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Cell Rep. 2018 Apr 24;23(4):1099-1111. doi: 10.1016/j.celrep.2018.03.109.

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

Author information

1
Department of Chemical and Biological Engineering, Tufts University, Medford, MA 02155, USA.
2
Department of Biomedical Engineering, Texas A&M University, College Station, TX 77843, USA.
3
Center for Engineering in Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
4
Department of Environmental Health, Boston University School of Public Health, Boston, MA 02118, USA.
5
Department of Microbial Pathogenesis and Immunology, College of Medicine, Texas Health Science Center, Texas A&M University, College Station, TX, USA.
6
Department of Biomedical Engineering, Texas A&M University, College Station, TX 77843, USA; Department of Microbial Pathogenesis and Immunology, College of Medicine, Texas Health Science Center, Texas A&M University, College Station, TX, USA; Artie McFerrin Department of Chemical Engineering, Texas A&M University, College Station, TX 77843, USA. Electronic address: arulj@tamu.edu.
7
Department of Chemical and Biological Engineering, Tufts University, Medford, MA 02155, USA. Electronic address: kyongbum.lee@tufts.edu.

Abstract

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

PMID:
29694888
DOI:
10.1016/j.celrep.2018.03.109
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