Epithelial 5-HT4 Receptors as a Target for Treating Constipation and Intestinal Inflammation

Mawe, Gary M.; Hurd, Molly; Hennig, Grant W.; Lavoie, Brigitte

doi:10.1007/978-3-031-05843-1_30

Cited by 3 publications

(5 citation statements)

References 12 publications

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“…What are the physiological consequences of tonic (nanomolar) versus stimulated (micromolar) serotonin release in crypts? We focused on 5-HT3 and 5-HT4 receptors as the most physiologically relevant targets in the intestine ( 5, 9 ). We first investigated the distribution of the 5-HT4 receptor, which is known to stimulate epithelial chloride secretion, thereby influencing the rate of fluid transfer into the intestinal lumen ( 14 ).…”

Section: Resultsmentioning

confidence: 99%

“…Several serotonin receptor subtypes are present in the gut ( 5 ), including ionotropic 5-HT3 and metabotropic 5-HT4 receptors, which have been pharmacologically targeted to treat GI dysregulation associated with diarrhea or constipation ( 5, 9 ). EC cells transduce signals to afferent sensory nerve fibers within the mucosa that express 5-HT3 receptors, excitatory ion channels that are activated by relatively high (micromolar) concentrations of serotonin ( 4, 5, 10 ).…”

Section: Introductionmentioning

confidence: 99%

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Crypt and Villus Enterochromaffin Cells are Distinct Stress Sensors in the Gut

Touhara,

Rossen,

Deng

et al. 2024

Preprint

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The crypt-villus structure of the small intestine serves as an essential protective barrier, with its integrity monitored by the gut’s sensory system. Enterochromaffin (EC) cells, a subtype of sensory epithelial cells that release serotonin (5-HT), surveil the mucosal environment and signal both within and outside the gut. However, it remains unclear whether EC cells in intestinal crypts and villi respond to different stimuli and elicit distinct responses. In this study, we introduce a new reporter mouse model to observe the release and propagation of serotonin in live intestines. Using this system, we show that crypt EC cells exhibit two modes of serotonin release: transient receptor potential A1 (TRPA1)-dependent tonic serotonin release that controls basal ionic secretion, and irritant-evoked serotonin release that activates gut sensory neurons. Furthermore, we find that a thick protective mucus layer prevents TRPA1 receptors on crypt EC cells from responding to luminal irritants such as reactive electrophiles; if this mucus layer is compromised, then crypt EC cells become susceptible to activation by luminal irritants. On the other hand, villus EC cells detect oxidative stress through TRPM2 channels and co-release serotonin and ATP. Our work highlights the physiological importance of intestinal architecture and differential TRP channel expression in sensing noxious stimuli that elicit nausea and/or pain sensations in the gut.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Crypt and Villus Enterochromaffin Cells are Distinct Stress Sensors in the Gut

Touhara,

Rossen,

Deng

et al. 2024

Preprint

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“…Serotonin can also be formed in the gut by tryptophan hydroxylase 1 (TPH1) in enterochromaffin cells and stored in blood platelets. Peripheral serotonin plays an important role in gastrointestinal motility [ 30 , 31 ] and liver regeneration [ 32 , 33 , 34 ]. It is vitally important that serotonin produced in the periphery cannot penetrate the blood–brain barrier.…”

Section: The Contribution Of Cytochrome P450 To the Synthesis Of Sero...mentioning

confidence: 99%

The Engagement of Cytochrome P450 Enzymes in Tryptophan Metabolism

et al. 2023

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Tryptophan is metabolized along three main metabolic pathways, namely the kynurenine, serotonin and indole pathways. The majority of tryptophan is transformed via the kynurenine pathway, catalyzed by tryptophan-2,3-dioxygenase or indoleamine-2,3-dioxygenase, leading to neuroprotective kynurenic acid or neurotoxic quinolinic acid. Serotonin synthesized by tryptophan hydroxylase, and aromatic L-amino acid decarboxylase enters the metabolic cycle: serotonin → N-acetylserotonin → melatonin → 5-methoxytryptamine→serotonin. Recent studies indicate that serotonin can also be synthesized by cytochrome P450 (CYP), via the CYP2D6-mediated 5-methoxytryptamine O-demethylation, while melatonin is catabolized by CYP1A2, CYP1A1 and CYP1B1 via aromatic 6-hydroxylation and by CYP2C19 and CYP1A2 via O-demethylation. In gut microbes, tryptophan is metabolized to indole and indole derivatives. Some of those metabolites act as activators or inhibitors of the aryl hydrocarbon receptor, thus regulating the expression of CYP1 family enzymes, xenobiotic metabolism and tumorigenesis. The indole formed in this way is further oxidized to indoxyl and indigoid pigments by CYP2A6, CYP2C19 and CYP2E1. The products of gut-microbial tryptophan metabolism can also inhibit the steroid-hormone-synthesizing CYP11A1. In plants, CYP79B2 and CYP79B3 were found to catalyze N-hydroxylation of tryptophan to form indole-3-acetaldoxime while CYP83B1 was reported to form indole-3-acetaldoxime N-oxide in the biosynthetic pathway of indole glucosinolates, considered to be defense compounds and intermediates in the biosynthesis of phytohormones. Thus, cytochrome P450 is engaged in the metabolism of tryptophan and its indole derivatives in humans, animals, plants and microbes, producing biologically active metabolites which exert positive or negative actions on living organisms. Some tryptophan-derived metabolites may influence cytochrome P450 expression, affecting cellular homeostasis and xenobiotic metabolism.

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“…The broadly distributed 5-HT4 receptors in the gastrointestinal tract have been well recognized as an important target for treating constipation and intestinal inflammation ( Mawe et al, 2022 ). Serotonergic agents such as fluoxetine are usually displaying the selective laxative action on 5-HT4 receptors.…”

Section: Role Of Aqp3 In Constipation and Regulation Of Laxatives On ...mentioning

confidence: 99%

“…Recent study has suggested that the enhancement of intestinal motility could be augmented by treatment with tryptophan-synthesizing bacteria through increased 5-HT signaling pathway with involvement of 5-HT4 receptor ( Legan et al, 2023 ). Thus, the 5-HT4 receptor agonists used to treat functional constipation and colitis may involve the increased colonic motility by stimulation of serotonin release from enterochromaffin cells ( Mawe et al, 2022 ) as well as the regulation of synthetic enzyme tryptophan hydroxylase in the intestine ( Mawe and Hoffman, 2013 ). Previous study has shown that pretreatment with fluoxetine (inhibitor of 5-HT reuptake transporter) inhibited the upregulated AQP3 mRNA expression in the colon of rats with constipation ( Kon et al, 2015 ).…”

Section: Role Of Aqp3 In Constipation and Regulation Of Laxatives On ...mentioning

confidence: 99%

Roles and regulation of Aquaporin-3 in maintaining the gut health: an updated review

Zhu,

Nie,

et al. 2023

Front. Physiol.

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Aquaporin-3 (AQP3) is a predominant water channel protein expressed in the intestine, and plays important roles in the gut physiology and pathophysiology due to its permeability to water, glycerol and hydrogen peroxide. In this review, we systematically summarized the current understanding of the expression of AQP3 in the intestine of different species, and focused on the potential roles of AQP3 in water transport, different types of diarrhea and constipation, intestinal inflammation, intestinal barrier function, oxidative stress, and autophagy. These updated findings have supported that AQP3 may function as an important target in maintaining gut health of human and animals.

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Epithelial 5-HT4 Receptors as a Target for Treating Constipation and Intestinal Inflammation

Cited by 3 publications

References 12 publications

Crypt and Villus Enterochromaffin Cells are Distinct Stress Sensors in the Gut

Crypt and Villus Enterochromaffin Cells are Distinct Stress Sensors in the Gut

The Engagement of Cytochrome P450 Enzymes in Tryptophan Metabolism

Roles and regulation of Aquaporin-3 in maintaining the gut health: an updated review

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