxy derivatives of cholanic acid, which compound can be obtained in vitrofrom sterols by degradation, and the principal bile acids bear the names of lithocholic acid (3-hydroxy-cholanic acid), deoxycholic acid (3: 12-dihydroxy-cholanic acid) and cholic acid (3: 7: 12-trihydroxy-cholanic acid). J. W. Cook and G. A. D. Haslewood in 19342 showed that, in the formation of dehydronor-cholene from deoxycholic acid by the procedure of Wieland, such a ring-closure to the 1: 2-benzanthra-cene ring system had actually occurred. Dehydronor-cholene gave on dehyclrogenation the benzanthracene hydrocarbon methylcholanthrene, which was found to be strongly carcinogenic. Afterwards, Fieser and Newman3 showed that methylcholanthrene could be obtained also from cholic acid, which is the chief acid of human bile, and the parent hydrocarbon cholanthrene was synthesized by J. W. Cook, G. A. D. Haslewood and A. M. Robinson4 and shown to be carcinogenic.

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E. L. Kennaway

Papers

Production of Tumours in Mice by Deoxycholic Acid