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

Cell Rep. 2018 Apr 24;23(4):1099-1111. 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.

Keywords: aryl hydrocarbon receptor; gut microbiota; indole-3-acetate; inflammation; metabolomics; nonalcoholic fatty liver disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cytokines / immunology
  • Cytokines / metabolism
  • Dietary Fats / pharmacology
  • Fatty Acid Synthase, Type I / immunology
  • Fatty Acid Synthase, Type I / metabolism
  • Gastrointestinal Microbiome / immunology*
  • Hep G2 Cells
  • Hepatocytes* / immunology
  • Hepatocytes* / metabolism
  • Hepatocytes* / pathology
  • Humans
  • Indoleacetic Acids* / immunology
  • Indoleacetic Acids* / metabolism
  • Inflammation
  • Macrophages* / immunology
  • Macrophages* / metabolism
  • Male
  • Mice
  • 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


  • Cytokines
  • Dietary Fats
  • Indoleacetic Acids
  • Receptors, Aryl Hydrocarbon
  • Srebf1 protein, mouse
  • Sterol Regulatory Element Binding Protein 1
  • Tryptamines
  • tryptamine
  • indoleacetic acid
  • Tryptophan
  • Fatty Acid Synthase, Type I