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Activation of AHR transcriptional activity upon treatment with indole-3-pyruvate

ABSTRACT: Activation of AHR transcriptional activity upon treatment with indole-3-pyruvate

PROVIDER: PRJNA599381 | ENA |

REPOSITORIES: ENA

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Activation of AHR transcriptional activity upon treatment with indole-3-pyruvate

Project description:Indole-3-pyruvate (I3P), an endogenous metabolite derived from tryptophan by gut microbiota and IL4I1 enzyme in humans can potentially activate the transcriptional activity of the Aryl Hydrocarbon receptor. Here we test this by stimulating AHR proficient U-87MG cells with I3P alone or in combination with the AHR antagonist SR1.

2020-08-19 | GSE143240 | GEO

Analysis of HeLa cell transcriptome changes induced by Indole-3-pyruvate and mIL4i1

Project description:We analyzed the mRNA changes induced by Indole-3-pyruvate (I3P) and WT or K351A mutant mIL4i1 in HeLa cells.

2021-03-07 | GSE167136 | GEO

Analysis of THP-1 cell transcriptome changes induced by Phenylpyruvate, 4-Hydroxyphenylpyruvate and Indole-3-pyruvate

Project description:We analyzed the mRNA changes iduced by the alpha keto acids Phenylpyruvate (PP), 4-Hydroxyphenylpyruvate (4HPP) or Indole-3-pyruvate (I3P) in THP-1 cells.

2021-03-07 | GSE161159 | GEO

Maternal indole supplementation protects offspring from NAFLD through altered microbiota- and AHR-mediated ceramide metabolism

Project description:MaternalWestern-style diet (WD) disrupts early life gut microbiota in the offspring and is associated with pediatric nonalcoholic fatty liver disease (NAFLD). Here, we report that oral supplementation with gut-derived tryptophan metabolites indole (Ind) or indole-3-acetate (I3A) during pregnancy and lactation in WD-fed dams had persistent effects in offspring liver, acting on key upstream regulators in WD-challenged offspring that suppress pathways for steatosis, fibrosis, and oxidative stress. Maternal Ind or I3A activated aryl hydrocarbon receptor (AHR) signaling, leading to increases in long-chain and very long-chain (VLC) ceramides in offspring liver and small intestine. These effects were evident as early as postnatal day 14. The tryptophan metabolite 5-hydroxyindoleacetate (5-HIAA), an AHR ligand, was depleted in offspring by maternal WD and restored by maternal I3A treatment. Fecal transplantation studies demonstrated that VLC ceramides and liver fibrosis remodeling were mediated by maternal indoles altering the gut microbiota, with strong associations with Lactobacillaceae. Collectively, these findings define a novel and persistent protective effect of maternal Ind and I3A to prevent NAFLD, acting both directly on the liver and through the microbiota. These tryptophan metabolites may serve as therapeutic targets for future interventional studies aimed at prevention of pediatric NAFLD.

2026-01-21 | GSE247323 | GEO

Gut Microbiota Metabolite Indole-3-Acetic Acid Maintains Intestinal Epithelial Homeostasis via the transcription factor AHR

Project description:The incidence and prevalence of inflammatory bowel disease (IBD) is gradually increasing. A high-fat diet (HFD) is known to disrupt intestinal homeostasis and aggravate IBD, yet the underlying mechanisms remain largely undefined. Here, a positive correlation between dietary fat intake and disease severity in both IBD patients and HFD-fed mice is observed. HFD induces a significant decrease in indole-3-acetic acid (IAA) and lead to intestinal barrier damage. Furthermore, IAA supplementation enhances the intestinal mucin sulfation and effectively alleviates colitis. Mechanistically, IAA upregulates key molecules involved in mucin sulfation, including Papss2 and Slc35b3, the synthesis enzyme and the transferase of 3'-phosphoadenosine-5'-phosphosulfate (PAPS), via the Aryl Hydrocarbon Receptor (AHR). More importantly, AHR can directly bind to the transcription start site of Papss2. Oral administration of Lactobacillus reuteri, which can produce IAA, contributes to protecting against colitis and promoting mucin sulfation, while the modified L. reuteri strain lacking the iaaM gene (LactobacillusΔiaaM) and the ability to produce IAA fails to exhibit such effects. Overall, IAA enhances intestinal mucin sulfation through AHR, contributing to the protection of intestinal homeostasis.

2025-12-11 | GSE255130 | GEO

Proteomic characterization of the cellular effects of AHR activation by microbial tryptophan catabolites in endotoxin-activated human macrophages

Project description:Sensing of microbial tryptophan catabolites by the aryl hydrocarbon receptor (AhR) plays a pivotal role in host-microbiome homeostasis by modulating the host immune response. Thereby the involved cellular processes triggered by the metabolites are largely unknown. We analyzed proteomic changes in macrophages trough 24h after treatment with the tryptophan metabolites indole-3-acetic acid (I3AA) or indole-3-aldehyde (IAld), as well as the prototypic AhR-ligand Benzo(a)pyrene (BaP) in the absence and presence of LPS to identify affected processes and pathways.

2021-11-03 | PXD025022 | Pride

Analysis of HeLa cell transcriptome changes induced by Indole-3-pyruvate and mIL4i1

Project description:Analysis of HeLa cell transcriptome changes induced by Indole-3-pyruvate and mIL4i1

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Hexokinase 2 is a transcriptional targetHexokinase 2 is a transcriptional target and a positive modulator of AHR signalling and a positive modulator of AHR signalling

Project description:The Aryl Hydrocarbon Receptor (AHR) regulates the expression of numerous genes in response to activation by agonists including xenobiotics. Although it is well appreciated that environmental signals and cell intrinsic features may modulate this transcriptional response, how it is mechanistically achieved remains poorly understood. We show that Hexokinase 2 (HK2) a metabolic enzyme fuelling cancer cell growth, is a transcriptional target of AHR as well as a modulator of its activity. Expression of HK2 is positively regulated by AHR upon exposure to agonists both in human cells and in mice lung tissues. Conversely, over-expression of HK2 regulates the abundance of many proteins involved in the regulation of AHR signalling and these changes are linked with altered AHR expression levels and transcriptional activity. HK2 expression also shows a negative correlation with AHR promoter methylation in tumours, and these tumours with high HK2 expression and low AHR methylation are associated with a worse overall survival in patients. In sum, our study provides novel insights into how AHR signalling is regulated which may help our understanding of the context-specific effects of this pathway and may have implications in cancer.

2022-05-31 | PXD028992 | Pride

Microbiome-Derived Indole-3-lactic Acid Attenuates Cutibacterium acnes–Induced Inflammation via the Aryl Hydrocarbon Receptor Pathway

Project description:Acne vulgaris is a chronic inflammatory dermatosis where conventional therapies of-ten face limitations in efficacy and safety, necessitating the development of microbi-ome-targeted interventions. This study investigated the immunomodulatory potential of microbiome-derived tryptophan metabolites as a novel therapeutic strategy for Cutibacterium acnes-induced inflammation, focusing on the aryl hydrocarbon receptor (AHR) pathway. We evaluated indole-3-lactic acid (ILA), indole-3-acrylic acid (IAA), and indole-3-propionic acid (IPA) in comparison to tapinarof, utilizing C. ac-nes-stimulated human epidermal keratinocytes and a C. acnes-induced acne mouse model. In vitro, ILA and IPA significantly suppressed C. acnes-driven inflammatory mediators, including TNF-α, IL-1β, and COX2, whereas IAA demonstrated limited ef-ficacy. In vivo, ILA treatment exhibited superior therapeutic activity, markedly reduc-ing inflammatory cell infiltration, epidermal hyperplasia, and IL-1β expression. Tran-scriptomic analysis confirmed that ILA attenuates inflammatory signaling (e.g., IL-17 and TNF pathways) while upregulating AHR-responsive genes such as CYP1A1 and CYP1B1. Collectively, these findings establish ILA as a potent postbiotic that mitigates cutaneous inflammation through selective activation of the AHR. Future studies should prioritize the clinical translation of ILA-based topical fomulations, with rigorous evaluation of their efficacy and safety in well-designed human trials, to support their development as a non-antibiotic therapeutic alternative for acne management.

2026-01-05 | GSE315350 | GEO

AhR activity directs BRAF inhibitors resistance in metastastic melanoma

Project description:AhR activity directs BRAF inhibitors resistance in metastastic melanoma

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