Oral supplementation of gut microbial metabolite indole-3-acetate alleviates diet-induced steatosis and inflammation in mice

• Published in: eLife Vol. 12
• Main Authors: Ding, Yufang, Yanagi, Karin, Yang, Fang, Callaway, Evelyn, Cheng, Clint, Hensel, Martha E, Menon, Rani, Alaniz, Robert C, Lee, Kyongbum, Jayaraman, Arul
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 27.02.2024; eLife Sciences Publications Ltd
• Subjects: Acetates; Acetic acid; AMP-activated protein kinase; Analysis; Animals; Bile; Cecum; Cytokines; Diet; Diet, Western - adverse effects; Dietary Supplements; Digestive system; Drinking water; Dysbacteriosis; Enzymes; Fatty acids; Fatty liver; Feces; Food; Gastrointestinal Microbiome; Gastrointestinal tract; Hepatocytes; High fat diet; indole-3-acetic acid; Indoles - pharmacology; Inflammation; Intestinal microflora; Intestine; Kinases; Lipogenesis; Liver; Liver diseases; Macrophages; Mann-Whitney U test; Metabolism; Metabolites; Metagenomics; Mice; Microbiomes; Microbiota; Microbiota (Symbiotic organisms); Non-alcoholic Fatty Liver Disease - drug therapy; Oral administration; Protein kinases; Proteomes; Scientific equipment and supplies industry; Steatosis; Triglycerides; Tryptophan; United States; Massachusetts; California; microbiota; mouse; inflammation; liver; medicine; immunology; indole-3-acetic acid
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.87458

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries. There is growing evidence that dysbiosis of the intestinal microbiota and disruption of microbiota-host interactions contribute to the pathology of NAFLD. We previously demonstrated that gut microbiota-derived tryptophan metabolite indole-3-acetate (I3A) was decreased in both cecum and liver of high-fat diet-fed mice and attenuated the expression of inflammatory cytokines in macrophages and Tnfa and fatty acid-induced inflammatory responses in an aryl-hydrocarbon receptor (AhR)-dependent manner in hepatocytes. In this study, we investigated the effect of orally administered I3A in a mouse model of diet-induced NAFLD. Western diet (WD)-fed mice given sugar water (SW) with I3A showed dramatically decreased serum ALT, hepatic triglycerides (TG), liver steatosis, hepatocyte ballooning, lobular inflammation, and hepatic production of inflammatory cytokines, compared to WD-fed mice given only SW. Metagenomic analysis show that I3A administration did not significantly modify the intestinal microbiome, suggesting that I3A’s beneficial effects likely reflect the metabolite’s direct actions on the liver. Administration of I3A partially reversed WD-induced alterations of liver metabolome and proteome, notably, decreasing expression of several enzymes in hepatic lipogenesis and β-oxidation. Mechanistically, we also show that AMP-activated protein kinase (AMPK) mediates the anti-inflammatory effects of I3A in macrophages. The potency of I3A in alleviating liver steatosis and inflammation clearly demonstrates its potential as a therapeutic modality for preventing the progression of steatosis to non-alcoholic steatohepatitis (NASH).