Journal Home Online First Current Issue Archive For Authors Journal Information 中文版

Engineering >> 2017, Volume 3, Issue 1 doi: 10.1016/J.ENG.2017.01.017

The Gut Microbiota, Tumorigenesis, and Liver Diseases

a International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, China
b National Center for Liver Cancer, Shanghai 201805, China

Accepted: 2017-02-03 Available online: 2017-02-28

Next Previous


In recent decades, diseases concerning the gut microbiota have presented some of the most serious public health problems worldwide. The human host’s physiological status is influenced by the intestinal microbiome, thus integrating external factors, such as diet, with genetic and immune signals. The notion that chronic inflammation drives carcinogenesis has been widely established for various tissues. It is surprising that the role of the microbiota in tumorigenesis has only recently been recognized, given that the presence of bacteria at tumor sites was first described more than a century ago. Extensive epidemiological studies have revealed that there is a strong link between the gut microbiota and some common cancers. However, the exact molecular mechanisms linking the gut microbiota and cancer are not yet fully understood. Changes to the gut microbiota are instrumental in determining the occurrence and progression of hepatocarcinoma, chronic liver diseases related to alcohol, nonalcoholic fatty liver disease (NAFLD), and cirrhosis. To be specific, the gut milieu may play an important role in systemic inflammation, endotoxemia, and vasodilation, which leads to complications such as spontaneous bacterial peritonitis and hepatic encephalopathy. Relevant animal studies involving gut microbiota manipulations, combined with observational studies on patients with NAFLD, have provided ample evidence pointing to the contribution of dysbiosis to the pathogenesis of NAFLD. Given the poor prognosis of these clinical events, their prevention and early management are essential. Studies of the composition and function of the gut microbiota could shed some light on understanding the prognosis because the microbiota serves as an essential component of the gut milieu that can impact the aforementioned clinical events. As far as disease management is concerned, probiotics may provide a novel direction for therapeutics for hepatocellular carcinoma (HCC) and NAFLD, given that probiotics function as a type of medicine that can improve human health by regulating the immune system. Here, we provide an overview of the relationships among the gut microbiota, tumors, and liver diseases. In addition, considering the significance of bacterial homeostasis, we discuss probiotics in this article in order to guide treatments for related diseases.


Fig. 1


[ 1 ] Qin J, Li R, Raes J, Arumugam M, Burgdorf KS, Manichanh C, et alA human gut microbial gene catalogue established by metagenomic sequencing. Nature 2010;464(7285):59–65 link1

[ 2 ] Zoetendal EG, Akkermans AD, De Vos WM. Temperature gradient gel electrophoresis analysis of 16S rRNA from human fecal samples reveals stable and host-specific communities of active bacteria. Appl Environ Microbiol 1998;64(10):3854–9.

[ 3 ] Eckburg PB, Bik EM, Bernstein CN, Purdom E, Dethlefsen L, Sargent M, et alDiversity of the human intestinal microbial flora. Science 2005;308(5728):1635–8 link1

[ 4 ] Hold GL, Pryde SE, Russell VJ, Furrie E, Flint HJ. Assessment of microbial diversity in human colonic samples by 16S rDNA sequence analysis. FEMS Microbiol Ecol 2002;39(1):33–9 link1

[ 5 ] Huttenhower C, Gevers D, Knight R, Abubucker S, Badger JH, Chinwalla AT, et alStructure, function and diversity of the healthy human microbiome. Nature 2012;486(7402):207–14 link1

[ 6 ] Tamburini S, Shen N, Wu HC, Clemente JC. The microbiome in early life: implications for health outcomes. Nat Med 2016;22(7):713–22 link1

[ 7 ] Thaiss CA, Zmora N, Levy M, Elinav E. The microbiome and innate immunity. Nature 2016;535(7610):65–74 link1

[ 8 ] Schroeder BO, B?ckhed F. Signals from the gut microbiota to distant organs in physiology and disease. Nat Med 2016;22(10):1079–89 link1

[ 9 ] Ou J, Carbonero F, Zoetendal EG, DeLany JP, Wang M, Newton K, et alDiet, microbiota, and microbial metabolites in colon cancer risk in rural Africans and African Americans. Am J Clin Nutr 2013;98(1):111–20 link1

[10] Uronis JM, Mühlbauer M, Herfarth HH, Rubinas TC, Jones GS, Jobin C. Modulation of the intestinal microbiota alters colitis-associated colorectal cancer susceptibility. PLoS One 2009;4(6):e6026 link1

[11] Irrazábal T, Belcheva A, Girardin SE, Martin A, Philpott DJ. The multifaceted role of the intestinal microbiota in colon cancer. Mol Cell 2014;54(2):309–20 link1

[12] Grivennikov SI, Wang K, Mucida D, Stewart CA, Schnabl B, Jauch D, et alAdenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth. Nature 2012;491(7423):254–8 link1

[13] Couturier-Maillard A, Secher T, Rehman A, Normand S, De Arcangelis A, Haesler R, et alNOD2-mediated dysbiosis predisposes mice to transmissible colitis and colorectal cancer. J Clin Invest 2013;123(2):700–11 link1

[14] Medzhitov R. Recognition of microorganisms and activation of the immune response. Nature 2007;449(7164):819–26 link1

[15] Yu L, Yan H, Liu Q, Yang W, Wu H, Dong W, et alEndotoxin accumulation prevents carcinogen-induced apoptosis and promotes liver tumorigenesis in rodents. Hepatology 2010;52(4):1322–33 link1

[16] Zhang H, Yu L, Yang W, Tang L, Lin Y, Wu H, et alProfound impact of gut homeostasis on chemically-induced pro-tumorigenic inflammation and hepatocarcinogenesis in rats. J Hepatol 2012;57(4):803–12 link1

[17] Dapito DH, Mencin A, Gwak GY, Pradere JP, Jang MK, Mederacke I, et alPromotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell 2012;21(4):504–16 link1

[18] Roderburg C, Luedde T. The role of the gut microbiome in the development and progression of liver cirrhosis and hepatocellular carcinoma. Gut Microbes 2014;5(4):441–5 link1

[19] Tao X, Wang N, Qin W. Gut microbiota and hepatocellular carcinoma. Gastrointest Tumors 2015;2(1):33–40 link1

[20] B?ckhed F, Manchester JK, Semenkovich CF, Gordon JI. Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc Natl Acad Sci USA 2007;104(3):979–84 link1

[21] Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 2006;444(7122):1027–31 link1

[22] Ding S, Chi MM, Scull BP, Rigby R, Schwerbrock NM, Magness S, et alHigh-fat diet: bacteria interactions promote intestinal inflammation which precedes and correlates with obesity and insulin resistance in mouse. PLoS One 2010;5(8):e12191 link1

[23] Fleissner CK, Huebel N, Abd El-Bary MM, Loh G, Klaus S, Blaut M. Absence of intestinal microbiota does not protect mice from diet-induced obesity. Br J Nutr 2010;104(6):919–29 link1

[24] Flint HJ, Scott KP, Louis P, Duncan SH. The role of the gut microbiota in nutrition and health. Nat Rev Gastroenterol Hepatol 2012;9(10):577–89 link1

[25] Yoshimoto S, Loo TM, Atarashi K, Kanda H, Sato S, Oyadomari S, et alObesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 2013;499(7456):97–101. Erratum in: Nature 2014;506(7488):396 link1

[26] Ray K. Gut microbiota: obesity-induced microbial metabolite promotes HCC. Nat Rev Gastroenterol Hepatol 2013;10(8):442 link1

[27] Li J, Sung CY, Lee N, Ni Y, Pihlajamaki J, Panagiotou G, et alProbiotics modulated gut microbiota suppresses hepatocellular carcinoma growth in mice. Proc Natl Acad Sci USA 2016;113(9):E1306–15 link1

[28] El-Nezami HS, Polychronaki NN, Ma J, Zhu H, Ling W, Salminen EK, et alProbiotic supplementation reduces a biomarker for increased risk of liver cancer in young men from Southern China. Am J Clin Nutr 2006;83(5):1199–203.

[29] de Alwis NMW, Day CP. Non-alcoholic fatty liver disease: the mist gradually clears. J Hepatol 2008;48(Suppl 1):S104–12 link1

[30] Sanyal AJ, Banas C, Sargeant C, Luketic VA, Sterling RK, Stravitz RT, et alSimilarities and differences in outcomes of cirrhosis due to non-alcoholic steatohepatitis and hepatitis C. Hepatology 2006;43(4):682–9 link1

[31] Nair S, Mason A, Eason J, Loss G, Perillo R. Is obesity an independent risk factor for hepatocellular carcinoma in cirrhosis? Hepatology 2002;36(1):150–5 link1

[32] Henao-Mejia J, Elinav E, Jin C, Hao L, Mehal WZ, Strowig T, et alInflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 2012;482(7384):179–85 link1

[33] Younossi ZM, Blissett D, Blissett R, Henry L, Stepanova M, Younossi Y, et alThe economic and clinical burden of nonalcoholic fatty liver disease in the United States and Europe. Hepatology 2016;64(5):1577–86 link1

[34] Elinav E, Strowig T, Kau AL, Henao-Mejia J, Thaiss CA, Booth CJ, et alNLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell 2011;145(5):745–57 link1

[35] Bajaj JS, Ridlon JM, Hylemon PB, Thacker LR, Heuman DM, Smith S, et alLinkage of gut microbiome with cognition in hepatic encephalopathy. Am J Physiol Gastrointest Liver Physiol 2012;302(1):G168–75 link1

[36] Makiura N, Ojima M, Kou Y, Furuta N, Okahashi N, Shizukuishi S, et alRelationship of Porphyromonas gingivalis with glycemic level in patients with type 2 diabetes following periodontal treatment. Oral Microbiol Immunol 2008;23(4):348–51 link1

[37] Gonzalez FJ, Jiang C, Patterson AD. An intestinal microbiota—farnesoid X receptor axis modulates metabolic disease. Gastroenterology 2016;151(5):845–59 link1

[38] Fang S, Suh JM, Reilly SM, Yu E, Osborn O, Lackey D, et alIntestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nat Med 2015;21(2):159–65 link1

[39] Jiang C, Xie C, Lv Y, Li J, Krausz KW, Shi J, et alIntestine-selective farnesoid X receptor inhibition improves obesity-related metabolic dysfunction. Nat Commun 2015;6:10166 link1

[40] Zitvogel L, Galluzzi L, Viaud S, Vétizou M, Daillère R, Merad M, et alCancer and the gut microbiota: an unexpected link. Sci Transl Med 2015;7(271):271ps1 link1

[41] Perez-Chanona E, Trinchieri G. The role of microbiota in cancer therapy. Curr Opin Immunol 2016;39:75–81 link1

[42] Arroyo R, Martin V, Maldonado A, Jimenez E, Fernandez L, Rodriguez JM. Treatment of infectious mastitis during lactation: antibiotics versus oral administration of lactobacilli isolated from breast milk. Clin Infec Dis 2010;50(12):1551–8 link1

[43] Barbonetti A, Vassallo MR, Cinque B, Filipponi S, Mastromarino P, Cifone MG, et alSoluble products of Escherichia coli induce mitochondrial dysfunction-related sperm membrane lipid peroxidation which is prevented by lactobacilli. PLoS One 2013;8(12):e83136 link1

[44] Sivan A, Corrales L, Hubert N, Williams JB, Aquino-Michaels K, Earley ZM, et alCommensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 2015;350(6264):1084–9 link1

[45] Alderton GK. Tumour immunology: intestinal bacteria are in command. Nat Rev Immunol 2016;16(1):5 link1

Related Research