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Influence of Bile Acids on Colorectal Cancer Risk: Potential Mechanisms Mediated by Diet-Gut Microbiota Interactions

  • Cancer (MF Leitzmann, Section Editor)
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Abstract

Purpose of Review

The purpose of this study is to review the evidence for the tumorigenic effects of food-stimulated bile acids on the colon and interaction with the gut microbiota.

Recent Findings

High-fat diets promote the hepatic synthesis of bile acids and increase their delivery to the colonic lumen. Here, they stimulate the growth and activity of 7α-dehydroxylating bacteria, which convert primary into secondary bile acids that show tumorigenic activity, especially deoxycholic acid (DCA). Fecal levels of secondary bile acids correlate with mucosal and metabolic markers of colorectal cancer (CRC) risk in high- and low-risk adult individuals and can be modified within a few weeks by dietary change. While gut bacteria regulate the bile acid pool via complex microbial biotransformation, bile acids alter the gut microbiota composition due to their antimicrobial properties. This mutual reaction induces altered bile acid pools and dysbiotic compositions of the gut microbiota that may show tumor-promoting activity of bile acids beyond their conversion to DCA.

Summary

Bile acids act as tumor promoters in the colon. Diet and the gut microbiota are most likely the key drivers that mediate and confer bile acid-associated tumorigenic activity. Bacterial conversion of bile acids in the colon has a significant impact on their tumorigenic activity, substantiating the hypothesis that diet affects CRC risk through its effects on colonic microbial metabolism.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136:E359–86.

    Article  CAS  PubMed  Google Scholar 

  2. Jasperson KW, Tuohy TM, Neklason DW, Burt RW. Hereditary and familial colon cancer. Gastroenterology. 2010;138:2044–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Doll R, Peto R. The causes of cancer: quantitative estimates of avoidable risks of cancer in the United States today. J Natl Cancer Inst. 1981;66:1191–308.

    Article  CAS  PubMed  Google Scholar 

  4. World Cancer Research Fund/American Institute for Cancer Research (2011) Continuous update project report. Food, Nutrition, Physical Activity, and the Prevention of Colorectal Cancer.

  5. Hofmann AF. The continuing importance of bile acids in liver and intestinal disease. Arch Intern Med. 1999;159:2647–58.

    Article  CAS  PubMed  Google Scholar 

  6. Ridlon JM, Kang D-J, Hylemon PB. Bile salt biotransformations by human intestinal bacteria. J Lipid Res. 2006;47:241–59.

    Article  CAS  PubMed  Google Scholar 

  7. Hill MJ, Drasar BS, Hawksworth G, Aries V, Crowther JS, Williams RE. Bacteria and aetiology of cancer of large bowel. Lancet Lond Engl. 1971;1:95–100.

    Article  CAS  Google Scholar 

  8. Reddy BS, Wynder EL. Large-bowel carcinogenesis: fecal constituents of populations with diverse incidence rates of colon cancer. J Natl Cancer Inst. 1973;50:1437–42.

    Article  CAS  PubMed  Google Scholar 

  9. Reddy BS. Role of bile metabolites in colon carcinogenesis. animal models. Cancer. 1975;36:2401–6.

    Article  CAS  PubMed  Google Scholar 

  10. Reddy BS, Wynder EL. Metabolic epidemiology of colon cancer. fecal bile acids and neutral sterols in colon cancer patients and patients with adenomatous polyps. Cancer. 1977;39:2533–9.

    Article  CAS  PubMed  Google Scholar 

  11. Imray CH, Radley S, Davis A, Barker G, Hendrickse CW, Donovan IA, et al. Faecal unconjugated bile acids in patients with colorectal cancer or polyps. Gut. 1992;33:1239–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ou J, DeLany JP, Zhang M, Sharma S, O’Keefe SJD. Association between low colonic short-chain fatty acids and high bile acids in high colon cancer risk populations. Nutr Cancer. 2012;64:34–40.

    Article  CAS  PubMed  Google Scholar 

  13. Ou J, Carbonero F, Zoetendal EG, DeLany JP, Wang M, Newton K, et al. Diet, microbiota, and microbial metabolites in colon cancer risk in rural Africans and African Americans. Am J Clin Nutr. 2013;98:111–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. •• O’Keefe SJD, Li JV, Lahti L, et al. Fat, fibre and cancer risk in African Americans and rural Africans. Nat Commun. 2015;6:6342. This publication shows how high-fat or high-fiber diets correlate with mucosal, microbial, and metabolic markers associated with colorectal cancer risk in humans. It provides evidence that directed dietary changes (diet switch from high-fat/low-fiber to low-fat/high-fiber diet and vice versa) have significant impact on colorectal cancer risk in humans.

    Article  PubMed  PubMed Central  Google Scholar 

  15. O’Keefe SJD. Diet, microorganisms and their metabolites, and colon cancer. Nat Rev Gastroenterol Hepatol. 2016;13:691–706.

    Article  PubMed  Google Scholar 

  16. Donohoe DR, Holley D, Collins LB, et al. A gnotobiotic mouse model demonstrates that dietary fiber protects against colorectal tumorigenesis in a microbiota- and butyrate-dependent manner. Cancer Discov. 2014;4:1387–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. • Schulz MD, Atay C, Heringer J, et al. High-fat-diet-mediated dysbiosis promotes intestinal carcinogenesis independently of obesity. Nature. 2014;514:508–12. This publication evaluates how high-fat diet-mediated alterations of the gut microbiota impact on intestinal tumorigenesis in a mouse model genetically susceptible to tumor formation in the small intestine.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Islam KBMS, Fukiya S, Hagio M, Fujii N, Ishizuka S, Ooka T, et al. Bile acid is a host factor that regulates the composition of the cecal microbiota in rats. Gastroenterology. 2011;141:1773–81.

    Article  CAS  PubMed  Google Scholar 

  19. Higashimura Y, Naito Y, Takagi T, et al. Protective effect of agaro-oligosaccharides on gut dysbiosis and colon tumorigenesis in high-fat diet-fed mice. Am J Physiol Gastrointest Liver Physiol. 2016;310:G367–75.

    Article  PubMed  Google Scholar 

  20. Lechner S, Müller-Ladner U, Schlottmann K, Jung B, McClelland M, Rüschoff J, et al. Bile acids mimic oxidative stress induced upregulation of thioredoxin reductase in colon cancer cell lines. Carcinogenesis. 2002;23:1281–8.

    Article  CAS  PubMed  Google Scholar 

  21. Dvorak K, Payne CM, Chavarria M, et al. Bile acids in combination with low pH induce oxidative stress and oxidative DNA damage: relevance to the pathogenesis of Barrett’s oesophagus. Gut. 2007;56:763–71.

    Article  CAS  PubMed  Google Scholar 

  22. Bayerdörffer E, Mannes GA, Richter WO, Ochsenkühn T, Wiebecke B, Köpcke W, et al. Increased serum deoxycholic acid levels in men with colorectal adenomas. Gastroenterology. 1993;104:145–51.

    Article  PubMed  Google Scholar 

  23. Narisawa T, Magadia NE, Weisburger JH, Wynder EL. Promoting effect of bile acids on colon carcinogenesis after intrarectal instillation of N-methyl-N’-nitro-N-nitrosoguanidine in rats. J Natl Cancer Inst. 1974;53:1093–7.

    Article  CAS  PubMed  Google Scholar 

  24. Flynn C, Montrose DC, Swank DL, Nakanishi M, Ilsley JNM, Rosenberg DW. Deoxycholic acid promotes the growth of colonic aberrant crypt foci. Mol Carcinog. 2007;46:60–70.

    Article  CAS  PubMed  Google Scholar 

  25. Bernstein C, Holubec H, Bhattacharyya AK, Nguyen H, Payne CM, Zaitlin B, et al. Carcinogenicity of deoxycholate, a secondary bile acid. Arch Toxicol. 2011;85:863–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Yoshimoto S, Loo TM, Atarashi K, et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature. 2013;499:97–101.

    Article  CAS  PubMed  Google Scholar 

  27. • Raufman J-P, Dawson PA, Rao A, Drachenberg CB, Heath J, Shang AC, et al. Slc10a2-null mice uncover colon cancer-promoting actions of endogenous fecal bile acids. Carcinogenesis. 2015;36:1193–200. This study evaluates the role of bile acids in colorectal cancer using a mouse model with increased fecal excretion of endogenous bile acids, highlighting their role as tumor-promoting agents.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Dawson PA, Haywood J, Craddock AL, Wilson M, Tietjen M, Kluckman K, et al. Targeted deletion of the ileal bile acid transporter eliminates enterohepatic cycling of bile acids in mice. J Biol Chem. 2003;278:33920–7.

    Article  CAS  PubMed  Google Scholar 

  29. Cao H, Xu M, Dong W, et al. Secondary bile acid-induced dysbiosis promotes intestinal carcinogenesis. Int J Cancer. 2017; https://doi.org/10.1002/ijc.30643.

  30. Ridlon JM, Harris SC, Bhowmik S, Kang D-J, Hylemon PB. Consequences of bile salt biotransformations by intestinal bacteria. Gut Microbes. 2016;7:22–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Staley C, Weingarden AR, Khoruts A, Sadowsky MJ. Interaction of gut microbiota with bile acid metabolism and its influence on disease states. Appl Microbiol Biotechnol. 2017;101:47–64.

    Article  CAS  PubMed  Google Scholar 

  32. Sayin SI, Wahlström A, Felin J, Jäntti S, Marschall H-U, Bamberg K, et al. Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab. 2013;17:225–35.

    Article  CAS  PubMed  Google Scholar 

  33. Kakiyama G, Pandak WM, Gillevet PM, et al. Modulation of the fecal bile acid profile by gut microbiota in cirrhosis. J Hepatol. 2013;58:949–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Komaki Y, Komaki F, Micic D, Ido A, Sakuraba A. Risk of colorectal cancer in chronic liver diseases: a systematic review and meta-analysis. Gastrointest Endosc. 2016; https://doi.org/10.1016/j.gie.2016.12.009.

  35. Floch MH, Binder HJ, Filburn B, Gershengoren W. The effect of bile acids on intestinal microflora. Am J Clin Nutr. 1972;25:1418–26.

    CAS  PubMed  Google Scholar 

  36. Kurdi P, Kawanishi K, Mizutani K, Yokota A. Mechanism of growth inhibition by free bile acids in lactobacilli and bifidobacteria. J Bacteriol. 2006;188:1979–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Inagaki T, Moschetta A, Lee Y-K, et al. Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor. Proc Natl Acad Sci U S A. 2006;103:3920–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Begley M, Gahan CGM, Hill C. The interaction between bacteria and bile. FEMS Microbiol Rev. 2005;29:625–51.

    Article  CAS  PubMed  Google Scholar 

  39. Ridlon JM, Alves JM, Hylemon PB, Bajaj JS. Cirrhosis, bile acids and gut microbiota. Gut Microbes. 2013;4:382–7.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Turnbaugh PJ, Bäckhed F, Fulton L, Gordon JI. Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome. Cell Host Microbe. 2008;3:213–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Hildebrandt MA, Hoffmann C, Sherrill-Mix SA, Keilbaugh SA, Hamady M, Chen Y-Y, et al. High-fat diet determines the composition of the murine gut microbiome independently of obesity. Gastroenterology. 2009;137:1716–24. e1–2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Weir TL, Manter DK, Sheflin AM, Barnett BA, Heuberger AL, Ryan EP. Stool microbiome and metabolome differences between colorectal cancer patients and healthy adults. PLoS One. 2013;8:e70803.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Feng Q, Liang S, Jia H, et al. Gut microbiome development along the colorectal adenoma–carcinoma sequence. Nat Commun. 2015; https://doi.org/10.1038/ncomms7528.

  44. Devkota S, Wang Y, Musch MW, Leone V, Fehlner-Peach H, Nadimpalli A, et al. Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10−/− mice. Nature. 2012;487:104–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. David LA, Maurice CF, Carmody RN, et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature. 2014;505:559–63.

    Article  CAS  PubMed  Google Scholar 

  46. Attene-Ramos MS, Wagner ED, Plewa MJ, Gaskins HR. Evidence that hydrogen sulfide is a genotoxic agent. Mol Cancer Res MCR. 2006;4:9–14.

    Article  CAS  PubMed  Google Scholar 

  47. Attene-Ramos MS, Nava GM, Muellner MG, Wagner ED, Plewa MJ, Gaskins HR. DNA damage and toxicogenomic analyses of hydrogen sulfide in human intestinal epithelial FHs 74 Int cells. Environ Mol Mutagen. 2010;51:304–14.

    CAS  PubMed  Google Scholar 

  48. Lepercq P, Gérard P, Béguet F, Grill J, Relano P, Cayuela C, et al. Isolates from normal human intestinal flora but not lactic acid bacteria exhibit 7α- and 7β-hydroxysteroid dehydrogenase activities. Microb Ecol Health Dis. 2004;16:195–201.

    Article  CAS  Google Scholar 

  49. Pardi DS, Loftus EV, Kremers WK, Keach J, Lindor KD. Ursodeoxycholic acid as a chemopreventive agent in patients with ulcerative colitis and primary sclerosing cholangitis. Gastroenterology. 2003;124:889–93.

    Article  CAS  PubMed  Google Scholar 

  50. Eaton JE, Silveira MG, Pardi DS, et al. High-dose ursodeoxycholic acid is associated with the development of colorectal neoplasia in patients with ulcerative colitis and primary sclerosing cholangitis. Am J Gastroenterol. 2011;106:1638–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Kulkarni MS, Heidepriem PM, Yielding KL. Production by lithocholic acid of DNA strand breaks in L1210 cells. Cancer Res. 1980;40:2666–9.

    CAS  PubMed  Google Scholar 

  52. Ward JBJ, Lajczak NK, Kelly OB, et al. Ursodeoxycholic acid and lithocholic acid exert anti-inflammatory actions in the colon. Am J Physiol Gastrointest Liver Physiol. 2017. ajpgi.00256.2016.

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Acknowledgements

S. Ocvirk is supported by the German Cancer Aid.

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Correspondence to Stephen JD O’Keefe.

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Soeren Ocvirk and Stephen J.D. O’Keefe declare they have no conflict of interest.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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This article is part of the Topical Collection on Cancer

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Ocvirk, S., O’Keefe, S.J. Influence of Bile Acids on Colorectal Cancer Risk: Potential Mechanisms Mediated by Diet-Gut Microbiota Interactions. Curr Nutr Rep 6, 315–322 (2017). https://doi.org/10.1007/s13668-017-0219-5

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