Gut microbiome and liver disease (original) (raw)
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Nonalcoholic Fatty Liver Disease (NAFLD) - A Disease of New Era
Journal of Medicine, 1970
Non-alcoholic fatty liver disease (NAFLD) is the term used to describe the alcohol-like liver injury that occurs in the absence of alcohol abuse (alcohol consumption of over 20 g/day excludes the condition). It includes a range of histological abnormalities including simple steatosis or fatty liver, non-alcoholic steatohepatitis (NASH) and NAFLD induced cirrhosis. Its increasing prevalence in western countries, the diagnostic difficulties by noninvasive tests, and the possibility of progression to advanced fibrosis and even cirrhosis make NASH a challenge for physicians. NASH is frequently associated with type 2 diabetes and the metabolic syndrome, and several genetic and acquired factors are involved in its pathogenesis. Insulin resistance plays a central role in the development of a steatotic liver, which becomes vulnerable to additional injuries. Several cyclic mechanisms leading to self-enhancement of insulin resistance and hepatic accumulation of fat have been recently identified. Excess intracellular fatty acids, oxidant stress, tumor necrosis factor, and mitochondrial dysfunction are causes of hepatocellular injury, thereby leading to disease progression and to the establishment of NASH. Intestinal bacterial overgrowth also plays a role, by increasing production of endogenous ethanol and proinflammatory cytokines. Therapeutic strategies aimed at modulating insulin resistance, managing risk factors, including reduction of weight normalizing lipoprotein metabolism, and down regulating inflammatory mediators with probiotics have promising potential.
REVIEW ARTICLE NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) - A DISEASE OF NEW ERA
2007
Non-alcoholic fatty liver disease (NAFLD) is the term used to describe the alcohol-like liver injury that occurs in the absence of alcohol abuse (alcohol consumption of over 20 g/day excludes the condition). It includes a range of histological abnormalities including simple steatosis or fatty liver, non-alcoholic steatohepatitis (NASH) and NAFLD induced cirrhosis. Its increasing prevalence in western countries, the diagnostic difficulties by noninvasive tests, and the possibility of progression to advanced fibrosis and even cirrhosis make NASH a challenge for physicians. NASH is frequently associated with type 2 diabetes and the metabolic syndrome, and several genetic and acquired factors are involved in its pathogenesis. Insulin resistance plays a central role in the development of a steatotic liver, which becomes vulnerable to additional injuries. Several cyclic mechanisms leading to self-enhancement of insulin resistance and hepatic accumulation of fat have been recently identified. Excess intracellular fatty acids, oxidant stress, tumor necrosis factor, and mitochondrial dysfunction are causes of hepatocellular injury, thereby leading to disease progression and to the establishment of NASH. Intestinal bacterial overgrowth also plays a role, by increasing production of endogenous ethanol and proinflammatory cytokines. Therapeutic strategies aimed at modulating insulin resistance, managing risk factors, including reduction of weight normalizing lipoprotein metabolism, and down regulating inflammatory mediators with probiotics have promising potential.
Gut Microbiome Modulation in the Management of Nonalcoholic Fatty Liver Disease
Academia Letters, 2021
Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease worldwide with a prevalence of approximately 25% among the adult population. The highest prevalence is observed in the Middle East (32%) and the lowest prevalence in Africa (13%). More than 1 billion people are affected by NAFLD worldwide. NAFLD is a disorder characterized by hepatic steatosis (at least 5% fat deposit) on either imaging or histology, with no excessive alcohol consumption (< 30 g/day for men and < 20 g/day for women), in the absence of other causes of steatosis (e.g., viral hepatitis and medications). It is a spectrum of liver disorders ranging from simple steatosis to nonalcoholic steatohepatitis (NASH). Up to 30% of NAFLD subjects develop NASH. NASH is the aggressive form of NAFLD that can progress to fibrosis, cirrhosis, and hepatocellular cancer. The presence of fibrosis is the strongest predictor of mortality. The pathogenesis of NAFLD is complex and multifactorial, involving both nongenetic and genetic factors. Pro-inflammatory diet, endocrine disruptors, overweight/obesity, inflammation, insulin resistance, prediabetes, type 2 diabetes, dyslipidemia, disrupted gut microbiome, and impaired intestinal barrier function (increased intestinal permeability or leaky gut) are important risk factors associated with and/or contributing to NAFLD. There are several genetic forms of NAFLD including variations in patatin-like phospholipase domaincontaining protein 3, transmembrane 6 superfamily 2, membrane-bound O-acyltransferase domain-containing protein 7, and glucokinase regulatory protein genes (1-6).
Gut Microbiota as a Driver of Inflammation in Nonalcoholic Fatty Liver Disease
Mediators of Inflammation
The prevalence of nonalcoholic fatty liver disease and the consequent burden of metabolic syndrome have increased in recent years. Although the pathogenesis of nonalcoholic fatty liver disease is not completely understood, it is thought to be the hepatic manifestation of the dysregulation of insulin-dependent pathways leading to insulin resistance and adipose tissue accumulation in the liver. Recently, the gut-liver axis has been proposed as a key player in the pathogenesis of NAFLD, as the passage of bacteria-derived products into the portal circulation could lead to a trigger of innate immunity, which in turn leads to liver inflammation. Additionally, higher prevalence of intestinal dysbiosis, larger production of endogenous ethanol, and higher prevalence of increased intestinal permeability and bacterial translocation were found in patients with liver injury. In this review, we describe the role of intestinal dysbiosis in the activation of the inflammatory cascade in NAFLD.
Aisf Position Paper on Nonalcoholic Fatty Liver Disease (Nafld): Updates and Future Directions
Digestive and Liver Disease, 2017
This review summarizes our current understanding of nonalcoholic fatty liver disease (NAFLD), a multifactorial systemic disease resulting from a complex interaction between a specific genetic background and multiple environmental/metabolic "hits". The role of gut microbiota, lipotoxicity, inflammation and their molecular pathways is reviewed indepth. We also discuss the epidemiology and natural history of NAFLD by pinpointing the remarkably high prevalence of NAFLD worldwide and its inherent systemic complications: hepatic (steatohepatitis, advanced fibrosis and cirrhosis), cardio-metabolic (cardiovascular disease, cardiomyopathy, arrhythmias and type 2 diabetes) and neoplastic (primary liver cancers and extra-hepatic cancers). Moreover, we critically report on the diagnostic role of non-invasive biomarkers, imaging techniques and liver biopsy, which remains the reference standard for diagnosing the disease, but cannot be proposed to all patients with suspected NAFLD. Finally, the management of NAFLD is also reviewed, by highlighting the lifestyle changes and the pharmacological options, with a focus on the innovative drugs. We conclude that the results of ongoing studies are eagerly expected to lead to introduce into the clinical arena new diagnostic and prognostic biomarkers, prevention and surveillance strategies as well as to new drugs for a tailored approach to the management of NAFLD in the individual patient.
Gut microbiome and nonalcoholic fatty liver diseases
Pediatric Research, 2014
Review nature publishing group We review recent findings and hypotheses on the roles of gut microbiome in the pathogenesis of nonalcoholic fatty liver diseases (NAFLD). Microbial metabolites and cell components contribute to the development of hepatic steatosis and inflammation, key components of nonalcoholic steatohepatitis (NASH), the severe form of NAFLD. Altered gut microbiome can independently cause obesity, the most important risk factor for NAFLD. This capability is attributed to short-chain fatty acids (SCFAs), major gut microbial fermentation products. SCFAs account for a large portion of caloric intake of the host, and they enhance intestinal absorption by activating GLP-2 signaling. However, elevated SCFAs may be an adaptive measure to suppress colitis, which could be a higher priority than imbalanced calorie intake. The microbiome of NASH patients features an elevated capacity for alcohol production. The pathomechanisms for alcoholic steatohepatitis may apply to NASH. NAFLD/ NASH is associated with elevated Gram-negative microbiome and endotoxemia. However, many NASH patients exhibited normal serum endotoxin indicating that endotoxemia is not required for the pathogenesis of NASH. These observations suggest that microbial intervention may benefit NAFLD/NASH patients. However, very limited effects were observed using traditional probiotic species. Novel probiotic therapy based on NAFLD/NASH specific microbial composition represents a promising future direction.
Gut-liver Axis and Microbiota in NAFLD: Insight Pathophysiology for Novel Therapeutic Target
Current Pharmaceutical Design, 2013
There is increasing evidence for a correlation between intestinal microbiota, bacterial translocation and hepatic steatosis. Intestinal microbiota affects nutrient absorption and energy homeostasis. Altered intestinal permeability may favor the passage of bacteriaderived compounds into systemic circulation, causing a systemic inflammatory state, characteristic of the metabolic syndrome. The interaction between intestinal permeability and luminal bacteria is involved in the pathogenesis and evolution of non-alcoholic liver disease. Microbiota pharmacological modulation could be a promising tool for a new therapeutical approach to non-alcoholic fatty liver disease.
Medical Hypotheses, 2015
Nonalcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (AFLD) are so similar that only a detailed history of alcohol intake can distinguish one from the other. Because subjects with NAFLD produce significantly more endogenous ethanol (EE) than controls, some researchers suspected that these similarities are not merely coincidental. For this reason, it was attempted to show that NAFLD is actually an endogenous alcoholic fatty liver disease (EAFLD). However, negligible blood-alcohol concentration (BAC) and the inability of gut microbiota to produce hepatotoxic concentrations of EE rejected this hypothesis. To clarify these conflicting results, we provide a mechanistic framework explaining how NAFLD may be an EAFLD. First of all, the key finding is that ethanol is a prodrug, enabling the idea that AFLD may develop with negligible/absent BAC. Second, extrahepatic acetaldehyde (ACD) alone recapitulates AFLD and is about 330-fold more hepatotoxic than that generated inside the liver. Third, gut microbiota can even produce much larger amounts of EE than those currently considered cirrhotogenic for man. Fourth, an extensive gut-liver axis first-pass metabolism of ethanol prevents the development of significant BAC in NAFLD. Fifth, all genes involved in EE metabolism are upregulated in the livers of patients with nonalcoholic steatohepatitis (NASH). Last, overexpression of the gene encoding alcohol dehydrogenase (ADH) 4 implicates liver exposure to high concentrations of EE. In conclusion, this work provides mechanistic explanation supporting the assumption that NAFLD may indeed be an EAFLD. If validated by further testing, the hypothesis may help develop novel therapeutic and preventive strategies against this ubiquitous condition.
Effects of Moderate Alcohol Consumption in Non-Alcoholic Fatty Liver Disease
Journal of Clinical Medicine
Alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) have emerged as leading causes of chronic liver diseases worldwide. ALD and NAFLD share several pathophysiological patterns as well as histological features, while clinically, they are distinguished by the amount of alcohol consumed daily. However, NAFLD coexists with moderate alcohol consumption in a growing proportion of the population. Here, we investigated the effects of moderate alcohol consumption on liver injury, lipid metabolism, and gut microbiota in 30 NAFLD-patients. We anonymously assessed drinking habits, applying the AUDIT- and CAGE-questionnaires and compared subgroups of abstainers vs. low to harmful alcohol consumers (AUDIT) and Cage 0–1 vs. Cage 2–4. Patients who did not drink any alcohol had lower levels of γGT, ALT, triglycerides, and total cholesterol. While the abundance of Bacteroidaceae, Bifidobacteriaceae, Streptococcaceae, and Ruminococcaceae was higher in the low to harmful alcohol...