Gut Microbiota-Derived Tryptophan Metabolites Modulate Inflammatory Response in Hepatocytes and Macrophages

• Published in: Cell reports (Cambridge) 2018-04, Vol.23 (4), p.1099-1111
• Main Authors: Krishnan, Smitha, Ding, Yufang, Saedi, Nima, Choi, Maria, Sridharan, Gautham V., Sherr, David H., Yarmush, Martin L., Alaniz, Robert C., Jayaraman, Arul, Lee, Kyongbum
• Format: Article
• Language: English
• Subjects: Animals; aryl hydrocarbon receptor; Cytokines - immunology; Cytokines - metabolism; Dietary Fats - pharmacology; Fatty Acid Synthase, Type I - immunology; Fatty Acid Synthase, Type I - metabolism; Gastrointestinal Microbiome - immunology; gut microbiota; Hep G2 Cells; Hepatocytes - immunology; Hepatocytes - metabolism; Hepatocytes - pathology; Humans; indole-3-acetate; Indoleacetic Acids - immunology; Indoleacetic Acids - metabolism; Inflammation; Macrophages - immunology; Macrophages - metabolism; Male; metabolomics; Mice; nonalcoholic fatty liver disease; RAW 264.7 Cells; Receptors, Aryl Hydrocarbon - immunology; Receptors, Aryl Hydrocarbon - metabolism; Sterol Regulatory Element Binding Protein 1 - immunology; Sterol Regulatory Element Binding Protein 1 - metabolism; Tryptamines - immunology; Tryptamines - metabolism; Tryptophan - immunology; Tryptophan - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2018.03.109

The gut microbiota plays a significant role in the progression of fatty liver disease; however, the mediators and their mechanisms remain to be elucidated. Comparing metabolite profile differences between germ-free and conventionally raised mice against differences between mice fed a low- and high-fat diet (HFD), we identified tryptamine and indole-3-acetate (I3A) as metabolites that depend on the microbiota and are depleted under a HFD. Both metabolites reduced fatty-acid- and LPS-stimulated production of pro-inflammatory cytokines in macrophages and inhibited the migration of cells toward a chemokine, with I3A exhibiting greater potency. In hepatocytes, I3A attenuated inflammatory responses under lipid loading and reduced the expression of fatty acid synthase and sterol regulatory element-binding protein-1c. These effects were abrogated in the presence of an aryl-hydrocarbon receptor (AhR) antagonist, indicating that the effects are AhR dependent. Our results suggest that gut microbiota could influence inflammatory responses in the liver through metabolites engaging host receptors. [Display omitted] •A high-fat diet depletes the microbiota metabolites indole-3-acetate and tryptamine•Indole-3-acetate and tryptamine attenuate indicators of inflammation in macrophages•Indole-3-acetate attenuates cytokine-mediated lipogenesis in hepatocytes Dysbiosis of the intestinal microbiota is an emerging factor contributing to the progression of fatty liver disease. Krishnan et al. utilize metabolomics and biochemical assays in conjunction with animal and cell culture models to identify microbiota-dependent metabolites that engage a host receptor to affect liver inflammatory responses under lipid loading.