Liver cirrhosis is a paradigm of intestinal dysbiosis. The qualitative and quantitative derangement of intestinal microbial community reported in cirrhotic patients seems to be strictly related with ...the impairment of liver function. A kind of gut microbial "fingerprint",characterized by the reduced ratio of "good" to "potentially pathogenic" bacteria has recently been outlined,and is associated with the increase in Model for End-Stage Liver Disease and Child Pugh scores. Moreover,in patients presenting with cirrhosis complications such as spontaneous bacterial peritonitis(SBP),hepatic encephalopathy(HE),and,portal hypertension intestinal microbiota modifications or the isolation of bacteria deriving from the gut are commonly reported. Rifaximin is a non-absorbable antibiotic used in the management of several gastrointestinal diseases. Beyond bactericidal/bacteriostatic,immune-modulating and anti-inflammatory activity,a little is known about its interaction with gut microbial environment. Rifaximin has been demonstrated to exert beneficial effects on cognitive function in patients with HE,and also to prevent the development of SBP,to reduce endotoxemia and to improve hemodynamics in cirrhotics. These results are linked to a shift in gut microbes functionality,triggering the production of favorable metabolites. The low incidence of drug-related adverse events due to the small amount of circulating drug makes rifaximin a relatively safe antibiotic for the modulation of gut microbiota in advanced liver disease.
Alterations in cellular signaling, chronic inflammation, and tissue remodeling contribute to hepatocellular carcinoma (HCC) development. The release of damage-associated molecular patterns (DAMPs) ...upon tissue injury and the ensuing sterile inflammation have also been attributed a role in HCC pathogenesis. Cargoes of extracellular vesicles (EVs) and/or EVs themselves have been listed among circulating DAMPs but only partially investigated in HCC. Mitochondria-derived vesicles (MDVs), a subpopulation of EVs, are another missing link in the comprehension of the molecular mechanisms underlying the onset and progression of HCC biology. EVs have been involved in HCC growth, dissemination, angiogenesis, and immunosurveillance escape. The contribution of MDVs to these processes is presently unclear. Pyroptosis triggers systemic inflammation through caspase-dependent apoptotic cell death and is implicated in tumor immunity. The analysis of this process, together with MDV characterization, may help capture the relationship among HCC development, mitochondrial quality control, and inflammation. The combination of immune checkpoint inhibitors (i.e., atezolizumab and bevacizumab) has been approved as a synergistic first-line systemic treatment for unresectable or advanced HCC. The lack of biomarkers that may allow prediction of treatment response and, therefore, patient selection, is a major unmet need. Herein, we overview the molecular mechanisms linking mitochondrial dysfunction, inflammation, and pyroptosis, and discuss how immunotherapy targets, at least partly, these routes.
Type 2 diabetes mellitus is a widespread disease worldwide, and is one of the cornerstones of metabolic syndrome. The existence of a strong relationship between diabetes and the progression of liver ...fibrosis has been demonstrated by several studies, using invasive and noninvasive techniques. Patients with type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD) show faster progression of fibrosis than patients without diabetes. Many confounding factors make it difficult to determine the exact mechanisms involved. What we know so far is that both liver fibrosis and T2DM are expressions of metabolic dysfunction, and we recognize similar risk factors. Interestingly, both are promoted by metabolic endotoxemia, a low-grade inflammatory condition caused by increased endotoxin levels and linked to intestinal dysbiosis and increased intestinal permeability. There is broad evidence on the role of the gut microbiota in the progression of liver disease, through both metabolic and inflammatory mechanisms. Therefore, dysbiosis that is associated with diabetes can act as a modifier of the natural evolution of NAFLD. In addition to diet, hypoglycemic drugs play an important role in this scenario, and their benefit is also the result of effects exerted in the gut. Here, we provide an overview of the mechanisms that explain why diabetic patients show a more rapid progression of liver disease up to hepatocellular carcinoma (HCC), focusing especially on those involving the gut-liver axis.
Liver lipid metabolism and its modulation are involved in many pathologic conditions, such as obesity, non-alcoholic fatty liver disease, diabetes mellitus, atherosclerosis and cardiovascular ...disease. Metabolic disorders seem to share a similar background of low-grade chronic inflammation, even if the pathophysiological mechanisms leading to tissue and organ damage have not been completely clarified yet. The accumulation of neutral lipids in the liver is now recognized as a beneficial and protective mechanism; on the other hand, lipoperoxidation is involved in the development and progression of non-alcoholic steatohepatitis. The role of the gut microbiota in liver lipid metabolism has been the object of recent scientific investigations. It is likely that the gut microbiota is involved in a complex metabolic modulation and the translocation of gut microflora may also contribute to maintaining the low-grade inflammatory status of metabolic syndrome. Therefore, lipid metabolism pathology has vague limits and complex mechanisms, and the knowledge of these is essential to guide diagnostic and therapeutic decisions.
Physical frailty and sarcopenia (PF&S) share multisystem derangements, including variations in circulating amino acids and chronic low-grade inflammation. Gut microbiota balances inflammatory ...responses in several conditions and according to nutritional status. Therefore, an altered gut-muscle crosstalk has been hypothesized in PF&S. We analyzed the gut microbial taxa, systemic inflammation, and metabolic characteristics of older adults with and without PF&S. An innovative multi-marker analytical approach was applied to explore the classification performance of potential biomarkers for PF&S. Thirty-five community dwellers aged 70+, 18 with PF&S, and 17 nonPF&S controls were enrolled. Sequential and Orthogonalized Covariance Selection (SO-CovSel), a multi-platform regression method developed to handle highly correlated variables, was applied. The SO-CovSel model with the best prediction ability using the smallest number of variables was built using seven mediators. The model correctly classified 91.7% participants with PF&S and 87.5% nonPF&S controls. Compared with the latter group, PF&S participants showed higher serum concentrations of aspartic acid, lower circulating levels of concentrations of threonine and macrophage inflammatory protein 1α, increased abundance of
and
microbial taxa, and decreased abundance of Barnesiellaceae and Christensenellaceae. Future investigations are warranted to determine whether these biomediators are involved in PF&S pathophysiology and may, therefore, provide new targets for interventions.
Vascular liver disorders (VLDs) comprise a wide spectrum of clinical-pathological entities that primarily affect the hepatic vascular system of both cirrhotic and non-cirrhotic patients. VLDs more ...frequently involve the portal and the hepatic veins, as well as liver sinusoids, resulting in an imbalance of liver homeostasis with serious consequences, such as the development of portal hypertension and liver fibrosis. Surprisingly, many VLDs are characterized by a prothrombotic phenotype. The molecular mechanisms that cause thrombosis in VLD are only partially explained by the alteration in the Virchow’s triad (hypercoagulability, blood stasis, and endothelial damage) and nowadays their pathogenesis is incompletely described and understood. Studies about this topic have been hampered by the low incidence of VLDs in the general population and by the absence of suitable animal models. Recently, the role of coagulation imbalance in liver disease has been postulated as one of the main mechanisms linked to fibrogenesis, so a novel interest in vascular alterations of the liver has been renewed. This review provides a detailed analysis of the current knowledge of molecular mechanisms of VLD. We also focus on the promising role of anticoagulation as a strategy to prevent liver complications and to improve the outcome of these patients.
Several studies in recent years have demonstrated that gut microbiota-host interactions play an important role in human health and disease, including inflammatory and cardiovascular diseases. ...Dysbiosis has been linked to not only well-known inflammatory diseases, such as inflammatory bowel diseases, rheumatoid arthritis, and systemic lupus erythematous, but also to cardiovascular risk factors, such as atherosclerosis, hypertension, heart failure, chronic kidney disease, obesity, and type 2 diabetes mellitus. The ways the microbiota is involved in modulating cardiovascular risk are multiple and not only related to inflammatory mechanisms. Indeed, human and the gut microbiome cooperate as a metabolically active superorganism, and this affects host physiology through metabolic pathways. In turn, congestion of the splanchnic circulation associated with heart failure, edema of the intestinal wall, and altered function and permeability of the intestinal barrier result in the translocation of bacteria and their products into the systemic circulation, further enhancing the pro-inflammatory conditions underlying cardiovascular disorders. The aim of the present review is to describe the complex interplay between gut microbiota, its metabolites, and the development and evolution of cardiovascular diseases. We also discuss the possible interventions intended to modulate the gut microbiota to reduce cardiovascular risk.
Although alcohol is one of the most important etiologic agents in the development of chronic liver disease worldwide, also recognized as a promoter of carcinogenesis, several studies have shown a ...beneficial effect of moderate consumption in terms of reduced cardiovascular morbidity and mortality. Whether this benefit is also present in patients with liver disease due to other causes (viral, metabolic, and others) is still debated. Although there is no clear evidence emerging from guidelines and scientific literature, total abstention from drinking is usually prescribed in clinical practice. In this review, we highlight the results of the most recent evidence on this controversial topic, in order to understand the effect of mild alcohol use in this category of individuals. The quantification of alcohol intake, the composition of the tested populations, and the discrepancy between different works in relation to the outcomes represent important limitations emerging from the scientific literature. In patients with NAFLD, a beneficial effect is demonstrated only in a few works. Even if there is limited evidence in patients affected by chronic viral hepatitis, a clear deleterious effect of drinking in determining disease progression in a dose-dependent manner emerges. Poor data are available about more uncommon pathologies such as hemochromatosis. Overall, based on available data, it is not possible to establish a safe threshold for alcohol intake in patients with liver disease.
Portal vein thrombosis （PVT） is one of the most com- mon complications occurring during the natural course of liver cirrhosis. Even though PVT is often asymptom- atic, the worsening of liver ...function, an unexpected episode of gastrointestinal bleeding or ascitic decom- pensation may be landmarks of PVT development. Beyond these clinical manifestations, it is debated whether PVT really has an impact on liver cirrhosis natural history or rather represents only one of its consequences. Probably PVT development should not only be considered as a matter of impaired blood flow or pro-coagulation tendency. On one hand, PVT seems a consequence of the worsening in portal vein outflow due to the increased hepatic resistance in cirrhotic livers. On the other hand, vascular microthrombosis secondary to necroinflammation may cause liver isch- emia and infarction, with loss of hepatic tissue （paren- chymal extinction） which is replaced by fibrotic tissue. Therefore, PVT might also be considered as the overt manifestation of the liver fibrosing process evolution and anticoagulant therapy may thus have microscopic indirect effects also on the progression of liver disease. At present, a connection between PVT development and the progression of liver fibrosis/cirrhosis has not yet been demonstrated. Nevertheless, it is not clear if PVT development may worsen cirrhotic patients＇ outcome by itself. Some authors tried to assess liver transplant benefit in PVT cirrhotic patients but data are contrasting. In this review, we will try to answer these questions, providing a critical analysis of data reported in literature.
Liver cirrhosis has been known to be associated with increased intestinal permeability (IP); however, little is known about the modification of IP after liver transplantation (LT). The present study ...was aimed to assess IP after LT and evaluated its association with laboratory tests and clinical parameters, as well as with the development of infections. LT recipients were consecutively enrolled and compared with an equal number of patients with liver cirrhosis and healthy subjects. IP was assessed by urinary excretion of chromium-51 ethylenediaminetetraacetic acid (.sup.51 Cr-EDTA). The median .sup.51 Cr-EDTA excretion was found to be higher in 35 LT recipients as compared with that in the healthy controls 4.77% (2.79-6.03) vs. 2.07% (1.57-2.42), p<0.0001, and comparable to that in the cirrhotic patients 3.69% (2.34-6.57), p = 0.445. .sup.51 Cr-EDTA excretion was not associated with clinical variables, the type of immunosuppressive therapy, donor-related factors, comorbidities and incidence of infections infection/no infection: 4.97% (3.14-7.03) vs 4.62% (2.79-5.82), p = 0.938. LT recipients show an increased IP, similar to that in patients with liver cirrhosis. However, it is not associated with a high risk of infections. Further investigations into the pathogenesis of this persistent impairment of the intestinal barrier are warranted.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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