The Role of the Gut Microbiome and the Hepatic Axis in the Pathogenesis of Metabolic Syndrome and Therapeutics

Toll-Like Receptor Signaling in Liver Diseases

Nonalcoholic fatty liver disease (NAFLD), the major reason for abnormal liver function in the Western world, is associated with obesity and diabetes and is characterized by insulin resistance (IR). IR is regulated by mediators released from cells of the immune system or adipocytes and proinflammatory cytokines such as tumor necrosis factor-α (TNFα). The importance of TNFα in human and animal fatty liver diseases, both caused by genetic manipulation and overnutrition, has been shown convincingly. Furthermore, neutralization of TNFα activity improves IR and fatty liver disease in animals. Adiponectin is a potent TNFα-neutralizing and anti-inflammatory adipokine and in vitro and experimental animal studies have proven the importance of this mediator in counteracting inflammation and IR. Anti-inflammatory effects of adiponectin are exerted both by suppressing TNFα synthesis and by induction of anti-inflammatory cytokines such as interleukin-10 or interleukin-1–receptor antagonist. Therefore, the balance between various mediators, either derived from the immune system or adipose tissue, appears to play an important role in hepatic and systemic insulin action and in the development of fatty liver disease.

The Gut Microbiome in Health and Disease

The role of the gut microbiome in chronic liver disease: the clinical evidence revised.

Changes in liver and spleen volumes in alcoholic liver disease

Autophagy in non-alcoholic fatty liver disease and alcoholic liver disease

To investigate the protein expression of phosphatase and tensin homolog (PTEN) in human liver biopsies of patients with alcoholic and non-alcoholic liver disease. PTEN protein expression was assessed by immunohistochemistry in formalin-fixed, paraffin-embedded liver sections of patients with non-alcoholic fatty liver disease (NAFLD) (n = 44) or alcoholic liver disease (ALD) (n = 25). Liver resections obtained from 3 healthy subjects candidate for partial liver donation served as controls. Histological evaluations were performed by two experienced pathologists, and diagnoses established based on international criteria. The intensity of the PTEN staining in nuclei was compared between steatotic and non-steatotic areas of each liver fragment analyzed. For each liver specimen, the antibody-stained sections were examined and scored blindly by three independent observers, who were unaware of the patients' clinical history. In healthy individuals, PTEN immunostaining was intense in both the cytoplasm and nuclei of all hepatocytes. However, PTEN was strongly downregulated in both the nucleus and the cytoplasm of hepatocytes from steatotic areas in patients with NAFLD, independently of the disease stage. In contrast, no changes in PTEN protein expression were observed in patients with ALD, regardless of the presence of steatosis or the stage of the disease. The degree of PTEN downregulation in hepatocytes of patients with NAFLD correlated with the percentage of steatosis (r = 0.3061, P = 0.0459) and the BMI (r = 0.4268, P = 0.0043). Hovewer, in patients with ALD, PTEN expression was not correlated with the percentage of steatosis with or without obesity as a confounding factor (P = 0.5574). Finally, PTEN expression level in steatotic areas of ALD patients was significantly different from that seen in steatotic areas of NAFLD patients (P < 0.0001). PTEN protein expression is downregulated early in NAFLD, but not in ALD. PTEN immunohistochemical detection could help in the differential diagnosis of NAFLD and ALD.

Fatty liver disease is defined as more than 5% of the hepatocytes containing fat or increase in the liver weight due to fat. The most Important contributing factor to non-alcoholic liver disease is dietary habits, life style habits etc., The aim of the study is to find out the associated dietary and life style risk factors of non-alcoholic liver disease. One hundred and fifty hospitalized subjects were selected for treatment of non alcoholic liver disease at Father Muller's hospital in Mangalore. The required data were collected referring the case record of patients. A structured questionnaire with interview was used during data collection. Diet counseling was given. All the variables were analyzed using SPSS software. The consumption of calories and chiefly the carbohydrates and fats were more than their recommended allowances. Non alcoholic liver disease was more in males than their counterparts (females) and individuals above 45 years were likely to be victims of this disease. Sedentary life style habits had a significant association with non alcoholic liver disease. The study concludes that obesity with sedentary life style, high calorie intake, gender was the major risk factors. It was considerably more common among diabetes of age &gt;40 years. Dyslipidemia was observed mainly in non alcoholic liver patients.

Changes in type IV collagen content in livers of patients with alcoholic liver disease

More than meets the eye: Severe alcoholic hepatitis can present as acute-on-chronic liver failure

Recent studies have made significant advances in understanding the mechanisms of gut microbiota involved in human health and disease [1, 2]. Now the gut microbiota has been recognized as a key player in a broad spectrum of human diseases from obesity associated liver and cardiovascular diseases to mental development and psychiatric diseases [3, 4]. Accordingly, modulations of gut microbial diversity and composition are expected to improve human health and to provide novel therapeutic modalities for human disease. The gut microbial modulators can be simply specific diets and drinks, natural tea and Chinese herbs, or specialized prebiotics and probiotics. In this special issue, authors presented a number of very interesting studies on changes of gut microbiota in digestive diseases. These review and original articles of research and clinical studies cover a range of topics, including the pathogenesis of alcoholic and nonalcoholic fatty liver diseases (NAFLD), the outcome of intestinal bacterial translocation in advanced cirrhosis, the gut microbiota changes in an animal colitis model after treatment with a monoclonal antibody, and fecal microbiota transplantation (FMT) in elderly patients with refractory Clostridium difficile infection. In these articles, authors have described mechanisms of disease development as well as therapeutic effects of specific antibodies, probiotics, and FMT. While we know the simple cause of alcoholic fatty liver disease (AFLD), its pathogenesis is complicated and it involves a wide range of changes in host metabolism and gut microbiota. Certainly, removal of the cause (alcohol abuse) is the first treatment for AFLD, and the use of probiotics can ameliorate its development as shown in recent clinical and animal studies [5–7]. Although sharing many pathological and clinical features with AFLD, NAFLD does not have a simple, single cause. Instead, NAFLD is the result of interactions between gut microbiota, host genetics, and diet. There have been a number of studies evaluating the effects and mechanisms of probiotics [8–10], natural tea [11, 12], and Chinese herbs/recipes [13, 14] on AFLD and NAFLD. These studies reported beneficial effects with promising perspectives for future development of novel therapeutic strategies. However, in light of the nature of gut microbiota being highly diverse and constitutional, built during the early life of individuals, cautious optimism is necessary for any future therapeutic developments aiming at modulations of gut microbiota, as we do not yet know long-term effects from those initial efforts or indeed which of those microbiota and metabolomics changes are contributory, causative, or simply a cofounder in AFLD and NAFLD, or indeed any other condition. Thus far, it is not clear whether the modulations by specific diets and drinks including natural tea, even by probiotics, are able to change the constitutional nature of gut microbiota, although the relative abundance of microbial species is altered upon administrating modulators [12, 13, 15]. Moreover, current analytic strategies on metagenomics data are focused on major changes in gut microbial compositions and have not paid sufficient attention to or have even ignored the changes in minor species with less than 1% abundance. Furthermore, sampling of microbiota in intestinal lumen may not necessarily represent the mucosal portion or the whole population of gut flora [16]. In fact, the true signal and messengers governing the alterations of gut microbiota and host metabolism are largely elusive. Enteric short-chain fatty acids (SCFAs), such as acetate, propionate, and butyrate, are fermentation metabolites by intestinal bacteria. Recent studies have suggested a messenger role of SCFAs in several human diseases including metabolic syndrome [17] and autism [4]. In short, careful designs of future studies should take these factors and host genetic background under consideration to discover the real effectors and to discern the true effects of gut microbial modulators in alcoholic and nonalcoholic fatty liver disease and other human diseases. Jinsheng Yu Sharon Marsh Junbo Hu Wenke Feng Chaodong Wu

Non-alcoholic fatty liver disease (NAFLD) and Alcoholic Liver Disease (ALD) are major causes of liver-related morbidity and mortality and constitute important causes of liver transplantation. The spectrum of the liver disease is wide and includes isolated steatosis, steatohepatitis, and cirrhosis. The treatment of NAFLD and ALD remains, however, an unmet need, and therefore it is a public health priority to develop effective treatments for these diseases. Alcoholic and non-alcoholic liver disease share common complex pathogenetic pathways that involve different organs and systems beyond the liver, including the gut, the adipose tissue, and the immune system, which cross-talk to generate damage. Myeloid-derived cells have been widely studied in the setting of NAFLD and ALD and are implicated at different levels in the onset and progression of this disease. Among these cells, monocytes and macrophages have been found to be involved in the induction of inflammation and in the progression to fibrosis, both in animal models and clinical studies and they have become interesting potential targets for the treatment of both NAFLD and ALD. The different mechanisms by which these cells can be targeted include modulation of Kupffer cell activation, monocyte recruitment in the liver and macrophage polarization and differentiation. Evidence from preclinical studies and clinical trials (some of them already in phase II and III) have shown encouraging results in ameliorating steatohepatitis, fibrosis, and the metabolic profile, individuating promising candidates for the pharmacological treatment of these diseases. The currently available results of myeloid-derived cells targeted treatments in NAFLD and ALD are covered in this review.

1. Liver biopsies were performed in healthy control subjects and in subjects with alcoholic and non-alcoholic liver disease in order to examine alcohol dehydrogenase (ADH; EC 1.1.1.1) and aldehyde dehydrogenase [ALDH; aldehyde dehydrogenase (NAD+); EC 1.2.1.3] activities. Erythrocyte ALDH and ethanol metabolism were also investigated in the same subjects. 2. Fifteen per cent of the subjects studied (seven of 48 subjects tested) presented atypical ADH activity, characterized by elevated activity at pH 7.4 or 8.8 compared with that found in subjects with the usual ADH form. However, the ethanol elimination curves obtained in two subjects with atypical ADH were indistinguishable from the kinetics of the group with normal ADH. Subjects displaying atypical ADH activity showed normal liver and erythrocyte ALDH activities. 3. Considering only the subjects with the normal ADH form, hepatic ADH activity was unaltered in subjects with non-alcoholic liver disease (chronic hepatitis or cirrhosis) and in those with alcoholic steatosis. Subjects with alcoholic hepatitis or alcoholic cirrhosis showed a lower ADH activity compared with the healthy control group. 4. In spite of the changes detected in subjects with alcoholic liver disease, curves of blood ethanol concentration after oral administration of 0.4 g of ethanol/kg were indistinguishable between the alcoholic hepatitis group and the control group. 5. Hepatic ALDH activity, assayed at 300 mumol/l acetaldehyde, was found to be diminished in all liver pathologies investigated, regardless of their aetiology. Nevertheless, erythrocyte ALDH activity was not modified in subjects with non-alcoholic or alcoholic liver disease. As a result of these findings, no relationship was found between hepatic and erythrocyte ALDH.(ABSTRACT TRUNCATED AT 250 WORDS)

Is It Time to Consider Gut Microbiome Readouts for Precision Diagnosis and Treatment of Alcoholic Liver Disease?

Physiology in Perspective: The New Normal-Life in a Pandemic.