Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1
Vanessa Stadlbauer
 + 1058 word(s) 1058 2021-03-25 07:20:30 |
2 update layout and reference
Rita Xu
 Meta information modification 1058 2021-03-26 05:15:09 |

Video Upload Options

Do you have a full video?
Send video materials Upload full video

Confirm

Are you sure to Delete?
Yes No
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Stadlbauer, V. Gut-Liver Axis. Encyclopedia. Available online: https://encyclopedia.pub/entry/8271 (accessed on 15 September 2024).
Stadlbauer V. Gut-Liver Axis. Encyclopedia. Available at: https://encyclopedia.pub/entry/8271. Accessed September 15, 2024.
Stadlbauer, Vanessa. "Gut-Liver Axis" Encyclopedia, https://encyclopedia.pub/entry/8271 (accessed September 15, 2024).
Stadlbauer, V. (2021, March 25). Gut-Liver Axis. In Encyclopedia. https://encyclopedia.pub/entry/8271
Stadlbauer, Vanessa. "Gut-Liver Axis." Encyclopedia. Web. 25 March, 2021.
Gut-Liver Axis
Edit
This entry is adapted from the peer-reviewed paper 10.3390/nu13031018

The gut-liver axis describes the physiological interplay between the gut and the liver and has important implications for the maintenance of health. Disruptions of this equilibrium are an important factor in the evolution and progression of many liver diseases. The composition of the gut microbiome, the gut barrier, bacterial translocation, and bile acid metabolism are key features of this cycle. 

gut-liver axis primary sclerosing cholangitis SC-CIP primary biliary cholangitis microbiome

1. Introduction

Impaired biliary formation or flow can lead to cholestasis [1]. Cholestatic liver diseases can be divided into acute (such as choledocholithiasis and malignancies) and chronic diseases. Chronic cholestatic liver diseases include inherit cholestatic diseases, primary sclerosing cholangitis (PSC), the generic term secondary sclerosing cholangitis (SSC) subsuming diseases caused by mechanical obstruction, ischemia, infections, immune-mediated diseases, or liver damage due to toxic substances, and primary biliary cholangitis (PBC) [2][3]. This review will focus on PSC, SSC in critically ill patients (SC-CIP) as a sub-entity of SSC and PBC because alterations of the gut-liver axis seem to play an important role in the pathogenesis of these diseases and knowledge about alterations of the gut-liver axis may influence future therapeutic strategies.

The occurrence of these diseases is rare, with an incidence between 0.3 and 5.8 per 100,000 people per year [4]. The pathogenesis is still not fully understood, but a multifactorial evolution seems likely. Clinical manifestations can happen in all ages, mainly in the form of elevated cholestasis parameters, jaundice and pruritus. Incidence is not equally distributed between women and men in all three disease types and prognosis without liver transplantation remains limited in many patients [2][4][5].

PSC can affect the intra- and extrahepatic biliary tree. Inflammation of bile ducts leads to progressive liver dysfunction and liver cirrhosis with the potential need for liver transplantation. This disease affects primary men (65–70%) and is associated with inflammatory bowel diseases (IBD) in the majority of patients (70–80%). The risk for hepatobiliary malignancies is increased [6][7][8]. Pharmaceutical treatment is currently not available and mean liver transplantation-free survival is 14.5 years [9][10]. SC-CIP occurs after long-term intensive care treatment with the need for catecholamine treatment and invasive ventilation. Male patients are affected more frequently than women [11]. Prognosis without liver transplantation is often poor and progression to liver cirrhosis can occur within a period of weeks [12][13][14]. PBC leads to progressive destruction of the intrahepatic biliary ducts and occurs most frequently in women of middle age with a sex ratio of 10:1. Clinical symptoms include fatigue, pruritus and jaundice. Due to improved pharmacological treatment options with ursodeoxycholic acid, bezafibrat, and obeticholic acid, liver transplantation is only necessary for 4% of affected patients [2][4][5][15].

The etiologies of these diseases remain widely enigmatic [2]. In PSC, genetic and environmental factors are proposed and associations with the human leukocyte antigen system and other gene loci could be shown, however, a clear causal relationship could not be proven [16][17]. Because recurrence of the disease is possible after liver transplantation, extrahepatic drivers are likely to play a significant role in the pathogenesis [7]. SC-CIP is most likely triggered by ischemic injury of the biliary system during critical illness with consecutive formation of biliary casts and recurrent biliary infections [18]. PBC is a multifactorial disease and environmental triggers like infections (urinary tract infections, infections with mycobacteria, Epstein-Barr virus, chlamydia, Helicobacter pylori) and smoking, as well as genetic predisposition and autoimmune factors have been described [5][19][20][21][22][23][24][25].

Recently, data has emerged highlighting the role of the microbiome and the gut barrier in liver diseases, leading to the concept of the gut-liver axis as a common pathogenetic principle and a potential therapeutic target [26].

2. The Gut-Liver Axis

The communication between the gut and the liver works bidirectionally [27][28][29] (Figure 1). The gut microbiome consists of a thousand species with trillions of microorganisms spanning from bacteria to fungi, protozoa, archaea, and viruses [30]. Composition of the gut microbiome is influenced in early life by mode of birth and breastfeeding, subsequently by age, genetics, food, and drug intake [31][32]. Disturbance of the gut microbiome leads to dysbiosis and further to increased gut permeability allowing translocation of microbes and microbial products named microbial or pathogen-associated molecular patterns (MAMPs/PAMPs) [28][33][34]. Immune receptors of liver cells can identify these patterns once they are in the blood circulation and they can lead to activation of inflammation cascades causing fibrosis and cirrhosis in the course of liver diseases [34]. Vice versa, the liver communicates with the gut through the biliary system and the systemic circulation by releasing bile acids and systemic inflammatory mediators like cytokines [35]. Primary bile acids are synthesized from cholesterol in the liver. Conjugation with taurine or glycine then happens in hepatocytes and the conjugated bile acids are released into the intestine, where they enable the uptake of lipids and fat-soluble vitamins. In the terminal ileum, the majority of bile acids is actively reabsorbed. The remaining 5% are transformed to secondary bile acids by microbial metabolisms in the colon and are passively reabsorbed or excreted. Transformation from primary to secondary bile acids (deconjugation and dihydroxylation) is facilitated by bile salt hydrolases (BSH) and 7α-dehydroxylase expressed by microbes of the gut microbiome including all major phyla (BSH) and the genera Bacteroides, Clostridium, Eubacterium, Lactobacillus, and Escherichia [34][36][37][38]. Bile acids do not act solely as agents involved in fat digestion, but they additionally work as signaling metabolites that can interact with luminal microbes and cellular receptors of the intestine [37][39][40].

Nutrients 13 01018 g001 550

Figure 1. The gut-liver axis in liver diseases. Dysbiosis of the microbiome leads to gut barrier damage enabling translocation of bacteria, toxins, pathogen associated molecular patterns (PAMPs), and metabolites of gut microbes. Via the portal vein, they reach the liver and trigger inflammation cascades leading to fibrosis and cirrhosis in disease courses. Bile acids are synthesized from cholesterol in hepatocytes. After conjugation, they are secreted into the bile ducts and reach the intestine as conjugated primary bile acids. In the gut, bile acids allow digestion of fat and they interact with gut microbes and cellular receptors. Takeda G-protein-coupled receptor 5 (TGR5) and farnesoid X receptor (FXR) are the most important of these receptors. Binding of bile acids to FXR induces formation of fibroblast growth factor 19 (FGF-19) which serves as negative feed-back mechanism for bile acid synthesis in the liver. The majority of bile acids are reabsorbed in the terminal ileum, whereas a small proportion is secreted into the colon, metabolized to secondary bile acids and then also reabsorbed or excreted. Created with BioRender.com. CYP7A1 = Cytochrome P450, Family 7, Subfamily A, Polypeptide 1; NLRP3 = NOD-, LRR- and pyrin domain-containing protein 3. Created with Biorender.com

References

  1. Onofrio, F.Q.; Hirschfield, G.M. The Pathophysiology of Cholestasis and Its Relevance to Clinical Practice. Clin. Liver Dis. 2020, 15, 110–114.
  2. Hilscher, M.B.; Kamath, P.S.; Eaton, J.E. Cholestatic Liver Diseases: A Primer for Generalists and Subspecialists. Mayo. Clin. Proc. 2020, 95, 2263–2279.
  3. Brooling, J.; Leal, R. Secondary Sclerosing Cholangitis: A Review of Recent Literature. Curr. Gastroenterol. Rep. 2017, 19, 44.
  4. Wagner, M.; Fickert, P. Drug Therapies for Chronic Cholestatic Liver Diseases. Annu. Rev. Pharmacol. Toxicol. 2020, 60, 503–527.
  5. Tanaka, A. Current understanding of primary biliary cholangitis. Clin. Mol. Hepatol. 2021, 27, 1–21.
  6. Dyson, J.K.; Beuers, U.; Jones, D.E.J.; Lohse, A.W.; Hudson, M. Primary sclerosing cholangitis. Lancet 2018, 391, 2547–2559.
  7. Dean, G.; Hanauer, S.; Levitsky, J. The Role of the Intestine in the Pathogenesis of Primary Sclerosing Cholangitis: Evidence and Therapeutic Implications. Hepatology 2020, 72, 1127–1138.
  8. LaRusso, N.F.; Tabibian, J.H.; O’Hara, S.P. Role of the Intestinal Microbiome in Cholestatic Liver Disease. Dig. Dis. 2017, 35, 166–168.
  9. Gochanour, E.; Jayasekera, C.; Kowdley, K. Primary Sclerosing Cholangitis: Epidemiology, Genetics, Diagnosis, and Current Management. Clin. Liver Dis. 2020, 15, 125–128.
  10. Dhillon, A.K.; Kummen, M.; Trøseid, M.; Åkra, S.; Liaskou, E.; Moum, B.; Vesterhus, M.; Karlsen, T.H.; Seljeflot, I.; Hov, J.R. Circulating markers of gut barrier function associated with disease severity in primary sclerosing cholangitis. Liver Int. 2018, 39, 371–381.
  11. Gudnason, H.O.; Björnsson, E.S. Secondary sclerosing cholangitis in critically ill patients: Current perspectives. Clin. Exp. Gastroenterol. 2017, 10, 105–111.
  12. Kirchner, G.I.; Rümmele, P. Update on Sclerosing Cholangitis in Critically Ill Patients. Visc. Med. 2015, 31, 178–184.
  13. Kirchner, G.I.; Scherer, M.N.; Obed, A.; Ruemmele, P.; Wiest, R.; Froh, M.; Loss, M.; Schlitt, H.-J.; Schölmerich, J.; Gelbmann, C.M. Outcome of patients with ischemic-like cholangiopathy with secondary sclerosing cholangitis after liver transplantation. Scand. J. Gastroenterol. 2010, 46, 471–478.
  14. Benninger, J.; Grobholz, R.; Oeztuerk, Y.; Antoni, C.H.; Hahn, E.G.; Singer, M.V.; Strauss, R. Sclerosing cholangitis following severe trauma: Description of a remarkable disease entity with emphasis on possible pathophysiologic mechanisms. World J. Gastroenterol. 2005, 11, 4199–4205.
  15. Selmi, C.; Bowlus, C.L.; Gershwin, M.E.; Coppel, R.L. Primary biliary cirrhosis. Lancet 2011, 377, 1600–1609.
  16. Ji, S.-G.; The UK-PSC Consortium; Juran, B.D.; Mucha, S.; Folseraas, T.; Jostins, L.; Melum, E.; Kumasaka, N.; Atkinson, E.J.; Schlicht, E.M.; et al. Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease. Nat. Genet. 2017, 49, 269–273.
  17. Liu, J.Z.; Hov, J.R.; Folseraas, T.; Ellinghaus, E.; Rushbrook, S.M.; Doncheva, N.T.; Andreassen, O.A.; Weersma, R.K.; Weismüller, T.J.; Eksteen, B.; et al. Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis. Nat. Genet. 2013, 45, 670–675.
  18. Blesl, A.; Jüngst, C.; Lammert, F.; Fauler, G.; Rainer, F.; Leber, B.; Feldbacher, N.; Stromberger, S.; Wildburger, R.; Spindelböck, W.; et al. Secondary Sclerosing Cholangitis in Critically Ill Patients Alters the Gut–Liver Axis: A Case Control Study. Nutrients 2020, 12, 2728.
  19. Tanaka, A.; Leung, P.S.; Gershwin, M.E. The genetics of primary biliary cholangitis. Curr. Opin. Gastroenterol. 2019, 35, 93–98.
  20. Corpechot, C.; Chrétien, Y.; Chazouillères, O.; Poupon, R. Demographic, lifestyle, medical and familial factors associated with primary biliary cirrhosis. J. Hepatol. 2010, 53, 162–169.
  21. Burroughs, A.K.; Rosenstein, I.J.; Epstein, O.; Hamilton-Miller, J.M.; Brumfitt, W.; Sherlock, S. Bacteriuria and primary biliary cirrhosis. Gut 1984, 25, 133–137.
  22. Quigley, E.M.M. Primary Biliary Cirrhosis and the Microbiome. Semin. Liver Dis. 2016, 36, 349–353.
  23. Smyk, D.; Rigopoulou, E.I.; Zen, Y.; Abeles, R.D.; Billinis, C.; Parés, A.; Bogdanos, D.P. Role for mycobacterial infection in pathogenesis of primary biliary cirrhosis? World J. Gastroenterol. 2012, 18, 4855–4865.
  24. Saadah, O.I.; Bokhary, R.Y. Anti-mitochondrial antibody positive autoimmune hepatitis triggered by EBV infection in a young girl. Arab. J. Gastroenterol. 2013, 14, 130–132.
  25. Abenavoli, L.; Arena, V.; Giancotti, F.; Vecchio, F.; Abenavoli, S. Celiac Disease, Primary Biliary Cirrhosis and Helicobacter Pylori Infection: One Link for Three Diseases. Int. J. Immunopathol. Pharmacol. 2010, 23, 1261–1265.
  26. Kummen, M.; Hov, J.R. The gut microbial influence on cholestatic liver disease. Liver Int. 2019, 39, 1186–1196.
  27. Kanmani, P.; Suganya, K.; Kim, H. The Gut Microbiota: How Does It Influence the Development and Progression of Liver Diseases. Biomedicines 2020, 8, 501.
  28. Maroni, L.; Ninfole, E.; Pinto, C.; Benedetti, A.; Marzioni, M. Gut–Liver Axis and Inflammasome Activation in Cholangiocyte Pathophysiology. Cells 2020, 9, 736.
  29. Wang, R.; Tang, R.; Li, B.; Ma, X.; Schnabl, B.; Tilg, H. Gut microbiome, liver immunology, and liver diseases. Cell. Mol. Immunol. 2021, 18, 4–17.
  30. Jennison, E.; Byrne, C.D. The role of the gut microbiome and diet in the pathogenesis of non-alcoholic fatty liver disease. Clin. Mol. Hepatol. 2021, 27, 22–43.
  31. Azad, M.B.; Konya, T.; Persaud, R.R.; Guttman, D.S.; Chari, R.S.; Field, C.J.; Sears, M.R.; Mandhane, P.J.; Turvey, S.E.; Subbarao, P.; et al. Impact of maternal intrapartum antibiotics, method of birth and breastfeeding on gut microbiota during the first year of life: A prospective cohort study. BJOG Int. J. Obstet. Gynaecol. 2015, 123, 983–993.
  32. Rinninella, E.; Raoul, P.; Cintoni, M.; Franceschi, F.; Miggiano, G.A.D.; Gasbarrini, A.; Mele, M.C. What is the Healthy Gut Microbiota Composition? A Changing Ecosystem across Age, Environment, Diet, and Diseases. Microorganisms 2019, 7, 14.
  33. Anand, G.; Zarrinpar, A.; Loomba, R. Targeting Dysbiosis for the Treatment of Liver Disease. Semin. Liver Dis. 2016, 36, 37–47.
  34. 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.
  35. Stärkel, P.; Schnabl, B. Bidirectional Communication between Liver and Gut during Alcoholic Liver Disease. Semin. Liver Dis. 2016, 36, 331–339.
  36. Fiorucci, S.; Carino, A.; Baldoni, M.; Santucci, L.; Costanzi, E.; Graziosi, L.; Distrutti, E.; Biagioli, M. Bile Acid Signaling in Inflammatory Bowel Diseases. Dig. Dis. Sci. 2021, 66, 674–693.
  37. Chen, M.L.; Takeda, K.; Sundrud, M.S. Emerging roles of bile acids in mucosal immunity and inflammation. Mucosal Immunol. 2019, 12, 851–861.
  38. Wahlström, A.; Sayin, S.I.; Marschall, H.-U.; Bäckhed, F. Intestinal Crosstalk between Bile Acids and Microbiota and Its Impact on Host Metabolism. Cell Metab. 2016, 24, 41–50.
  39. De Aguiar Vallim, T.Q.; Tarling, E.J.; Edwards, P.A. Pleiotropic roles of bile acids in metabolism. Cell Metab. 2013, 17, 657–669.
  40. Lefebvre, P.; Cariou, B.; Lien, F.; Kuipers, F.; Staels, B. Role of Bile Acids and Bile Acid Receptors in Metabolic Regulation. Physiol. Rev. 2009, 89, 147–191.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
Upload a video for this entry
Information
Subjects: Nutrition & Dietetics
Contributor MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Vanessa Stadlbauer
View Times: 813
Revisions: 2 times (View History)
Update Date: 26 Mar 2021
Table of Contents
    1000/1000
    Hot Most Recent
    ScholarVision Creations
    Feedback