Gut Microbiome and Liver Diseases: Comparison
Please note this is a comparison between Version 2 by Conner Chen and Version 1 by Tao Zuo.

The important role of human gut microbiota in liver diseases has long been recognized as dysbiosis and the translocation of certain microbes from the gut to liver. With the development of high-throughput DNA sequencing, the complexity and integrity of the gut microbiome in the whole spectrum of liver diseases is emerging. Specific patterns of gut microbiota have been identified in liver diseases with different causes, including alcoholic, non-alcoholic, and virus induced liver diseases, or even at different stages, ranging from steatohepatitis, fibrosis, cirrhosis, to hepatocellular carcinoma. At the same time, the mechanism of how microbiota contributes to liver diseases goes beyond the traditional function of the gut–liver axis which could lead to liver injury and inflammation.

  • gut microbiota
  • chronic liver diseases
  • metabolites
  • immune system
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References

  1. Tripathi, A.; Debelius, J.; Brenner, D.A.; Karin, M.; Loomba, R.; Schnabl, B.; Knight, R. The gut-liver axis and the intersection with the microbiome. Nat. Rev. Gastroenterol. Hepatol. 2018, 15, 397–411.
  2. Schnabl, B.; Brenner, D.A. Interactions between the intestinal microbiome and liver diseases. Gastroenterology 2014, 146, 1513–1524.
  3. Tilg, H.; Cani, P.D.; Mayer, E.A. Gut microbiome and liver diseases. Gut 2016, 65, 2035–2044.
  4. Marchesi, J.R.; Adams, D.H.; Fava, F.; Hermes, G.D.; Hirschfield, G.M.; Hold, G.; Quraishi, M.N.; Kinross, J.; Smidt, H.; Tuohy, K.M.; et al. The gut microbiota and host health: A new clinical frontier. Gut 2016, 65, 330–339.
  5. Asrani, S.K.; Devarbhavi, H.; Eaton, J.; Kamath, P.S. Burden of liver diseases in the world. J. Hepatol. 2019, 70, 151–171.
  6. Dapito, D.H.; Mencin, A.; Gwak, G.Y.; Pradere, J.P.; Jang, M.K.; Mederacke, I.; Caviglia, J.M.; Khiabanian, H.; Adeyemi, A.; Bataller, R.; et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell 2012, 21, 504–516.
  7. Boursier, J.; Mueller, O.; Barret, M.; Machado, M.; Fizanne, L.; Araujo-Perez, F.; Guy, C.D.; Seed, P.C.; Rawls, J.F.; David, L.A.; 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 2016, 63, 764–775.
  8. Ponziani, F.R.; Bhoori, S.; Castelli, C.; Putignani, L.; Rivoltini, L.; Del Chierico, F.; Sanguinetti, M.; Morelli, D.; Paroni Sterbini, F.; Petito, V.; et al. Hepatocellular Carcinoma Is Associated With Gut Microbiota Profile and Inflammation in Nonalcoholic Fatty Liver Disease. Hepatology 2019, 69, 107–120.
  9. Dubinkina, V.B.; Tyakht, A.V.; Odintsova, V.Y.; Yarygin, K.S.; Kovarsky, B.A.; Pavlenko, A.V.; Ischenko, D.S.; Popenko, A.S.; Alexeev, D.G.; Taraskina, A.Y.; et al. Links of gut microbiota composition with alcohol dependence syndrome and alcoholic liver disease. Microbiome 2017, 5, 141.
  10. Hoyles, L.; Fernandez-Real, J.M.; Federici, M.; Serino, M.; Abbott, J.; Charpentier, J.; Heymes, C.; Luque, J.L.; Anthony, E.; Barton, R.H.; et al. Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women. Nat. Med. 2018, 24, 1070–1080.
  11. Ma, C.; Han, M.; Heinrich, B.; Fu, Q.; Zhang, Q.; Sandhu, M.; Agdashian, D.; Terabe, M.; Berzofsky, J.A.; Fako, V.; et al. Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells. Science 2018, 360.
  12. Csak, T.; Ganz, M.; Pespisa, J.; Kodys, K.; Dolganiuc, A.; Szabo, G. Fatty acid and endotoxin activate inflammasomes in mouse hepatocytes that release danger signals to stimulate immune cells. Hepatology 2011, 54, 133–144.
  13. Zuo, T.; Zhang, F.; Lui, G.C.Y.; Yeoh, Y.K.; Li, A.Y.L.; Zhan, H.; Wan, Y.; Chung, A.; Cheung, C.P.; Chen, N.; et al. Alterations in Gut Microbiota of Patients With COVID-19 During Time of Hospitalization. Gastroenterology 2020.
  14. Phipps, M.M.; Barraza, L.H.; LaSota, E.D.; Sobieszczyk, M.E.; Pereira, M.R.; Zheng, E.X.; Fox, A.N.; Zucker, J.; Verna, E.C. Acute Liver Injury in COVID-19: Prevalence and Association with Clinical Outcomes in a Large US Cohort. Hepatology 2020.
  15. Ferrere, G.; Wrzosek, L.; Cailleux, F.; Turpin, W.; Puchois, V.; Spatz, M.; Ciocan, D.; Rainteau, D.; Humbert, L.; Hugot, C.; et al. Fecal microbiota manipulation prevents dysbiosis and alcohol-induced liver injury in mice. J. Hepatol. 2017, 66, 806–815.
  16. Liu, Q.; Duan, Z.P.; Ha, D.K.; Bengmark, S.; Kurtovic, J.; Riordan, S.M. Synbiotic modulation of gut flora: Effect on minimal hepatic encephalopathy in patients with cirrhosis. Hepatology 2004, 39, 1441–1449.
  17. Loomba, R.; Seguritan, V.; Li, W.; Long, T.; Klitgord, N.; Bhatt, A.; Dulai, P.S.; Caussy, C.; Bettencourt, R.; Highlander, S.K.; et al. Gut Microbiome-Based Metagenomic Signature for Non-invasive Detection of Advanced Fibrosis in Human Nonalcoholic Fatty Liver Disease. Cell Metab. 2017, 25, 1054–1062.e1055.
  18. Day, C.P.; James, O.F. Steatohepatitis: A tale of two “hits”? Gastroenterology 1998, 114, 842–845.
  19. Tilg, H.; Moschen, A.R. Evolution of inflammation in nonalcoholic fatty liver disease: The multiple parallel hits hypothesis. Hepatology 2010, 52, 1836–1846.
  20. Wieland, A.; Frank, D.N.; Harnke, B.; Bambha, K. Systematic review: Microbial dysbiosis and nonalcoholic fatty liver disease. Aliment Pharmacol. Ther. 2015, 42, 1051–1063.
  21. Le Chatelier, E.; Nielsen, T.; Qin, J.; Prifti, E.; Hildebrand, F.; Falony, G.; Almeida, M.; Arumugam, M.; Batto, J.M.; Kennedy, S.; et al. Richness of human gut microbiome correlates with metabolic markers. Nature 2013, 500, 541–546.
  22. Perry, R.J.; Peng, L.; Barry, N.A.; Cline, G.W.; Zhang, D.; Cardone, R.L.; Petersen, K.F.; Kibbey, R.G.; Goodman, A.L.; Shulman, G.I. Acetate mediates a microbiome-brain-beta-cell axis to promote metabolic syndrome. Nature 2016, 534, 213–217.
  23. Qin, J.; Li, Y.; Cai, Z.; Li, S.; Zhu, J.; Zhang, F.; Liang, S.; Zhang, W.; Guan, Y.; Shen, D.; et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature 2012, 490, 55–60.
  24. Wang, Z.; Klipfell, E.; Bennett, B.J.; Koeth, R.; Levison, B.S.; Dugar, B.; Feldstein, A.E.; Britt, E.B.; Fu, X.; Chung, Y.M.; et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 2011, 472, 57–63.
  25. Forslund, K.; Hildebrand, F.; Nielsen, T.; Falony, G.; Le Chatelier, E.; Sunagawa, S.; Prifti, E.; Vieira-Silva, S.; Gudmundsdottir, V.; Pedersen, H.K.; et al. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature 2015, 528, 262–266.
  26. Ley, R.E.; Turnbaugh, P.J.; Klein, S.; Gordon, J.I. Microbial ecology: Human gut microbes associated with obesity. Nature 2006, 444, 1022–1023.
  27. Schwiertz, A.; Taras, D.; Schafer, K.; Beijer, S.; Bos, N.A.; Donus, C.; Hardt, P.D. Microbiota and SCFA in lean and overweight healthy subjects. Obesity 2010, 18, 190–195.
  28. Pedersen, H.K.; Gudmundsdottir, V.; Nielsen, H.B.; Hyotylainen, T.; Nielsen, T.; Jensen, B.A.; Forslund, K.; Hildebrand, F.; Prifti, E.; Falony, G.; et al. Human gut microbes impact host serum metabolome and insulin sensitivity. Nature 2016, 535, 376–381.
  29. Zhu, L.; Baker, S.S.; Gill, C.; Liu, W.; Alkhouri, R.; Baker, R.D.; Gill, S.R. Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: A connection between endogenous alcohol and NASH. Hepatology 2013, 57, 601–609.
  30. Mouzaki, M.; Comelli, E.M.; Arendt, B.M.; Bonengel, J.; Fung, S.K.; Fischer, S.E.; McGilvray, I.D.; Allard, J.P. Intestinal microbiota in patients with nonalcoholic fatty liver disease. Hepatology 2013, 58, 120–127.
  31. Wong, V.W.; Tse, C.H.; Lam, T.T.; Wong, G.L.; Chim, A.M.; Chu, W.C.; Yeung, D.K.; Law, P.T.; Kwan, H.S.; Yu, J.; et al. Molecular characterization of the fecal microbiota in patients with nonalcoholic steatohepatitis—A longitudinal study. PLoS ONE 2013, 8, e62885.
  32. Yuan, J.; Chen, C.; Cui, J.; Lu, J.; Yan, C.; Wei, X.; Zhao, X.; Li, N.; Li, S.; Xue, G.; et al. Fatty Liver Disease Caused by High-Alcohol-Producing Klebsiella pneumoniae. Cell Metab. 2019, 30, 1172.
  33. Spencer, M.D.; Hamp, T.J.; Reid, R.W.; Fischer, L.M.; Zeisel, S.H.; Fodor, A.A. Association between composition of the human gastrointestinal microbiome and development of fatty liver with choline deficiency. Gastroenterology 2011, 140, 976–986.
  34. Raman, M.; Ahmed, I.; Gillevet, P.M.; Probert, C.S.; Ratcliffe, N.M.; Smith, S.; Greenwood, R.; Sikaroodi, M.; Lam, V.; Crotty, P.; et al. Fecal microbiome and volatile organic compound metabolome in obese humans with nonalcoholic fatty liver disease. Clin. Gastroenterol. Hepatol. 2013, 11, 868.e861–875.e863.
  35. Backhed, F.; Manchester, J.K.; Semenkovich, C.F.; Gordon, J.I. Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc. Natl. Acad. Sci. USA 2007, 104, 979–984.
  36. Rabot, S.; Membrez, M.; Bruneau, A.; Gerard, P.; Harach, T.; Moser, M.; Raymond, F.; Mansourian, R.; Chou, C.J. Germ-free C57BL/6J. mice are resistant to high-fat-diet-induced insulin resistance and have altered cholesterol metabolism. FASEB J. 2010, 24, 4948–4959.
  37. Backhed, F.; Ding, H.; Wang, T.; Hooper, L.V.; Koh, G.Y.; Nagy, A.; Semenkovich, C.F.; Gordon, J.I. The gut microbiota as an environmental factor that regulates fat storage. Proc. Natl. Acad. Sci. USA 2004, 101, 15718–15723.
  38. Turnbaugh, P.J.; Ley, R.E.; Mahowald, M.A.; Magrini, V.; Mardis, E.R.; Gordon, J.I. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 2006, 444, 1027–1031.
  39. Le Roy, T.; Llopis, M.; Lepage, P.; Bruneau, A.; Rabot, S.; Bevilacqua, C.; Martin, P.; Philippe, C.; Walker, F.; Bado, A.; et al. Intestinal microbiota determines development of non-alcoholic fatty liver disease in mice. Gut 2013, 62, 1787–1794.
  40. Mutlu, E.A.; Gillevet, P.M.; Rangwala, H.; Sikaroodi, M.; Naqvi, A.; Engen, P.A.; Kwasny, M.; Lau, C.K.; Keshavarzian, A. Colonic microbiome is altered in alcoholism. Am. J. Physiol. Gastrointest. Liver Physiol. 2012, 302, G966–G978.
  41. Chen, Y.; Yang, F.; Lu, H.; Wang, B.; Chen, Y.; Lei, D.; Wang, Y.; Zhu, B.; Li, L. Characterization of fecal microbial communities in patients with liver cirrhosis. Hepatology 2011, 54, 562–572.
  42. Bajaj, J.S.; Heuman, D.M.; Hylemon, P.B.; Sanyal, A.J.; White, M.B.; Monteith, P.; Noble, N.A.; Unser, A.B.; Daita, K.; Fisher, A.R.; et al. Altered profile of human gut microbiome is associated with cirrhosis and its complications. J. Hepatol. 2014, 60, 940–947.
  43. Qin, N.; Yang, F.; Li, A.; Prifti, E.; Chen, Y.; Shao, L.; Guo, J.; Le Chatelier, E.; Yao, J.; Wu, L.; et al. Alterations of the human gut microbiome in liver cirrhosis. Nature 2014, 513, 59–64.
  44. Caussy, C.; Tripathi, A.; Humphrey, G.; Bassirian, S.; Singh, S.; Faulkner, C.; Bettencourt, R.; Rizo, E.; Richards, L.; Xu, Z.Z.; et al. A gut microbiome signature for cirrhosis due to nonalcoholic fatty liver disease. Nat. Commun. 2019, 10, 1406.
  45. Seitz, H.K.; Bataller, R.; Cortez-Pinto, H.; Gao, B.; Gual, A.; Lackner, C.; Mathurin, P.; Mueller, S.; Szabo, G.; Tsukamoto, H. Alcoholic liver disease. Nat. Rev. Dis. Primers 2018, 4, 16.
  46. Vassallo, G.; Mirijello, A.; Ferrulli, A.; Antonelli, M.; Landolfi, R.; Gasbarrini, A.; Addolorato, G. Review article: Alcohol and gut microbiota—The possible role of gut microbiota modulation in the treatment of alcoholic liver disease. Aliment Pharmacol. Ther. 2015, 41, 917–927.
  47. Bode, J.C.; Bode, C.; Heidelbach, R.; Durr, H.K.; Martini, G.A. Jejunal microflora in patients with chronic alcohol abuse. Hepatogastroenterology 1984, 31, 30–34.
  48. Tuomisto, S.; Pessi, T.; Collin, P.; Vuento, R.; Aittoniemi, J.; Karhunen, P.J. Changes in gut bacterial populations and their translocation into liver and ascites in alcoholic liver cirrhotics. BMC Gastroenterol. 2014, 14, 40.
  49. Yan, A.W.; Fouts, D.E.; Brandl, J.; Starkel, P.; Torralba, M.; Schott, E.; Tsukamoto, H.; Nelson, K.E.; Brenner, D.A.; Schnabl, B. Enteric dysbiosis associated with a mouse model of alcoholic liver disease. Hepatology 2011, 53, 96–105.
  50. Canesso, M.C.; Lacerda, N.L.; Ferreira, C.M.; Gonçalves, J.L.; Almeida, D.; Gamba, C.; Cassali, G.; Pedroso, S.H.; Moreira, C.; Martins, F.S.; et al. Comparing the effects of acute alcohol consumption in germ-free and conventional mice: The role of the gut microbiota. BMC Microbiol. 2014, 14, 240.
  51. Chen, P.; Schnabl, B. Host-microbiome interactions in alcoholic liver disease. Gut Liver 2014, 8, 237–241.
  52. Bjarnason, I.; Peters, T.J.; Wise, R.J. The leaky gut of alcoholism: Possible route of entry for toxic compounds. Lancet 1984, 1, 179–182.
  53. Keshavarzian, A.; Holmes, E.W.; Patel, M.; Iber, F.; Fields, J.Z.; Pethkar, S. Leaky gut in alcoholic cirrhosis: A possible mechanism for alcohol-induced liver damage. Am. J. Gastroenterol. 1999, 94, 200–207.
  54. Rao, R. Endotoxemia and gut barrier dysfunction in alcoholic liver disease. Hepatology 2009, 50, 638–644.
  55. Ferrier, L.; Berard, F.; Debrauwer, L.; Chabo, C.; Langella, P.; Bueno, L.; Fioramonti, J. Impairment of the intestinal barrier by ethanol involves enteric microflora and mast cell activation in rodents. Am. J. Pathol. 2006, 168, 1148–1154.
  56. Keshavarzian, A.; Choudhary, S.; Holmes, E.W.; Yong, S.; Banan, A.; Jakate, S.; Fields, J.Z. Preventing gut leakiness by oats supplementation ameliorates alcohol-induced liver damage in rats. J. Pharmacol. Exp. Ther. 2001, 299, 442–448.
  57. Keshavarzian, A.; Farhadi, A.; Forsyth, C.B.; Rangan, J.; Jakate, S.; Shaikh, M.; Banan, A.; Fields, J.Z. Evidence that chronic alcohol exposure promotes intestinal oxidative stress, intestinal hyperpermeability and endotoxemia prior to development of alcoholic steatohepatitis in rats. J. Hepatol. 2009, 50, 538–547.
  58. Kirpich, I.A.; Solovieva, N.V.; Leikhter, S.N.; Shidakova, N.A.; Lebedeva, O.V.; Sidorov, P.I.; Bazhukova, T.A.; Soloviev, A.G.; Barve, S.S.; McClain, C.J.; et al. Probiotics restore bowel flora and improve liver enzymes in human alcohol-induced liver injury: A pilot study. Alcohol 2008, 42, 675–682.
  59. Philips, C.A.; Pande, A.; Shasthry, S.M.; Jamwal, K.D.; Khillan, V.; Chandel, S.S.; Kumar, G.; Sharma, M.K.; Maiwall, R.; Jindal, A.; et al. Healthy Donor Fecal Microbiota Transplantation in Steroid-Ineligible Severe Alcoholic Hepatitis: A Pilot Study. Clin. Gastroenterol. Hepatol. 2017, 15, 600–602.
  60. Grander, C.; Adolph, T.E.; Wieser, V.; Lowe, P.; Wrzosek, L.; Gyongyosi, B.; Ward, D.V.; Grabherr, F.; Gerner, R.R.; Pfister, A.; et al. Recovery of ethanol-induced Akkermansia muciniphila depletion ameliorates alcoholic liver disease. Gut 2018, 67, 891–901.
  61. Ahluwalia, V.; Betrapally, N.S.; Hylemon, P.B.; White, M.B.; Gillevet, P.M.; Unser, A.B.; Fagan, A.; Daita, K.; Heuman, D.M.; Zhou, H.; et al. Impaired Gut-Liver-Brain Axis in Patients with Cirrhosis. Sci. Rep. 2016, 6, 26800.
  62. Yanguas, S.C.; Cogliati, B.; Willebrords, J.; Maes, M.; Colle, I.; van den Bossche, B.; de Oliveira, C.; Andraus, W.; Alves, V.A.F.; Leclercq, I.; et al. Experimental models of liver fibrosis. Arch. Toxicol. 2016, 90, 1025–1048.
  63. 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. 2012, 56, 1283–1292.
  64. Brenner, D.A.; Paik, Y.H.; Schnabl, B. Role of Gut Microbiota in Liver Disease. J. Clin. Gastroenterol. 2015, 49 (Suppl. 1), S25–S27.
  65. Hugenholtz, F.; de Vos, W.M. Mouse models for human intestinal microbiota research: A critical evaluation. Cell Mol. Life Sci. 2018, 75, 149–160.
  66. Walter, J.; Armet, A.M.; Finlay, B.B.; Shanahan, F. Establishing or Exaggerating Causality for the Gut Microbiome: Lessons from Human Microbiota-Associated Rodents. Cell 2020, 180, 221–232.
  67. Fessler, J.; Matson, V.; Gajewski, T.F. Exploring the emerging role of the microbiome in cancer immunotherapy. J. Immunother. Cancer 2019, 7, 108.
  68. Grat, M.; Wronka, K.M.; Krasnodebski, M.; Masior, L.; Lewandowski, Z.; Kosinska, I.; Grat, K.; Stypulkowski, J.; Rejowski, S.; Wasilewicz, M.; et al. Profile of Gut Microbiota Associated With the Presence of Hepatocellular Cancer in Patients With Liver Cirrhosis. Transpl. Proc. 2016, 48, 1687–1691.
  69. Huang, Y.; Fan, X.G.; Wang, Z.M.; Zhou, J.H.; Tian, X.F.; Li, N. Identification of helicobacter species in human liver samples from patients with primary hepatocellular carcinoma. J. Clin. Pathol. 2004, 57, 1273–1277.
  70. Yoshimoto, S.; Loo, T.M.; Atarashi, K.; Kanda, H.; Sato, S.; Oyadomari, S.; Iwakura, Y.; Oshima, K.; Morita, H.; Hattori, M.; et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 2013, 499, 97–101.
  71. Gopalakrishnan, V.; Spencer, C.N.; Nezi, L.; Reuben, A.; Andrews, M.C.; Karpinets, T.V.; Prieto, P.A.; Vicente, D.; Hoffman, K.; Wei, S.C.; et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 2018, 359, 97–103.
  72. Viaud, S.; Saccheri, F.; Mignot, G.; Yamazaki, T.; Daillere, R.; Hannani, D.; Enot, D.P.; Pfirschke, C.; Engblom, C.; Pittet, M.J.; et al. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science 2013, 342, 971–976.
  73. Yu, L.X.; Schwabe, R.F. The gut microbiome and liver cancer: Mechanisms and clinical translation. Nat. Rev. Gastroenterol. Hepatol. 2017, 14, 527–539.
  74. Bajaj, J.S.; Betrapally, N.S.; Hylemon, P.B.; Heuman, D.M.; Daita, K.; White, M.B.; Unser, A.; Thacker, L.R.; Sanyal, A.J.; Kang, D.J.; et al. Salivary microbiota reflects changes in gut microbiota in cirrhosis with hepatic encephalopathy. Hepatology 2015, 62, 1260–1271.
  75. Bajaj, J.S.; Hylemon, P.B.; Ridlon, J.M.; Heuman, D.M.; Daita, K.; White, M.B.; Monteith, P.; Noble, N.A.; Sikaroodi, M.; Gillevet, P.M. Colonic mucosal microbiome differs from stool microbiome in cirrhosis and hepatic encephalopathy and is linked to cognition and inflammation. Am. J. Physiol. Gastrointest. Liver Physiol. 2012, 303, G675–G685.
  76. Bajaj, J.S.; Betrapally, N.S.; Hylemon, P.B.; Thacker, L.R.; Daita, K.; Kang, D.J.; White, M.B.; Unser, A.B.; Fagan, A.; Gavis, E.A.; et al. Gut Microbiota Alterations can predict Hospitalizations in Cirrhosis Independent of Diabetes Mellitus. Sci. Rep. 2015, 5, 18559.
  77. Chen, Y.; Ji, F.; Guo, J.; Shi, D.; Fang, D.; Li, L. Dysbiosis of small intestinal microbiota in liver cirrhosis and its association with etiology. Sci. Rep. 2016, 6, 34055.
  78. Lloyd-Price, J.; Abu-Ali, G.; Huttenhower, C. The healthy human microbiome. Genome Med. 2016, 8, 51.
  79. Bajaj, J.S.; Liu, E.J.; Kheradman, R.; Fagan, A.; Heuman, D.M.; White, M.; Gavis, E.A.; Hylemon, P.; Sikaroodi, M.; Gillevet, P.M. Fungal dysbiosis in cirrhosis. Gut 2018, 67, 1146–1154.
  80. Yang, A.M.; Inamine, T.; Hochrath, K.; Chen, P.; Wang, L.; Llorente, C.; Bluemel, S.; Hartmann, P.; Xu, J.; Koyama, Y.; et al. Intestinal fungi contribute to development of alcoholic liver disease. J. Clin. Investig. 2017, 127, 2829–2841.
  81. Lang, S.; Demir, M.; Martin, A.; Jiang, L.; Zhang, X.; Duan, Y.; Gao, B.; Wisplinghoff, H.; Kasper, P.; Roderburg, C.; et al. Intestinal Virome Signature Associated With Severity of Nonalcoholic Fatty Liver Disease. Gastroenterology 2020, 159, 1839–1852.
  82. Jiang, L.; Lang, S.; Duan, Y.; Zhang, X.; Gao, B.; Chopyk, J.; Schwanemann, L.K.; Ventura-Cots, M.; Bataller, R.; Bosques-Padilla, F.; et al. Intestinal Virome in Patients With Alcoholic Hepatitis. Hepatology 2020, 72, 2182–2196.
  83. Bajaj, J.S.; Sikaroodi, M.; Shamsaddini, A.; Henseler, Z.; Santiago-Rodriguez, T.; Acharya, C.; Fagan, A.; Hylemon, P.B.; Fuchs, M.; Gavis, E.; et al. Interaction of bacterial metagenome and virome in patients with cirrhosis and hepatic encephalopathy. Gut 2020.
  84. Duan, Y.; Llorente, C.; Lang, S.; Brandl, K.; Chu, H.; Jiang, L.; White, R.C.; Clarke, T.H.; Nguyen, K.; Torralba, M.; et al. Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease. Nature 2019, 575, 505–511.
  85. Aguilar-Toalá, J.; Garcia-Varela, R.; Garcia, H.; Mata-Haro, V.; González-Córdova, A.; Vallejo-Cordoba, B.; Hernández-Mendoza, A. Postbiotics: An evolving term within the functional foods field. Trends Food Sci. Technol. 2018, 75, 105–114.
  86. Haileselassie, Y.; Navis, M.; Vu, N.; Qazi, K.R.; Rethi, B.; Sverremark-Ekström, E. Postbiotic modulation of retinoic acid imprinted mucosal-like dendritic cells by probiotic Lactobacillus reuteri 17938 in vitro. Front. Immunol. 2016, 7, 96.
  87. Gómez-Guzmán, M.; Toral, M.; Romero, M.; Jiménez, R.; Galindo, P.; Sánchez, M.; Zarzuelo, M.J.; Olivares, M.; Gálvez, J.; Duarte, J. Antihypertensive effects of probiotics Lactobacillus strains in spontaneously hypertensive rats. Mol. Nutr. Food Res. 2015, 59, 2326–2336.
  88. Xu, R.; Shang, N.; Li, P. In vitro and in vivo antioxidant activity of exopolysaccharide fractions from Bifidobacterium animalis RH. Anaerobe 2011, 17, 226–231.
  89. Jensen, B.A.H.; Holm, J.B.; Larsen, I.S.; von Burg, N.; Derer, S.; Sonne, S.B.; Paerregaard, S.I.; Damgaard, M.V.; Indrelid, S.A.; Rivollier, A.; et al. Lysates of Methylococcus capsulatus Bath induce a lean-like microbiota, intestinal FoxP3(+)RORgammat(+)IL-17(+) Tregs and improve metabolism. Nat. Commun. 2021, 12, 1093.
  90. Russo, E.; Giudici, F.; Fiorindi, C.; Ficari, F.; Scaringi, S.; Amedei, A. Immunomodulating Activity and Therapeutic Effects of Short Chain Fatty Acids and Tryptophan Post-biotics in Inflammatory Bowel Disease. Front. Immunol. 2019, 10, 2754.
  91. Homayouni Rad, A.; Aghebati Maleki, L.; Samadi Kafil, H.; Fathi Zavoshti, H.; Abbasi, A. Postbiotics as Promising Tools for Cancer Adjuvant Therapy. Adv. Pharm. Bull. 2021, 11, 1–5.
  92. Ridlon, J.M.; Bajaj, J.S. The human gut sterolbiome: Bile acid-microbiome endocrine aspects and therapeutics. Acta Pharm. Sin. B 2015, 5, 99–105.
  93. Abu-Shanab, A.; Quigley, E.M. The role of the gut microbiota in nonalcoholic fatty liver disease. Nat. Rev. Gastroenterol. Hepatol. 2010, 7, 691–701.
  94. Lambertucci, F.; Arboatti, A.; Sedlmeier, M.G.; Motino, O.; Alvarez, M.L.; Ceballos, M.P.; Villar, S.R.; Roggero, E.; Monti, J.A.; Pisani, G.; et al. Disruption of tumor necrosis factor alpha receptor 1 signaling accelerates NAFLD progression in mice upon a high-fat diet. J. Nutr. Biochem. 2018, 58, 17–27.
  95. Gorjifard, S.; Goldszmid, R.S. Microbiota-myeloid cell crosstalk beyond the gut. J. Leukoc. Biol. 2016, 100, 865–879.
  96. Vaikunthanathan, T.; Safinia, N.; Lombardi, G.; Lechler, R.I. Microbiota, immunity and the liver. Immunol. Lett. 2016, 171, 36–49.
  97. Brestoff, J.R.; Artis, D. Commensal bacteria at the interface of host metabolism and the immune system. Nat. Immunol. 2013, 14, 676–684.
  98. Zelante, T.; Iannitti, R.G.; Cunha, C.; De Luca, A.; Giovannini, G.; Pieraccini, G.; Zecchi, R.; D’Angelo, C.; Massi-Benedetti, C.; Fallarino, F.; et al. Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity 2013, 39, 372–385.
  99. Sayin, S.I.; Wahlstrom, A.; Felin, J.; Jantti, S.; Marschall, H.U.; Bamberg, K.; Angelin, B.; Hyotylainen, T.; Oresic, M.; Backhed, F. Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab. 2013, 17, 225–235.
  100. Hylemon, P.B.; Zhou, H.; Pandak, W.M.; Ren, S.; Gil, G.; Dent, P. Bile acids as regulatory molecules. J. Lipid Res. 2009, 50, 1509–1520.
  101. Clausen, M.R.; Mortensen, P.B. Kinetic studies on colonocyte metabolism of short chain fatty acids and glucose in ulcerative colitis. Gut 1995, 37, 684–689.
  102. Musso, G.; Gambino, R.; Cassader, M. Obesity, diabetes, and gut microbiota: The hygiene hypothesis expanded? Diabetes Care 2010, 33, 2277–2284.
  103. Den Besten, G.; Bleeker, A.; Gerding, A.; van Eunen, K.; Havinga, R.; van Dijk, T.H.; Oosterveer, M.H.; Jonker, J.W.; Groen, A.K.; Reijngoud, D.J.; et al. Short-Chain Fatty Acids Protect Against High-Fat Diet-Induced Obesity via a PPARgamma-Dependent Switch From Lipogenesis to Fat Oxidation. Diabetes 2015, 64, 2398–2408.
  104. Furusawa, Y.; Obata, Y.; Fukuda, S.; Endo, T.A.; Nakato, G.; Takahashi, D.; Nakanishi, Y.; Uetake, C.; Kato, K.; Kato, T.; et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 2013, 504, 446–450.
  105. Lieber, C.S. Alcoholic fatty liver: Its pathogenesis and mechanism of progression to inflammation and fibrosis. Alcohol 2004, 34, 9–19.
  106. Hoek, J.B.; Pastorino, J.G. Ethanol, oxidative stress, and cytokine-induced liver cell injury. Alcohol 2002, 27, 63–68.
  107. Mehedint, M.G.; Zeisel, S.H. Choline’s role in maintaining liver function: New evidence for epigenetic mechanisms. Curr. Opin. Clin. Nutr. Metab. Care 2013, 16, 339–345.
  108. Chen, Y.M.; Liu, Y.; Zhou, R.F.; Chen, X.L.; Wang, C.; Tan, X.Y.; Wang, L.J.; Zheng, R.D.; Zhang, H.W.; Ling, W.H.; et al. Associations of gut-flora-dependent metabolite trimethylamine-N-oxide, betaine and choline with non-alcoholic fatty liver disease in adults. Sci. Rep. 2016, 6, 19076.
  109. Abreu, M.T. Toll-like receptor signalling in the intestinal epithelium: How bacterial recognition shapes intestinal function. Nat. Rev. Immunol. 2010, 10, 131–144.
  110. Mencin, A.; Kluwe, J.; Schwabe, R.F. Toll-like receptors as targets in chronic liver diseases. Gut 2009, 58, 704–720.
  111. Jones, B.V.; Begley, M.; Hill, C.; Gahan, C.G.; Marchesi, J.R. Functional and comparative metagenomic analysis of bile salt hydrolase activity in the human gut microbiome. Proc. Natl. Acad. Sci. USA 2008, 105, 13580–13585.
  112. Ridlon, J.M.; Kang, D.J.; Hylemon, P.B. Bile salt biotransformations by human intestinal bacteria. J. Lipid Res. 2006, 47, 241–259.
  113. Kellogg, T.F.; Wostmann, B.S. Fecal neutral steroids and bile acids from germfree rats. J. Lipid Res. 1969, 10, 495–503.
  114. Selwyn, F.P.; Csanaky, I.L.; Zhang, Y.; Klaassen, C.D. Importance of Large Intestine in Regulating Bile Acids and Glucagon-Like Peptide-1 in Germ-Free Mice. Drug Metab. Dispos. 2015, 43, 1544–1556.
  115. Wahlstrom, A.; Sayin, S.I.; Marschall, H.U.; Backhed, F. Intestinal Crosstalk between Bile Acids and Microbiota and Its Impact on Host Metabolism. Cell Metab. 2016, 24, 41–50.
  116. Devlin, A.S.; Fischbach, M.A. A biosynthetic pathway for a prominent class of microbiota-derived bile acids. Nat. Chem. Biol. 2015, 11, 685–690.
  117. Hirano, S.; Masuda, N. Transformation of bile acids by Eubacterium lentum. Appl. Environ. Microbiol. 1981, 42, 912–915.
  118. Hirano, S.; Masuda, N.; Oda, H.; Mukai, H. Transformation of bile acids by Clostridium perfringens. Appl. Environ. Microbiol. 1981, 42, 394–399.
  119. Kuipers, F.; Bloks, V.W.; Groen, A.K. Beyond intestinal soap--bile acids in metabolic control. Nat. Rev. Endocrinol. 2014, 10, 488–498.
  120. Xie, G.; Wang, X.; Huang, F.; Zhao, A.; Chen, W.; Yan, J.; Zhang, Y.; Lei, S.; Ge, K.; Zheng, X.; et al. Dysregulated hepatic bile acids collaboratively promote liver carcinogenesis. Int. J. Cancer 2016, 139, 1764–1775.
  121. Dermadi, D.; Valo, S.; Ollila, S.; Soliymani, R.; Sipari, N.; Pussila, M.; Sarantaus, L.; Linden, J.; Baumann, M.; Nystrom, M. Western Diet Deregulates Bile Acid Homeostasis, Cell Proliferation, and Tumorigenesis in Colon. Cancer Res. 2017, 77, 3352–3363.
  122. Pai, R.; Tarnawski, A.S.; Tran, T. Deoxycholic acid activates beta-catenin signaling pathway and increases colon cell cancer growth and invasiveness. Mol. Biol. Cell 2004, 15, 2156–2163.
  123. Nguyen, T.T.; Ung, T.T.; Kim, N.H.; Jung, Y.D. Role of bile acids in colon carcinogenesis. World J. Clin. Cases 2018, 6, 577–588.
  124. Jacoby, R.F.; Cole, C.E.; Hawk, E.T.; Lubet, R.A. Ursodeoxycholate/Sulindac combination treatment effectively prevents intestinal adenomas in a mouse model of polyposis. Gastroenterology 2004, 127, 838–844.
  125. Clements, W.D.; Parks, R.; Erwin, P.; Halliday, M.I.; Barr, J.; Rowlands, B.J. Role of the gut in the pathophysiology of extrahepatic biliary obstruction. Gut 1996, 39, 587–593.
  126. Kakiyama, G.; Pandak, W.M.; Gillevet, P.M.; Hylemon, P.B.; Heuman, D.M.; Daita, K.; Takei, H.; Muto, A.; Nittono, H.; Ridlon, J.M.; et al. Modulation of the fecal bile acid profile by gut microbiota in cirrhosis. J. Hepatol. 2013, 58, 949–955.
  127. Rodriguez-Carrio, J.; Salazar, N.; Margolles, A.; Gonzalez, S.; Gueimonde, M.; de Los Reyes-Gavilan, C.G.; Suarez, A. Free Fatty Acids Profiles Are Related to Gut Microbiota Signatures and Short-Chain Fatty Acids. Front. Immunol. 2017, 8, 823.
  128. Sharon, G.; Garg, N.; Debelius, J.; Knight, R.; Dorrestein, P.C.; Mazmanian, S.K. Specialized metabolites from the microbiome in health and disease. Cell Metab. 2014, 20, 719–730.
  129. Wachtershauser, A.; Stein, J. Rationale for the luminal provision of butyrate in intestinal diseases. Eur. J. Nutr. 2000, 39, 164–171.
  130. Ziegler, K.; Kerimi, A.; Poquet, L.; Williamson, G. Butyric acid increases transepithelial transport of ferulic acid through upregulation of the monocarboxylate transporters SLC16A1 (MCT1) and SLC16A3 (MCT4). Arch. Biochem. Biophys. 2016, 599, 3–12.
  131. Cresci, G.A.; Glueck, B.; McMullen, M.R.; Xin, W.; Allende, D.; Nagy, L.E. Prophylactic tributyrin treatment mitigates chronic-binge ethanol-induced intestinal barrier and liver injury. J. Gastroenterol. Hepatol. 2017, 32, 1587–1597.
  132. Yamashita, H.; Maruta, H.; Jozuka, M.; Kimura, R.; Iwabuchi, H.; Yamato, M.; Saito, T.; Fujisawa, K.; Takahashi, Y.; Kimoto, M.; et al. Effects of acetate on lipid metabolism in muscles and adipose tissues of type 2 diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Biosci. Biotechnol. Biochem. 2009, 73, 570–576.
  133. Al-Lahham, S.; Roelofsen, H.; Rezaee, F.; Weening, D.; Hoek, A.; Vonk, R.; Venema, K. Propionic acid affects immune status and metabolism in adipose tissue from overweight subjects. Eur. J. Clin. Investig. 2012, 42, 357–364.
  134. Ridaura, V.K.; Faith, J.J.; Rey, F.E.; Cheng, J.; Duncan, A.E.; Kau, A.L.; Griffin, N.W.; Lombard, V.; Henrissat, B.; Bain, J.R.; et al. Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science 2013, 341, 1241214.
  135. Gao, Z.; Yin, J.; Zhang, J.; Ward, R.E.; Martin, R.J.; Lefevre, M.; Cefalu, W.T.; Ye, J. Butyrate improves insulin sensitivity and increases energy expenditure in mice. Diabetes 2009, 58, 1509–1517.
  136. Vrieze, A.; Van Nood, E.; Holleman, F.; Salojarvi, J.; Kootte, R.S.; Bartelsman, J.F.; Dallinga-Thie, G.M.; Ackermans, M.T.; Serlie, M.J.; Oozeer, R.; et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology 2012, 143, 913–916.e917.
  137. Chambers, E.S.; Viardot, A.; Psichas, A.; Morrison, D.J.; Murphy, K.G.; Zac-Varghese, S.E.; MacDougall, K.; Preston, T.; Tedford, C.; Finlayson, G.S.; et al. Effects of targeted delivery of propionate to the human colon on appetite regulation, body weight maintenance and adiposity in overweight adults. Gut 2015, 64, 1744–1754.
  138. Szabo, G.; Mandrekar, P. Focus on: Alcohol and the liver. Alcohol Res. Health 2010, 33, 87–96.
  139. Chen, P.; Miyamoto, Y.; Mazagova, M.; Lee, K.C.; Eckmann, L.; Schnabl, B. Microbiota Protects Mice Against Acute Alcohol-Induced Liver Injury. Alcohol Clin. Exp. Res. 2015, 39, 2313–2323.
  140. Hamarneh, S.R.; Kim, B.M.; Kaliannan, K.; Morrison, S.A.; Tantillo, T.J.; Tao, Q.; Mohamed, M.M.R.; Ramirez, J.M.; Karas, A.; Liu, W.; et al. Intestinal Alkaline Phosphatase Attenuates Alcohol-Induced Hepatosteatosis in Mice. Dig. Dis. Sci. 2017, 62, 2021–2034.
  141. Rao, R.K. Acetaldehyde-induced barrier disruption and paracellular permeability in Caco-2 cell monolayer. Methods Mol. Biol. 2008, 447, 171–183.
  142. 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 2001, 34, 101–108.
  143. 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 1995, 108, 218–224.
  144. Elamin, E.E.; Masclee, A.A.; Dekker, J.; Jonkers, D.M. Ethanol metabolism and its effects on the intestinal epithelial barrier. Nutr. Rev. 2013, 71, 483–499.
  145. Nair, S.; Cope, K.; Risby, T.H.; Diehl, A.M. Obesity and female gender increase breath ethanol concentration: Potential implications for the pathogenesis of nonalcoholic steatohepatitis. Am. J. Gastroenterol. 2001, 96, 1200–1204.
  146. Cope, K.; Risby, T.; Diehl, A.M. Increased gastrointestinal ethanol production in obese mice: Implications for fatty liver disease pathogenesis. Gastroenterology 2000, 119, 1340–1347.
  147. Zeisel, S.H.; da Costa, K.A. Choline: An essential nutrient for public health. Nutr. Rev. 2009, 67, 615–623.
  148. Han, J.; Dzierlenga, A.L.; Lu, Z.; Billheimer, D.D.; Torabzadeh, E.; Lake, A.D.; Li, H.; Novak, P.; Shipkova, P.; Aranibar, N.; et al. Metabolomic profiling distinction of human nonalcoholic fatty liver disease progression from a common rat model. Obesity 2017, 25, 1069–1076.
  149. Muraki, Y.; Makita, Y.; Yamasaki, M.; Amano, Y.; Matsuo, T. Elevation of liver endoplasmic reticulum stress in a modified choline-deficient l-amino acid-defined diet-fed non-alcoholic steatohepatitis mouse model. Biochem. Biophys. Res. Commun. 2017, 486, 632–638.
  150. Zeisel, S.H.; Wishnok, J.S.; Blusztajn, J.K. Formation of methylamines from ingested choline and lecithin. J. Pharmacol. Exp. Ther. 1983, 225, 320–324.
  151. Al-Waiz, M.; Mikov, M.; Mitchell, S.C.; Smith, R.L. The exogenous origin of trimethylamine in the mouse. Metabolism 1992, 41, 135–136.
  152. Lang, D.H.; Yeung, C.K.; Peter, R.M.; Ibarra, C.; Gasser, R.; Itagaki, K.; Philpot, R.M.; Rettie, A.E. Isoform specificity of trimethylamine N-oxygenation by human flavin-containing monooxygenase (FMO) and P450 enzymes: Selective catalysis by FMO3. Biochem. Pharmacol. 1998, 56, 1005–1012.
  153. Tang, W.H.; Wang, Z.; Levison, B.S.; Koeth, R.A.; Britt, E.B.; Fu, X.; Wu, Y.; Hazen, S.L. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N. Engl. J. Med. 2013, 368, 1575–1584.
  154. Arslan, N. Obesity, fatty liver disease and intestinal microbiota. World J. Gastroenterol. 2014, 20, 16452–16463.
  155. Dumas, M.E.; Barton, R.H.; Toye, A.; Cloarec, O.; Blancher, C.; Rothwell, A.; Fearnside, J.; Tatoud, R.; Blanc, V.; Lindon, J.C.; et al. Metabolic profiling reveals a contribution of gut microbiota to fatty liver phenotype in insulin-resistant mice. Proc. Natl. Acad. Sci. USA 2006, 103, 12511–12516.
  156. Odamaki, T.; Kato, K.; Sugahara, H.; Hashikura, N.; Takahashi, S.; Xiao, J.Z.; Abe, F.; Osawa, R. Age-related changes in gut microbiota composition from newborn to centenarian: A cross-sectional study. BMC Microbiol. 2016, 16, 90.
  157. Francino, M.P. Antibiotics and the Human Gut Microbiome: Dysbioses and Accumulation of Resistances. Front. Microbiol. 2015, 6, 1543.
  158. Wu, H.; Esteve, E.; Tremaroli, V.; Khan, M.T.; Caesar, R.; Manneras-Holm, L.; Stahlman, M.; Olsson, L.M.; Serino, M.; Planas-Felix, M.; et al. Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. Nat. Med. 2017, 23, 850–858.
  159. Rogers, M.A.M.; Aronoff, D.M. The influence of non-steroidal anti-inflammatory drugs on the gut microbiome. Clin. Microbiol. Infect 2016, 22, 178.e1–e178.e9.
  160. Hill, D.A.; Siracusa, M.C.; Abt, M.C.; Kim, B.S.; Kobuley, D.; Kubo, M.; Kambayashi, T.; Larosa, D.F.; Renner, E.D.; Orange, J.S.; et al. Commensal bacteria-derived signals regulate basophil hematopoiesis and allergic inflammation. Nat. Med. 2012, 18, 538–546.
  161. Deplancke, B.; Gaskins, H.R. Microbial modulation of innate defense: Goblet cells and the intestinal mucus layer. Am. J. Clin. Nutr. 2001, 73, 1131S–1141S.
  162. Gordon, H.A.; Pesti, L. The gnotobiotic animal as a tool in the study of host microbial relationships. Bacteriol. Rev. 1971, 35, 390–429.
  163. Smith, K.; McCoy, K.D.; Macpherson, A.J. Use of axenic animals in studying the adaptation of mammals to their commensal intestinal microbiota. Semin. Immunol. 2007, 19, 59–69.
  164. Lecuyer, E.; Rakotobe, S.; Lengline-Garnier, H.; Lebreton, C.; Picard, M.; Juste, C.; Fritzen, R.; Eberl, G.; McCoy, K.D.; Macpherson, A.J.; et al. Segmented filamentous bacterium uses secondary and tertiary lymphoid tissues to induce gut IgA and specific T helper 17 cell responses. Immunity 2014, 40, 608–620.
  165. Weinstein, P.D.; Cebra, J.J. The preference for switching to IgA expression by Peyer’s patch germinal center B cells is likely due to the intrinsic influence of their microenvironment. J. Immunol. 1991, 147, 4126–4135.
  166. Bouskra, D.; Brezillon, C.; Berard, M.; Werts, C.; Varona, R.; Boneca, I.G.; Eberl, G. Lymphoid tissue genesis induced by commensals through NOD1 regulates intestinal homeostasis. Nature 2008, 456, 507–510.
  167. Macpherson, A.J.; Martinic, M.M.; Harris, N. The functions of mucosal T cells in containing the indigenous commensal flora of the intestine. Cell Mol. Life Sci. 2002, 59, 2088–2096.
  168. Macpherson, A.J.; Hunziker, L.; McCoy, K.; Lamarre, A. IgA responses in the intestinal mucosa against pathogenic and non-pathogenic microorganisms. Microbes Infect. 2001, 3, 1021–1035.
  169. Hall, J.A.; Bouladoux, N.; Sun, C.M.; Wohlfert, E.A.; Blank, R.B.; Zhu, Q.; Grigg, M.E.; Berzofsky, J.A.; Belkaid, Y. Commensal DNA limits regulatory T cell conversion and is a natural adjuvant of intestinal immune responses. Immunity 2008, 29, 637–649.
  170. Uzbay, T. Germ-free animal experiments in the gut microbiota studies. Curr. Opin. Pharmacol. 2019, 49, 6–10.
  171. Hernandez-Chirlaque, C.; Aranda, C.J.; Ocon, B.; Capitan-Canadas, F.; Ortega-Gonzalez, M.; Carrero, J.J.; Suarez, M.D.; Zarzuelo, A.; Sanchez de Medina, F.; Martinez-Augustin, O. Germ-free and Antibiotic-treated Mice are Highly Susceptible to Epithelial Injury in DSS Colitis. J. Crohns Colitis 2016, 10, 1324–1335.
  172. Al-Asmakh, M.; Zadjali, F. Use of Germ-Free Animal Models in Microbiota-Related Research. J. Microbiol. Biotechnol. 2015, 25, 1583–1588.
  173. Tada, T.; Yamamura, S.; Kuwano, Y.; Abo, T. Level of myelopoiesis in the bone marrow is influenced by intestinal flora. Cell Immunol. 1996, 173, 155–161.
  174. Staber, F.G.; Tarcsay, L.; Dukor, P. Modulations of myelopoiesis in vivo by chemically pure preparations of cell wall components from gram-negative bacteria: Effects at different stages. Infect Immun. 1978, 20, 40–49.
  175. Khosravi, A.; Yanez, A.; Price, J.G.; Chow, A.; Merad, M.; Goodridge, H.S.; Mazmanian, S.K. Gut microbiota promote hematopoiesis to control bacterial infection. Cell Host Microbe 2014, 15, 374–381.
  176. Lee, Y.K.; Menezes, J.S.; Umesaki, Y.; Mazmanian, S.K. Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis. Proc. Natl. Acad. Sci. USA 2011, 108 (Suppl. 1), 4615–4622.
  177. Thaiss, C.A.; Zmora, N.; Levy, M.; Elinav, E. The microbiome and innate immunity. Nature 2016, 535, 65–74.
  178. Vijay-Kumar, M.; Aitken, J.D.; Carvalho, F.A.; Cullender, T.C.; Mwangi, S.; Srinivasan, S.; Sitaraman, S.V.; Knight, R.; Ley, R.E.; Gewirtz, A.T. Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5. Science 2010, 328, 228–231.
  179. Ramanan, D.; Tang, M.S.; Bowcutt, R.; Loke, P.; Cadwell, K. Bacterial sensor Nod2 prevents inflammation of the small intestine by restricting the expansion of the commensal Bacteroides vulgatus. Immunity 2014, 41, 311–324.
  180. Macia, L.; Tan, J.; Vieira, A.T.; Leach, K.; Stanley, D.; Luong, S.; Maruya, M.; Ian McKenzie, C.; Hijikata, A.; Wong, C.; et al. Metabolite-sensing receptors GPR43 and GPR109A facilitate dietary fibre-induced gut homeostasis through regulation of the inflammasome. Nat. Commun. 2015, 6, 6734.
  181. Levy, M.; Thaiss, C.A.; Zeevi, D.; Dohnalova, L.; Zilberman-Schapira, G.; Mahdi, J.A.; David, E.; Savidor, A.; Korem, T.; Herzig, Y.; et al. Microbiota-Modulated Metabolites Shape the Intestinal Microenvironment by Regulating NLRP6 Inflammasome Signaling. Cell 2015, 163, 1428–1443.
  182. Chudnovskiy, A.; Mortha, A.; Kana, V.; Kennard, A.; Ramirez, J.D.; Rahman, A.; Remark, R.; Mogno, I.; Ng, R.; Gnjatic, S.; et al. Host-Protozoan Interactions Protect from Mucosal Infections through Activation of the Inflammasome. Cell 2016, 167, 444–456 e414.
  183. Gury-BenAri, M.; Thaiss, C.A.; Serafini, N.; Winter, D.R.; Giladi, A.; Lara-Astiaso, D.; Levy, M.; Salame, T.M.; Weiner, A.; David, E.; et al. The Spectrum and Regulatory Landscape of Intestinal Innate Lymphoid Cells Are Shaped by the Microbiome. Cell 2016, 166, 1231–1246.e1213.
  184. Li, F.; Hao, X.; Chen, Y.; Bai, L.; Gao, X.; Lian, Z.; Wei, H.; Sun, R.; Tian, Z. The microbiota maintain homeostasis of liver-resident gammadeltaT-17 cells in a lipid antigen/CD1d-dependent manner. Nat. Commun. 2017, 7, 13839.
  185. Honda, K.; Littman, D.R. The microbiota in adaptive immune homeostasis and disease. Nature 2016, 535, 75–84.
  186. Peterson, D.A.; McNulty, N.P.; Guruge, J.L.; Gordon, J.I. IgA response to symbiotic bacteria as a mediator of gut homeostasis. Cell Host Microbe 2007, 2, 328–339.
  187. Kunisawa, J.; Kiyono, H. Alcaligenes is Commensal Bacteria Habituating in the Gut-Associated Lymphoid Tissue for the Regulation of Intestinal IgA Responses. Front Immunol. 2012, 3, 65.
  188. Bunker, J.J.; Flynn, T.M.; Koval, J.C.; Shaw, D.G.; Meisel, M.; McDonald, B.D.; Ishizuka, I.E.; Dent, A.L.; Wilson, P.C.; Jabri, B.; et al. Innate and Adaptive Humoral Responses Coat Distinct Commensal Bacteria with Immunoglobulin A. Immunity 2015, 43, 541–553.
  189. Pabst, O. New concepts in the generation and functions of IgA. Nat. Rev. Immunol. 2012, 12, 821–832.
  190. Bemark, M.; Boysen, P.; Lycke, N.Y. Induction of gut IgA production through T cell-dependent and T cell-independent pathways. Ann. N. Y. Acad. Sci. 2012, 1247, 97–116.
  191. Macpherson, A.J.; Gatto, D.; Sainsbury, E.; Harriman, G.R.; Hengartner, H.; Zinkernagel, R.M. A primitive T cell-independent mechanism of intestinal mucosal IgA responses to commensal bacteria. Science 2000, 288, 2222–2226.
  192. Moon, C.; Baldridge, M.T.; Wallace, M.A.; Burnham, C.A.D.; Virgin, H.W.; Stappenbeck, T.S. Vertically transmitted faecal IgA levels determine extra-chromosomal phenotypic variation. Nature 2015, 521, 90–93.
  193. Fransen, F.; Zagato, E.; Mazzini, E.; Fosso, B.; Manzari, C.; El Aidy, S.; Chiavelli, A.; D’Erchia, A.M.; Sethi, M.K.; Pabst, O.; et al. BALB/c and C57BL/6 Mice Differ in Polyreactive IgA Abundance, which Impacts the Generation of Antigen-Specific IgA and Microbiota Diversity. Immunity 2015, 43, 527–540.
  194. Viladomiu, M.; Kivolowitz, C.; Abdulhamid, A.; Dogan, B.; Victorio, D.; Castellanos, J.G.; Woo, V.; Teng, F.; Tran, N.L.; Sczesnak, A.; et al. IgA-coated E. coli enriched in Crohn’s disease spondyloarthritis promote TH17-dependent inflammation. Sci. Transl. Med. 2017, 9.
  195. Atarashi, K.; Tanoue, T.; Ando, M.; Kamada, N.; Nagano, Y.; Narushima, S.; Suda, W.; Imaoka, A.; Setoyama, H.; Nagamori, T.; et al. Th17 Cell Induction by Adhesion of Microbes to Intestinal Epithelial Cells. Cell 2015, 163, 367–380.
  196. Britton, G.J.; Contijoch, E.J.; Mogno, I.; Vennaro, O.H.; Llewellyn, S.R.; Ng, R.; Li, Z.; Mortha, A.; Merad, M.; Das, A.; et al. Microbiotas from Humans with Inflammatory Bowel Disease Alter the Balance of Gut Th17 and RORgammat(+) Regulatory T Cells and Exacerbate Colitis in Mice. Immunity 2019, 50, 212–224.e214.
  197. Tanoue, T.; Atarashi, K.; Honda, K. Development and maintenance of intestinal regulatory T cells. Nat. Rev. Immunol. 2016, 16, 295–309.
  198. Atarashi, K.; Tanoue, T.; Shima, T.; Imaoka, A.; Kuwahara, T.; Momose, Y.; Cheng, G.; Yamasaki, S.; Saito, T.; Ohba, Y.; et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 2011, 331, 337–341.
  199. Round, J.L.; Mazmanian, S.K. Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota. Proc. Natl. Acad. Sci. USA 2010, 107, 12204–12209.
  200. Smith, P.M.; Howitt, M.R.; Panikov, N.; Michaud, M.; Gallini, C.A.; Bohlooly, Y.M.; Glickman, J.N.; Garrett, W.S. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 2013, 341, 569–573.
  201. Park, J.; Kim, M.; Kang, S.G.; Jannasch, A.H.; Cooper, B.; Patterson, J.; Kim, C.H. Short-chain fatty acids induce both effector and regulatory T cells by suppression of histone deacetylases and regulation of the mTOR-S6K pathway. Mucosal Immunol. 2015, 8, 80–93.
  202. Cani, P.D.; Amar, J.; Iglesias, M.A.; Poggi, M.; Knauf, C.; Bastelica, D.; Neyrinck, A.M.; Fava, F.; Tuohy, K.M.; Chabo, C.; et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 2007, 56, 1761–1772.
  203. Weiss, D.S. The great escape: Microbiotal LPS takes a toll on the liver. Cancer Prev. Res. 2012, 5, 1078–1080.
  204. Carpino, G.; Del Ben, M.; Pastori, D.; Carnevale, R.; Baratta, F.; Overi, D.; Francis, H.; Cardinale, V.; Onori, P.; Safarikia, S.; et al. Increased Liver Localization of Lipopolysaccharides in Human and Experimental NAFLD. Hepatology 2019.
  205. Szabo, G.; Velayudham, A.; Romics, L., Jr.; Mandrekar, P. Modulation of non-alcoholic steatohepatitis by pattern recognition receptors in mice: The role of toll-like receptors 2 and 4. Alcohol Clin. Exp. Res. 2005, 29, 140S–145S.
  206. Ramos, H.C.; Rumbo, M.; Sirard, J.C. Bacterial flagellins: Mediators of pathogenicity and host immune responses in mucosa. Trends Microbiol. 2004, 12, 509–517.
  207. Xiao, Y.; Liu, F.; Yang, J.; Zhong, M.; Zhang, E.; Li, Y.; Zhou, D.; Cao, Y.; Li, W.; Yu, J.; et al. Over-activation of TLR5 signaling by high-dose flagellin induces liver injury in mice. Cell Mol. Immunol. 2015, 12, 729–742.
  208. Weiss, E.; Kretschmer, D. Formyl-Peptide Receptors in Infection, Inflammation, and Cancer. Trends Immunol. 2018, 39, 815–829.
  209. Liu, M.; Chen, K.; Yoshimura, T.; Liu, Y.; Gong, W.; Wang, A.; Gao, J.L.; Murphy, P.M.; Wang, J.M. Formylpeptide receptors are critical for rapid neutrophil mobilization in host defense against Listeria monocytogenes. Sci. Rep. 2012, 2, 786.
  210. Pasare, C.; Medzhitov, R. Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science 2003, 299, 1033–1036.
  211. Roh, Y.S.; Zhang, B.; Loomba, R.; Seki, E. TLR2 and TLR9 contribute to alcohol-mediated liver injury through induction of CXCL1 and neutrophil infiltration. Am. J. Physiol. Gastrointest. Liver Physiol. 2015, 309, G30–G41.
  212. Bergheim, I.; Weber, S.; Vos, M.; Kramer, S.; Volynets, V.; Kaserouni, S.; McClain, C.J.; Bischoff, S.C. Antibiotics protect against fructose-induced hepatic lipid accumulation in mice: Role of endotoxin. J. Hepatol. 2008, 48, 983–992.
  213. Li, Z.; Yang, S.; Lin, H.; Huang, J.; Watkins, P.A.; Moser, A.B.; Desimone, C.; Song, X.Y.; Diehl, A.M. Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease. Hepatology 2003, 37, 343–350.
  214. Cani, P.D.; Neyrinck, A.M.; Fava, F.; Knauf, C.; Burcelin, R.G.; Tuohy, K.M.; Gibson, G.R.; Delzenne, N.M. Selective increases of bifidobacteria in gut microflora improve high-fat-diet-induced diabetes in mice through a mechanism associated with endotoxaemia. Diabetologia 2007, 50, 2374–2383.
  215. Wagnerberger, S.; Spruss, A.; Kanuri, G.; Stahl, C.; Schroder, M.; Vetter, W.; Bischoff, S.C.; Bergheim, I. Lactobacillus casei Shirota protects from fructose-induced liver steatosis: A mouse model. J. Nutr. Biochem. 2013, 24, 531–538.
  216. Esposito, E.; Iacono, A.; Bianco, G.; Autore, G.; Cuzzocrea, S.; Vajro, P.; Canani, R.B.; Calignano, A.; Raso, G.M.; Meli, R. Probiotics reduce the inflammatory response induced by a high-fat diet in the liver of young rats. J. Nutr. 2009, 139, 905–911.
  217. Daubioul, C.A.; Horsmans, Y.; Lambert, P.; Danse, E.; Delzenne, N.M. Effects of oligofructose on glucose and lipid metabolism in patients with nonalcoholic steatohepatitis: Results of a pilot study. Eur. J. Clin. Nutr. 2005, 59, 723–726.
  218. Jena, P.K.; Sheng, L.; Nagar, N.; Wu, C.; Barile, D.; Mills, D.A.; Wan, Y.Y. Synbiotics Bifidobacterium infantis and milk oligosaccharides are effective in reversing cancer-prone nonalcoholic steatohepatitis using western diet-fed FXR knockout mouse models. J. Nutr. Biochem. 2018, 57, 246–254.
  219. Dhiman, R.K.; Rana, B.; Agrawal, S.; Garg, A.; Chopra, M.; Thumburu, K.K.; Khattri, A.; Malhotra, S.; Duseja, A.; Chawla, Y.K. Probiotic VSL#3 reduces liver disease severity and hospitalization in patients with cirrhosis: A randomized, controlled trial. Gastroenterology 2014, 147, 1327–1337.e1323.
  220. Bajaj, J.S.; Kassam, Z.; Fagan, A.; Gavis, E.A.; Liu, E.; Cox, I.J.; Kheradman, R.; Heuman, D.; Wang, J.; Gurry, T.; et al. Fecal microbiota transplant from a rational stool donor improves hepatic encephalopathy: A randomized clinical trial. Hepatology 2017, 66, 1727–1738.
  221. Wang, W.W.; Zhang, Y.; Huang, X.B.; You, N.; Zheng, L.; Li, J. Fecal microbiota transplantation prevents hepatic encephalopathy in rats with carbon tetrachloride-induced acute hepatic dysfunction. World J. Gastroenterol. 2017, 23, 6983–6994.
  222. Vetizou, M.; Pitt, J.M.; Daillere, R.; Lepage, P.; Waldschmitt, N.; Flament, C.; Rusakiewicz, S.; Routy, B.; Roberti, M.P.; Duong, C.P.; et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 2015, 350, 1079–1084.
  223. Sivan, A.; Corrales, L.; Hubert, N.; Williams, J.B.; Aquino-Michaels, K.; Earley, Z.M.; Benyamin, F.W.; Lei, Y.M.; Jabri, B.; Alegre, M.L.; et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 2015, 350, 1084–1089.
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