New Data Linking Microbiota and Liver Disorders
The gut microbiota continues to be implicated in an increasing number of disease processes, with a plethora of new studies now available regarding its complexity and role in the maintenance of intestinal homeostasis. With more than 100 trillion different micro-organisms, the gut microbiota is considered a major metabolic internal organ, intimately involved in molecular "cross-talk" with the intestinal epithelium and affecting the intestinal barrier function.
Nonalcoholic fatty liver disease (NAFLD), now the most common liver disease worldwide, is associated with diabetes and obesity. Recent evidence supports a role for the gut microbiota in the pathogenesis of these risk factors as well.[1,2,3] Additionally, changes in the gut microbiota can lead to activation of immune responses that have the potential to promote progression of NAFLD to the more severe nonalcoholic steatohepatitis (NASH).[1,2,3]
Recent attention has focused around the gut microbiota not only as part of the disease process but also as a potential target for treatment. This commentary, in turn, explores how disruption of the human gut microbiota may predispose patients to developing NAFLD.
NAFLD's Pathogenic Pathways
The liver is the main warehouse for various lipids, including triglycerides, free fatty acids (FFAs), diacylglycerol, free cholesterol, cholesterol esters, ceramides, and phospholipids. The hallmark pathogenesis of NAFLD is the presence of ectopic fat within hepatocytes, which results from an imbalance in the levels of lipogenesis and lipolysis. Triglycerides are synthesized from FFAs that accumulate within the liver; therefore, the concentration of FFAs functions as a regulator of lipogenesis.
The hepatic uptake of FFAs is unregulated and directly proportional to the level of nonesterified fatty acids, which accounts for 60% of the accumulation of FFAs within the liver, primarily from lipolysis in adipose tissue. Other sources of FFAs include de novo lipogenesis (25%) and dietary fatty acids (15%) in the form of chylomicron lipoproteins.
After FFAs are taken up by the liver, they have three potential fates: oxidation within mitochondria, very low-density lipoprotein assembly and export, or triglyceride synthesis and storage as lipid droplets. Over time, an abundance of triglycerides accumulates and leads to increased hepatic storage of lipid droplets, promoting the progression toward NAFLD. The excessive accumulation of fat in adipocytes promotes an increase in oxidative stress and low-grade inflammatory state through the release of inflammatory markers, including interleukin-6 and monocyte chemotactic protein 1. Subsequently, the activation of macrophages and lymphocytes promotes further release of proinflammatory cytokines associated with insulin resistance, namely tumor necrosis factor-α and interferon-γ, thereby promoting a continuation of the cycle.
Medscape Gastroenterology © 2015 WebMD, LLC
Any views expressed above are the author's own and do not necessarily reflect the views of WebMD or Medscape.
Cite this: The Gut Microbiome's Role in Nonalcoholic Fatty Liver Disease - Medscape - Nov 19, 2015.