Recovery of Bacteroides thetaiotaomicron ameliorates hepatic steatosis in experimental alcohol-related liver disease

Abstract

Alcohol-related liver disease (ALD) is a major cause of liver disease and represents a global burden, as treatment options are scarce. Whereas 90% of ethanol abusers develop alcoholic fatty liver disease (AFLD), only a minority evolves to steatohepatitis and cirrhosis. Alcohol increases lipogenesis and suppresses lipid-oxidation implying steatosis, although the key role of intestinal barrier integrity and microbiota in ALD has recently emerged. Bacteroides thetaiotaomicron ( Bt ) is a prominent member of human and murine intestinal microbiota, and plays important functions in metabolism, gut immunity, and mucosal barrier. We aimed to investigate the role of Bt in the genesis of ethanol-induced liver steatosis. Bt DNA was measured in feces of wild-type mice receiving a Lieber-DeCarli diet supplemented with an increase in alcohol concentration. In a second step, ethanol-fed mice were orally treated with living Bt , followed by analysis of intestinal homeostasis and histological and biochemical alterations in the liver. Alcohol feeding reduced Bt abundance, which was preserved by Bt oral supplementation. Bt -treated mice displayed lower hepatic steatosis and triglyceride content. Bt restored mucosal barrier and reduced LPS translocation by enhancing mucus thickness and production of Mucin2. Furthermore, Bt up-regulated Glucagon-like peptide-1 (GLP-1) expression and restored ethanol-induced Fibroblast growth factor 15 (FGF15) down-regulation. Lipid metabolism was consequently affected as Bt administration reduced fatty acid synthesis (FA) and improved FA oxidation and lipid exportation. Moreover, treatment with Bt preserved the mitochondrial fitness and redox state in alcohol-fed mice. In conclusion, recovery of ethanol-induced Bt depletion by oral supplementation was associated with restored intestinal homeostasis and ameliorated experimental ALD. Bt could serve as a novel probiotic to treat ALD in the future.

Therapeutic modulation of the liver immune microenvironment

“…[249] In these experiments, B. thetaiotaomicron upregulated glucagon-like peptide-1 expression and restored ethanol-induced FGF-15 downregulation and improved intestinal barrier function. [249] Probiotics dominated by the use of lactic acid-producing bacteria at 1 billion/CFU/g protected against NASH observed in a specific mouse model, that is, PTEN-knockout mice by decreasing liver inflammation and fibrosis, and against inflammationdriven HCC. [250] Probiotics and antibiotics have demonstrated treatment benefits in various other liver disorders besides ALD and NAFLD.…”

“…Various other bacteria might contribute to control of liver inflammation when administered orally to mice. For example, Bacteroides thetaiotaomicron , a preferentially anti-inflammatory bacterium, ameliorates alcohol-induced acute liver injury 249 . In these experiments, B. thetaiotaomicron upregulated glucagon-like peptide-1 expression and restored ethanol-induced FGF-15 downregulation and improved intestinal barrier function 249 .…”

“…For example, Bacteroides thetaiotaomicron , a preferentially anti-inflammatory bacterium, ameliorates alcohol-induced acute liver injury 249 . In these experiments, B. thetaiotaomicron upregulated glucagon-like peptide-1 expression and restored ethanol-induced FGF-15 downregulation and improved intestinal barrier function 249 . Probiotics dominated by the use of lactic acid-producing bacteria at 1 billion/CFU/g protected against NASH observed in a specific mouse model, that is, PTEN-knockout mice by decreasing liver inflammation and fibrosis, and against inflammation-driven HCC 250 …”

The roles of different Bacteroides uniformis strains in alleviating DSS-induced ulcerative colitis and related functional genes

“…However, there are still some problems in leveraging Bacteroides probiotics: (1) the Bacteroides genus is relatively complex and diverse, 7,8 but the existing literature predominantly focuses on B. fragilis, 9 B. vulgatus, 10 and B. thetaiotaomicron. 11 (2) Mouse models are the most used animal models in probiotic screening studies. However, only 4% of the intestinal flora is highly similar between mice and humans.…”

Akkermansia muciniphila and Alcohol‐Related Liver Diseases. A Systematic Review

“…The gut‐liver axis has implications in hepatic and systemic inflammation, but also in intestinal barrier function and local immune response. [ 1 ] This axis appears severely disrupted during alcohol‐related liver diseases (ALDs). Excessive ethanol consumption is one of the most common forms of substance abuse in the world with significant social and economic consequences.…”