Download PDF
Semin Liver Dis 2022; 42(02): 122-137
DOI: 10.1055/s-0042-1748037
Review Article

Intestinal Barrier Dysfunction in Fatty Liver Disease: Roles of Microbiota, Mucosal Immune System, and Bile Acids

Biki Gupta
1   Division of Experimental Pathology, Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania
,
Ravi Rai
1   Division of Experimental Pathology, Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania
,
Michael Oertel
1   Division of Experimental Pathology, Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania
2   Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
3   McGowan Institute for Regenerative Medicine, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
,
Reben Raeman
1   Division of Experimental Pathology, Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania
2   Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
› Author Affiliations Funding This work was supported by the NIH/NIDDK awards K01DK110264 and R01DK124351 to R.R., R01DK130949 to R.R. and M.O., and P30DK120531 to Pittsburgh Liver Research Center.
› Further Information
    Permissions and Reprints


Abstract

Nonalcoholic fatty liver disease (NAFLD) describes a spectrum of progressive liver diseases ranging from simple steatosis to steatohepatitis and fibrosis. Globally, NAFLD is the leading cause of morbidity and mortality associated with chronic liver disease, and NAFLD patients are at a higher risk of developing cirrhosis and hepatocellular carcinoma. While there is a consensus that inflammation plays a key role in promoting NAFLD progression, the underlying mechanisms are not well understood. Recent clinical and experimental evidence suggest that increased hepatic translocation of gut microbial antigens, secondary to diet-induced impairment of the intestinal barrier may be important in driving hepatic inflammation in NAFLD. Here, we briefly review various endogenous and exogenous factors influencing the intestinal barrier and present recent advances in our understanding of cellular and molecular mechanisms underlying intestinal barrier dysfunction in NAFLD.

Keywords

NAFLD - NASH - intestinal permeability - leaky gut - microbiome - bile acids - inflammation - mucosal immune cells


Publication History

Article published online:
23 June 2022

© 2022. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Schuppan D, Schattenberg JM. Non-alcoholic steatohepatitis: pathogenesis and novel therapeutic approaches. J Gastroenterol Hepatol 2013; 28 (Suppl. 01) 68-76
    CrossrefPubMedGoogle Scholar
  • 2 Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016; 64 (01) 73-84
    CrossrefPubMedGoogle Scholar
  • 3 Chalasani N, Younossi Z, Lavine JE. et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology 2018; 67 (01) 328-357
    CrossrefPubMedGoogle Scholar
  • 4 Paik JM, Golabi P, Younossi Y, Mishra A, Younossi ZM. Changes in the global burden of chronic liver diseases from 2012 to 2017: the growing impact of NAFLD. Hepatology 2020; 72 (05) 1605-1616
    CrossrefPubMedGoogle Scholar
  • 5 Anstee QM, Reeves HL, Kotsiliti E, Govaere O, Heikenwalder M. From NASH to HCC: current concepts and future challenges. Nat Rev Gastroenterol Hepatol 2019; 16 (07) 411-428
    Google Scholar
  • 6 Huang DQ, El-Serag HB, Loomba R. Global epidemiology of NAFLD-related HCC: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol 2021; 18 (04) 223-238
    CrossrefPubMedGoogle Scholar
  • 7 Younossi ZM. Non-alcoholic fatty liver disease - a global public health perspective. J Hepatol 2019; 70 (03) 531-544
    Google Scholar
  • 8 Estes C, Razavi H, Loomba R, Younossi Z, Sanyal AJ. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology 2018; 67 (01) 123-133
    CrossrefPubMedGoogle Scholar
  • 9 Harmon RC, Tiniakos DG, Argo CK. Inflammation in nonalcoholic steatohepatitis. Expert Rev Gastroenterol Hepatol 2011; 5 (02) 189-200
    CrossrefPubMedGoogle Scholar
  • 10 Gao B, Tsukamoto H. Inflammation in alcoholic and nonalcoholic fatty liver disease: friend or foe?. Gastroenterology 2016; 150 (08) 1704-1709
    CrossrefPubMedGoogle Scholar
  • 11 Diehl AM, Day C. Cause, pathogenesis, and treatment of nonalcoholic steatohepatitis. N Engl J Med 2017; 377 (21) 2063-2072
    CrossrefPubMedGoogle Scholar
  • 12 Schuster S, Cabrera D, Arrese M, Feldstein AE. Triggering and resolution of inflammation in NASH. Nat Rev Gastroenterol Hepatol 2018; 15 (06) 349-364
    CrossrefPubMedGoogle Scholar
  • 13 Luci C, Bourinet M, Leclère PS, Anty R, Gual P. Chronic inflammation in non-alcoholic steatohepatitis: molecular mechanisms and therapeutic strategies. Front Endocrinol (Lausanne) 2020; 11: 597648
    CrossrefPubMedGoogle Scholar
  • 14 Parthasarathy G, Revelo X, Malhi H. Pathogenesis of nonalcoholic steatohepatitis: an overview. Hepatol Commun 2020; 4 (04) 478-492
    CrossrefPubMedGoogle Scholar
  • 15 Peterson LW, Artis D. Intestinal epithelial cells: regulators of barrier function and immune homeostasis. Nat Rev Immunol 2014; 14 (03) 141-153
    CrossrefPubMedGoogle Scholar
  • 16 Odenwald MA, Turner JR. The intestinal epithelial barrier: a therapeutic target?. Nat Rev Gastroenterol Hepatol 2017; 14 (01) 9-21
    CrossrefPubMedGoogle Scholar
  • 17 Okumura R, Takeda K. Roles of intestinal epithelial cells in the maintenance of gut homeostasis. Exp Mol Med 2017; 49 (05) e338
    CrossrefPubMedGoogle Scholar
  • 18 Chelakkot C, Ghim J, Ryu SH. Mechanisms regulating intestinal barrier integrity and its pathological implications. Exp Mol Med 2018; 50 (08) 1-9
    CrossrefPubMedGoogle Scholar
  • 19 Ohno H. Intestinal M cells. J Biochem 2016; 159 (02) 151-160
    CrossrefPubMedGoogle Scholar
  • 20 Birchenough GM, Johansson ME, Gustafsson JK, Bergström JH, Hansson GC. New developments in goblet cell mucus secretion and function. Mucosal Immunol 2015; 8 (04) 712-719
    CrossrefPubMedGoogle Scholar
  • 21 Paone P, Cani PD. Mucus barrier, mucins and gut microbiota: the expected slimy partners?. Gut 2020; 69 (12) 2232-2243
    CrossrefPubMedGoogle Scholar
  • 22 Ahluwalia B, Magnusson MK, Öhman L. Mucosal immune system of the gastrointestinal tract: maintaining balance between the good and the bad. Scand J Gastroenterol 2017; 52 (11) 1185-1193
    CrossrefPubMedGoogle Scholar
  • 23 Karasov WH. Integrative physiology of transcellular and paracellular intestinal absorption. J Exp Biol 2017; 220 (Pt 14): 2495-2501
    CrossrefPubMedGoogle Scholar
  • 24 Hartsock A, Nelson WJ. Adherens and tight junctions: structure, function and connections to the actin cytoskeleton. Biochim Biophys Acta 2008; 1778 (03) 660-669
    CrossrefPubMedGoogle Scholar
  • 25 Harris TJ, Tepass U. Adherens junctions: from molecules to morphogenesis. Nat Rev Mol Cell Biol 2010; 11 (07) 502-514
    CrossrefPubMedGoogle Scholar
  • 26 Zihni C, Mills C, Matter K, Balda MS. Tight junctions: from simple barriers to multifunctional molecular gates. Nat Rev Mol Cell Biol 2016; 17 (09) 564-580
    CrossrefPubMedGoogle Scholar
  • 27 Garcia MA, Nelson WJ, Chavez N. Cell-cell junctions organize structural and signaling networks. Cold Spring Harb Perspect Biol 2018; 10 (04) a029181
    CrossrefPubMedGoogle Scholar
  • 28 Aijaz S, Balda MS, Matter K. Tight junctions: molecular architecture and function. Int Rev Cytol 2006; 248: 261-298
    CrossrefPubMedGoogle Scholar
  • 29 Krug SM, Schulzke JD, Fromm M. Tight junction, selective permeability, and related diseases. Semin Cell Dev Biol 2014; 36: 166-176
    CrossrefPubMedGoogle Scholar
  • 30 Luissint AC, Parkos CA, Nusrat A. Inflammation and the intestinal barrier: leukocyte-epithelial cell interactions, cell junction remodeling, and mucosal repair. Gastroenterology 2016; 151 (04) 616-632
    CrossrefPubMedGoogle Scholar
  • 31 Buckley A, Turner JR. Cell biology of tight junction barrier regulation and mucosal disease. Cold Spring Harb Perspect Biol 2018; 10 (01) a029314
    CrossrefPubMedGoogle Scholar
  • 32 Shen L, Weber CR, Raleigh DR, Yu D, Turner JR. Tight junction pore and leak pathways: a dynamic duo. Annu Rev Physiol 2011; 73: 283-309
    CrossrefPubMedGoogle Scholar
  • 33 Tsukita S, Tanaka H, Tamura A. The claudins: from tight junctions to biological systems. Trends Biochem Sci 2019; 44 (02) 141-152
    CrossrefPubMedGoogle Scholar
  • 34 Lin PW, Stoll BJ. Necrotising enterocolitis. Lancet 2006; 368 (9543): 1271-1283
    CrossrefPubMedGoogle Scholar
  • 35 Shen L, Su L, Turner JR. Mechanisms and functional implications of intestinal barrier defects. Dig Dis 2009; 27 (04) 443-449
    CrossrefPubMedGoogle Scholar
  • 36 Niño DF, Sodhi CP, Hackam DJ. Necrotizing enterocolitis: new insights into pathogenesis and mechanisms. Nat Rev Gastroenterol Hepatol 2016; 13 (10) 590-600
    CrossrefPubMedGoogle Scholar
  • 37 France MM, Turner JR. The mucosal barrier at a glance. J Cell Sci 2017; 130 (02) 307-314
    PubMedGoogle Scholar
  • 38 He WQ, Wang J, Sheng JY, Zha JM, Graham WV, Turner JR. Contributions of myosin light chain kinase to regulation of epithelial paracellular permeability and mucosal homeostasis. Int J Mol Sci 2020; 21 (03) E993
    CrossrefPubMedGoogle Scholar
  • 39 Mooradian AD, Morley JE, Levine AS, Prigge WF, Gebhard RL. Abnormal intestinal permeability to sugars in diabetes mellitus. Diabetologia 1986; 29 (04) 221-224
    CrossrefPubMedGoogle Scholar
  • 40 Cani PD, Amar J, Iglesias MA. et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 2007; 56 (07) 1761-1772
    CrossrefPubMedGoogle Scholar
  • 41 Brun P, Castagliuolo I, Di Leo V. et al. Increased intestinal permeability in obese mice: new evidence in the pathogenesis of nonalcoholic steatohepatitis. Am J Physiol Gastrointest Liver Physiol 2007; 292 (02) G518-G525
    CrossrefPubMedGoogle Scholar
  • 42 Cani PD, Bibiloni R, Knauf C. et al. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 2008; 57 (06) 1470-1481
    CrossrefPubMedGoogle Scholar
  • 43 Stenman LK, Holma R, Korpela R. High-fat-induced intestinal permeability dysfunction associated with altered fecal bile acids. World J Gastroenterol 2012; 18 (09) 923-929
    CrossrefPubMedGoogle Scholar
  • 44 Pendyala S, Walker JM, Holt PR. A high-fat diet is associated with endotoxemia that originates from the gut. Gastroenterology 2012; 142 (05) 1100-1101.e2
    CrossrefPubMedGoogle Scholar
  • 45 Jin R, Willment A, Patel SS. et al. Fructose induced endotoxemia in pediatric nonalcoholic fatty liver disease. Int J Hepatol 2014; 2014: 560620
    PubMedGoogle Scholar
  • 46 Kavanagh K, Wylie AT, Tucker KL. et al. Dietary fructose induces endotoxemia and hepatic injury in calorically controlled primates. Am J Clin Nutr 2013; 98 (02) 349-357
    CrossrefPubMedGoogle Scholar
  • 47 Bergheim I, Weber S, Vos M. et al. Antibiotics protect against fructose-induced hepatic lipid accumulation in mice: role of endotoxin. J Hepatol 2008; 48 (06) 983-992
    CrossrefPubMedGoogle Scholar
  • 48 Tilg H, Zmora N, Adolph TE, Elinav E. The intestinal microbiota fuelling metabolic inflammation. Nat Rev Immunol 2020; 20 (01) 40-54
    CrossrefPubMedGoogle Scholar
  • 49 Massier L, Blüher M, Kovacs P, Chakaroun RM. Impaired intestinal barrier and tissue bacteria: pathomechanisms for metabolic diseases. Front Endocrinol (Lausanne) 2021; 12: 616506
    CrossrefPubMedGoogle Scholar
  • 50 Miele L, Valenza V, La Torre G. et al. Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology 2009; 49 (06) 1877-1887
    CrossrefPubMedGoogle Scholar
  • 51 Alisi A, Manco M, Devito R, Piemonte F, Nobili V. Endotoxin and plasminogen activator inhibitor-1 serum levels associated with nonalcoholic steatohepatitis in children. J Pediatr Gastroenterol Nutr 2010; 50 (06) 645-649
    CrossrefPubMedGoogle Scholar
  • 52 Giorgio V, Miele L, Principessa L. et al. Intestinal permeability is increased in children with non-alcoholic fatty liver disease, and correlates with liver disease severity. Dig Liver Dis 2014; 46 (06) 556-560
    CrossrefPubMedGoogle Scholar
  • 53 Guercio Nuzio S, Di Stasi M, Pierri L. et al. Multiple gut-liver axis abnormalities in children with obesity with and without hepatic involvement. Pediatr Obes 2017; 12 (06) 446-452
    CrossrefPubMedGoogle Scholar
  • 54 Sharifnia T, Antoun J, Verriere TG. et al. Hepatic TLR4 signaling in obese NAFLD. Am J Physiol Gastrointest Liver Physiol 2015; 309 (04) G270-G278
    CrossrefPubMedGoogle Scholar
  • 55 Kapil S, Duseja A, Sharma BK. et al. Small intestinal bacterial overgrowth and toll-like receptor signaling in patients with non-alcoholic fatty liver disease. J Gastroenterol Hepatol 2016; 31 (01) 213-221
    CrossrefPubMedGoogle Scholar
  • 56 Kiziltas S, Ata P, Colak Y. et al. TLR4 gene polymorphism in patients with nonalcoholic fatty liver disease in comparison to healthy controls. Metab Syndr Relat Disord 2014; 12 (03) 165-170
    CrossrefPubMedGoogle Scholar
  • 57 Luther J, Garber JJ, Khalili H. et al. Hepatic injury in nonalcoholic steatohepatitis contributes to altered intestinal permeability. Cell Mol Gastroenterol Hepatol 2015; 1 (02) 222-232
    CrossrefPubMedGoogle Scholar
  • 58 Loomba R, Seguritan V, Li W. et al. Gut microbiome-based metagenomic signature for non-invasive detection of advanced fibrosis in human nonalcoholic fatty liver disease. Cell Metab 2017; 25 (05) 1054-1062.e5
    CrossrefPubMedGoogle Scholar
  • 59 Rahman K, Desai C, Iyer SS. et al. Loss of junctional adhesion molecule A promotes severe steatohepatitis in mice on a diet high in saturated fat, fructose, and cholesterol. Gastroenterology 2016; 151 (04) 733-746.e12
    CrossrefPubMedGoogle Scholar
  • 60 MacPherson G, Milling S, Yrlid U, Cousins L, Turnbull E, Huang FP. Uptake of antigens from the intestine by dendritic cells. Ann N Y Acad Sci 2004; 1029: 75-82
    CrossrefPubMedGoogle Scholar
  • 61 Koboziev I, Karlsson F, Grisham MB. Gut-associated lymphoid tissue, T cell trafficking, and chronic intestinal inflammation. Ann N Y Acad Sci 2010; 1207 (Suppl. 01) E86-E93
    CrossrefPubMedGoogle Scholar
  • 62 Campbell DJ, Butcher EC. Rapid acquisition of tissue-specific homing phenotypes by CD4(+) T cells activated in cutaneous or mucosal lymphoid tissues. J Exp Med 2002; 195 (01) 135-141
    CrossrefPubMedGoogle Scholar
  • 63 McGhee JR, Fujihashi K. Inside the mucosal immune system. PLoS Biol 2012; 10 (09) e1001397
    CrossrefPubMedGoogle Scholar
  • 64 Littman DR, Rudensky AY. Th17 and regulatory T cells in mediating and restraining inflammation. Cell 2010; 140 (06) 845-858
    CrossrefPubMedGoogle Scholar
  • 65 Wu W, Chen F, Liu Z, Cong Y. Microbiota-specific Th17 cells: Yin and Yang in regulation of inflammatory bowel disease. Inflamm Bowel Dis 2016; 22 (06) 1473-1482
    CrossrefPubMedGoogle Scholar
  • 66 Sun M, He C, Cong Y, Liu Z. Regulatory immune cells in regulation of intestinal inflammatory response to microbiota. Mucosal Immunol 2015; 8 (05) 969-978
    CrossrefPubMedGoogle Scholar
  • 67 Keir M, Yi Y, Lu T, Ghilardi N. The role of IL-22 in intestinal health and disease. J Exp Med 2020; 217 (03) e20192195
    CrossrefPubMedGoogle Scholar
  • 68 Harbour SN, Maynard CL, Zindl CL, Schoeb TR, Weaver CT. Th17 cells give rise to Th1 cells that are required for the pathogenesis of colitis. Proc Natl Acad Sci U S A 2015; 112 (22) 7061-7066
    CrossrefPubMedGoogle Scholar
  • 69 Imam T, Park S, Kaplan MH, Olson MR. Effector T helper cell subsets in inflammatory bowel diseases. Front Immunol 2018; 9: 1212
    CrossrefPubMedGoogle Scholar
  • 70 Tindemans I, Joosse ME, Samsom JN. Dissecting the heterogeneity in T-cell mediated inflammation in IBD. Cells 2020; 9 (01) E110
    CrossrefPubMedGoogle Scholar
  • 71 Musch MW, Clarke LL, Mamah D. et al. T cell activation causes diarrhea by increasing intestinal permeability and inhibiting epithelial Na+/K+-ATPase. J Clin Invest 2002; 110 (11) 1739-1747
    CrossrefPubMedGoogle Scholar
  • 72 Clayburgh DR, Barrett TA, Tang Y. et al. Epithelial myosin light chain kinase-dependent barrier dysfunction mediates T cell activation-induced diarrhea in vivo. J Clin Invest 2005; 115 (10) 2702-2715
    CrossrefPubMedGoogle Scholar
  • 73 Bruewer M, Luegering A, Kucharzik T. et al. Proinflammatory cytokines disrupt epithelial barrier function by apoptosis-independent mechanisms. J Immunol 2003; 171 (11) 6164-6172
    CrossrefPubMedGoogle Scholar
  • 74 Bruewer M, Utech M, Ivanov AI, Hopkins AM, Parkos CA, Nusrat A. Interferon-gamma induces internalization of epithelial tight junction proteins via a macropinocytosis-like process. FASEB J 2005; 19 (08) 923-933
    CrossrefPubMedGoogle Scholar
  • 75 Watson CJ, Hoare CJ, Garrod DR, Carlson GL, Warhurst G. Interferon-gamma selectively increases epithelial permeability to large molecules by activating different populations of paracellular pores. J Cell Sci 2005; 118 (Pt 22): 5221-5230
    CrossrefPubMedGoogle Scholar
  • 76 Wang F, Schwarz BT, Graham WV. et al. IFN-gamma-induced TNFR2 expression is required for TNF-dependent intestinal epithelial barrier dysfunction. Gastroenterology 2006; 131 (04) 1153-1163
    CrossrefPubMedGoogle Scholar
  • 77 Leach MW, Davidson NJ, Fort MM, Powrie F, Rennick DM. The role of IL-10 in inflammatory bowel disease: “of mice and men”. Toxicol Pathol 1999; 27 (01) 123-133
    CrossrefPubMedGoogle Scholar
  • 78 Ihara S, Hirata Y, Koike K. TGF-β in inflammatory bowel disease: a key regulator of immune cells, epithelium, and the intestinal microbiota. J Gastroenterol 2017; 52 (07) 777-787
    CrossrefPubMedGoogle Scholar
  • 79 Friedrich M, Pohin M, Powrie F. Cytokine networks in the pathophysiology of inflammatory bowel disease. Immunity 2019; 50 (04) 992-1006
    CrossrefPubMedGoogle Scholar
  • 80 Mahida YR. The key role of macrophages in the immunopathogenesis of inflammatory bowel disease. Inflamm Bowel Dis 2000; 6 (01) 21-33
    CrossrefPubMedGoogle Scholar
  • 81 Koch S, Kucharzik T, Heidemann J, Nusrat A, Luegering A. Investigating the role of proinflammatory CD16+ monocytes in the pathogenesis of inflammatory bowel disease. Clin Exp Immunol 2010; 161 (02) 332-341
    CrossrefPubMedGoogle Scholar
  • 82 Zhou GX, Liu ZJ. Potential roles of neutrophils in regulating intestinal mucosal inflammation of inflammatory bowel disease. J Dig Dis 2017; 18 (09) 495-503
    CrossrefPubMedGoogle Scholar
  • 83 Liu H, Dasgupta S, Fu Y. et al. Subsets of mononuclear phagocytes are enriched in the inflamed colons of patients with IBD. BMC Immunol 2019; 20 (01) 42
    CrossrefPubMedGoogle Scholar
  • 84 Na YR, Stakenborg M, Seok SH, Matteoli G. Macrophages in intestinal inflammation and resolution: a potential therapeutic target in IBD. Nat Rev Gastroenterol Hepatol 2019; 16 (09) 531-543
    CrossrefPubMedGoogle Scholar
  • 85 Geremia A, Arancibia-Cárcamo CV. Innate lymphoid cells in intestinal inflammation. Front Immunol 2017; 8: 1296
    CrossrefPubMedGoogle Scholar
  • 86 Wu Y, Shen J. Innate lymphoid cells in Crohn's disease. Front Immunol 2020; 11: 554880
    CrossrefPubMedGoogle Scholar
  • 87 Saez A, Gomez-Bris R, Herrero-Fernandez B, Mingorance C, Rius C, Gonzalez-Granado JM. Innate lymphoid cells in intestinal homeostasis and inflammatory bowel disease. Int J Mol Sci 2021; 22 (14) 7618
    CrossrefPubMedGoogle Scholar
  • 88 Colonna M. Innate lymphoid cells: diversity, plasticity, and unique functions in immunity. Immunity 2018; 48 (06) 1104-1117
    CrossrefPubMedGoogle Scholar
  • 89 Cherrier M, Ramachandran G, Golub R. The interplay between innate lymphoid cells and T cells. Mucosal Immunol 2020; 13 (05) 732-742
    CrossrefPubMedGoogle Scholar
  • 90 Pearson T, Shultz LD, Miller D. et al. Non-obese diabetic-recombination activating gene-1 (NOD-Rag1 null) interleukin (IL)-2 receptor common gamma chain (IL2r gamma null) null mice: a radioresistant model for human lymphohaematopoietic engraftment. Clin Exp Immunol 2008; 154 (02) 270-284
    CrossrefPubMedGoogle Scholar
  • 91 Panda SK, Colonna M. Innate lymphoid cells in mucosal immunity. Front Immunol 2019; 10: 861
    CrossrefPubMedGoogle Scholar
  • 92 Castellanos JG, Longman RS. Innate lymphoid cells link gut microbes with mucosal T cell immunity. Gut Microbes 2020; 11 (02) 231-236
    CrossrefPubMedGoogle Scholar
  • 93 Zmora N, Bashiardes S, Levy M, Elinav E. The role of the immune system in metabolic health and disease. Cell Metab 2017; 25 (03) 506-521
    CrossrefPubMedGoogle Scholar
  • 94 Lee SH, Kwon JE, Cho ML. Immunological pathogenesis of inflammatory bowel disease. Intest Res 2018; 16 (01) 26-42
    CrossrefPubMedGoogle Scholar
  • 95 Rai RP, Liu Y, Iyer SS. et al. Blocking integrin α4β7-mediated CD4 T cell recruitment to the intestine and liver protects mice from western diet-induced non-alcoholic steatohepatitis. J Hepatol 2020; 73 (05) 1013-1022
    CrossrefPubMedGoogle Scholar
  • 96 Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature 2012; 486 (7402): 207-214
    CrossrefPubMedGoogle Scholar
  • 97 Heintz-Buschart A, Wilmes P. Human gut microbiome: function matters. Trends Microbiol 2018; 26 (07) 563-574
    CrossrefPubMedGoogle Scholar
  • 98 Rowland I, Gibson G, Heinken A. et al. Gut microbiota functions: metabolism of nutrients and other food components. Eur J Nutr 2018; 57 (01) 1-24
    CrossrefPubMedGoogle Scholar
  • 99 Oliphant K, Allen-Vercoe E. Macronutrient metabolism by the human gut microbiome: major fermentation by-products and their impact on host health. Microbiome 2019; 7 (01) 91
    CrossrefPubMedGoogle Scholar
  • 100 Krautkramer KA, Fan J, Bäckhed F. Gut microbial metabolites as multi-kingdom intermediates. Nat Rev Microbiol 2021; 19 (02) 77-94
    CrossrefPubMedGoogle Scholar
  • 101 Sharon G, Garg N, Debelius J, Knight R, Dorrestein PC, Mazmanian SK. Specialized metabolites from the microbiome in health and disease. Cell Metab 2014; 20 (05) 719-730
    CrossrefPubMedGoogle Scholar
  • 102 Lin L, Zhang J. Role of intestinal microbiota and metabolites on gut homeostasis and human diseases. BMC Immunol 2017; 18 (01) 2
    CrossrefPubMedGoogle Scholar
  • 103 Man AWC, Zhou Y, Xia N, Li H. Involvement of gut microbiota, microbial metabolites and interaction with polyphenol in host immunometabolism. Nutrients 2020; 12 (10) E3054
    CrossrefPubMedGoogle Scholar
  • 104 Belkaid Y, Hand TW. Role of the microbiota in immunity and inflammation. Cell 2014; 157 (01) 121-141
    CrossrefPubMedGoogle Scholar
  • 105 Zheng D, Liwinski T, Elinav E. Interaction between microbiota and immunity in health and disease. Cell Res 2020; 30 (06) 492-506
    CrossrefPubMedGoogle Scholar
  • 106 Tang WH, Kitai T, Hazen SL. Gut microbiota in cardiovascular health and disease. Circ Res 2017; 120 (07) 1183-1196
    CrossrefPubMedGoogle Scholar
  • 107 Tsilimigras MC, Fodor A, Jobin C. Carcinogenesis and therapeutics: the microbiota perspective. Nat Microbiol 2017; 2: 17008
    CrossrefPubMedGoogle Scholar
  • 108 Pei LY, Ke YS, Zhao HH. et al. Role of colonic microbiota in the pathogenesis of ulcerative colitis. BMC Gastroenterol 2019; 19 (01) 10
    CrossrefPubMedGoogle Scholar
  • 109 Dabke K, Hendrick G, Devkota S. The gut microbiome and metabolic syndrome. J Clin Invest 2019; 129 (10) 4050-4057
    CrossrefPubMedGoogle Scholar
  • 110 Lee CJ, Sears CL, Maruthur N. Gut microbiome and its role in obesity and insulin resistance. Ann N Y Acad Sci 2020; 1461 (01) 37-52
    CrossrefPubMedGoogle Scholar
  • 111 Quesada-Vázquez S, Aragonès G, Del Bas JM, Escoté X. Diet, gut microbiota and non-alcoholic fatty liver disease: three parts of the same axis. Cells 2020; 9 (01) E176
    CrossrefPubMedGoogle Scholar
  • 112 Aron-Wisnewsky J, Vigliotti C, Witjes J. et al. Gut microbiota and human NAFLD: disentangling microbial signatures from metabolic disorders. Nat Rev Gastroenterol Hepatol 2020; 17 (05) 279-297
    CrossrefPubMedGoogle Scholar
  • 113 Fan Y, Pedersen O. Gut microbiota in human metabolic health and disease. Nat Rev Microbiol 2021; 19 (01) 55-71
    CrossrefPubMedGoogle Scholar
  • 114 Rodríguez JM, Murphy K, Stanton C. et al. The composition of the gut microbiota throughout life, with an emphasis on early life. Microb Ecol Health Dis 2015; 26: 26050
    PubMedGoogle Scholar
  • 115 Falony G, Vieira-Silva S, Raes J. Richness and ecosystem development across faecal snapshots of the gut microbiota. Nat Microbiol 2018; 3 (05) 526-528
    CrossrefPubMedGoogle Scholar
  • 116 Zeevi D, Korem T, Godneva A. et al. Structural variation in the gut microbiome associates with host health. Nature 2019; 568 (7750): 43-48
    CrossrefPubMedGoogle Scholar
  • 117 Fukata M, Michelsen KS, Eri R. et al. Toll-like receptor-4 is required for intestinal response to epithelial injury and limiting bacterial translocation in a murine model of acute colitis. Am J Physiol Gastrointest Liver Physiol 2005; 288 (05) G1055-G1065
    CrossrefPubMedGoogle Scholar
  • 118 Chen GY, Shaw MH, Redondo G, Núñez G. The innate immune receptor Nod1 protects the intestine from inflammation-induced tumorigenesis. Cancer Res 2008; 68 (24) 10060-10067
    CrossrefPubMedGoogle Scholar
  • 119 Claes AK, Zhou JY, Philpott DJ. NOD-like receptors: guardians of intestinal mucosal barriers. Physiology (Bethesda) 2015; 30 (03) 241-250
    PubMedGoogle Scholar
  • 120 Hernández-Chirlaque C, Aranda CJ, Ocón B. et al. Germ-free and antibiotic-treated mice are highly susceptible to epithelial injury in DSS colitis. J Crohn's Colitis 2016; 10 (11) 1324-1335
    CrossrefPubMedGoogle Scholar
  • 121 Khosravi A, Mazmanian SK. Disruption of the gut microbiome as a risk factor for microbial infections. Curr Opin Microbiol 2013; 16 (02) 221-227
    CrossrefPubMedGoogle Scholar
  • 122 Falk PG, Hooper LV, Midtvedt T, Gordon JI. Creating and maintaining the gastrointestinal ecosystem: what we know and need to know from gnotobiology. Microbiol Mol Biol Rev 1998; 62 (04) 1157-1170
    CrossrefPubMedGoogle Scholar
  • 123 Slezak K, Krupova Z, Rabot S. et al. Association of germ-free mice with a simplified human intestinal microbiota results in a shortened intestine. Gut Microbes 2014; 5 (02) 176-182
    CrossrefPubMedGoogle Scholar
  • 124 Sharma R, Young C, Neu J. Molecular modulation of intestinal epithelial barrier: contribution of microbiota. J Biomed Biotechnol 2010; 2010: 305879
    CrossrefPubMedGoogle Scholar
  • 125 Khosravi A, Yáñez A, Price JG. et al. Gut microbiota promote hematopoiesis to control bacterial infection. Cell Host Microbe 2014; 15 (03) 374-381
    CrossrefPubMedGoogle Scholar
  • 126 Crabbé PA, Bazin H, Eyssen H, Heremans JF. The normal microbial flora as a major stimulus for proliferation of plasma cells synthesizing IgA in the gut. The germ-free intestinal tract. Int Arch Allergy Appl Immunol 1968; 34 (04) 362-375
    CrossrefPubMedGoogle Scholar
  • 127 Ivanov II, Atarashi K, Manel N. et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 2009; 139 (03) 485-498
    CrossrefPubMedGoogle Scholar
  • 128 Atarashi K, Tanoue T, Shima T. et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 2011; 331 (6015): 337-341
    CrossrefPubMedGoogle Scholar
  • 129 Ohnmacht C, Park JH, Cording S. et al. Mucosal immunology. The microbiota regulates type 2 immunity through RORγt+ T cells. Science 2015; 349 (6251): 989-993
    CrossrefPubMedGoogle Scholar
  • 130 Cervantes-Barragan L, Chai JN, Tianero MD. et al. Lactobacillus reuteri induces gut intraepithelial CD4+CD8αα+ T cells. Science 2017; 357 (6353): 806-810
    CrossrefPubMedGoogle Scholar
  • 131 Tan TG, Sefik E, Geva-Zatorsky N. et al. Identifying species of symbiont bacteria from the human gut that, alone, can induce intestinal Th17 cells in mice. Proc Natl Acad Sci U S A 2016; 113 (50) E8141-E8150
    PubMedGoogle Scholar
  • 132 Geva-Zatorsky N, Sefik E, Kua L. et al. Mining the human gut microbiota for immunomodulatory organisms. Cell 2017; 168 (05) 928-943.e11
    CrossrefPubMedGoogle Scholar
  • 133 Dasgupta S, Erturk-Hasdemir D, Ochoa-Reparaz J, Reinecker HC, Kasper DL. Plasmacytoid dendritic cells mediate anti-inflammatory responses to a gut commensal molecule via both innate and adaptive mechanisms. Cell Host Microbe 2014; 15 (04) 413-423
    CrossrefPubMedGoogle Scholar
  • 134 Atarashi K, Tanoue T, Oshima K. et al. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature 2013; 500 (7461): 232-236
    CrossrefPubMedGoogle Scholar
  • 135 Sefik E, Geva-Zatorsky N, Oh S. et al. Mucosal immunology. Individual intestinal symbionts induce a distinct population of RORγ+ regulatory T cells. Science 2015; 349 (6251): 993-997
    CrossrefPubMedGoogle Scholar
  • 136 Muniz LR, Knosp C, Yeretssian G. Intestinal antimicrobial peptides during homeostasis, infection, and disease. Front Immunol 2012; 3: 310
    CrossrefPubMedGoogle Scholar
  • 137 Pickard JM, Zeng MY, Caruso R, Núñez G. Gut microbiota: role in pathogen colonization, immune responses, and inflammatory disease. Immunol Rev 2017; 279 (01) 70-89
    CrossrefPubMedGoogle Scholar
  • 138 Alam A, Neish A. Role of gut microbiota in intestinal wound healing and barrier function. Tissue Barriers 2018; 6 (03) 1539595
    CrossrefPubMedGoogle Scholar
  • 139 Ghosh S, Whitley CS, Haribabu B, Jala VR. Regulation of intestinal barrier function by microbial metabolites. Cell Mol Gastroenterol Hepatol 2021; 11 (05) 1463-1482
    CrossrefPubMedGoogle Scholar
  • 140 Kim MS, Park EJ, Roh SW, Bae JW. Diversity and abundance of single-stranded DNA viruses in human feces. Appl Environ Microbiol 2011; 77 (22) 8062-8070
    CrossrefPubMedGoogle Scholar
  • 141 Minot S, Bryson A, Chehoud C, Wu GD, Lewis JD, Bushman FD. Rapid evolution of the human gut virome. Proc Natl Acad Sci U S A 2013; 110 (30) 12450-12455
    CrossrefPubMedGoogle Scholar
  • 142 Guerin E, Shkoporov A, Stockdale SR. et al. Biology and taxonomy of crAss-like bacteriophages, the most abundant virus in the human gut. Cell Host Microbe 2018; 24 (05) 653-664.e6
    CrossrefPubMedGoogle Scholar
  • 143 Reyes A, Semenkovich NP, Whiteson K, Rohwer F, Gordon JI. Going viral: next-generation sequencing applied to phage populations in the human gut. Nat Rev Microbiol 2012; 10 (09) 607-617
    CrossrefPubMedGoogle Scholar
  • 144 Reyes A, Blanton LV, Cao S. et al. Gut DNA viromes of Malawian twins discordant for severe acute malnutrition. Proc Natl Acad Sci U S A 2015; 112 (38) 11941-11946
    CrossrefPubMedGoogle Scholar
  • 145 Norman JM, Handley SA, Baldridge MT. et al. Disease-specific alterations in the enteric virome in inflammatory bowel disease. Cell 2015; 160 (03) 447-460
    CrossrefPubMedGoogle Scholar
  • 146 Monaco CL, Gootenberg DB, Zhao G. et al. Altered virome and bacterial microbiome in human immunodeficiency virus-associated acquired immunodeficiency syndrome. Cell Host Microbe 2016; 19 (03) 311-322
    CrossrefPubMedGoogle Scholar
  • 147 Ma Y, You X, Mai G, Tokuyasu T, Liu C. A human gut phage catalog correlates the gut phageome with type 2 diabetes. Microbiome 2018; 6 (01) 24
    CrossrefPubMedGoogle Scholar
  • 148 Zuo T, Lu XJ, Zhang Y. et al. Gut mucosal virome alterations in ulcerative colitis. Gut 2019; 68 (07) 1169-1179
    CrossrefPubMedGoogle Scholar
  • 149 Lang S, Demir M, Martin A. et al. Intestinal virome signature associated with severity of nonalcoholic fatty liver disease. Gastroenterology 2020; 159 (05) 1839-1852
    CrossrefPubMedGoogle Scholar
  • 150 Chen Q, Ma X, Li C. et al. Enteric phageome alterations in patients with type 2 diabetes. Front Cell Infect Microbiol 2021; 10: 575084
    CrossrefPubMedGoogle Scholar
  • 151 Jiang L, Lang S, Duan Y. et al. Intestinal virome in patients with alcoholic hepatitis. Hepatology 2020; 72 (06) 2182-2196
    CrossrefPubMedGoogle Scholar
  • 152 Hsu CL, Duan Y, Fouts DE, Schnabl B. Intestinal virome and therapeutic potential of bacteriophages in liver disease. J Hepatol 2021; 75 (06) 1465-1475
    CrossrefPubMedGoogle Scholar
  • 153 Yang K, Niu J, Zuo T. et al. Alterations in the gut virome in obesity and type 2 diabetes mellitus. Gastroenterology 2021; 161 (04) 1257-1269.e13
    CrossrefPubMedGoogle Scholar
  • 154 Bikel S, López-Leal G, Cornejo-Granados F. et al. Gut dsDNA virome shows diversity and richness alterations associated with childhood obesity and metabolic syndrome. iScience 2021; 24 (08) 102900
    CrossrefPubMedGoogle Scholar
  • 155 Liang G, Cobián-Güemes AG, Albenberg L, Bushman F. The gut virome in inflammatory bowel diseases. Curr Opin Virol 2021; 51: 190-198
    CrossrefPubMedGoogle Scholar
  • 156 Fairfield B, Schnabl B. Gut dysbiosis as a driver in alcohol-induced liver injury. JHEP Rep 2020; 3 (02) 100220
    CrossrefPubMedGoogle Scholar
  • 157 Gao W, Zhu Y, Ye J, Chu H. Gut non-bacterial microbiota contributing to alcohol-associated liver disease. Gut Microbes 2021; 13 (01) 1984122
    CrossrefPubMedGoogle Scholar
  • 158 De Sordi L, Lourenço M, Debarbieux L. The battle within: interactions of Bacteriophages and Bacteria in the gastrointestinal tract. Cell Host Microbe 2019; 25 (02) 210-218
    CrossrefPubMedGoogle Scholar
  • 159 Yang JY, Kim MS, Kim E. et al. Enteric viruses ameliorate gut inflammation via Toll-like receptor 3 and Toll-like receptor 7-mediated interferon-β production. Immunity 2016; 44 (04) 889-900
    CrossrefPubMedGoogle Scholar
  • 160 Barr JJ, Auro R, Furlan M. et al. Bacteriophage adhering to mucus provide a non-host-derived immunity. Proc Natl Acad Sci U S A 2013; 110 (26) 10771-10776
    CrossrefPubMedGoogle Scholar
  • 161 Almeida GMF, Laanto E, Ashrafi R, Sundberg LR. Bacteriophage adherence to mucus mediates preventive protection against pathogenic bacteria. MBio 2019; 10 (06) e01984-19
    CrossrefPubMedGoogle Scholar
  • 162 Cornuault JK, Petit MA, Mariadassou M. et al. Phages infecting Faecalibacterium prausnitzii belong to novel viral genera that help to decipher intestinal viromes. Microbiome 2018; 6 (01) 65
    CrossrefPubMedGoogle Scholar
  • 163 Gogokhia L, Buhrke K, Bell R. et al. Expansion of Bacteriophages is linked to aggravated intestinal inflammation and colitis. Cell Host Microbe 2019; 25 (02) 285-299.e8
    CrossrefPubMedGoogle Scholar
  • 164 Fiers WD, Gao IH, Iliev ID. Gut mycobiota under scrutiny: fungal symbionts or environmental transients?. Curr Opin Microbiol 2019; 50: 79-86
    CrossrefPubMedGoogle Scholar
  • 165 Jiang TT, Shao TY, Ang WXG. et al. Commensal fungi recapitulate the protective benefits of intestinal bacteria. Cell Host Microbe 2017; 22 (06) 809-816.e4
    CrossrefPubMedGoogle Scholar
  • 166 Iliev ID, Leonardi I. Fungal dysbiosis: immunity and interactions at mucosal barriers. Nat Rev Immunol 2017; 17 (10) 635-646
    CrossrefPubMedGoogle Scholar
  • 167 Li XV, Leonardi I, Iliev ID. Gut mycobiota in immunity and inflammatory disease. Immunity 2019; 50 (06) 1365-1379
    CrossrefPubMedGoogle Scholar
  • 168 Muratori P, Muratori L, Guidi M. et al. Anti-Saccharomyces cerevisiae antibodies (ASCA) and autoimmune liver diseases. Clin Exp Immunol 2003; 132 (03) 473-476
    CrossrefPubMedGoogle Scholar
  • 169 Mar Rodríguez M, Pérez D, Javier Chaves F. et al. Obesity changes the human gut mycobiome. Sci Rep 2015; 5: 14600
    CrossrefPubMedGoogle Scholar
  • 170 Huseyin CE, O'Toole PW, Cotter PD, Scanlan PD. Forgotten fungi-the gut mycobiome in human health and disease. FEMS Microbiol Rev 2017; 41 (04) 479-511
    CrossrefPubMedGoogle Scholar
  • 171 Yang AM, Inamine T, Hochrath K. et al. Intestinal fungi contribute to development of alcoholic liver disease. J Clin Invest 2017; 127 (07) 2829-2841
    CrossrefPubMedGoogle Scholar
  • 172 Jayasudha R, Das T, Kalyana Chakravarthy S. et al. Gut mycobiomes are altered in people with type 2 diabetes mellitus and diabetic retinopathy. PLoS One 2020; 15 (12) e0243077
    CrossrefPubMedGoogle Scholar
  • 173 Lang S, Duan Y, Liu J. et al. Intestinal fungal dysbiosis and systemic immune response to fungi in patients with alcoholic hepatitis. Hepatology 2020; 71 (02) 522-538
    CrossrefPubMedGoogle Scholar
  • 174 Iliev ID. Mycobiota-host immune interactions in IBD: coming out of the shadows. Nat Rev Gastroenterol Hepatol 2022; 19 (02) 91-92
    CrossrefPubMedGoogle Scholar
  • 175 Jiang L, Stärkel P, Fan JG, Fouts DE, Bacher P, Schnabl B. The gut mycobiome: a novel player in chronic liver diseases. J Gastroenterol 2021; 56 (01) 1-11
    CrossrefPubMedGoogle Scholar
  • 176 Hartmann P, Lang S, Zeng S. et al. Dynamic changes of the fungal microbiome in alcohol use disorder. Front Physiol 2021; 12: 699253
    CrossrefPubMedGoogle Scholar
  • 177 Richard ML, Sokol H. The gut mycobiota: insights into analysis, environmental interactions and role in gastrointestinal diseases. Nat Rev Gastroenterol Hepatol 2019; 16 (06) 331-345
    PubMedGoogle Scholar
  • 178 Mouzaki M, Comelli EM, Arendt BM. et al. Intestinal microbiota in patients with nonalcoholic fatty liver disease. Hepatology 2013; 58 (01) 120-127
    CrossrefPubMedGoogle Scholar
  • 179 Boursier J, Mueller O, Barret M. 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 (03) 764-775
    CrossrefPubMedGoogle Scholar
  • 180 Del Chierico F, Nobili V, Vernocchi P. et al. Gut microbiota profiling of pediatric nonalcoholic fatty liver disease and obese patients unveiled by an integrated meta-omics-based approach. Hepatology 2017; 65 (02) 451-464
    CrossrefPubMedGoogle Scholar
  • 181 Caussy C, Tripathi A, Humphrey G. et al. A gut microbiome signature for cirrhosis due to nonalcoholic fatty liver disease. Nat Commun 2019; 10 (01) 1406
    CrossrefPubMedGoogle Scholar
  • 182 Bastian WP, Hasan I, Lesmana CRA, Rinaldi I, Gani RA. Gut microbiota profiles in nonalcoholic fatty liver disease and its possible impact on disease progression evaluated with transient elastography: lesson learnt from 60 cases. Case Rep Gastroenterol 2019; 13 (01) 125-133
    CrossrefPubMedGoogle Scholar
  • 183 Wigg AJ, Roberts-Thomson IC, Dymock RB, McCarthy PJ, Grose RH, Cummins AG. The role of small intestinal bacterial overgrowth, intestinal permeability, endotoxaemia, and tumour necrosis factor alpha in the pathogenesis of non-alcoholic steatohepatitis. Gut 2001; 48 (02) 206-211
    CrossrefPubMedGoogle Scholar
  • 184 Shanab AA, Scully P, Crosbie O. et al. Small intestinal bacterial overgrowth in nonalcoholic steatohepatitis: association with toll-like receptor 4 expression and plasma levels of interleukin 8. Dig Dis Sci 2011; 56 (05) 1524-1534
    CrossrefPubMedGoogle Scholar
  • 185 Chiang JY. Bile acids: regulation of synthesis. J Lipid Res 2009; 50 (10) 1955-1966
    CrossrefPubMedGoogle Scholar
  • 186 Chiang JY. Recent advances in understanding bile acid homeostasis. F1000 Res 2017; 6: 2029
    CrossrefPubMedGoogle Scholar
  • 187 Dawson PA, Karpen SJ. Intestinal transport and metabolism of bile acids. J Lipid Res 2015; 56 (06) 1085-1099
    CrossrefPubMedGoogle Scholar
  • 188 Ridlon JM, Kang DJ, Hylemon PB, Bajaj JS. Bile acids and the gut microbiome. Curr Opin Gastroenterol 2014; 30 (03) 332-338
    CrossrefPubMedGoogle Scholar
  • 189 Wahlström A, Sayin SI, Marschall HU, Bäckhed F. Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism. Cell Metab 2016; 24 (01) 41-50
    CrossrefPubMedGoogle Scholar
  • 190 Ramírez-Pérez O, Cruz-Ramón V, Chinchilla-López P, Méndez-Sánchez N. The role of the gut microbiota in bile acid metabolism. Ann Hepatol 2017; 16 (Suppl. 1: s3-105.): s15-s20
    CrossrefPubMedGoogle Scholar
  • 191 Camilleri M. Bile acid diarrhea: prevalence, pathogenesis, and therapy. Gut Liver 2015; 9 (03) 332-339
    CrossrefPubMedGoogle Scholar
  • 192 Oduyebo I, Camilleri M. Bile acid disease: the emerging epidemic. Curr Opin Gastroenterol 2017; 33 (03) 189-195
    CrossrefPubMedGoogle Scholar
  • 193 Staley C, Weingarden AR, Khoruts A, Sadowsky MJ. Interaction of gut microbiota with bile acid metabolism and its influence on disease states. Appl Microbiol Biotechnol 2017; 101 (01) 47-64
    CrossrefPubMedGoogle Scholar
  • 194 Powolny A, Xu J, Loo G. Deoxycholate induces DNA damage and apoptosis in human colon epithelial cells expressing either mutant or wild-type p53. Int J Biochem Cell Biol 2001; 33 (02) 193-203
    CrossrefPubMedGoogle Scholar
  • 195 Ignacio Barrasa J, Olmo N, Pérez-Ramos P. et al. Deoxycholic and chenodeoxycholic bile acids induce apoptosis via oxidative stress in human colon adenocarcinoma cells. Apoptosis 2011; 16 (10) 1054-1067
    CrossrefPubMedGoogle Scholar
  • 196 Wei S, Ma X, Zhao Y. Mechanism of hydrophobic bile acid-induced hepatocyte injury and drug discovery. Front Pharmacol 2020; 11: 1084
    CrossrefPubMedGoogle Scholar
  • 197 Lajczak-McGinley NK, Porru E, Fallon CM. et al. The secondary bile acids, ursodeoxycholic acid and lithocholic acid, protect against intestinal inflammation by inhibition of epithelial apoptosis. Physiol Rep 2020; 8 (12) e14456
    CrossrefPubMedGoogle Scholar
  • 198 Jenkins GJ, Harries K, Doak SH. et al. The bile acid deoxycholic acid (DCA) at neutral pH activates NF-kappaB and induces IL-8 expression in oesophageal cells in vitro. Carcinogenesis 2004; 25 (03) 317-323
    CrossrefPubMedGoogle Scholar
  • 199 Mühlbauer M, Allard B, Bosserhoff AK. et al. Differential effects of deoxycholic acid and taurodeoxycholic acid on NF-kappa B signal transduction and IL-8 gene expression in colonic epithelial cells. Am J Physiol Gastrointest Liver Physiol 2004; 286 (06) G1000-G1008
    CrossrefPubMedGoogle Scholar
  • 200 O'Dwyer AM, Lajczak NK, Keyes JA, Ward JB, Greene CM, Keely SJ. Ursodeoxycholic acid inhibits TNFα-induced IL-8 release from monocytes. Am J Physiol Gastrointest Liver Physiol 2016; 311 (02) G334-G341
    CrossrefPubMedGoogle Scholar
  • 201 Kim SJ, Ko W-K, Jo M-J. et al. Anti-inflammatory effect of Tauroursodeoxycholic acid in RAW 264.7 macrophages, bone marrow-derived macrophages, BV2 microglial cells, and spinal cord injury. Sci Rep 2018; 8 (01) 3176
    CrossrefPubMedGoogle Scholar
  • 202 Araki Y, Katoh T, Ogawa A. et al. Bile acid modulates transepithelial permeability via the generation of reactive oxygen species in the Caco-2 cell line. Free Radic Biol Med 2005; 39 (06) 769-780
    CrossrefPubMedGoogle Scholar
  • 203 Hegyi P, Maléth J, Walters JR, Hofmann AF, Keely SJ. Guts and gall: bile acids in regulation of intestinal epithelial function in health and disease. Physiol Rev 2018; 98 (04) 1983-2023
    CrossrefPubMedGoogle Scholar
  • 204 Debruyne PR, Bruyneel EA, Li X, Zimber A, Gespach C, Mareel MM. The role of bile acids in carcinogenesis. Mutat Res 2001; 480-481: 359-369
    CrossrefPubMedGoogle Scholar
  • 205 Bernstein C, Holubec H, Bhattacharyya AK. et al. Carcinogenicity of deoxycholate, a secondary bile acid. Arch Toxicol 2011; 85 (08) 863-871
    CrossrefPubMedGoogle Scholar
  • 206 Dossa AY, Escobar O, Golden J, Frey MR, Ford HR, Gayer CP. Bile acids regulate intestinal cell proliferation by modulating EGFR and FXR signaling. Am J Physiol Gastrointest Liver Physiol 2016; 310 (02) G81-G92
    CrossrefPubMedGoogle Scholar
  • 207 Ijssennagger N, van Rooijen KS, Magnúsdóttir S. et al. Ablation of liver Fxr results in an increased colonic mucus barrier in mice. JHEP Rep 2021; 3 (05) 100344
    CrossrefPubMedGoogle Scholar
  • 208 Mouzaki M, Wang AY, Bandsma R. et al. Bile acids and dysbiosis in non-alcoholic fatty liver disease. PLoS One 2016; 11 (05) e0151829
    CrossrefPubMedGoogle Scholar
  • 209 Gupta B, Liu Y, Chopyk DM. et al. Western diet-induced increase in colonic bile acids compromises epithelial barrier in nonalcoholic steatohepatitis. FASEB J 2020; 34 (05) 7089-7102
    CrossrefPubMedGoogle Scholar
  • 210 Kitahara M, Takamine F, Imamura T, Benno Y. Assignment of Eubacterium sp. VPI 12708 and related strains with high bile acid 7alpha-dehydroxylating activity to Clostridium scindens and proposal of Clostridium hylemonae sp. nov., isolated from human faeces. Int J Syst Evol Microbiol 2000; 50 (Pt 3): 971-978
    CrossrefPubMedGoogle Scholar
  • 211 Ridlon JM, Kang DJ, Hylemon PB. Bile salt biotransformations by human intestinal bacteria. J Lipid Res 2006; 47 (02) 241-259
    CrossrefPubMedGoogle Scholar
  • 212 Narushima S, Ito K, Kuruma K, Uchida K. Composition of cecal bile acids in ex-germfree mice inoculated with human intestinal bacteria. Lipids 2000; 35 (06) 639-644
    CrossrefPubMedGoogle Scholar
  • 213 Sayin SI, Wahlström A, Felin J. et al. Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab 2013; 17 (02) 225-235
    CrossrefPubMedGoogle Scholar
  • 214 Molinero N, Ruiz L, Sánchez B, Margolles A, Delgado S. Intestinal bacteria interplay with bile and cholesterol metabolism: implications on host physiology. Front Physiol 2019; 10: 185
    CrossrefPubMedGoogle Scholar
  • 215 Kessoku T, Imajo K, Kobayashi T. et al. Lubiprostone in patients with non-alcoholic fatty liver disease: a randomised, double-blind, placebo-controlled, phase 2a trial. Lancet Gastroenterol Hepatol 2020; 5 (11) 996-1007
    CrossrefPubMedGoogle Scholar