Indole supplementation ameliorates MCD-induced NASH in mice

Area of Science:

• Metabolomics and Gut Microbiome Research
• Hepatology and Liver Disease Pathogenesis
• Inflammation and Immunology

Background:

• Non-alcoholic fatty liver disease (NAFLD) progresses to non-alcoholic steatohepatitis (NASH), a severe inflammatory liver condition.
• Indole, a metabolite produced by gut microbiota, is known to protect against obesity-associated NAFLD.
• The therapeutic potential of indole in mitigating established NASH remains to be fully elucidated.

Purpose of the Study:

• To investigate the efficacy of indole supplementation in alleviating the severity of diet-induced non-alcoholic steatohepatitis (NASH) in a mouse model.
• To explore the underlying mechanisms by which indole exerts its protective effects against NASH progression.
• To assess the impact of indole on liver steatosis, inflammation, fibrosis, and intestinal inflammation.

Main Methods:

• C57BL/6J mice were fed a methionine- and choline-deficient (MCD) diet to induce NASH.
• Indole was supplemented to assess its effects on MCD-induced hepatic steatosis, inflammation, and fibrosis.
• In vitro studies utilized hepatocytes and bone marrow-derived macrophages, along with LX2 hepatic stellate cells, to examine indole's cellular mechanisms.

Main Results:

• Indole supplementation significantly reduced hepatic steatosis, inflammation, and liver fibrosis in MCD-fed mice.
• In vitro, indole suppressed lipopolysaccharide-induced proinflammatory responses in hepatocytes and hepatic stellate cells.
• Indole also decreased intestinal inflammation, contributing to the overall alleviation of NASH.

Conclusions:

• Indole supplementation effectively alleviates diet-induced NASH in mice.
• The protective effects are largely attributed to indole's suppression of hepatocyte and hepatic stellate cell proinflammatory and fibrogenic responses.
• Reduced intestinal inflammation also plays a role in indole's therapeutic benefit against NASH.