ArticleThe Journal of clinical investigation2018
Intestinal P-glycoprotein exports endocannabinoids to prevent inflammation and maintain homeostasis.
Article in The Journal of clinical investigation, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers, 1 of them a synthesis that pooled it.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
43 citing papers in PubMed, 1 synthesis or guideline pooled it, 66 citations in OpenAlex.
- Gut Microbiota Dysbiosis and Neuroinflammation in Alzheimer's Disease: a Systematic Review of Mechanistic Insights.Molecular neurobiology · 2026Pooled it
- Untargeted Metabolomics Reveal New Endogenous Plasma Biomarkers Associated with CYP3A Inhibition in Humans.Clinical pharmacology and therapeutics · 2026Article
- Transient receptor potential vanilloid 2 functions as a directional driver for hepoxilin AScience advances · 2026Article
- Decrease in In Vivo Efflux Transport via P-glycoprotein at the Rat Inner Blood-Retinal Barrier by Peripheral Administration of Lipopolysaccharide.Pharmaceutical research · 2025Article
- Beyond ADME: The Endogenous Functions of Drug Transporters and Its Impact on Human Disease.Pharmaceutics · 2025Review
- Pharmacological potential of endocannabinoid and endocannabinoid-like compounds in protecting intestinal structure and metabolism under high-fat conditions.Frontiers in pharmacology · 2025Review
- Identification of Senescence-Related Genes for the Prediction of Ulcerative Colitis Based on Interpretable Machine Learning Models.Journal of inflammation research · 2025Article
- Neutrophil extracellular traps and cannabinoids: potential in cancer metastasis.Frontiers in oncology · 2025Review
- Isoorientin Modulates Gut Microbes and Their Metabolites to Alleviate Caco-2 Cell Monolayer Inflammation by Reducing Intestinal Permeability via P-Gp/eCBs.Journal of inflammation research · 2025Article
- Exploring the versatile roles of the endocannabinoid system and phytocannabinoids in modulating bacterial infections.Infection and immunity · 2024Review
- Xixin Decoction's novel mechanism for alleviating Alzheimer's disease cognitive dysfunction by modulating amyloid-β transport across the blood-brain barrier to reduce neuroinflammation.Frontiers in pharmacology · 2024Article
- Gut Microbiome in Alzheimer's Disease: from Mice to Humans.Current neuropharmacology · 2024Review
- Pharmacohistory of Cannabis Use-A New Possibility in Future Drug Development for Gastrointestinal Diseases.International journal of molecular sciences · 2023Review
- Development of ADS051, an oral, gut-restricted, small molecule neutrophil modulator for the treatment of neutrophil-mediated inflammatory diseases.FEBS open bio · 2023Article
- Lipopolysaccharide-Induced Functional Alteration of P-glycoprotein in the Ex Vivo Rat Inner Blood-Retinal Barrier.International journal of molecular sciences · 2022Article
- Clinical Significance of Lipid Transport Function of ABC Transporters in the Innate Immune System.Membranes · 2022Review
- The gut microbiome and Alzheimer's disease: Complex and bidirectional interactions.Neuroscience and biobehavioral reviews · 2022Review
- Article
- The Gut Microbiome-Brain Crosstalk in Neurodegenerative Diseases.Biomedicines · 2022Review
- Role of the Endocannabinoid System in the Regulation of Intestinal Homeostasis.Cellular and molecular gastroenterology and hepatology · 2022Review
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Authors and funding
13 authors at 3 institutions in 2 countries.
Funding
Abstract
Neutrophil influx into the intestinal lumen is a critical response to infectious agents, but is also associated with severe intestinal damage observed in idiopathic inflammatory bowel disease. The chemoattractant hepoxilin A3, an eicosanoid secreted from intestinal epithelial cells by the apically restricted efflux pump multidrug resistance protein 2 (MRP2), mediates this neutrophil influx. Information about a possible counterbalance pathway that could signal the lack of or resolution of an apical inflammatory signal, however, has yet to be described. We now report a system with such hallmarks. Specifically, we identify endocannabinoids as the first known endogenous substrates of the apically restricted multidrug resistance transporter P-glycoprotein (P-gp) and reveal a mechanism, which we believe is novel, for endocannabinoid secretion into the intestinal lumen. Knockdown or inhibition of P-gp reduced luminal secretion levels of N-acyl ethanolamine-type endocannabinoids, which correlated with increased neutrophil transmigration in vitro and in vivo. Additionally, loss of CB2, the peripheral cannabinoid receptor, led to increased pathology and neutrophil influx in models of acute intestinal inflammation. These results define a key role for epithelial cells in balancing the constitutive secretion of antiinflammatory lipids with the stimulated secretion of proinflammatory lipids via surface efflux pumps in order to control neutrophil infiltration into the intestinal lumen and maintain homeostasis in the healthy intestine.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.