Bile acids as carcinogens in the colon and at other sites in the gastrointestinal system

Abstract

Colon cancer incidence is associated with a high-fat diet. Such a diet is linked to elevated levels of bile acids in the gastrointestinal system and the circulation. Secondary bile acids are produced by microorganisms present at high concentrations in the colon. Recent prospective studies and a retrospective study in humans associate high circulating blood levels of secondary bile acids with increased risk of colon cancer. Feeding mice a diet containing a secondary bile acid, so their feces have the bile acid at a level comparable to that in the feces of humans on a high-fat diet, also causes colon cancer in the mice. Studies using human cells grown in culture illuminate some mechanisms by which bile acids cause cancer. In human cells, bile acids cause oxidative stress leading to oxidative DNA damage. Increased DNA damage increases the occurrence of mutations and epimutations, some of which provide a cellular growth advantage such as apoptosis resistance. Cells with such mutations/epimutations increase by natural selection. Apoptosis, or programmed cell death, is a beneficial process that eliminates cells with unrepaired DNA damage, whereas apoptosis-resistant cells are able to survive DNA damage using inaccurate repair processes. This results in apoptosis-resistant cells having more frequent mutations/epimutations, some of which are carcinogenic. The experiments on cultured human cells have provided a basis for understanding at the molecular level the human studies that recently reported an association of bile acids with colon cancer, and the mouse studies showing directly that bile acids cause colon cancer. Similar, but more limited, findings of an association of dietary bile acids with other cancers of the gastrointestinal system suggest that understanding the role of bile acids in colon carcinogenesis may contribute to understanding carcinogenesis in other organs.

Keywords: Carcinogenesis; DNA damage; apoptosis; gastrointestinal cancer; oxidative stress.

Figure 1.

Colonic crypts in epithelium from two mice. (a) Photomicrograph of tissue from a mouse fed a standard diet. Scale bar: 50 μm. (b) Photomicrograph of tissue from a mouse fed a diet supplemented with deoxycholate. Scale bar: 50 μm. Cell nuclei are stained dark blue with hematoxylin (for nucleic acid) and immunostained brown for 8-OHdG. The level of 8-OHdG was graded in the nuclei of colonic crypt cells on a scale of 0–4. Mice fed standard diet had crypt 8-OHdG at levels 0 to 2 ((a) level 1) while mice fed diet supplemented with deoxycholate had 8-OHdG in colonic crypts at levels 3 and 4 ((b) level 4). Deoxycholate added to the mouse diet gave a concentration of deoxycholate in the mouse colon similar to the concentration in the colon of humans on a high-fat diet. (A color version of this figure is available in the online journal.) Source: Modified from Chaya5260 CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=41679524.

Figure 2.

A colon cancer within a field defect in which four precancerous polyps are also arising. This was a patient with sporadic colon cancer. (A color version of this figure is available in the online journal.) Source: Part of Bernstein0275 CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?>curid=25453056.

Figure 3.

Initiation of DNA demethylation at a CpG site. In adult somatic cells, DNA methylation typically occurs in the context of CpG dinucleotides (CpG sites), forming 5-methylcytosine-pG, or 5mCpG. Reactive oxygen species (ROS) may attack guanine at the dinucleotide site, forming 8-hydroxy-2’-deoxyguanosine (8-OHdG) and resulting in a 5mCp-8-OHdG dinucleotide site. The base excision repair enzyme OGG1 targets 8-OHdG and binds to the lesion without immediate excision. OGG1 present at a 5mCp-8-OHdG site recruits TET1, and TET1 oxidizes the 5mC adjacent to the 8-OHdG. This initiates demethylation of 5mC. (A color version of this figure is available in the online journal.) Source: Bernstein0275, CC BY-SA 4.0 https://creativecommons.org/licenses/by-sa/4.0.