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Gut-Liver Immune Traffic: Deciphering Immune-Pathogenesis to Underpin Translational Therapy.
Bozward, AG, Ronca, V, Osei-Bordom, D, Oo, YH
Frontiers in immunology. 2021;:711217
Abstract
The tight relationship between the gut and liver on embryological, anatomical and physiological levels inspired the concept of a gut-liver axis as a central element in the pathogenesis of gut-liver axis diseases. This axis refers to the reciprocal regulation between these two organs causing an integrated system of immune homeostasis or tolerance breakdown guided by the microbiota, the diet, genetic background, and environmental factors. Continuous exposure of gut microbiome, various hormones, drugs and toxins, or metabolites from the diet through the portal vein adapt the liver to maintain its tolerogenic state. This is orchestrated by the combined effort of immune cells network: behaving as a sinusoidal and biliary firewall, along with a regulatory network of immune cells including, regulatory T cells and tolerogenic dendritic cells (DC). In addition, downregulation of costimulatory molecules on hepatic sinusoids, hepatocytes and biliary epithelial cells as well as regulating the bile acids chain also play a part in hepatic immune homeostasis. Recent evidence also demonstrated the link between changes in the gut microbiome and liver resident immune cells in the progression of cirrhosis and the tight correlation among primary sclerosing cholangitis (PSC) and also checkpoint induced liver and gut injury. In this review, we will summarize the most recent evidence of the bidirectional relationship among the gut and the liver and how it contributes to liver disease, focusing mainly on PSC and checkpoint induced hepatitis and colitis. We will also focus on completed therapeutic options and on potential targets for future treatment linking with immunology and describe the future direction of this research, taking advantage of modern technologies.
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Alcohol's Impact on the Gut and Liver.
Pohl, K, Moodley, P, Dhanda, AD
Nutrients. 2021;(9)
Abstract
Alcohol is inextricably linked with the digestive system. It is absorbed through the gut and metabolised by hepatocytes within the liver. Excessive alcohol use results in alterations to the gut microbiome and gut epithelial integrity. It contributes to important micronutrient deficiencies including short-chain fatty acids and trace elements that can influence immune function and lead to liver damage. In some people, long-term alcohol misuse results in liver disease progressing from fatty liver to cirrhosis and hepatocellular carcinoma, and results in over half of all deaths from chronic liver disease, over half a million globally per year. In this review, we will describe the effect of alcohol on the gut, the gut microbiome and liver function and structure, with a specific focus on micronutrients and areas for future research.
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Effects of dual plasma molecular adsorption system on liver function, electrolytes, inflammation, and immunity in patients with chronic severe hepatitis.
Chen, G, Wu, M, Wu, B, Liu, F, Liu, J, Liu, L
Journal of clinical laboratory analysis. 2019;(7):e22926
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Abstract
BACKGROUND To investigate the effects of dual plasma molecular adsorption system (DPMAS) on the liver function, electrolytes, inflammation, and immunity in patients with chronic severe hepatitis (CSH). METHODS Total of 162 patients with CSH treated in our hospital from March 2016 to December 2018 were enrolled and equally randomly divided into control group (n = 81) and observation group (n = 81). The patients in control group were treated with plasma exchange, while those in observation group were additionally treated with DPMAS based on the treatment in control group. The liver function, electrolytes, inflammation, and immunity were evaluated and compared between the two groups. RESULTS After treatment, the liver function indexes in observation group were significantly favorable compared with those in control group, with the reduction in TBIL, DBIL, ALT, and rise of CHE levels (P < 0.05). The levels of K+ , Na+ , Cl- , and Ca2+ in both groups were significantly improved after treatment (P < 0.05), although there were no significant differences between the two groups (P > 0.05). The levels of C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in both groups declined after treatment compared with those before treatment, and those levels in observation group were higher than that in control group (P < 0.05). After treatment, the levels of cluster of differentiation 3+ (CD3+ ), CD4+ , and CD4+ /CD8+ were higher in observation group than those in control group, with decreasing level of CD8+ (P < 0.05). CONCLUSION Dual plasma molecular adsorption system can effectively improve the liver function, effectively correct the electrolyte disorders, reduce the inflammatory response, and adjust the immunity in patients with CSH.
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Zinc and Sepsis.
Alker, W, Haase, H
Nutrients. 2018;(8)
Abstract
Sepsis, defined as a "life-threatening organ dysfunction caused by a dysregulated host-response to infection" is a major health issue worldwide and still lacks a fully elucidated pathobiology and uniform diagnostic tests. The trace element zinc is known to be crucial to ensure an appropriate immune response. During sepsis a redistribution of zinc from serum into the liver has been observed and several studies imply a correlation between zinc and sepsis outcome. Therefore the alterations of zinc concentrations in different tissues might serve as one part of the host's defense mechanism against pathogens during sepsis by diverse mechanisms. It has been suggested that zinc is involved in nutritional immunity, acts as a hepatoprotective agent, or a differentiation signal for innate immune cells, or supports the synthesis of acute phase proteins. Further knowledge about these events could help in the evaluation of how zinc could be optimally applied to improve treatment of septic patients. Moreover, the changes in zinc homeostasis are substantial and correlate with the severity of the disease, suggesting that zinc might also be useful as a diagnostic marker for evaluating the severity and predicting the outcome of sepsis.
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Pointing at Ito cell, from structure to function (⃛ or Cinderella story in liver histology).
Grigoraş, A, Giuşcă, SE, Avădănei, ER, Amălinei, C, Căruntu, ID
Romanian journal of morphology and embryology = Revue roumaine de morphologie et embryologie. 2016;(3):915-923
Abstract
For more than 130 years, the hepatic stellate cells (also known as Ito cells) have been the object of numerous studies that aimed at their characterization both in normal and postlesional status, where they play a key role in fibrosis progression specific for chronic hepatic pathology. Converged studies on their histophysiology have revealed other functions, namely the involvement in liver embryological development and regeneration, metabolisms regulation, modulation of local inflammatory and immune reactions. Ito cells plasticity is surprising, as they are able to provide the connection between the complex sinusoidal and parenchymal microenvironment, influencing by autocrine and paracrine mechanisms the extracellular matrix content in tight correlation to growth and repair necessities. Last but not least, Ito cells take an active part in systemic homeostasis maintenance by their capacity to store and mobilize vitamin A, respectively. The evolving interest in their research will be undoubtedly followed by a better knowledge of the physiopathological sequences responsible for liver diseases, as new targets for the development of new therapeutic approaches directed toward improvement of prognosis and patients' quality of life.
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Bile Acids and the Potential Role in Primary Biliary Cirrhosis.
Yang, H, Duan, Z
Digestion. 2016;(3):145-153
Abstract
BACKGROUND Bile acids (BAs) play a potential role in regulating the whole-body metabolic homeostasis via the interaction with gut microbiome and the signal transduction as messengers, which establish a link between the primary biliary cirrhosis (PBC) and gut microbiome in many aspects, particularly with regard to the immune system of the body. PBC, as a chronic cholestatic liver disease characterised by the destruction of small intrahepatic bile ducts, causes fibrosis and potential cirrhosis without efficient therapies. SUMMARY Recent researches show BAs can induce the differentiation of hepatic stellate cells, suggesting that it may serve as a novel therapy to resist, even changeover the irreversible liver cirrhosis in PBC. Key Messages: In this review, we conclude and provide information on the possible mechanism of pleiotropic BAs in homeostasis of the gut microbiome and liver regeneration, and hope to broaden the therapy of PBC and promote the relevant drugs' development.
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The effects of heparins on the liver: application of mechanistic serum biomarkers in a randomized study in healthy volunteers.
Harrill, AH, Roach, J, Fier, I, Eaddy, JS, Kurtz, CL, Antoine, DJ, Spencer, DM, Kishimoto, TK, Pisetsky, DS, Park, BK, et al
Clinical pharmacology and therapeutics. 2012;(2):214-20
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Abstract
Heparins have been reported to cause elevations in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) but have not been associated with clinically significant liver injury. The mechanisms underlying these benign laboratory abnormalities are unknown. Forty-eight healthy men were randomized to receive subcutaneous injections of unfractionated heparin (UFH; 150 U/kg), enoxaparin sodium (1 mg/kg), dalteparin sodium (120 IU/kg), or adomiparin sodium (125 IU/kg; a novel heparin) every 12 h for 4.5 days. Asymptomatic elevations in serum ALT or AST were observed in >90% of the subjects. Elevations were also observed in the levels of serum sorbitol dehydrogenase (SDH), glutamate dehydrogenase (GLDH), miR-122, high-mobility group box-1 protein (including the acetylated form), full-length keratin 18, and DNA. Keratin 18 fragments, which are apoptosis biomarkers, were not detected. Biomarker profiles did not differ significantly across heparin treatments. We conclude that heparins as a class cause self-limited and mild hepatocyte necrosis with secondary activation of an innate immune response.
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Heavy smoking and liver.
El-Zayadi, AR
World journal of gastroenterology. 2006;(38):6098-101
Abstract
Smoking causes a variety of adverse effects on organs that have no direct contact with the smoke itself such as the liver. It induces three major adverse effects on the liver: direct or indirect toxic effects, immunological effects and oncogenic effects. Smoking yields chemical substances with cytotoxic potential which increase necro-inflammation and fibrosis. In addition, smoking increases the production of pro-inflammatory cytokines (IL-1, IL-6 and TNF- alpha) that would be involved in liver cell injury. It contributes to the development of secondary polycythemia and in turn to increased red cell mass and turnover which might be a contributing factor to secondary iron overload disease promoting oxidative stress of hepatocytes. Increased red cell mass and turnover are associated with increased purine catabolism which promotes excessive production of uric acid. Smoking affects both cell-mediated and humoral immune responses by blocking lymphocyte proliferation and inducing apoptosis of lymphocytes. Smoking also increases serum and hepatic iron which induce oxidative stress and lipid peroxidation that lead to activation of stellate cells and development of fibrosis. Smoking yields chemicals with oncogenic potential that increase the risk of hepatocellular carcinoma (HCC) in patients with viral hepatitis and are independent of viral infection as well. Tobacco smoking has been associated with suppression of p53 (tumour suppressor gene). In addition, smoking causes suppression of T-cell responses and is associated with decreased surveillance for tumour cells. Moreover, it has been reported that heavy smoking affects the sustained virological response to interferon (IFN) therapy in hepatitis C patients which can be improved by repeated phlebotomy. Smoker's syndrome is a clinico-pathological condition where patients complain of episodes of facial flushing, warmth of the palms and soles of feet, throbbing headache, fullness in the head, dizziness, lethargy, prickling sensation, pruritus and arthralgia.