Global profiling for human feces
Ontology highlight
ABSTRACT:
ORGANISM(S): Human Homo Sapiens
TISSUE(S): Feces
SUBMITTER: 
FANGCONG DONG
PROVIDER: ST001337 | MetabolomicsWorkbench | Thu Mar 26 00:00:00 GMT 2020
REPOSITORIES: MetabolomicsWorkbench
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Project description:The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that responds to a variety of structurally diverse exogenous and endogenous small molecules. Gut microbiota utilizing tryptophan and indole metabolism as a reservoir, has been demonstrated to provide an abundant source of AHR ligands. So differential analysis was performed to find the potential candidates of AHR activator in cecal contents between conventional and germ-free mice with the help of untargeted global profiling.
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Project description:Understanding the mechanisms of host macrophage responses to M. tuberculosis (M.tb.) is essential for uncovering potential avenues of intervention to boost host resistance to infection. Macrophage transcriptome profiling revealed M.tb. infection strongly induced expression of several enzymes controlling tryptophan (Trp) catabolism. This included indole 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO2), which catalyze the rate-limiting step in the kynurenine pathway, producing ligands for the aryl hydrocarbon receptor (AHR). The AHR and heterodimeric partners AHR nuclear translocator (ARNT) and RELB are robustly expressed, and AHR and RELB levels further increased during infection. Infection enhanced AHR/ARNT and AHR/RELB DNA binding, and stimulated expression of AHR target genes, including that encoding the inflammatory cytokine IL1beta. AHR target gene expression was further enhanced by exogenous kynurenine, and exogenous Trp, kynurenine or synthetic agonist indirubin reduced mycobacterial viability. Comparative expression profiling revealed that AHR ablation diminished expression of numerous genes implicated in innate immune responses, including several cytokines. Notably, AHR depletion reduced expression of IL23A and IL12B transcripts, which encode subunits of interleukin 23 (IL23), a macrophage cytokine that stimulates production of IL22 by innate lymphoid cells. The AHR directly induced IL23A transcription in human and mouse macrophages through near-upstream enhancer regions. Taken together, these findings show that AHR signaling is strongly engaged in Mtb-infected macrophages, and has widespread effects on innate immune responses. Moreover, they reveal a cascade of AHR-driven innate immune signaling, as IL1B (IL-1β) and IL23 stimulate T cell subsets producing IL22, another direct target of AHR transactivation. Gene expression profiling of Mtb-infected THP-1 monocytic cells following siRNA-mediated Aryl hydrocarbon receptor (AHR) knockdown.
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