Role of innate immunity and the microbiota in liver fibrosis: crosstalk between the liver and gut - PubMed (original) (raw)
Review
Role of innate immunity and the microbiota in liver fibrosis: crosstalk between the liver and gut
Ekihiro Seki et al. J Physiol. 2012.
Abstract
Liver fibrosis occurs as a wound-healing scar response following chronic liver inflammation including alcoholic liver disease, non-alcoholic steatohepatitis, viral hepatitis, cholestatic liver disease and autoimmune liver diseases. The liver has a unique vascular system within the gastrointestinal tract, as the majority of the liver's blood supply comes from the intestine through the portal vein. When the intestinal barrier function is disrupted, an increase in intestinal permeability leads to the translocation of intestine-derived bacterial products such as lipopolysaccharide (LPS) and unmethylated CpG containing DNA to the liver via the portal vein. These gut-derived bacterial products stimulate innate immune receptors, namely Toll-like receptors (TLRs), in the liver. TLRs are expressed on Kupffer cells, endothelial cells, dendritic cells, biliary epithelial cells, hepatic stellate cells, and hepatocytes. TLRs activate these cells to contribute to acute and chronic liver diseases. This review summarizes recent studies investigating the role of TLRs, intestinal microbiota and bacterial translocation in liver fibrosis, alcoholic liver disease and non-alcoholic steatohepatitis.
Figures
Figure 1. Overview of TLR signalling
TLR1, TLR2, TLR4, TLR5 and TLR6 are expressed on cell membrane. TLR3, TLR7/8 and TLR9 are expressed in endosome. All TLRs except for TLR3 activate MyD88-dependent pathway to induce NF-κB and p38/JNK activation. TLR2 and TLR4 signalling require TIRAP and MyD88. TLR3 requires TRAF to activate TBK1/IKKɛ. After TLR4 internalization, TLR4 signalling activates TRAM/TRIF-dependent pathway. TLR3/4-dependent TRIF-dependent signalling induces IRF-3 activation and IFN-β production. TLR7/8 and TLR9 induce IFN-α production through IRF7.
Figure 2. TLR4 signalling in hepatic stellate cells during liver fibrosis
In chronic liver damage, intestinal permeability is increased due to systemic inflammation, portal hypertension, intestinal dysbiosis or tight junction disintegrity, which allows translocation of gut microflora-derived LPS into the liver through the portal vein. Translocated LPS stimulates TLR4 on hepatic stellate cells (HSCs). High expression of Bambi prevents TGF-β signalling in quiescent HSCs. Upon activation of TLR4, HSCs produce chemokines (MCP-1, MIP-1β and RANTES) that recruit Kupffer cells through CCR1 and CCR2. TLR4-activated HSCs downregulate Bambi and increase its sensitivity to TGF-β released from Kupffer cells. The fully activated TGF-β signalling then induces HSC activation. TLR4 signalling-mediated Bambi downregulation requires MyD88 and NF-κB.
Figure 3. Bacterial translocation and hepatic TLR4 signalling in alcoholic liver disease
Excessive intake of alcohol induces changes in composition of intestinal microflora and bacterial overgrowth. In addition, tight junction disruption causes an increase in intestinal permeability, leading to translocation of gut microflora-derived LPS into the liver through the portal vein. Translocated LPS stimulates TLR4 on both Kupffer cells and hepatic stellate cells (HSCs). Upon activation of TLR4, Kupffer cells and HSCs produce chemokines (MCP-1, MIP-1α, MIP-1β and RANTES) that recruit Kupffer cells as well as HSCs. This activation of cells participates in liver inflammation, hepatocyte steatosis and fibrosis.
Similar articles
- Toll-like receptor signaling and liver fibrosis.
Aoyama T, Paik YH, Seki E. Aoyama T, et al. Gastroenterol Res Pract. 2010;2010:192543. doi: 10.1155/2010/192543. Epub 2010 Jul 25. Gastroenterol Res Pract. 2010. PMID: 20706677 Free PMC article. - Gut-liver axis and fibrosis in nonalcoholic fatty liver disease: an input for novel therapies.
Frasinariu OE, Ceccarelli S, Alisi A, Moraru E, Nobili V. Frasinariu OE, et al. Dig Liver Dis. 2013 Jul;45(7):543-51. doi: 10.1016/j.dld.2012.11.010. Epub 2012 Dec 29. Dig Liver Dis. 2013. PMID: 23280158 Review. - Common pathogenic mechanism in development progression of liver injury caused by non-alcoholic or alcoholic steatohepatitis.
Nagata K, Suzuki H, Sakaguchi S. Nagata K, et al. J Toxicol Sci. 2007 Dec;32(5):453-68. doi: 10.2131/jts.32.453. J Toxicol Sci. 2007. PMID: 18198478 Review. - The role of gut-liver axis in the pathogenesis of liver cirrhosis and portal hypertension.
Seo YS, Shah VH. Seo YS, et al. Clin Mol Hepatol. 2012 Dec;18(4):337-46. doi: 10.3350/cmh.2012.18.4.337. Epub 2012 Dec 21. Clin Mol Hepatol. 2012. PMID: 23323248 Free PMC article. Review. - The Role of Gut-Derived Microbial Antigens on Liver Fibrosis Initiation and Progression.
Chen D, Le TH, Shahidipour H, Read SA, Ahlenstiel G. Chen D, et al. Cells. 2019 Oct 27;8(11):1324. doi: 10.3390/cells8111324. Cells. 2019. PMID: 31717860 Free PMC article. Review.
Cited by
- Effect and Mechanism of Apple Polyphenols in Regulating Intestinal Flora and Inhibiting the TLR4/NF-κB/TGF-β Signaling Pathway to Alleviate Alcoholic Liver Fibrosis.
Meng X, Ma Y, Li K, Ji M, Lin L, Xiao X, Zhao Y, Su G. Meng X, et al. Plant Foods Hum Nutr. 2024 Sep 19. doi: 10.1007/s11130-024-01235-1. Online ahead of print. Plant Foods Hum Nutr. 2024. PMID: 39298074 - Hepatic Gα13 ablation shifts region-specific colonic inflammatory status by modulating the bile acid synthetic pathway in mice.
Kwon SJ, Kim YS, Tak J, Lee SG, Lee EB, Kim SG. Kwon SJ, et al. Sci Rep. 2024 Aug 23;14(1):19580. doi: 10.1038/s41598-024-70254-4. Sci Rep. 2024. PMID: 39179591 Free PMC article. - Impact of small intestinal bacterial overgrowth on systemic inflammation, circulatory and renal function, and liver fibrosis in patients with cirrhosis and ascites.
Alexiou O, Despotis G, Kalambokis G, Tsiakas I, Christaki M, Tsiouris S, Xourgia X, Lakkas L, Markopoulos GS, Kolios G, Kolios D, Tsiara S, Milionis H, Christodoulou D, Baltayiannis G. Alexiou O, et al. Ann Gastroenterol. 2024 May-Jun;37(3):348-355. doi: 10.20524/aog.2024.0881. Epub 2024 Apr 26. Ann Gastroenterol. 2024. PMID: 38779647 Free PMC article. - Role of the gut microbiota in tumorigenesis and treatment.
Liu Q, Yang Y, Pan M, Yang F, Yu Y, Qian Z. Liu Q, et al. Theranostics. 2024 Mar 17;14(6):2304-2328. doi: 10.7150/thno.91700. eCollection 2024. Theranostics. 2024. PMID: 38646653 Free PMC article. Review. - Exploring the complex interplay: gut microbiome, stress, and leptospirosis.
Petakh P, Oksenych V, Kamyshna I, Boisak I, Lyubomirskaya K, Kamyshnyi O. Petakh P, et al. Front Microbiol. 2024 Feb 27;15:1345684. doi: 10.3389/fmicb.2024.1345684. eCollection 2024. Front Microbiol. 2024. PMID: 38476949 Free PMC article. Review.
References
- Adachi Y, Bradford BU, Gao W, Bojes HK, Thurman RG. Inactivation of Kupffer cells prevents early alcohol-induced liver injury. Hepatology. 1994;20:453–460. - PubMed
- Adachi Y, Moore LE, Bradford BU, Gao W, Thurman RG. Antibiotics prevent liver injury in rats following long-term exposure to ethanol. Gastroenterology. 1995;108:218–224. - PubMed
- Baeck C, Wehr A, Karlmark KR, Heymann F, Vucur M, Gassler N, Huss S, Klussmann S, Eulberg D, Luedde T, Trautwein C, Tacke F. Pharmacological inhibition of the chemokine CCL2 (MCP-1) diminishes liver macrophage infiltration and steatohepatitis in chronic hepatic injury. Gut. 2011 (in press) - PubMed
Publication types
MeSH terms
Substances
Grants and funding
- R01 AA020703/AA/NIAAA NIH HHS/United States
- K08DK081830/DK/NIDDK NIH HHS/United States
- R24 DK080506/DK/NIDDK NIH HHS/United States
- R01AA02172/AA/NIAAA NIH HHS/United States
- R01 AA020172/AA/NIAAA NIH HHS/United States
- K08 DK081830/DK/NIDDK NIH HHS/United States
- R01DK085252/DK/NIDDK NIH HHS/United States
- DK080506/DK/NIDDK NIH HHS/United States
- R01AA020703/AA/NIAAA NIH HHS/United States
- R01 DK085252/DK/NIDDK NIH HHS/United States
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical