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

Abstract

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 TNF-a 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 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 NASH.

Vertical Transfer of Maternal Gut Microbes to Offspring of Western Diet-Fed Dams Drives Reduced Levels of Tryptophan Metabolites and Postnatal Innate Immune Response

“…In our microbiome analysis of GF offspring, we found I3A was positively associated with S24-7 (also known as Muribaculaceae), and negatively associated with both Parabacteroides and unclassified Mogibacteriaceae. Other studies have shown that maternal WD exposure reduces offspring I3A in the liver and cecum and is associated with depleted abundances of Bacteroidetes and Muribaculaceae (S24-7) [82]. Lactobacillus and S24-7 family members are considered beneficial bacteria and are typically associated with a "healthy" microbiome.…”

Vertical Transfer of Maternal Gut Microbes to Offspring of Western Diet-Fed Dams Drives Reduced Levels of Tryptophan Metabolites and Postnatal Innate Immune Response

“…In our microbiome analysis of GF offspring, we found I3A was positively associated with S24-7 (also known as Muribaculaceae ) and negatively associated with both Parabacteroides and unclassified Mogibacteriaceae . Other studies have shown that maternal WD exposure reduces offspring I3A in the liver and cecum and is associated with depleted abundances of Bacteroidetes and Muribaculaceae ( S24-7 ) [ 77 ]. Lactobacillus and S24-7 family members are considered beneficial bacteria and are typically associated with a “healthy” microbiome.…”

Aryl Hydrocarbon Receptor Signalling in the Control of Gut Inflammation

“…Orally administered I3A, a gut microbiota-derived tryptophan metabolite, alleviates liver steatosis and inflammation in a mouse model of diet-induced non-alcoholic fatty liver disease. Notably, I3A does not alter the intestinal microbiome, suggesting that the I3A's beneficial effects likely reflect the metabolite's direct actions on the liver [38]. In colitic mice, the administration of I3C triggers an IL-22-dependent mechanism that attenuates colonic inflammation, and prevents the microbial dysbiosis caused by colitis by increasing a subset of Gram-positive bacteria known to produce butyrate [39].…”