ArticleCellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology2020
Serotonin Modulates AhR Activation by Interfering with CYP1A1-Mediated Clearance of AhR Ligands.
Article in Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 34 citations in OpenAlex.
- Bacterial serine protease EspP induces differentiation and expansion of enteroendocrine cells in human colonoids.Physiological genomics · 2026Article
- Tryptophan metabolism in glaucomatous optic neuropathy: from metabolic dysregulation to therapeutic opportunities.Journal of translational medicine · 2026Review
- Metabolomics and metagenomics in mice reveal the role of the gut microbiota in tryptophan metabolism.iScience · 2025Article
- Novel Insights into Psychosis and Antipsychotic Interventions: From Managing Symptoms to Improving Outcomes.International journal of molecular sciences · 2024Review
- The aryl hydrocarbon receptor pathway: a linking bridge between the gut microbiome and neurodegenerative diseases.Frontiers in cellular neuroscience · 2024Review
- Tryptophan metabolites and incident cardiovascular disease: The EPIC-Norfolk prospective population study.Atherosclerosis · 2023Article
- Knockdown of IL4I1 Improved High Glucose-evoked Insulin Resistance in HepG2 Cells by Alleviating Inflammation and Lipotoxicity Through AHR Activation.Applied biochemistry and biotechnology · 2023Article
- Effects of Serotonin on Cell Viability, Permeability of Bovine Mammary Gland Epithelial Cells and Their Transcriptome Analysis.International journal of molecular sciences · 2023Article
- Article
- Host-Microbiome Interactions: Tryptophan Metabolism and Aromatic Hydrocarbon Receptors after Traumatic Brain Injury.International journal of molecular sciences · 2023Review
- Engineered bacteria producing aryl-hydrocarbon receptor agonists protect against ethanol-induced liver disease in mice.Alcohol, clinical & experimental research · 2023Article
- Activation of aryl hydrocarbon receptor (AhR) in Alzheimer's disease: role of tryptophan metabolites generated by gut host-microbiota.Journal of molecular medicine (Berlin, Germany) · 2023Review
- Activation of the aryl hydrocarbon receptor in inflammatory bowel disease: insights from gut microbiota.Frontiers in cellular and infection microbiology · 2023Review
- Enterochromaffin Cells-Gut Microbiota Crosstalk: Underpinning the Symptoms, Pathogenesis, and Pharmacotherapy in Disorders of Gut-Brain Interaction.Journal of neurogastroenterology and motility · 2022Review
- Kynurenine Pathway of Tryptophan Metabolism in Migraine and Functional Gastrointestinal Disorders.International journal of molecular sciences · 2021Review
- AHR in the intestinal microenvironment: safeguarding barrier function.Nature reviews. Gastroenterology & hepatology · 2021Review
- Gut microbiota-derived tryptophan metabolism mediates renal fibrosis by aryl hydrocarbon receptor signaling activation.Cellular and molecular life sciences : CMLS · 2021Review
- How Ah Receptor Ligand Specificity Became Important in Understanding Its Physiological Function.International journal of molecular sciences · 2020Review
- Intestinal microbiota-derived tryptophan metabolites are predictive of Ah receptor activity.Gut microbes · 2020Article
- The aryl hydrocarbon receptor as a mediator of host-microbiota interplay.Gut microbes · 2020Review
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
BACKGROUND/
aimsSerotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter and hormone with important physiological functions in many organs, including the intestine. We have previously shown that 5-HT activates the aryl hydrocarbon receptor (AhR) in intestinal epithelial cells (IECs) via a serotonin transporter (SERT)-dependent mechanism. AhR is a nuclear receptor that binds a variety of molecules including tryptophan (TRP) metabolites to regulate physiological processes in the intestine including xenobiotic detoxification and immune modulation. We hypothesized that 5-HT activates AhR indirectly by interfering with metabolic clearance of AhR ligands by cytochrome P450 1A1 (CYP1A1).
methodsInhibition of CYP1A1 activity by 5-HT was assessed in the human intestinal epithelial cell line Caco-2 and recombinant CYP1A1 microsomes using both luciferase and LC-MS/MS. Degradation of 5-HT by recombinant CYP1A1 was measured by LC-MS/MS. For in vitro studies, CYP1A1 and CYP1B1 mRNA expression levels were measured by RT-PCR and CYP1A1 activity was measured by ethoxyresorufin-O-deethylase (EROD) assays. For in vivo studies, AhR ligands were administered to SERT KO mice and WT littermates and intestinal mucosa CYP1A1 mRNA was measured.
resultsWe show that 5-HT inhibits metabolism of both the pro-luciferin CYP1A1 substrate Luc-CEE as well as the high affinity AhR ligand 6-formylindolo[3,2-b] carbazole (FICZ). Recombinant CYP1A1 assays revealed that 5-HT is metabolized by CYP1A1 in an NADPH dependent manner. Treatment with 5-HT in TRP-free medium, which is devoid of trace AhR ligands, showed that 5-HT requires the presence of AhR ligands to activate AhR. Cotreatment with 5-HT and FICZ confirmed that 5-HT potentiates induction of AhR target genes by AhR ligands. However, this was only true for ligands which are CYP1A1 substrates such as FICZ. Administration of β-napthoflavone by gavage or indole-3-carbinol via diet to SERT KO mice revealed that lack of SERT impairs intestinal AhR activation.
conclusionOur studies provide novel evidence of crosstalk between serotonergic and AhR signaling where 5-HT can influence the ability of AhR ligands to activate the receptor in the intestine.
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