The Role of Leaky Gut in Nonalcoholic Fatty Liver Disease: A Novel Therapeutic Target

The liver directly accepts blood from the gut and is, therefore, exposed to intestinal bacteria. Recent studies have demonstrated a relationship between gut bacteria and nonalcoholic fatty liver disease (NAFLD). Approximately 10%–20% of NAFLD patients develop nonalcoholic steatohepatitis (NASH), and endotoxins produced by Gram-negative bacilli may be involved in NAFLD pathogenesis. NAFLD hyperendotoxicemia has intestinal and hepatic factors. The intestinal factors include impaired intestinal barrier function (leaky gut syndrome) and dysbiosis due to increased abundance of ethanol-producing bacteria, which can change endogenous alcohol concentrations. The hepatic factors include hyperleptinemia, which is associated with an excessive response to endotoxins, leading to intrahepatic inflammation and fibrosis. Clinically, the relationship between gut bacteria and NAFLD has been targeted in some randomized controlled trials of probiotics and other agents, but the results have been inconsistent. A recent randomized, placebo-controlled study explored the utility of lubiprostone, a treatment for constipation, in restoring intestinal barrier function and improving the outcomes of NAFLD patients, marking a new phase in the development of novel therapies targeting the intestinal barrier. This review summarizes recent data from studies in animal models and randomized clinical trials on the role of the gut–liver axis in NAFLD pathogenesis and progression.

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Diets rich in fructose, fat or fructose and fat alter intestinal barrier function and lead to the development of nonalcoholic fatty liver disease over time

The Journal of Nutritional Biochemistry ◽

10.1016/j.jnutbio.2015.05.011 ◽

2015 ◽

Vol 26 (11) ◽

pp. 1183-1192 ◽

Cited By ~ 74

Author(s):

Cathrin Sellmann ◽

Josephine Priebs ◽

Marianne Landmann ◽

Christian Degen ◽

Anna Janina Engstler ◽

...

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Barrier Function ◽

Fatty Liver Disease ◽

Intestinal Barrier ◽

Intestinal Barrier Function ◽

Nonalcoholic Fatty Liver ◽

Over Time

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Role of Gut Barrier Function in the Pathogenesis of Nonalcoholic Fatty Liver Disease

Gastroenterology Research and Practice ◽

10.1155/2015/287348 ◽

2015 ◽

Vol 2015 ◽

pp. 1-6 ◽

Cited By ~ 23

Author(s):

Xin Dai ◽

Bangmao Wang

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Barrier Function ◽

Fatty Liver Disease ◽

Barrier Dysfunction ◽

Gut Barrier ◽

Nonalcoholic Fatty Liver ◽

Gut Barrier Function

Nonalcoholic fatty liver disease (NAFLD) is one of the most common forms of chronic liver disease, and its incidence is increasing year by year. Many efforts have been made to investigate the pathogenesis of this disease. Since 1998 when Marshall proposed the conception of “gut-liver axis,” more and more researchers have paid close attention to the role of gut barrier function in the pathogenesis of NAFLD. The four aspects of gut barrier function, including physical, chemical, biological, and immunological barriers, are interrelated closely and related to NAFLD. In this paper, we present a summary of research findings on the relationship between gut barrier dysfunction and the development of NAFLD, aiming at illustrating the role of gut barrier function in the pathogenesis of this disease.

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Endotoxins and Non-Alcoholic Fatty Liver Disease

Frontiers in Endocrinology ◽

10.3389/fendo.2021.770986 ◽

2021 ◽

Vol 12 ◽

Author(s):

Takaomi Kessoku ◽

Takashi Kobayashi ◽

Kento Imajo ◽

Kosuke Tanaka ◽

Atsushi Yamamoto ◽

...

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Liver Damage ◽

Fatty Liver Disease ◽

Controlled Trial ◽

Intestinal Barrier ◽

Intestinal Barrier Function ◽

Leaky Gut ◽

Alcoholic Fatty Liver ◽

Nonalcoholic Fatty Liver

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. It occurs with a prevalence of up to 25%, of which 10–20% cases progress to nonalcoholic steatohepatitis (NASH), cirrhosis, and liver cancer. The histopathology of NASH is characterized by neutrophilic infiltration, and endotoxins from gram-negative rods have been postulated as a contributing factor. Elevations in endotoxin levels in the blood can be classified as intestinal and hepatic factors. In recent years, leaky gut syndrome, which is characterized by impaired intestinal barrier function, has become a significant issue. A leaky gut may prompt intestinal bacteria dysbiosis and increase the amount of endotoxin that enters the liver from the portal vein. These contribute to persistent chronic inflammation and progressive liver damage. In addition, hepatic factors suggest that liver damage can be induced by low-dose endotoxins, which does not occur in healthy individuals. In particular, increased expression of CD14, an endotoxin co-receptor in the liver, may result in leptin-induced endotoxin hyper-responsiveness in obese individuals. Thus, elevated blood endotoxin levels contribute to the progression of NASH. The current therapeutic targets for NASH treat steatosis and liver inflammation and fibrosis. While many clinical trials are underway, no studies have been performed on therapeutic agents that target the intestinal barrier. Recently, a randomized placebo-controlled trial examined the role of the intestinal barrier in patients with NAFLD. To our knowledge, this study was the first of its kind and study suggested that the intestinal barrier may be a novel target in the future treatment of NAFLD.

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