The gut microbiome and liver cancer: Mechanisms and clinical translation

Nature Reviews Gastroenterology and Hepatology

Volumn 14, Issue 9, 2017, Pages 527-539

  Yu, Le Xing ^a   Schwabe, Robert F ^a,b  

^a Columbia University ^*  (United States)

^b Clinical Nutrition   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

3 [2 [2 CHLORO 4 [3 (2,6 DICHLOROPHENYL) 5 ISOPROPYL 4 ISOXAZOLYLMETHOXY]PHENYL]VINYL]BENZOIC ACID; AMPICILLIN; ANTIBIOTIC AGENT; ANTINEOPLASTIC AGENT; CARBON TETRACHLORIDE; CISAPRIDE; DIETHYLNITROSAMINE; ERITORAN; LIPOPOLYSACCHARIDE; METRONIDAZOLE; NEOMYCIN; NORFLOXACIN; OBETICHOLIC ACID; PROBIOTIC AGENT; PROKINETIC AGENT; PROPRANOLOL; RESATORVID; RIFAXIMIN; TOLL LIKE RECEPTOR 4; TOLL LIKE RECEPTOR ANTAGONIST; VANCOMYCIN;

ALCOHOL LIVER DISEASE; ANTINEOPLASTIC ACTIVITY; BACTERIAL DYSBIOSIS; BACTERIAL METABOLISM; BIFIDOBACTERIUM BREVE; BIFIDOBACTERIUM LONGUM; BIFIDOBACTERIUM LONGUM SUBSP. INFANTIS; CANCER INHIBITION; CHRONIC LIVER DISEASE; CHRONIC VIRAL HEPATITIS; DISEASE COURSE; DRUG EFFICACY; DRUG SAFETY; DYSBIOSIS; FECAL MICROBIOTA TRANSPLANTATION; GASTROINTESTINAL DISEASE; GENOTOXICITY; GUT BARRIER; GUT LEAKAGE; HEPATITIS; HEPATITIS C; HUMAN; IMMUNOSUPPRESSIVE TREATMENT; INTESTINAL EPITHELIAL BARRIER; INTESTINE EPITHELIUM; INTESTINE FLORA; LACTOBACILLUS ACIDOPHILUS; LACTOBACILLUS DELBRUECKII SUBSP. BULGARICUS; LACTOBACILLUS PARACASEI; LACTOBACILLUS PLANTARUM; LACTOBACILLUS RHAMNOSUS; LIVER CARCINOGENESIS; LIVER CELL CARCINOMA; LIVER FIBROSIS; MICROORGANISM; NONALCOHOLIC FATTY LIVER; NONHUMAN; OSCILLIBACTER; OVERALL SURVIVAL; PEPTOCLOSTRIDIUM DIFFICILE; PERMEABILITY BARRIER; PREVOTELLA; PRIORITY JOURNAL; REVIEW; STREPTOCOCCUS THERMOPHILUS; VIRUS HEPATITIS; CARCINOMA, HEPATOCELLULAR; LIVER NEOPLASMS; MICROBIOLOGY; PATHOLOGY;

CARCINOMA, HEPATOCELLULAR; GASTROINTESTINAL MICROBIOME; HUMANS; LIVER NEOPLASMS;

EID: 85028471063     PISSN: 17595045     EISSN: 17595053     Source Type: Journal    
DOI: 10.1038/nrgastro.2017.72     Document Type: Review

References (161)

1. Rooks, M. G. & Garrett, W. S. Gut microbiota, metabolites and host immunity. Nat. Rev. Immunol. 16, 341-352 (2016).
2. Tremaroli, V. & Backhed, F. Functional interactions between the gut microbiota and host metabolism. Nature 489, 242-249 (2012).
3. Schroeder, B. O. & Backhed, F. Signals from the gut microbiota to distant organs in physiology and disease. Nat. Med. 22, 1079-1089 (2016).
4. Chu, H. et al. Gene-microbiota interactions contribute to the pathogenesis of inflammatory bowel disease. Science 352, 1116-1120 (2016).
5. Lamas, B. et al. CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands. Nat. Med. 22, 598-605 (2016).
6. Koeth, R. A. et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat. Med. 19, 576-585 (2013).
7. Rothhammer, V. et al. Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor. Nat. Med. 22, 586-597 (2016).
8. Tang, W. H. et al. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N. Engl. J. Med. 368, 1575-1584 (2013).
9. Wang, Z. et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472, 57-63 (2011).
10. Zhu, W. et al. Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk. Cell 165, 111-124 (2016).
11. Schwabe, R. F. & Jobin, C. The microbiome and cancer. Nat. Rev. Cancer 13, 800-812 (2013).
12. Schnabl, B. & Brenner, D. A. Interactions between the intestinal microbiome and liver diseases. Gastroenterology 146, 1513-1524 (2014).
13. Dapito, D. H. et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell 21, 504-516 (2012).
14. Yu, L. X. et al. Endotoxin accumulation prevents carcinogen-induced apoptosis and promotes liver tumorigenesis in rodents. Hepatology 52, 1322-1333 (2010).
15. Yoshimoto, S. et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 499, 97-101 (2013).
16. Pradere, J. P., Troeger, J. S., Dapito, D. H., Mencin, A. A. & Schwabe, R. F. Toll-like receptor 4 and hepatic fibrogenesis. Semin. Liver Dis. 30, 232-244 (2010).
17. Peterson, L. W. & Artis, D. Intestinal epithelial cells: regulators of barrier function and immune homeostasis. Nat. Rev. Immunol. 14, 141-153 (2014).
18. van Nood, E. et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N. Engl. J. Med. 368, 407-415 (2013).
19. Kamada, N. et al. Regulated virulence controls the ability of a pathogen to compete with the gut microbiota. Science 336, 1325-1329 (2012).
20. Inagaki, T. et al. Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor. Proc. Natl Acad. Sci. USA 103, 3920-3925 (2006).
21. Gadaleta, R. M. et al. Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease. Gut 60, 463-472 (2011).
22. Dossa, A. Y. et al. Bile acids regulate intestinal cell proliferation by modulating EGFR and FXR signaling. Am. J. Physiol. Gastrointest. Liver Physiol. 310, G81-G92 (2016).
23. Modica, S. et al. Selective activation of nuclear bile acid receptor FXR in the intestine protects mice against cholestasis. Gastroenterology 142, 355-365. e4 (2012).
24. Lin, R. S. et al. Endotoxemia in patients with chronic liver diseases: relationship to severity of liver diseases, presence of esophageal varices, and hyperdynamic circulation. J. Hepatol. 22, 165-172 (1995).
25. Fukui, H., Brauner, B., Bode, J. C. & Bode, C. Plasma endotoxin concentrations in patients with alcoholic and non-alcoholic liver disease: reevaluation with an improved chromogenic assay. J. Hepatol. 12, 162-169 (1991).
26. Parlesak, A., Schafer, C., Schutz, T., Bode, J. C. & Bode, C. Increased intestinal permeability to macromolecules and endotoxemia in patients with chronic alcohol abuse in different stages of alcohol-induced liver disease. J. Hepatol. 32, 742-747 (2000).
27. Yan, A. W. et al. Enteric dysbiosis associated with a mouse model of alcoholic liver disease. Hepatology 53, 96-105 (2011).
28. Fouts, D. E., Torralba, M., Nelson, K. E., Brenner, D. A. & Schnabl, B. Bacterial translocation and changes in the intestinal microbiome in mouse models of liver disease. J. Hepatol. 56, 1283-1292 (2012).
29. Bellot, P. et al. Bacterial DNA translocation is associated with systemic circulatory abnormalities and intrahepatic endothelial dysfunction in patients with cirrhosis. Hepatology 52, 2044-2052 (2010).
30. Spadoni, I. et al. A gut-vascular barrier controls the systemic dissemination of bacteria. Science 350, 830-834 (2015).
31. Wiest, R. & Garcia-Tsao, G. Bacterial translocation (BT) in cirrhosis. Hepatology 41, 422-433 (2005).
32. Qin, N. et al. Alterations of the human gut microbiome in liver cirrhosis. Nature 513, 59-64 (2014).
33. Chen, Y. et al. Characterization of fecal microbial communities in patients with liver cirrhosis. Hepatology 54, 562-572 (2011).
34. Bajaj, J. S., Betrapally, N. S. & Gillevet, P. M. Decompensated cirrhosis and microbiome interpretation. Nature 525, E1-E2 (2015).
35. Mouzaki, M. et al. Bile acids and dysbiosis in non-alcoholic fatty liver disease. PLoS ONE 11, e0151829 (2016).
36. Boursier, J. et al. The severity of nonalcoholic fatty liver disease is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota. Hepatology 63, 764-775 (2016).
37. Cabrera, R. & Nelson, D. R. Review article: the management of hepatocellular carcinoma. Aliment. Pharmacol. Ther. 31, 461-476 (2010).
38. El-Serag, H. B. Hepatocellular carcinoma. N. Engl. J. Med. 365, 1118-1127 (2011).
39. Sanyal, A. J., Yoon, S. K. & Lencioni, R. The etiology of hepatocellular carcinoma and consequences for treatment. Oncologist 15 (Suppl. 4), 14-22 (2010).
40. Singal, A. G. & El-Serag, H. B. Hepatocellular carcinoma from epidemiology to prevention: translating knowledge into practice. Clin. Gastroenterol. Hepatol. 13, 2140-2151 (2015).
41. Gao, B. & Bataller, R. Alcoholic liver disease: pathogenesis and new therapeutic targets. Gastroenterology 141, 1572-1585 (2011).
42. Joshi, K., Kohli, A., Manch, R. & Gish, R. Alcoholic liver disease: high risk or low risk for developing hepatocellular carcinoma? Clin. Liver Dis. 20, 563-580 (2016).
43. Rao, R. K., Seth, A. & Sheth, P. Recent advances in alcoholic liver disease I. Role of intestinal permeability and endotoxemia in alcoholic liver disease. Am. J. Physiol. Gastrointest. Liver Physiol. 286, G881-G884 (2004).
44. Chen, P. et al. Supplementation of saturated long-chain fatty acids maintains intestinal eubiosis and reduces ethanol-induced liver injury in mice. Gastroenterology 148, 203-214. e16 (2015).
45. Szabo, G. Gut-liver axis in alcoholic liver disease. Gastroenterology 148, 30-36 (2015).
46. Uesugi, T., Froh, M., Arteel, G. E., Bradford, B. U. & Thurman, R. G. Toll-like receptor 4 is involved in the mechanism of early alcohol-induced liver injury in mice. Hepatology 34, 101-108 (2001).
47. Hritz, I. et al. The critical role of toll-like receptor (TLR) 4 in alcoholic liver disease is independent of the common TLR adapter MyD88. Hepatology 48, 1224-1231 (2008).
48. Adachi, Y., Moore, L. E., Bradford, B. U., Gao, W. & Thurman, R. G. Antibiotics prevent liver injury in rats following long-term exposure to ethanol. Gastroenterology 108, 218-224 (1995).
49. Machida, K. et al. Toll-like receptor 4 mediates synergism between alcohol and HCV in hepatic oncogenesis involving stem cell marker Nanog. Proc. Natl Acad. Sci. USA 106, 1548-1553 (2009).
50. Siu, L., Foont, J. & Wands, J. R. Hepatitis C virus and alcohol. Semin. Liver Dis. 29, 188-199 (2009).
51. Michelotti, G. A., Machado, M. V. & Diehl, A. M. NAFLD, NASH and liver cancer. Nat. Rev. Gastroenterol. Hepatol. 10, 656-665 (2013).
52. Backhed, F. et al. The gut microbiota as an environmental factor that regulates fat storage. Proc. Natl Acad. Sci. USA 101, 15718-15723 (2004).
53. Turnbaugh, P. J. et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444, 1027-1031 (2006).
54. Turnbaugh, P. J. et al. A core gut microbiome in obese and lean twins. Nature 457, 480-484 (2009).
55. Jiang, C. et al. Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease. J. Clin. Invest. 125, 386-402 (2015).
56. Zhu, L. et al. Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: a connection between endogenous alcohol and NASH. Hepatology 57, 601-609 (2013).
57. Del Chierico, F. et al. Gut microbiota profiling of pediatric NAFLD and obese patients unveiled by an integrated meta-omics based approach. Hepatology 65, 451-464 (2016).
58. Mouzaki, M. et al. Intestinal microbiota in patients with nonalcoholic fatty liver disease. Hepatology 58, 120-127 (2013).
59. Leung, C., Rivera, L., Furness, J. B. & Angus, P. W. The role of the gut microbiota in NAFLD. Nat. Rev. Gastroenterol. Hepatol. 13, 412-425 (2016).
60. Dumas, M. E. et al. Metabolic profiling reveals a contribution of gut microbiota to fatty liver phenotype in insulin-resistant mice. Proc. Natl Acad. Sci. USA 103, 12511-12516 (2006).
61. Jiang, X. C. et al. Phospholipid transfer protein deficiency impairs apolipoprotein-B secretion from hepatocytes by stimulating a proteolytic pathway through a relative deficiency of vitamin E and an increase in intracellular oxidants. J. Biol. Chem. 280, 18336-18340 (2005).
62. Cani, P. D. et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56, 1761-1772 (2007).
63. Miele, L. et al. Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology 49, 1877-1887 (2009).
64. Ye, D. et al. Toll-like receptor-4 mediates obesity-induced non-alcoholic steatohepatitis through activation of X-box binding protein-1 in mice. Gut 61, 1058-1067 (2012).
65. Henao-Mejia, J. et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 482, 179-185 (2012).
66. Zhou, D. et al. Total fecal microbiota transplantation alleviates high-fat diet-induced steatohepatitis in mice via beneficial regulation of gut microbiota. Sci. Rep. 7, 1529 (2017).
67. Bajaj, J. S. et al. HCV eradication does not impact gut dysbiosis or systemic inflammation in cirrhotic patients. Aliment. Pharmacol. Ther. 44, 638-643 (2016).
68. Chou, H. H. et al. Age-related immune clearance of hepatitis B virus infection requires the establishment of gut microbiota. Proc. Natl Acad. Sci. USA 112, 2175-2180 (2015).
69. Chen, C. J. et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA 295, 65-73 (2006).
70. Affo, S., Yu, L. X. & Schwabe, R. F. The role of cancer-associated fibroblasts and fibrosis in liver cancer. Annu. Rev. Pathol. 12, 153-186 (2017).
71. Luckey, T. D., Reyniers, J. A., Gyorgy, P. & Forbes, M. Germfree animals and liver necrosis. Ann. NY Acad. Sci. 57, 932-935 (1954).
72. Rutenburg, A. M. et al. The role of intestinal bacteria in the development of dietary cirrhosis in rats. J. Exp. Med. 106, 1-14 (1957).
73. Seki, E. et al. TLR4 enhances TGF-beta signaling and hepatic fibrosis. Nat. Med. 13, 1324-1332 (2007).
74. Isayama, F. et al. LPS signaling enhances hepatic fibrogenesis caused by experimental cholestasis in mice. Am. J. Physiol. Gastrointest. Liver Physiol. 290, G1318-G1328 (2006).
75. Mazagova, M. et al. Commensal microbiota is hepatoprotective and prevents liver fibrosis in mice. FASEB J. 29, 1043-1055 (2015).
76. Tabibian, J. H. et al. Absence of the intestinal microbiota exacerbates hepatobiliary disease in a murine model of primary sclerosing cholangitis. Hepatology 63, 185-196 (2016).
77. Zhang, H. L. et al. Profound impact of gut homeostasis on chemically-induced pro-tumorigenic inflammation and hepatocarcinogenesis in rats. J. Hepatol. 57, 803-812 (2012).
78. Nolan, J. P. The role of intestinal endotoxin in liver injury: a long and evolving history. Hepatology 52, 1829-1835 (2010).
79. Takeuchi, O. & Akira, S. Pattern recognition receptors and inflammation. Cell 140, 805-820 (2010).
80. Gabele, E. et al. DSS induced colitis increases portal LPS levels and enhances hepatic inflammation and fibrogenesis in experimental NASH. J. Hepatol. 55, 1391-1399 (2011).
81. Achiwa, K. et al. DSS colitis promotes tumorigenesis and fibrogenesis in a choline-deficient high-fat diet-induced NASH mouse model. Biochem. Biophys. Res. Commun. 470, 15-21 (2016).
82. Toyoda, H. et al. Epiregulin. A novel epidermal growth factor with mitogenic activity for rat primary hepatocytes. J. Biol. Chem. 270, 7495-7500 (1995).
83. Jing, Y. Y. et al. Toll-like receptor 4 signaling promotes epithelial-mesenchymal transition in human hepatocellular carcinoma induced by lipopolysaccharide. BMC Med. 10, 98 (2012).
84. Wei, X. et al. Cirrhosis related functionality characteristic of the fecal microbiota as revealed by a metaproteomic approach. BMC Gastroenterol. 16, 121 (2016).
85. Lv, L. X. et al. Alterations and correlations of the gut microbiome, metabolism and immunity in patients with primary biliary cirrhosis. Environ. Microbiol. 18, 2272-2286 (2016).
86. Chen, Y. et al. Dysbiosis of small intestinal microbiota in liver cirrhosis and its association with etiology. Sci. Rep. 6, 34055 (2016).
87. Bauer, T. M. et al. Small intestinal bacterial overgrowth in human cirrhosis is associated with systemic endotoxemia. Am. J. Gastroenterol. 97, 2364-2370 (2002).
88. Bajaj, J. S. et al. Salivary microbiota reflects changes in gut microbiota in cirrhosis with hepatic encephalopathy. Hepatology 62, 1260-1271 (2015).
89. De Minicis, S. et al. Dysbiosis contributes to fibrogenesis in the course of chronic liver injury in mice. Hepatology 59, 1738-1749 (2014).
90. Loo, T. M. et al. Gut microbiota promotes obesity-associated liver cancer through PGE2-mediated suppression of antitumor immunity. Cancer Discov. 7, 522-538 (2017).
91. Lee, W. J. & Hase, K. Gut microbiota-generated metabolites in animal health and disease. Nat. Chem. Biol. 10, 416-424 (2014).
92. Fernandez, J. et al. Primary prophylaxis of spontaneous bacterial peritonitis delays hepatorenal syndrome and improves survival in cirrhosis. Gastroenterology 133, 818-824 (2007).
93. Vlachogiannakos, J. et al. Long-term administration of rifaximin improves the prognosis of patients with decompensated alcoholic cirrhosis. J. Gastroenterol. Hepatol. 28, 450-455 (2013).
94. Elfert, A., Abo Ali, L., Soliman, S., Ibrahim, S. & Abd-Elsalam, S. Randomized-controlled trial of rifaximin versus norfloxacin for secondary prophylaxis of spontaneous bacterial peritonitis. Eur. J. Gastroenterol. Hepatol. 28, 1450-1454 (2016).
95. Sharma, B. C. et al. A randomized, double-blind, controlled trial comparing rifaximin plus lactulose with lactulose alone in treatment of overt hepatic encephalopathy. Am. J. Gastroenterol. 108, 1458-1463 (2013).
96. Zhu, Q. et al. Intestinal decontamination inhibits TLR4 dependent fibronectin-mediated cross-talk between stellate cells and endothelial cells in liver fibrosis in mice. J. Hepatol. 56, 893-899 (2012).
97. Steib, C. J. et al. Intraperitoneal LPS amplifies portal hypertension in rat liver fibrosis. Lab. Invest. 90, 1024-1032 (2010).
98. Lutz, P. et al. Impact of rifaximin on the frequency and characteristics of spontaneous bacterial peritonitis in patients with liver cirrhosis and ascites. PLoS ONE 9, e93909 (2014).
99. Bass, N. M. et al. Rifaximin treatment in hepatic encephalopathy. N. Engl. J. Med. 362, 1071-1081 (2010).
100. Iida, N. et al. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science 342, 967-970 (2013).
101. Viaud, S. et al. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science 342, 971-976 (2013).
102. Vetizou, M. et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 350, 1079-1084 (2015).
103. Sivan, A. et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 350, 1084-1089 (2015).
104. Rakoff-Nahoum, S., Paglino, J., Eslami-Varzaneh, F., Edberg, S. & Medzhitov, R. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 118, 229-241 (2004).
105. Steffen, E. K., Berg, R. D. & Deitch, E. A. Comparison of translocation rates of various indigenous bacteria from the gastrointestinal tract to the mesenteric lymph node. J. Infect. Dis. 157, 1032-1038 (1988).
106. Navasa, M. et al. Randomized, comparative study of oral ofloxacin versus intravenous cefotaxime in spontaneous bacterial peritonitis. Gastroenterology 111, 1011-1017 (1996).
107. Bert, F. et al. Genetic diversity and virulence profiles of Escherichia coli isolates causing spontaneous bacterial peritonitis and bacteremia in patients with cirrhosis. J. Clin. Microbiol. 48, 2709-2714 (2010).
108. Jalan, R. et al. Bacterial infections in cirrhosis: a position statement based on the EASL Special Conference 2013. J. Hepatol. 60, 1310-1324 (2014).
109. Gines, P. et al. Norfloxacin prevents spontaneous bacterial peritonitis recurrence in cirrhosis: results of a double-blind, placebo-controlled trial. Hepatology 12, 716-724 (1990).
110. Fernandez, J. et al. Bacterial infections in cirrhosis: epidemiological changes with invasive procedures and norfloxacin prophylaxis. Hepatology 35, 140-148 (2002).
111. Fernandez, J. et al. Prevalence and risk factors of infections by multiresistant bacteria in cirrhosis: a prospective study. Hepatology 55, 1551-1561 (2012).
112. Tandon, P., Delisle, A., Topal, J. E. & Garcia-Tsao, G. High prevalence of antibiotic-resistant bacterial infections among patients with cirrhosis at a US liver center. Clin. Gastroenterol. Hepatol. 10, 1291-1298 (2012).
113. Koo, H. L. & DuPont, H. L. Rifaximin: a unique gastrointestinal-selective antibiotic for enteric diseases. Curr. Opin. Gastroenterol. 26, 17-25 (2010).
114. Vlachogiannakos, J. et al. Intestinal decontamination improves liver haemodynamics in patients with alcohol-related decompensated cirrhosis. Aliment. Pharmacol. Ther. 29, 992-999 (2009).
115. Kalambokis, G. N. et al. Rifaximin improves systemic hemodynamics and renal function in patients with alcohol-related cirrhosis and ascites. Clin. Gastroenterol. Hepatol. 10, 815-818 (2012).
116. Chen, P., Starkel, P., Turner, J. R., Ho, S. B. & Schnabl, B. Dysbiosis-induced intestinal inflammation activates tumor necrosis factor receptor I and mediates alcoholic liver disease in mice. Hepatology 61, 883-894 (2015).
117. Membrez, M. et al. Gut microbiota modulation with norfloxacin and ampicillin enhances glucose tolerance in mice. FASEB J. 22, 2416-2426 (2008).
118. Natividad, J. M. & Verdu, E. F. Modulation of intestinal barrier by intestinal microbiota: pathological and therapeutic implications. Pharmacol. Res. 69, 42-51 (2013).
119. Cesaro, C. et al. Gut microbiota and probiotics in chronic liver diseases. Dig. Liver Dis. 43, 431-438 (2011).
120. Li, J. et al. Probiotics modulated gut microbiota suppresses hepatocellular carcinoma growth in mice. Proc. Natl Acad. Sci. USA 113, E1306-E1315 (2016).
121. Dhiman, R. K. et al. Probiotic VSL#3 reduces liver disease severity and hospitalization in patients with cirrhosis: a randomized, controlled trial. Gastroenterology 147, 1327-1337. e3 (2014).
122. Alisi, A. et al. Randomised clinical trial: the beneficial effects of VSL#3 in obese children with non-alcoholic steatohepatitis. Aliment. Pharmacol. Ther. 39, 1276-1285 (2014).
123. Arthur, J. C. et al. VSL#3 probiotic modifies mucosal microbial composition but does not reduce colitis-associated colorectal cancer. Sci. Rep. 3, 2868 (2013).
124. US National Library of Medicine. ClinicalTrials. gov https://clinicaltrials. gov/ct2/show/NCT02496390 (2016).
125. US National Library of Medicine. ClinicalTrials. gov https://clinicaltrials. gov/ct2/show/NCT02862249 (2016).
126. Vrieze, A. et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology 143, 913-916. e7 (2012).
127. Kelly, C. P. Fecal microbiota transplantation-an old therapy comes of age. N. Engl. J. Med. 368, 474-475 (2013).
128. Piazza, M. et al. Glycolipids and benzylammonium lipids as novel antisepsis agents: synthesis and biological characterization. J. Med. Chem. 52, 1209-1213 (2009).
129. Peri, F. & Piazza, M. Therapeutic targeting of innate immunity with Toll-like receptor 4 (TLR4) antagonists. Biotechnol. Adv. 30, 251-260 (2012).
130. Barochia, A., Solomon, S., Cui, X., Natanson, C. & Eichacker, P. Q. Eritoran tetrasodium (E5564) treatment for sepsis: review of preclinical and clinical studies. Expert Opin. Drug Metab. Toxicol. 7, 479-494 (2011).
131. Naugler, W. E. et al. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 317, 121-124 (2007).
132. Opal, S. M. et al. Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: the ACCESS randomized trial. JAMA 309, 1154-1162 (2013).
133. Rice, T. W. et al. A randomized, double-blind, placebo-controlled trial of TAK-242 for the treatment of severe sepsis. Crit. Care Med. 38, 1685-1694 (2010).
134. Lorenzo-Zuniga, V. et al. Oral bile acids reduce bacterial overgrowth, bacterial translocation, and endotoxemia in cirrhotic rats. Hepatology 37, 551-557 (2003).
135. Ding, J. W., Andersson, R., Soltesz, V., Willen, R. & Bengmark, S. The role of bile and bile acids in bacterial translocation in obstructive jaundice in rats. Eur. Surg. Res. 25, 11-19 (1993).
136. Schaap, F. G., Trauner, M. & Jansen, P. L. Bile acid receptors as targets for drug development. Nat. Rev. Gastroenterol. Hepatol. 11, 55-67 (2014).
137. Thomas, C., Pellicciari, R., Pruzanski, M., Auwerx, J. & Schoonjans, K. Targeting bile-acid signalling for metabolic diseases. Nat. Rev. Drug Discov. 7, 678-693 (2008).
138. Degirolamo, C. et al. Prevention of spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice by intestinal-specific farnesoid X receptor reactivation. Hepatology 61, 161-170 (2015).
139. Marschall, H.-U. et al. The farnesoid X receptor (FXR) agonist (OCA) increases plasma FGF-19 concentrations and decreases bile acid synthesis in primary biliary cirrhosis (PBC). J. Hepatol. 56, S377 (2012).
140. Kim, I. et al. Spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice. Carcinogenesis 28, 940-946 (2007).
141. Verbeke, L. et al. The FXR agonist obeticholic acid prevents gut barrier dysfunction and bacterial translocation in cholestatic rats. Am. J. Pathol. 185, 409-419 (2015).
142. Ubeda, M. et al. Obeticholic acid reduces bacterial translocation and inhibits intestinal inflammation in cirrhotic rats. J. Hepatol. 64, 1049-1057 (2016).
143. Verbeke, L. et al. Obeticholic acid, a farnesoid X receptor agonist, improves portal hypertension by two distinct pathways in cirrhotic rats. Hepatology 59, 2286-2298 (2014).
144. Neuschwander-Tetri, B. A. et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 385, 956-965 (2015).
145. Munoz, L. et al. Mesenteric Th1 polarization and monocyte TNF-alpha production: first steps to systemic inflammation in rats with cirrhosis. Hepatology 42, 411-419 (2005).
146. Genesca, J. et al. Increased tumour necrosis factor alpha production in mesenteric lymph nodes of cirrhotic patients with ascites. Gut 52, 1054-1059 (2003).
147. Taylor, C. T., Dzus, A. L. & Colgan, S. P. Autocrine regulation of epithelial permeability by hypoxia: role for polarized release of tumor necrosis factor alpha. Gastroenterology 114, 657-668 (1998).
148. Frances, R. et al. Bacterial translocation is downregulated by anti-TNF-alpha monoclonal antibody administration in rats with cirrhosis and ascites. J. Hepatol. 46, 797-803 (2007).
149. Kalaitzakis, E. Gastrointestinal dysfunction in liver cirrhosis. World J. Gastroenterol. 20, 14686-14695 (2014).
150. Pardo, A. et al. Effect of cisapride on intestinal bacterial overgrowth and bacterial translocation in cirrhosis. Hepatology 31, 858-863 (2000).
151. Zhang, S. C. et al. Effect of cisapride on intestinal bacterial and endotoxin translocation in cirrhosis. World J. Gastroenterol. 9, 534-538 (2003).
152. Madrid, A. M., Hurtado, C., Venegas, M., Cumsille, F. & Defilippi, C. Long-term treatment with cisapride and antibiotics in liver cirrhosis: effect on small intestinal motility, bacterial overgrowth, and liver function. Am. J. Gastroenterol. 96, 1251-1255 (2001).
153. Perez-Paramo, M. et al. Effect of propranolol on the factors promoting bacterial translocation in cirrhotic rats with ascites. Hepatology 31, 43-48 (2000).
154. Madsen, B. S., Havelund, T. & Krag, A. Targeting the gut-liver axis in cirrhosis: antibiotics and non-selective beta-blockers. Adv. Ther. 30, 659-670 (2013).
155. Mookerjee, R. P. et al. Treatment with non-selective beta blockers is associated with reduced severity of systemic inflammation and improved survival of patients with acute-on-chronic liver failure. J. Hepatol. 64, 574-582 (2016).
156. Senzolo, M. et al. Oral propranolol decreases intestinal permeability in patients with cirrhosis: another protective mechanism against bleeding? Am. J. Gastroenterol. 104, 3115-3116 (2009).
157. Senzolo, M. et al. ?-blockers protect against spontaneous bacterial peritonitis in cirrhotic patients: a meta-analysis. Liver Int. 29, 1189-1193 (2009).
158. Nkontchou, G. et al. Effect of long-term propranolol treatment on hepatocellular carcinoma incidence in patients with HCV-associated cirrhosis. Cancer Prev. Res. (Phila.) 5, 1007-1014 (2012).
159. De Santis, S., Cavalcanti, E., Mastronardi, M., Jirillo, E. & Chieppa, M. Nutritional keys for intestinal barrier modulation. Front. Immunol. 6, 612 (2015).
160. Zapater, P. et al. Norfloxacin modulates the inflammatory response and directly affects neutrophils in patients with decompensated cirrhosis. Gastroenterology 137, 1669-1679. e1 (2009).
161. Frances, R. et al. Bacterial DNA in patients with cirrhosis and noninfected ascites mimics the soluble immune response established in patients with spontaneous bacterial peritonitis. Hepatology 47, 978-985 (2008).