Aryl Hydrocarbon Receptor Activation Coordinates Mouse Small Intestinal Epithelial Cell Programming

Zhou, Xiaoliang; Chakraborty, Debopriya; Murray, Iain A.; Coslo, Denise M.; Kehs, Zoe; Vijay, Anitha; Ton, Carolyn; Desai, Dhimant; Amin, Shantu; Patterson, Andrew D.; Perdew, Gary H.

doi:10.1016/j.labinv.2022.100012

Cited by 19 publications

(31 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The presence of a proximal to distal basal (and inducible) Cyp1a1 gradient within the small intestine would suggest that small intestinal CYP1A1 metabolism of broccoli-derived ICZ would restrict its systemic distribution. 30 Such digestive metabolism is consistent with the protective role of the intestine to limit systemic exposure to potentially toxic dietary secondary metabolites. Conversely, loss of AHR and thus CYP1A1 expression within the duodenum of Villin Cre Ahr fl/fl mice appears to increase systemic ICZ distribution, as evidenced by lung Cyp1a1 induction relative to control diet.…”

Section: Discussionsupporting

confidence: 53%

“…In the intestinal tract, especially the duodenum, enterocytes express significant amounts of CYP1A1 that metabolically restricts systemic circulation of a specific subset of AHR ligands that also manifest as CYP1A1 substrates. 30 This was first demonstrated in vivo by the observation that the deletion of ARNT expression from the intestinal epithelium leads to extra-intestinal AHR activation, likely due to a lack of intestinal CYP1A1 expression 31 . Conversely, constitutive expression of CYP1A1 in the intestinal epithelial cells leads to a depleted AHR activation potential, resulting in significant changes in type 3 innate lymphoid cells within the intestinal tract 22 .…”

Section: Discussionmentioning

confidence: 99%

“…Congenic Ahr fl/fl and Villin Cre Ahr fl/fl mice on a C57BL6/J background were generated as previously described. 30…”

Section: Methodsmentioning

confidence: 99%

“…Congenic Ahr fl/fl and Villin Cre Ahr fl/fl mice on a C57BL6/J background were generated as previously described. 30 Pluronic L-81 treatment Female C57BL6/J mice were maintained with ad libitum access to a semi-synthetic diet (AIN93G) and water for 1 week. On day of treatment, mice were food restricted for 3 h (18:00-21:00 h) prior to oral administration of either 0.2 ml water (vehicle) or 5% (v/v) Pluronic L-81.…”

Section: Broccoli Glucobrassicin Quantificationmentioning

confidence: 99%

See 3 more Smart Citations

Complex chemical signals dictate Ah receptor activation through the gut-lung axis

Dong

Murray

Annalora

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

The aryl hydrocarbon receptor (AHR) mediates intestinal barrier homeostasis. Many AHR ligands are also CYP1A1/1B1 substrates, which can result in the rapid clearance within the intestinal tract, limiting AHR activation. This led us to the hypothesis that there are dietary substrates of CYP1A1/1B1 that increase the half-life of potent AHR ligands. We examined the potential of urolithin A (UroA) as a CYP1A1/1B1 substrate to enhance AHR activity in vivo. UroA is a competitive substrate for CYP1A1/1B1 in an in vitro competition assay. A broccoli-containing diet promotes the gastric formation of the potent hydrophobic AHR ligand and CYP1A1/1B1 substrate, 5,11-dihydroindolo[3,2-b]carbazole (ICZ). Dietary exposure to UroA in a broccoli diet led to a coordinated increase in duodenal, cardiac, and pulmonary AHR activity, but no increase in activity in liver. Thus, CYP1A1 dietary competitive substrates can lead to intestinal escape, likely through the lymphatic system, increasing AHR activation in key barrier tissues.

show abstract

Section: Discussionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 99%

“…Congenic Ahr fl/fl and Villin Cre Ahr fl/fl mice on a C57BL6/J background were generated as previously described. 30…”

Section: Methodsmentioning

confidence: 99%

Section: Broccoli Glucobrassicin Quantificationmentioning

confidence: 99%

See 2 more Smart Citations

Complex chemical signals dictate Ah receptor activation through the gut-lung axis

Dong

Murray

Annalora

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…30,31 Moreover, our lab has previously shown that, despite high expression of AHR in the colon of conventional C57BL/6J mice and high concentrations of Trp metabolites, there is little to no Cyp1a1 expression. 32 Taken together, these observations imply that mouse AHR is relatively insensitive to changes in Trp metabolites in the context of detectable serum concentrations. These distinctions present the biological challenges limiting the accuracy of mouse models to provide specific insights into physiologically induced human AHR activity.…”

Section: Discussionmentioning

confidence: 85%

Contribution of circulating host and microbial tryptophan metabolites towards Ah receptor activation

Morgan¹,

Dong

Annalora

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

The aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor that plays an integral role in homeostatic maintenance by regulating cellular functions such as cellular differentiation, metabolism, barrier function, and immune response. An important but poorly understood class of AHR activators are compounds derived from host and bacterial metabolism of tryptophan. The commensal bacteria of the gut microbiome are major producers of tryptophan metabolites known to activate the AHR, while the host also produces AHR activators through tryptophan metabolism. We used targeted mass spectrometry-based metabolite profiling to determine the presence and metabolic source of these metabolites in the sera of conventional mice, germ-free mice, and humans. Surprisingly, sera concentrations of many tryptophan metabolites are comparable between germ-free and conventional mice. Therefore, many major AHR-activating tryptophan metabolites in mouse sera are produced by the host, despite their presence in feces and mouse cecal contents. AHR activation is rarely studied in the context of a mixture at relevant concentrations, as we present here. The AHR activation potentials of individual and pooled metabolites were explored using cell-based assays, while ligand binding competition assays and ligand docking simulations were used to assess the detected metabolites as AHR agonists. The physiological and biomedical relevance of the identified metabolites was investigated in the context of cell-based models for cancer and rheumatoid arthritis. We present data here that reframe AHR biology to include the presence of ubiquitous tryptophan metabolites, improving our understanding of homeostatic AHR activity and models of AHR-linked diseases.

show abstract

Sphingosine Kinase 2 Regulates Aryl Hydrocarbon Receptor Nuclear Translocation and Target Gene Activation

Yokoyama,

Koo,

Aibara

et al. 2024

Advanced Science

View full text Add to dashboard Cite

Sphingolipids play vital roles in metabolism and regulation. Previously, the aryl hydrocarbon receptor (AHR), a ligand‐activated transcription factor, was reported to directly regulate ceramide synthesis genes by binding to their promoters. Herein, sphingosine kinase 2 (SPHK2), responsible for producing sphingosine‐1‐phosphate (S1P), was found to interact with AHR through LXXLL motifs, influencing AHR nuclear localization. Through mutagenesis and co‐transfection studies, AHR activation and subsequent nuclear translocation was hindered by SPHK2 LXXLL mutants or SPHK2 lacking a nuclear localization signal (NLS). Similarly, an NLS‐deficient AHR mutant impaired SPHK2 nuclear translocation. Silencing SPHK2 reduced AHR expression and its target gene CYP1A1, while SPHK2 overexpression enhanced AHR activity. SPHK2 was found enriched on the CYP1A1 promoter, underscoring its role in AHR target gene activation. Additionally, S1P rapidly increased AHR expression at both the mRNA and protein levels and promoted AHR recruitment to the CYP1A1 promoter. Using mouse models, AHR deficiency compromised SPHK2 nuclear translocation, illustrating a critical interaction where SPHK2 facilitates AHR nuclear localization and supports a positive feedback loop between AHR and sphingolipid enzyme activity in the nucleus. These findings highlight a novel function of SPHK2 in regulating AHR activity and gene expression.

show abstract

Aryl Hydrocarbon Receptor Activation Coordinates Mouse Small Intestinal Epithelial Cell Programming

Cited by 19 publications

References 70 publications

Complex chemical signals dictate Ah receptor activation through the gut-lung axis

Complex chemical signals dictate Ah receptor activation through the gut-lung axis

Contribution of circulating host and microbial tryptophan metabolites towards Ah receptor activation

Sphingosine Kinase 2 Regulates Aryl Hydrocarbon Receptor Nuclear Translocation and Target Gene Activation

Contact Info

Product

Resources

About