Serotonin Modulates AhR Activation by Interfering with CYP1A1-Mediated Clearance of AhR Ligands

Manzella, Christopher R.; Ackerman, Max; Singhal, Megha; Ticho, Alexander L.; Ceh, Justin; Alrefai, Waddah A.; Saksena, Seema; Dudeja, Pradeep K.; Gill, Ravinder K.

doi:10.33594/000000209

Cited by 19 publications

(10 citation statements)

References 53 publications

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“…Yet another potential mechanism that can modulate AHR activation is the presence of CYP1A1 inhibitors/competitive substrates that can increase the half-life of AHR ligands, such as FICZ or serotonin. 10,44,60 With the exception of 2-oxindole, no single tryptophan metabolite could account for the observed AHR activity across both cohorts. Previous metabolomic analyses examining serum concentrations of microbially derived metabolites are indicative of gastrointestinal absorption; however, to our knowledge, the active transport or passive absorption kinetics of the tryptophan metabolites studied here have not been elucidated in vivo.…”

Section: Discussionmentioning

confidence: 97%

“…However, serotonin appears to be an indirect ligand through inhibition of CYP1A1 activity. 44 All compounds were quantified by LC/MS with the exception of indole, which by virtue of its high volatility was quantified by GC/MS. Sample extracts derived from fresh mouse cecal contents were quantified through interpolation of standard curves and corrected for recovery and matrix effects.…”

Section: Quantification Of Tryptophan Metabolites In Mouse Cecal Contmentioning

confidence: 99%

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Intestinal microbiota-derived tryptophan metabolites are predictive of Ah receptor activity

et al. 2020

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Commensal microbiota-dependent tryptophan catabolism within the gastrointestinal tract is known to exert profound effects upon host physiology, including the maintenance of epithelial barrier and immune function. A number of abundant microbiota-derived tryptophan metabolites exhibit activation potential for the aryl hydrocarbon receptor (AHR). Gene expression facilitated by AHR activation through the presence of dietary or microbiota-generated metabolites can influence gastrointestinal homeostasis and confer protection from intestinal challenges. Utilizing untargeted mass spectrometry-based metabolomics profiling, combined with AHR activity screening assays, we identify four previously unrecognized tryptophan metabolites, present in mouse cecal contents and human stool, with the capacity to activate AHR. Using GC/MS and LC/MS platforms, quantification of these novel AHR activators, along with previously established AHR-activating tryptophan metabolites, was achieved, providing a relative order of abundance. Using physiologically relevant concentrations and quantitative gene expression analyses, the relative efficacy of these tryptophan metabolites with regard to mouse or human AHR activation potential is examined. These data reveal indole, 2-oxindole, indole-3-acetic acid and kynurenic acid as the dominant AHR activators in mouse cecal contents and human stool from participants on a controlled diet. Here we provide the first documentation of the relative abundance and AHR activation potential of a panel of microbiota-derived tryptophan metabolites. Furthermore, these data reveal the human AHR to be more sensitive, at physiologically relevant concentrations, to tryptophan metabolite activation than mouse AHR. Additionally, correlation analyses indicate a relationship linking major tryptophan metabolite abundance with AHR activity, suggesting these cecal/fecal metabolites represent biomarkers of intestinal AHR activity.

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Section: Discussionmentioning

confidence: 97%

Section: Quantification Of Tryptophan Metabolites In Mouse Cecal Contmentioning

confidence: 99%

Intestinal microbiota-derived tryptophan metabolites are predictive of Ah receptor activity

et al. 2020

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“…Recently, we showed that 5-HT, which is taken up intracellularly via SERT, can activate AhR. 63 , 64 As activation of the AhR pathway has been shown to be protective against intestinal inflammation, 65–67 it is plausible that disruption of the SERT-5-HT-AhR axis has an additional role in IBD pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Serum Serotonin Differentiates Between Disease Activity States in Crohn’s Patients

Manzella

Jayawardena

Pagani

et al. 2020

Inflammatory Bowel Diseases

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Background Diagnosis and monitoring of inflammatory bowel diseases (IBDs) utilize invasive methods including endoscopy and tissue biopsy, with blood tests being less specific for IBDs. Substantial evidence has implicated involvement of the neurohormone serotonin (5-hydroxytryptamine, 5-HT) in the pathophysiology of IBDs. The current study investigated whether serum 5-HT is elevated in patients with active ulcerative colitis (UC) or Crohn’s disease (CD). Methods Serum samples were obtained from a German cohort of 96 CD and UC patients with active disease, refractory disease, or remission of disease based upon their disease activity index (DAI) and disease history. High pressure liquid chromatography with tandemmass spectrometry was used to measure 5-HT, tryptophan (TRP), and kynurenine (KYN) levels in the serum samples, and Luminex Multiplex ELISA was used to measure cytokine levels. Intestinal mucosal biopsies were obtained from a separate cohort of healthy and CD patients, and the immunoreactivity of the serotonin transporter (SERT) was determined. Results There was no statistically significant difference in TRP or KYN levels between disease categories in either UC or CD. Interestingly, 5-HT levels were significantly elevated in patients with active CD but not active UC when compared with the levels in remission or refractory disease. Serum 5-HT was superior to C-reactive protein and circulating cytokines in differentiating between disease categories in CD. Additionally, SERT immunoreactivity was decreased in the ileum and colon of patients with CD compared to healthy controls. Conclusion We have shown that the serum 5-HT can differentiate between active disease and refractory disease or remission among CD patients, emphasizing the potential suitability of serum 5-HT as an auxiliary measure in diagnosing active CD.

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“… 59 While it is not a ligand for AHR, serotonin acting as a CYP1A1 substrate, interferes with metabolic clearance of AHR ligands through inhibition of CYP1A1 activity leading to a decrease in ligand degradation and promotion of AHR activation in intestinal epithelial cells. 60 , 61 Clearly, whether other microbial metabolites are capable of modulating AHR activity through inhibition of CYP1A1 should be explored. In a recent study, a novel AHR ligand of 5-HIAA derived from serotonin by monoamine oxidase (MAO) activity was discovered to be a transcriptional marker for regulatory B cells function via AHR activation.…”

Section: Ahr Ligands and Host Metabolism In Tryptophan Catabolismmentioning

confidence: 99%

The aryl hydrocarbon receptor as a mediator of host-microbiota interplay

Dong

Perdew

2020

Gut Microbes

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Serotonin Modulates AhR Activation by Interfering with CYP1A1-Mediated Clearance of AhR Ligands

Abstract: This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND). Usage and distribution for commercial purposes as well as any distribution of modified material requires written permission.

Cited by 19 publications

References 53 publications

Intestinal microbiota-derived tryptophan metabolites are predictive of Ah receptor activity

Intestinal microbiota-derived tryptophan metabolites are predictive of Ah receptor activity

Serum Serotonin Differentiates Between Disease Activity States in Crohn’s Patients

The aryl hydrocarbon receptor as a mediator of host-microbiota interplay

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