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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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Signaling from Intestine to the Host: How Bile Acids Regulate Intestinal and Liver Immunity.
Biagioli, M, Carino, A
Handbook of experimental pharmacology. 2019;:95-108
Abstract
Primary bile acids (BAs) are generated in the liver as the end products of cholesterol catabolism; they are then conjugated and accumulated in the gallbladder. After a meal ingestion, BAs are reversed into the duodenum to facilitate the lipid absorption. At the intestinal level, the 95% of BAs are reabsorbed and redirected into enterohepatic circulation; indeed only a small amount of them are then subjected to chemical modifications by the intestinal microbiota, which plays a very important role in the generation of secondary bile acids and in regulating host's metabolism and activity of the immune system. Behind their role in nutrients absorption, bile acids act as signaling molecules, activating several receptors, known as bile acid-activated receptors (BARs), including the farnesoid-X-receptor (FXR) and the G protein-coupled bile acid receptor 1 (GPBAR1 or Takeda G-protein receptor 5). Both receptors appear to contribute to maintain the tolerogenic state of the liver and intestine immunity. In particular, FXR and GPBAR1 are highly expressed in cells of innate immunity including intestinal and liver macrophages, dendritic cells, and natural killer T cells. In this chapter, we provide an overview on mechanisms through which FXR and GPBAR1 modulate the signaling between microbiota and intestinal and liver innate immune system. This overview could help to explain beneficial effects exerted by GPBAR1 and FXR agonists in the treatment of metabolic and immuno-mediated diseases.
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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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Interplay between early-life malnutrition, epigenetic modulation of the immune function and liver diseases.
Campisano, S, La Colla, A, Echarte, SM, Chisari, AN
Nutrition research reviews. 2019;(1):128-145
Abstract
Early-life nutrition plays a critical role in fetal growth and development. Food intake absence and excess are the two main types of energy malnutrition that predispose to the appearance of diseases in adulthood, according to the hypothesis of 'developmental origins of health and disease'. Epidemiological data have shown an association between early-life malnutrition and the metabolic syndrome in later life. Evidence has also demonstrated that nutrition during this period of life can affect the development of the immune system through epigenetic mechanisms. Thus, epigenetics has an essential role in the complex interplay between environmental factors and genetics. Altogether, this leads to the inflammatory response that is commonly seen in non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome. In conjunction, DNA methylation, covalent modification of histones and the expression of non-coding RNA are the epigenetic phenomena that affect inflammatory processes in the context of NAFLD. Here, we highlight current understanding of the mechanisms underlying developmental programming of NAFLD linked to epigenetic modulation of the immune system and environmental factors, such as malnutrition.
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[An overview of bile acid synthesis and its physiological and pathological functions].
Liu, X, Wang, Y
Yi chuan = Hereditas. 2019;(5):365-374
Abstract
Bile acids are a class of cholesterol derivatives that play important roles in cholesterol and energy homeostasis and intestinal nutrition absorption. Bile acids are mainly synthesized in the liver. During fasting, bile acids are secreted from the liver and stored in the gallbladder. After a meal, the stored bile acids are released into small intestines. In the intestine, about 95% of bile acids will be re-absorbed and travel back into the liver through port veins, which is called bile acid enterohepatic circulation. This enterohepatic circulation of bile acids plays important roles in the emulsification and intestinal absorption of lipids and other nutrition. On the other hand, bile acids function as ligands for a number of receptors, such as farnesoid X receptor (FXR), proterane X receptor (PXR), vitamin D receptor (VDR) and cell membrane surface receptor-G protein coupled receptor (TGR5), which play important roles from metabolic homeostasis to innate immunity. A number of cytokines such as hepatocyte growth factor (HGF), interleukin-1β (IL-1β) and tumor necrosis factor α (TNF-α) regulate the homeostasis of bile acids. In the current review, we will summarize the recent progress in the regulation of bile acid synthesis and its physiological and pathological functions from energy homeostasis to innate immunity and cancer progression to provide a reference for the study of bile acid metabolism.