The Intestinal Microbiome and the Metabolic Syndrome-How Its Manipulation May Affect Metabolic-Associated Fatty Liver Disease (MAFLD).

Metabolic-associated fatty liver disease (MAFLD) is now the predominant liver disease worldwide consequent to the epidemic of obesity. The intestinal microbiome (IM), consisting of the bacteria, fungi, archaea, and viruses residing in the gastrointestinal tract, plays an important role in human metabolism and preserving the epithelial barrier function. Disturbances in the IM have been shown to influence the development and progression of MAFLD and play a role in the development of metabolic syndrome (MS). The main treatment for MAFLD involves lifestyle changes, which also influence the IM. Manipulation of the IM by fecal microbial transplantation (FMT) has been approved for the treatment of recurrent Closteroides difficile infection. This may be administered by endoscopic administration from the lower or upper GI tract. Other methods of administration include nasogastric tube, enema, and oral capsules of stool from healthy donors. In this narrative review, we elaborate on the role of the IM in developing MS and MAFLD and on the current experience with IM modulation by FMT on MAFLD.

Manipulation of the intestinal microbiome-a slow journey to primetime.

The gut microbiota has important functions in the regulation of normal body functions. Alterations of the microbiota are being increasingly linked to various disease states. The microbiome has been manipulated via the administration of stool from animals or humans, for more than 1000 years. Currently, fecal microbiota transplantation can be performed via endoscopic administration of fecal matter to the duodenum or colon or via capsules of lyophilized stools. More recently fecal microbial transplantation has been shown to be very effective for recurrent Clostridoides difficile infection (CDI). In addition there is some evidence of efficacy in the metabolic syndrome and its hepatic manifestation, metabolic associated fatty liver disease (MAFLD), irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). We review the current literature regarding the microbiome and the pathogenesis and treatment of CDI, MAFLD, IBS and IBD.

Fatty Liver Disease-Alcoholic and Non-Alcoholic: Similar but Different.

In alcohol-induced liver disease (ALD) and in non-alcoholic fatty liver disease (NAFLD), there are abnormal accumulations of fat in the liver. This phenomenon may be related to excessive alcohol consumption, as well as the combination of alcohol consumption and medications. There is an evolution from simple steatosis to steatohepatitis, fibrosis and cirrhosis leading to hepatocellular carcinoma (HCC). Hepatic pathology is very similar regarding non-alcoholic fatty liver disease (NAFLD) and ALD. Initially, there is lipid accumulation in parenchyma and progression to lobular inflammation. The morphological changes in the liver mitochondria, perivenular and perisinusoidal fibrosis, and hepatocellular ballooning, apoptosis and necrosis and accumulation of fibrosis may lead to the development of cirrhosis and HCC. Medical history of ethanol consumption, laboratory markers of chronic ethanol intake, AST/ALT ratio on the one hand and features of the metabolic syndrome on the other hand, may help in estimating the contribution of alcohol intake and the metabolic syndrome, respectively, to liver steatosis.

Diet-induced modifications to human microbiome reshape colonic homeostasis in irritable bowel syndrome.

Changes in microbiome composition are associated with a wide array of human diseases, turning the human microbiota into an attractive target for therapeutic intervention. Yet, clinical translation of these findings requires the establishment of causative connections between specific microbial taxa and their functional impact on host tissues. Here, we infuse gut organ cultures with longitudinal microbiota samples collected from therapy-naive patients with irritable bowel syndrome (IBS) under a low-fermentable oligo-, di-, mono-saccharides and polyols (FODMAP) diet. We show that post-diet microbiota regulates intestinal expression of inflammatory and neuro-muscular gene sets. Specifically, we identify Bifidobacterium adolescentis as a diet-sensitive pathobiont that alters tight junction integrity and disrupts gut barrier functions. Collectively, we present a pathway discovery platform for mechanistic dissection and identification of functional diet-host-microbiota modules. Our data support the hypothesis that the gut microbiota mediates the beneficial effects of a low-FODMAP diet and reinforce the potential feasibility of microbiome-based therapies in IBS.

Elevated Serum Levels of IgG4 in Patients with Heart Failure with Reduced Ejection Fraction: A Prospective Controlled Study.

(1) Background: Immunoglobulin gamma subclass 4 (IgG4) is a serum protein belonging to the immunoglobulin superfamily. It has a central role in certain immune-mediated conditions defined as IgG4-related disease. There is a paucity of data regarding the potential association of IgG4 and cardiovascular diseases. Our aim is to study the serum levels of IgG4 in patients with ischemic and non-ischemic dilated cardiomyopathy (DCM). (2) Methods: patients with ischemic and non-ischemic DCM were included in this study. Non-ischemic DCM was defined as a left ventricular ejection fraction (LVEF) < 40% without coronary artery disease (CAD). Ischemic DCM was defined as a LVEF < 40% and proven CAD. The serum concentrations of IgG4 were measured by turbidimetry. (3) Results: Overall 98 patients with cardiomyopathy had significantly higher levels of IgG4 compared with the control group (77.4 ± 64.0 vs. 50.3 ± 28.8 mg/dL, p < 0.01). Although there was no difference in the total IgG levels in patients with ischemic DCM, the serum concentrations of IgG4 were significantly higher than the corresponding values in the control group (89.8 ± 67.3 vs. 50.3 ± 28.8 mg/dL; interquartile ranges: 40.4−126.5 vs. 31.8−66.8 mg/dL, p < 0.01). This was altered by gender and smoking. (4) Conclusions: The patients with ischemic DCM had increased serum concentrations of IgG4. Future studies are warranted to explore the potential role of an IgG4-mediated process in patients with heart failure with reduced LVEF.

Molecular, Viral and Clinical Features of Alcohol- and Non-Alcohol-Induced Liver Injury.

Hepatic cells are sensitive to internal and external signals. Ethanol is one of the oldest and most widely used drugs in the world. The focus on the mechanistic engine of the alcohol-induced injury has been in the liver, which is responsible for the pathways of alcohol metabolism. Ethanol undergoes a phase I type of reaction, mainly catalyzed by the cytoplasmic enzyme, alcohol dehydrogenase (ADH), and by the microsomal ethanol-oxidizing system (MEOS). Reactive oxygen species (ROS) generated by cytochrome (CYP) 2E1 activity and MEOS contribute to ethanol-induced toxicity. We aimed to: (1) Describe the cellular, pathophysiological and clinical effects of alcohol misuse on the liver; (2) Select the biomarkers and analytical methods utilized by the clinical laboratory to assess alcohol exposure; (3) Provide therapeutic ideas to prevent/reduce alcohol-induced liver injury; (4) Provide up-to-date knowledge regarding the Corona virus and its affect on the liver; (5) Link rare diseases with alcohol consumption. The current review contributes to risk identification of patients with alcoholic, as well as non-alcoholic, liver disease and metabolic syndrome. Additional prevalence of ethnic, genetic, and viral vulnerabilities are presented.

Treating the Metabolic Syndrome by Fecal Transplantation-Current Status.

The intestinal microbiome (IM) is important for normal gastrointestinal (GI) and other organ systems' functioning. An alteration in the normal IM, dysbiosis, and changes in intestinal motility result in microorganisms' overgrowth and an alteration in intestinal permeability. The gut-brain axis is also of importance in the irritable bowel syndrome (IBS) and associated bowel overgrowth. Secondary to the epidemic of obesity, the metabolic syndrome has become a major health problem. Disturbances in the fecal microbiome are associated with the metabolic syndrome. Metabolic-associated fatty liver disease (MAFLD) is now the current terminology for non-alcoholic fatty liver disease. IM alteration by fecal transplantation is an approved treatment method for recurrent Clostridioides difficile infection. Initially performed by either duodenal infusion or colonoscopy, it is now easily performed by the administration of capsules containing stools. We discuss the intestinal microbiome-its composition, as well as the qualitative changes of microbiome composition leading to inflammation. In addition, we discuss the evidence of the effect of fecal transplantation on the metabolic syndrome and MAFLD, as well as its clinical indications.

The Evidence for High-Titer Convalescent Plasma in SARS-CoV-2.

Convalescent plasma therapy has been used successfully in the past to treat respiratory infections. In SARS-CoV-2, there was initially strong evidence in favor of convalescent plasma therapy from a large observational study but the evidence from recent randomized controlled trials has been mixed. However, two of those studies provided convalescent plasma therapy on average 8 days after diagnosis despite earlier data proving that the therapy is most effective when given within 3 days of diagnosis. Another more recent randomized controlled trial found evidence in support of convalescent plasma therapy and we believe that it is no coincidence that they administered convalescent plasma therapy within 3 days of symptom onset. We call for more robustly planned randomized controlled studies to further reliably determine the efficacy of convalescent plasma therapy against SARS-CoV-2. Progress has been made with developing a vaccine but there is likely to be a substantial lag in widespread administration of the vaccine, especially in poorer countries. We therefore propose that patients with SARS-CoV-2 infection should be considered for early ambulatory administration of high-dose convalescent plasma in order to reduce the burden of severe SARS-CoV-2 disease.

Liraglutide-Induced Hepatotoxicity.

A 52-year-old woman with a BMI of 31.2 kg/m2 was treated with the glucagon-like peptide 1 (GLP-1) agonist liraglutide as part of her weight-reduction program. Following this, she developed an idiosyncratic drug-related liver injury (IDILI). Advances in noninvasive techniques enabled this diagnosis to be established. By employing easily quantifiable methods based on serum biomarkers, we could explore a wide variety of endpoints in assessing personalized DILI. In addition, we can test endpoints that are associated with the drug's mechanism of action. Personalized medicine and therapeutic pharmacovigilance of incretin-based hypoglycemic agents are needed to ensure the safety of patients.

Checkpoint Inhibitors and Hepatotoxicity.

Uncontrolled immune response to a pathogen or any protein can lead to tissue damage and autoimmune diseases, that represent aberrant immune responses of the individual to its own cells and/or proteins. The immune checkpoint system is the regulatory mechanism that controls immune responses. Tumor cells escape the immune surveillance mechanism, avoiding immune detection and elimination by activating these checkpoints and suppressing the anti-tumor response, thus allowing formation of tumors. Antigenic modulation facilitates masking and contributes to the escape of tumor cells. In addition, there are growing cell promoters, like transforming growth factor ß (TGF-ß), contributing to escape mechanisms. Targeting the immunological escape of malignant cells is the basis of immune oncology. Checkpoint inhibitors, cytokines and their antibodies may enhance the immune system's response to tumors. Currently, immunomodulatory agents have been designed, evaluated in clinical trials and have been approved by both European and United States Drug Agencies. The present review is a reflection of the increasingly important role of the checkpoint inhibitors. Our aim is to review the side effects with the emphasis on hepatic adverse reactions of these novel biological drug interventions.

Denosumab-Induced Immune Hepatitis.

Denosumab-Prolia®, Xgeva® (Amgen) is a fully human antibody to the receptor activator of the nuclear factor-K ligand (RANKL). Hepatotoxicity is extremely rare, with only one reported case of immune origin. We present a second case of hepatotoxicity resulting from an immune reaction to denosumab. A 43-year-old female was referred to the Endocrinology, Diabetes & Metabolism Department for treatment of low bone mineral density (BMD) following endocrine therapy with letrozole and lucrin because of breast cancer. She developed premature menopause at the age of 36 years when she underwent a left lumpectomy due to an infiltrating duct carcinoma of the breast (T1 NO MO) and was subsequently started on endocrine therapy. Denosumab was started to prevent osteoporosis. On the third year after starting on denosumab and one month after she received the last injection, she became ill. The routine biochemical analysis showed that the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) rose appreciatively to 10 times the upper limit of normal (ULN). The gamma-glutamyl transferase (GGT) level was elevated slightly to 67 U/L (0-38 U/L). The serum gamma-globulin level was elevated to 1.72 g/dL (0.7-1.6 gr/dl), while the total bilirubin (TB) and serum albumin levels were normal. A liver biopsy revealed a moderate to severe chronic inflammatory infiltrate containing MUM-1 positive plasma cells. In addition, numerous CD-3 positive small T lymphocytes and few CD-20 positive B lymphocytes and eosinophils were seen in the portal tracts. Moderate to severe interface hepatitis, bile duct proliferation and mild portal fibrosis were also identified. The results could be consistent with the diagnosis of drug-induced liver injury (DILI).

The Interplay between Alcoholic Liver Disease, Obesity, and the Metabolic Syndrome.

BACKGROUND: Fatty liver may be the result of several factors. The two main contributors are nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD). SUMMARY: NAFLD is the hepatic manifestation of the metabolic syndrome (MetS) and is the major cause of chronic liver disease worldwide as a result of the obesity epidemic. ALD is also a common cause of chronic liver disease. Obesity is a major contributory factor to MetS and is also common in individuals who consume large amounts of alcohol. There is a similar hepatic pathology and both can result in severe fibrosis, cirrhosis, and its complications including hepatocellular carcinoma. This review discusses the etiology, pathogenesis, and genetics of both NAFLD and ALD and their interaction. It is necessary to understand this better in order to prevent and treat these important causes of liver disease worldwide. KEY MESSAGE: Obesity, MetS, and alcohol consumption are linked to the development and progression of fatty liver disease. The coexistence of these factors in many patients requires a reassessment of many aspects of treatment of fatty liver disease.

Gamma glutamyl transferase - an underestimated marker for cardiovascular disease and the metabolic syndrome.

Gamma glutamyl transferase (GGT) is an enzyme in glutathione and cysteine metabolism. GGT is a standard liver enzyme test reflecting biliary tract involvement. It also has a prooxoidant activity and a modulating influence on endothelia dysfunction. GGT is associated with the metabolic syndrome and is often elevated in patients with NAFLD. There is also a role for GGT activity in several aspects cardiovascular disease. There is an association between elevated GGT and cardiovascular mortality, atrial fibrillation, exacerbation of congestive heart failure . In addition there is an association with obstructive sleep apnea. We review the evidence available and suggest that there is a need for further assessing the use of GGT, together with the presence of the metabolic syndrome as a prognostic marker.

Familial non-alcoholic steatohepatitis leading to hepatocellular carcinoma.

BACKGROUND AND AIMS: Non-alcoholic steatohepatitis (NASH) has been associated with fibrosis that may progress to cirrhosis. The purpose of this study was to examine hepatocytes and perisinusoidal cells in liver biopsies of 3 families (3 males and 4 females) with non-cirrhotic and cirrhotic NASH to determine unique histological changes during a period of 2-7 years from diagnosis. METHODS: In this study, hepatocytes, stellate cells and Kupffer cells were analyzed using light and electron microscopy, and immunohistochemistry with specific anti-macrophage antibody staining of liver biopsies. RESULTS: Body mass index of all patients was over 28, and all viral, metabolic markers were negative. Alcohol consumption was insignificant. In all liver biopsies, diffuse, non-zonal macrovesicular steatosis involved 40-70% of liver samples. The lobular hepatocytes showed prominent ballooning hepatocyte degeneration. No Mallory Denk hyaline bodies (MDBs) were observed in three of the patients. MDBs developed in ballooned hepatocytes of four individuals that also presented foci of lobular inflammation. The apoptotic bodies were stained by cytokeratin 18. The trichrome stain revealed portal to portal bridging fibrosis. In one family, there was a three-fold increase in relative numbers of perisinusoidal macrophages in the older sister with NASH compared to livers of the younger siblings. The special finding in livers of patients with NASH was accumulation of groups of perisinusoidal macrophages, which was not associated with focal necrosis. CONCLUSION: Perisinusoidal macrophages appear to accumulate in NASH. It is possible that collections of macrophages are a response to chronic portal endotoxemia or lipotoxic activation of immuno-mediators. The persistent activation of these macrophages could lead to the chronic release of pro-inflammatory cytokines and contribute to chronic inflammation, fibrosis and cirrhosis leading to HCC.

Alcoholic-Hepatitis, Links to Brain and Microbiome: Mechanisms, Clinical and Experimental Research.

The following review article presents clinical and experimental features of alcohol-induced liver disease (ALD). Basic aspects of alcohol metabolism leading to the development of liver hepatotoxicity are discussed. ALD includes fatty liver, acute alcoholic hepatitis with or without liver failure, alcoholic steatohepatitis (ASH) leading to fibrosis and cirrhosis, and hepatocellular cancer (HCC). ALD is fully attributable to alcohol consumption. However, only 10-20% of heavy drinkers (persons consuming more than 40 g of ethanol/day) develop clinical ALD. Moreover, there is a link between behaviour and environmental factors that determine the amount of alcohol misuse and their liver disease. The range of clinical presentation varies from reversible alcoholic hepatic steatosis to cirrhosis, hepatic failure, and hepatocellular carcinoma. We aimed to (1) describe the clinico-pathology of ALD, (2) examine the role of immune responses in the development of alcoholic hepatitis (ASH), (3) propose diagnostic markers of ASH, (4) analyze the experimental models of ALD, (5) study the role of alcohol in changing the microbiota, and (6) articulate how findings in the liver and/or intestine influence the brain (and/or vice versa) on ASH; (7) identify pathways in alcohol-induced organ damage and (8) to target new innovative experimental concepts modeling the experimental approaches. The present review includes evidence recognizing the key toxic role of alcohol in ALD severity. Cytochrome p450 CYP2E1 activation may change the severity of ASH. The microbiota is a key element in immune responses, being an inducer of proinflammatory T helper 17 cells and regulatory T cells in the intestine. Alcohol consumption changes the intestinal microbiota and influences liver steatosis and liver inflammation. Knowing how to exploit the microbiome to modulate the immune system might lead to a new form of personalized medicine in ALF and ASH.