scholarly journals The Role of Gut-Derived Microbial Antigens on Liver Fibrosis Initiation and Progression

Cells ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 1324 ◽  
Author(s):  
Dishen Chen ◽  
Thanh H. Le ◽  
Haleh Shahidipour ◽  
Scott A. Read ◽  
Golo Ahlenstiel
Keyword(s):  
Immune Response ◽  
Liver Disease ◽  
Liver Fibrosis ◽  
Intestinal Permeability ◽  
Systemic Circulation ◽  
Hepatic Inflammation ◽  
Intestinal Dysbiosis ◽  
End Stage ◽  
Gastrointestinal Microbes

Intestinal dysbiosis has recently become known as an important driver of gastrointestinal and liver disease. It remains poorly understood, however, how gastrointestinal microbes bypass the intestinal mucosa and enter systemic circulation to enact an inflammatory immune response. In the context of chronic liver disease (CLD), insults that drive hepatic inflammation and fibrogenesis (alcohol, fat) can drastically increase intestinal permeability, hence flooding the liver with gut-derived microbiota. Consequently, this may result in exacerbated liver inflammation and fibrosis through activation of liver-resident Kupffer and stellate cells by bacterial, viral, and fungal antigens transported to the liver via the portal vein. This review summarizes the current understanding of microbial translocation in CLD, the cell-specific hepatic response to intestinal antigens, and how this drives the development and progression of hepatic inflammation and fibrosis. Further, we reviewed current and future therapies targeting intestinal permeability and the associated, potentially harmful anti-microbial immune response with respect to their potential in terms of limiting the development and progression of liver fibrosis and end-stage cirrhosis.

scholarly journals Host–Microbiota Interactions in Liver Inflammation and Cancer

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4342
Author(s):  
Julie Giraud ◽  
Maya Saleh
Keyword(s):  
Liver Disease ◽  
Liver Diseases ◽  
Hepatic Inflammation ◽  
Nonalcoholic Fatty Liver ◽  
Intestinal Dysbiosis ◽  
Key Characteristics ◽  
Microbial Products ◽  
Molecular Patterns ◽  
Ethanol Metabolites

Hepatocellular carcinoma (HCC) is a classical inflammation-promoted cancer that occurs in a setting of liver diseases, including nonalcoholic fatty liver disease (NAFLD) or alcoholic liver disease (ALD). These pathologies share key characteristics, notably intestinal dysbiosis, increased intestinal permeability and an imbalance in bile acids, choline, fatty acids and ethanol metabolites. Translocation of microbial- and danger-associated molecular patterns (MAMPs and DAMPs) from the gut to the liver elicits profound chronic inflammation, leading to severe hepatic injury and eventually HCC progression. In this review, we first describe how the gut and the liver communicate and discuss mechanisms by which the intestinal microbiota elicit hepatic inflammation and HCC. We focus on the role of microbial products, e.g., MAMPs, host inflammatory effectors and host–microbiome-derived metabolites in tumor-promoting mechanisms, including cell death and senescence. Last, we explore the potential of harnessing the microbiota to treat liver diseases and HCC.

scholarly journals The Role of the Gut Microbiome in Liver Cirrhosis Treatment

2020 ◽  
Vol 22 (1) ◽  
pp. 199
Author(s):  
Na Young Lee ◽  
Ki Tae Suk
Keyword(s):  
Liver Cirrhosis ◽  
Liver Disease ◽  
Liver Fibrosis ◽  
Gut Microbiota ◽  
Gut Microbiome ◽  
Liver Diseases ◽  
Sclerosing Cholangitis ◽  
Chronic Liver ◽  
Chronic Liver Diseases

Liver cirrhosis is one of the most prevalent chronic liver diseases worldwide. In addition to viral hepatitis, diseases such as steatohepatitis, autoimmune hepatitis, sclerosing cholangitis and Wilson’s disease can also lead to cirrhosis. Moreover, alcohol can cause cirrhosis on its own and exacerbate chronic liver disease of other causes. The treatment of cirrhosis can be divided into addressing the cause of cirrhosis and reversing liver fibrosis. To this date, there is still no clear consensus on the treatment of cirrhosis. Recently, there has been a lot of interest in potential treatments that modulate the gut microbiota and gut-liver axis for the treatment of cirrhosis. According to recent studies, modulation of the gut microbiome by probiotics ameliorates the progression of liver disease. The precise mechanism for relieving cirrhosis via gut microbial modulation has not been identified. This paper summarizes the role and effects of the gut microbiome in cirrhosis based on experimental and clinical studies on absorbable antibiotics, probiotics, prebiotics, and synbiotics. Moreover, it provides evidence of a relationship between the gut microbiome and liver fibrosis.

Intestinal dysbiosis augments liver disease progression via NLRP3 in a murine model of primary sclerosing cholangitis

Gut ◽  
2019 ◽  
Vol 68 (8) ◽  
pp. 1477-1492 ◽  
Author(s):  
Lijun Liao ◽  
Kai Markus Schneider ◽  
Eric J C Galvez ◽  
Mick Frissen ◽  
Hanns-Ulrich Marschall ◽  
...  
Keyword(s):  
Immune Response ◽  
Liver Injury ◽  
Sclerosing Cholangitis ◽  
Functional Role ◽  
Innate Immune ◽  
Caspase 8 ◽  
Inflammasome Activation ◽  
Intestinal Dysbiosis ◽  
Nlrp3 Inflammasome Activation

ObjectiveThere is a striking association between human cholestatic liver disease (CLD) and inflammatory bowel disease. However, the functional implications for intestinal microbiota and inflammasome-mediated innate immune response in CLD remain elusive. Here we investigated the functional role of gut–liver crosstalk for CLD in the murine Mdr2 knockout (Mdr2−/−) model resembling human primary sclerosing cholangitis (PSC).DesignMale Mdr2−/−, Mdr2−/− crossed with hepatocyte-specific deletion of caspase-8 (Mdr2−/−/Casp8∆hepa) and wild-type (WT) control mice were housed for 8 or 52 weeks, respectively, to characterise the impact of Mdr2 deletion on liver and gut including bile acid and microbiota profiling. To block caspase activation, a pan-caspase inhibitor (IDN-7314) was administered. Finally, the functional role of Mdr2−/−-associated intestinal dysbiosis was studied by microbiota transfer experiments.ResultsMdr2−/− mice displayed an unfavourable intestinal microbiota signature and pronounced NLRP3 inflammasome activation within the gut–liver axis. Intestinal dysbiosis in Mdr2−/− mice prompted intestinal barrier dysfunction and increased bacterial translocation amplifying the hepatic NLRP3-mediated innate immune response. Transfer of Mdr2−/− microbiota into healthy WT control mice induced significant liver injury in recipient mice, highlighting the causal role of intestinal dysbiosis for disease progression. Strikingly, IDN-7314 dampened inflammasome activation, ameliorated liver injury, reversed serum bile acid profile and cholestasis-associated microbiota signature.ConclusionsMDR2-associated cholestasis triggers intestinal dysbiosis. In turn, translocation of endotoxin into the portal vein and subsequent NLRP3 inflammasome activation contribute to higher liver injury. This process does not essentially depend on caspase-8 in hepatocytes, but can be blocked by IDN-7314.

scholarly journals Current Concepts of Biliary Atresia and Matrix Metalloproteinase-7: A Review of Literature

2020 ◽  
Vol 7 ◽  
Author(s):  
Mark Nomden ◽  
Leonie Beljaars ◽  
Henkjan J. Verkade ◽  
Jan B. F. Hulscher ◽  
Peter Olinga
Keyword(s):  
Immune Response ◽  
Liver Fibrosis ◽  
Pulmonary Fibrosis ◽  
Matrix Metalloproteinase ◽  
Biliary Atresia ◽  
Adaptive Immune Response ◽  
Cell Contact ◽  
T Helper 1 ◽  
Matrix Metalloproteinase 7

Biliary atresia (BA) is a rare cholangiopathy of infancy in which the bile ducts obliterate, leading to profound cholestasis and liver fibrosis. BA is hypothesized to be caused by a viral insult that leads to over-activation of the immune system. Patients with BA are surgically treated with a Kasai portoenterostomy (KPE), which aims to restore bile flow from the liver to the intestines. After KPE, progressive liver fibrosis is often observed in BA patients, even despite surgical success and clearance of their jaundice. The innate immune response is involved during the initial damage to the cholangiocytes and further differentiation of the adaptive immune response into a T-helper 1 cell (Th1) response. Multiple studies have shown that there is continuing elevation of involved cytokines that can lead to the progressive liver fibrosis. However, the mechanism by which the progressive injury occurs is not fully elucidated. Recently, matrix metalloproteinase-7 (MMP-7) has been investigated to be used as a biomarker to diagnose BA. MMPs are involved in extracellular matrix (ECM) turnover, but also have non-ECM related functions. The role of MMP-7 and other MMPs in liver fibrosis is just starting to be elucidated. Multiple studies have shown that serum MMP-7 measurements are able to accurately diagnose BA in a cohort of cholestatic patients while hepatic MMP-7 expression correlated with BA-related liver fibrosis. While the mechanism by which MMP-7 can be involved in the pathophysiology of BA is unclear, MMP-7 has been investigated in other fibrotic pathologies such as renal and idiopathic pulmonary fibrosis. MMP-7 is involved in Wnt/β-catenin signaling, reducing cell-to-cell contact by shedding of E-cadherin, amplifying inflammation and fibrosis via osteopontin (OPN) and TNF-α while it also appears to play a role in induction of angiogenesis This review aims to describe the current understandings of the pathophysiology of BA. Subsequently, we describe how MMP-7 is involved in other pathologies, such as renal and pulmonary fibrosis. Then, we propose how MMP-7 can potentially be involved in BA. By doing this, we aim to describe the putative role of MMP-7 as a prognostic biomarker in BA and to provide possible new therapeutic and research targets that can be investigated in the future.

Glomerular injury in end-stage liver disease — role of circulating IgG and IgM immune complexes

1993 ◽  
Vol 7 (1) ◽  
pp. 6-10 ◽  
Author(s):  
Lawrence S. Milner ◽  
Mark T. Houser ◽  
Peter C. Kolbeck ◽  
Dean L. Antonson ◽  
Thomas L. McDonald ◽  
...  
Keyword(s):  
Liver Disease ◽  
Immune Complexes ◽  
Glomerular Injury ◽  
End Stage Liver Disease ◽  
End Stage

The Role of Model of End-Stage Liver Disease Score in Predicting Outcomes of Carotid Endarterectomy in Patients with Liver Disease

2015 ◽  
Vol 221 (4) ◽  
pp. S185-S186
Author(s):  
Brianna M. Krafcik ◽  
Denis Rybin ◽  
Gheorghe Doros ◽  
Mohammed H. Eslami ◽  
Alik Farber ◽  
...  
Keyword(s):  
Liver Disease ◽  
Carotid Endarterectomy ◽  
Disease Score ◽  
End Stage Liver Disease ◽  
End Stage

Abstract 12917: Prognostic Value of the Combination of Model for End-stage Liver Disease Excluding Inr Score and Non-alcoholic Fatty Liver Disease Fibrosis Score in Patients Admitted for Acute Heart Failure

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Masatsugu Kawahira ◽  
Takahisa Yamada ◽  
Tetsuya Watanabe ◽  
Takashi Morita ◽  
Yoshio Furukawa ◽  
...  
Keyword(s):  
Heart Failure ◽  
Liver Disease ◽  
Liver Fibrosis ◽  
Ejection Fraction ◽  
Fatty Liver Disease ◽  
Fibrosis Score ◽  
Alcoholic Fatty Liver ◽  
End Stage Liver Disease ◽  
End Stage ◽  
Alcoholic Fatty Liver Disease

Background: Cardiohepatic interactions have been a focus of attention in heart failure(HF), and the model for end-stage liver disease excluding INR (MELD-XI) has been shown to be useful for prediction of poor outcome in patients (pts) with acute decompensated heart failure (ADHF). Furthermore, it has been reported that liver stiffness predicts adverse prognosis in pts with HF. Liver fibrosis is assessed by non-invasive fibrosis markers such as Fibrosis-4 (FIB4) index, non-alcoholic fatty liver disease fibrosis score (NFS) and aminotransferase to platelet ratio index (APRI). Recently, a new group of HF pts with mid-range ejection fraction (HFmrEF) has been defined, separated from reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF). However, there is little information available on the comparison of prognostic significance of MELD-XI and liver fibrosis scores in ADHF pts, relating to LVEF. Methods: We prospectively studied 466 consecutive ADHF pts (HFrEF (LVEF≦40%): n=164, HFmrEF (40<LVEF<50): n=104 and HFpEF (LVEF≧50%): n=198). At the discharge, we calculated MELD-XI, FIB4 index , NFS, and APRI. The endpoint was all cause death (ACD). Results: During a follow-up period of 2.8±1.5 years, 143 pts had ACD. At multivariate Cox analysis, MELD-XI and FIB4 index was independently associated with ACD irrespective of LVEF. The pts with both greater MELD-XI ([HFrEF]≥25.8, [HFmrEF]≥33.2, [HFpEF]≥30.1) and greater FIB4 index ([HFrEF]≥2.58, [HFmrEF]≥2.58, [HFpEF]≥2.22) had a significantly increased risk of ACD than those with either and none of them in all three groups. Conclusions: The combination of MELD-XI and FIB4 index might be useful for stratifying pts at risk for ACD in ADHF pts with irrespective of LVEF.

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