Digestive Diseases and Sciences

, Volume 38, Issue 3, pp 514–519 | Cite as

Role of bile acids and metabolic activity of colonic bacteria in increased risk of colon cancer after cholecystectomy

  • Ettore Zuccato
  • Marco Venturi
  • Giuseppe Di Leo
  • Laura Colombo
  • Cristina Bertolo
  • Santo Bressani Doldi
  • Emilio Mussini
Original Articles


Since the metabolic activity of the colonic flora plays a definite role in colon cancer and an increased incidence of this disease is reported after cholecystectomy, we studied the metabolic activity of the colonic flora in a group of postcholecystectomy patients and matched controls by measuring, as representative end products of the bacterial metabolism, their fecal bile acids (BA), fecal 3-methylindole (SK) and indole (IN), and respiratory methane and hydrogen. Patients had significantly higher SK and lower IN, and, among BA, higher lithocholic (LCA) and chenodeoxycholic acid concentrations and LCA/deoxycholic acid ratio in the stools than controls. Similar differences from controls were reported for colon cancer. Comparable bacterial metabolic activities are thus operative in the large bowel of postcholecystectomized and colon cancer patients. This supports the biological plausibility of the association of cholecystectomy and colon cancer.

Key Words

cholecystectomy colon cancer bile acids colonic flora skatole methane 


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  1. 1.
    Linos DA, Beard CM, O'Fallon WM, Dockerty MB, Beart RW Jr, Kurland LT: Cholecystectomy and carcinoma of the colon. Lancet 2:379–383, 1981Google Scholar
  2. 2.
    Vernick LJ, Kuller LH, Lohsoonthorn P, Rycheck RR, Redmond CK: Relationship between cholecystectomy and ascending colon cancer. Cancer 45:392–395, 1980Google Scholar
  3. 3.
    Vernick LJ, Kuller LH: Cholecystectomy and right-sided colon cancer: An epidemiological study. Lancet 2:381–383, 1981Google Scholar
  4. 4.
    McMichael AJ, Potter JD: Host factors in carcinogenesis: Certain bile-acid metabolic profiles that selectively increase the risk of proximal colon cancer. J Natl Cancer Inst 75:185–191, 1985Google Scholar
  5. 5.
    Moorehead RJ, McKelvey STD: Cholecystectomy and colorectal cancer. Br J Surg 76:250–253, 1989Google Scholar
  6. 6.
    Hill MJ, Drasar BS, Williams REO, Meade TW, Cox AG, Simpson JEP, Morson BC: Faecal bile-acids and clostridia in patients with cancer of the large bowel. Lancet 1:535–539, 1975Google Scholar
  7. 7.
    Mastromarino A, Reddy BS, Wynder EL: Metabolic epidemiology of colon cancer: Enzymic activity of fecal flora. Am J Clin Nutr 29:1455–1460, 1976Google Scholar
  8. 8.
    Gorbach SL, Goldin BR: The intestinal microflora and the colon cancer connection. Rev Infect Dis 12 (suppl 2):S252-S261, 1990Google Scholar
  9. 9.
    Scheline RR: Metabolism of foreign compounds by gastrointestinal microorganisms. Pharm Rev 25:451–523, 1973Google Scholar
  10. 10.
    Goldin BR, Gorbach SL: The relationship between diet and rat fecal bacterial enzymes implicated in colon cancer. J Natl Cancer Inst 57:371–375, 1976Google Scholar
  11. 11.
    Malagelada JR, Go VL, Summerskill WHJ, Gamble WS: Bile acid secretion and biliary bile acid composition altered by cholecystectomy. Am J Dig Dis 18:455–459, 1973Google Scholar
  12. 12.
    Hepner GW, Hofmann AF, Malagelada JR, Szczepanik PA, Klein PD: Increased bacterial degradation of bile acids in cholecystectomized patients. Gastroenterology 66:556–564, 1974Google Scholar
  13. 13.
    Pomare EW, Heaton KW: The effect of cholecystectomy on bile salt metabolism. Gut 14:753–762, 1973Google Scholar
  14. 14.
    White BA, Lipsky RL, Fricke RJ, Hylemon PB: Bile acid induction specificity of 7 alpha-dehydroxylase activity in an intestinalEubacterium species. Steroids 35:103–109, 1980Google Scholar
  15. 15.
    Aries VC, Crowther JS, Drasar BS, Hill MJ, Williams REO: Bacteria and the etiology of cancer of the large bowel. Gut 10:334–335, 1969Google Scholar
  16. 16.
    Hill MJ, Drasar BS, Aries V, Crowther JS, Hawksworth G, Williams REO: Bacteria and aetiology of cancer of large bowel. Lancet 1:95–100, 1971Google Scholar
  17. 17.
    Simon GL, Gorbach SL: The human intestinal microflora. Dig Dis Sci 31:147S-162S, 1986Google Scholar
  18. 18.
    Reddy BS, Weisburger JH, Wynder EL: Effects of high risk and low risk diets for colon carcinogenesis on fecal microflora and steroids in man. J Nutr 105:878–884, 1975Google Scholar
  19. 19.
    Reddy BS, Wynder EL: Large bowel carcinogenesis: Fecal constituents of populations with diverse incidence rates of colon cancer. J Natl Cancer Inst 50:1437–1442, 1973Google Scholar
  20. 20.
    Hill MJ: The role of colon anaerobes in the metabolism of bile acids and steroids, and its relation to colon cancer. Cancer 36:2387–2400, 1975Google Scholar
  21. 21.
    Hill MJ, Taylor AJ, Thompson MH, Wait R: Fecal steroids and urinary volatile phenols in four Scandinavian populations. Nutr Cancer 4:67–73, 1982Google Scholar
  22. 22.
    Turjman N, Goodman GT, Jaeger B, Nair PP: Diet, nutrition intake, and metabolism in populations at high and low risk for colon cancer. Metabolism of bile acids. Am J Clin Nutr 40 (suppl):937–941, 1984Google Scholar
  23. 23.
    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 39:2533–2539, 1977Google Scholar
  24. 24.
    Faivre J, Boutron MC: Precancerous lesions of the colorectum. Descriptive epidemiology and diet-related aetiological factors.In Causation and Prevention of Human Cancer. MJ Hill, A Giacosa (eds). Dordrecht, Kluver Academic Publishers, 1990, pp 33–47Google Scholar
  25. 25.
    Owen RW, Dodo M, Thompson MH, Hill MJ: Fecal steroids and colorectal cancer. Nutr Cancer 9:73–80, 1987Google Scholar
  26. 26.
    Haines A, Metz G, Dilawari J, Blendis L, Wiggins H: Breath-methane in patients with cancer of the large bowel. Lancet 2:481–483, 1977Google Scholar
  27. 27.
    Karlin DA, Jones RD, Stroehlein JR, Mastromarino AJ, Potter GD, Breath methane excretion in patients with unresected colorectal cancer. J Natl Cancer Inst 69:573–576, 1982Google Scholar
  28. 28.
    Karlin DA, Mastromarino AJ, Jones RD, Stroehlein JR, Lorentz O: Fecal skatole and indole and breath methane and hydrogen in patients with large bowel polyps or cancer. J Cancer Res Clin Oncol 109:135–141, 1985Google Scholar
  29. 29.
    Reddy BS: Diet and excretion of bile acids. Cancer Res 41:3766–3768, 1981Google Scholar
  30. 30.
    Reddy BS, Sharma C, Simi B, Engle A, Laakso K, Puska P, Korpela R: Metabolic epidemiology of colon cancer: Effect of dietary fiber on fecal mutagens and bile acids in healthy subjects. Cancer Res 47:644–648, 1987Google Scholar
  31. 31.
    Nair PP: Role of bile acids and neutral sterols in carcinogenesis. Am J Clin Nutr 48:768–774, 1988Google Scholar
  32. 32.
    Narisawa T, Magadia NE, Weisburger JH, Wynder EL: Promoting effect of bile acids on colon carcinogenesis after intrarectal instillation ofN-methyl-N′-nitro-N-nitrosoguanidine in rats. J Natl Cancer Inst 53:1093–1097, 1974Google Scholar
  33. 33.
    Reddy BS, Narasawa T, Weisburger JH, Wynder EL: Promoting effect of sodium deoxycholate on colon adenocarcinomas in germfree rats. J Natl Cancer Inst 56:441–442, 1976Google Scholar
  34. 34.
    Reddy BS, Watanabe K, Weisburger JH, Wynder EL: Promoting effect of bile acids in colon carcinogenesis in germ-free and conventional F344 rats. Cancer Res 37:3238–3242, 1977Google Scholar
  35. 35.
    Levitt MD, French P, Donaldson RM: Use of hydrogen and methane excretion in the study of the intestinal flora. J Lab Clin Med 72:988–989, 1968Google Scholar
  36. 36.
    Pitt P, De Bruijn KM, Beeching MF, Goldberg E, Blendis LM: Studies on breath methane: The effect of ethnic origins and lactulose. Gut 21:951–954, 1980Google Scholar
  37. 37.
    Zuccato E, Andreoletti M, Bozzani A, Marcucci F, Velio P, Bianchi P, Mussini E: Respiratory excretion of hydrogen and methane in Italian subjects after ingestion of lactose and milk. Eur J Clin Invest 13:261–266, 1983Google Scholar
  38. 38.
    Levitt MD, Donaldson RM: Use of respiratory hydrogen (H2) excretion to detect carbohydrate malabsorption. J Lab Clin Med 75:937–945, 1970Google Scholar
  39. 39.
    Ceriani R, Zuccato E, Fontana M, Zuin G, Ferrari L, Principi N, Paccagnini S, Mussini E: Lactose malabsorption and recurrent abdominal pain in Italian children. J Pediatr Gastroenterol Nutr 7:852–857, 1988Google Scholar
  40. 40.
    Miller TL, Wolin MJ: Oxidation of hydrogen and reduction of methanol to methane is the sole energy source for a methanogen isolated from human feces. J Bacteriol 153: 1051–1055, 1983Google Scholar
  41. 41.
    Goto J, Hasegawa M, Kato H, Nambara T: A new method for simultaneous determination of bile acids in human bile without hydrolysis. Clin Chim Acta 87:141–147, 1978Google Scholar
  42. 42.
    Mussini E, Marcucci F, Canobbio ML, Geretto S, Poy F: Glass capillary separation and quantitative determination of free bile acids.In Recents Developments in Chromathography and Electrophoresis, Vol. 10. A Frigerio, M McCamish (eds). Amsterdam, Elsevier, 1980, pp 183–192Google Scholar
  43. 43.
    Wilpart M, Mainguet P, Maskens A, Roberfroid M: Mutagenicity of 1,2-dimethylhydrazine towardsSalmonella typhimurium, co-mutagenic effect of secondary bile acids. Carcinogenesis 4:45–48, 1983Google Scholar
  44. 44.
    Hiasa Y, Konishi Y, Kamamoto Y, Watnabe T, Ito N: Effect of lithocolic acid ondl-ethionine carcinogenesis in rat liver. Gann 62:239–245, 1971Google Scholar
  45. 45.
    Silverman SJ, Andrews AW: Bile acids: Comutagenic activity in theSalmonella-mammalian-microsome mutagenicity test: Brief communication. J Natl Cancer Inst 59:1557–1559, 1977Google Scholar
  46. 46.
    Kelsey MI, Pienta RJ: Transformation of hamster embryo cells by cholesterol-alpha-epoxide and lithocholic acid. Cancer Lett 6:143–149, 1979Google Scholar
  47. 47.
    Kulkarni MS, Cox BA, Yielding KL: Requirements for induction of DNA strand breaks by lithocholic acid. Cancer Res 42:2792–2795, 1982Google Scholar
  48. 48.
    Turjman N, Nair PP: Nature of tissue-bound lithocholic acid and its implications in the role of bile acids in carcinogenesis. Cancer Res 41:3761–3763, 1981Google Scholar
  49. 49.
    Moorehead RJ, Campbell GR, Donaldson JD, McKelvey STD: Relationship between duodenal bile acids and colorectal neoplasia. Gut 28:1454–1459, 1987Google Scholar
  50. 50.
    van der Linden W, Katzenstein B, Nakayama F: The possible carcinogenic effect of cholecystectomy. No postoperative increase in the proportion of secondary bile acids. Cancer 52:1265–1268, 1983Google Scholar
  51. 51.
    van der Werf SDJ, Huijbregts AWM, Lamers HLM, van Berge Henegouwen GP, van Tongeren JHM: Age dependent differences in human bile acid metabolism and 7a-dehydroxylation. Eur J Clin Invest 11:425–431, 1981Google Scholar
  52. 52.
    Nagengast FM, van der Werf SDJ, Lamers HLM, Hectors MPC, Buys WCAM, van Tongeren JMH: Influence of age, intestinal transit time, and dietary composition on fecal bile acid profiles in healthy subjects. Dig Dis Sci 33:673–678, 1988Google Scholar
  53. 53.
    Kay RM: Effects of diet on the fecal excretion and bacterial modification of acidic and neutral steroids, and implications for colon carcinogenesis. Cancer Res 41:3774–3777, 1981Google Scholar
  54. 54.
    Cummings JH, Wiggins HS, Jenkins DJA, Houston H, Jivraj T, Drasar BS, Hill MJ: Influence of diets high and low in animal fat on bowel habit, gastrointestinal transit time, fecal microflora, bile acid, and fat excretion. J Clin Invest 61:953–963, 1978Google Scholar
  55. 55.
    Lampe JW, Slavin JL, Baglien KS, Thompson WO, Duane WC, Zavoral JH: Serum lipid and serum bile acids changes with cereal, vegetable, and sugar-beet fiber feeding. Am J Clin Nutr 53:1235–1241, 1991Google Scholar
  56. 56.
    Michael AF, Drummond KN, Doeden D, Anderson JA, Good RA: Tryptophan metabolism in man. J Clin Invest 43:1730–1746, 1964Google Scholar
  57. 57.
    Zuccato E, Venturi M, Granelli P, Bertolo C, Rosina M, Pagani M, Mussini E, Zennaro F: Bacterial metabolism and colon cancer risk in postcholecystectomized patients.In Digestive Surgery: Liver and Biliary Tract. M Montorsi, F Zennaro (eds). Bologna, Monduzzi Editore, 1990, pp 321–325Google Scholar
  58. 58.
    Breuer NF, Katschinski B, Mortl E, Leder LD, Goebell H: Large bowel cancer risk in cholelithiasis and after cholecystectomy. Postmortem study. Digestion 40:219–226, 1988Google Scholar
  59. 59.
    Hladik V, Nozicka Z, Maslowska H: Colorectal carcinoma and cholecystectomy. Neoplasma 34:361–366, 1987Google Scholar
  60. 60.
    Cheah PY: Hypotheses for the etiology of colorectal cancer. An overview. Nutr Cancer 14:5–13, 1990Google Scholar

Copyright information

© Plenum Publishing Corporation 1993

Authors and Affiliations

  • Ettore Zuccato
    • 1
    • 2
  • Marco Venturi
    • 1
    • 2
  • Giuseppe Di Leo
    • 1
    • 2
  • Laura Colombo
    • 1
    • 2
  • Cristina Bertolo
    • 1
    • 2
  • Santo Bressani Doldi
    • 1
    • 2
  • Emilio Mussini
    • 1
    • 2
  1. 1.Istituto di Ricerche Farmacologiche “Mario Negri”MilanItaly
  2. 2.Clinica Chirurgica TerzaUniversità di MilanoMilanItaly

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