-
Immunity Jul 2023The crosstalk between the immune and neuroendocrine systems is critical for intestinal homeostasis and gut-brain communications. However, it remains unclear how immune...
The crosstalk between the immune and neuroendocrine systems is critical for intestinal homeostasis and gut-brain communications. However, it remains unclear how immune cells participate in gut sensation of hormones and neurotransmitters release in response to environmental cues, such as self-lipids and microbial lipids. We show here that lipid-mediated engagement of invariant natural killer T (iNKT) cells with enterochromaffin (EC) cells, a subset of intestinal epithelial cells, promoted peripheral serotonin (5-HT) release via a CD1d-dependent manner, regulating gut motility and hemostasis. We also demonstrated that inhibitory sphingolipids from symbiotic microbe Bacteroides fragilis represses 5-HT release. Mechanistically, CD1d ligation on EC cells transduced a signal and restrained potassium conductance through activation of protein tyrosine kinase Pyk2, leading to calcium influx and 5-HT secretion. Together, our data reveal that by engaging with iNKT cells, gut chemosensory cells selectively perceive lipid antigens via CD1d to control 5-HT release, modulating intestinal and systemic homeostasis.
Topics: Serotonin; Lipids; Antigens, CD1d; Natural Killer T-Cells
PubMed: 37354904
DOI: 10.1016/j.immuni.2023.06.001 -
Regulatory Toxicology and Pharmacology... Aug 2023Tegoprazan is a novel potassium-competitive acid blocker (P-CAB) that reversibly inhibits the proton pump in gastric parietal cells and has been approved for the...
Tegoprazan is a novel potassium-competitive acid blocker (P-CAB) that reversibly inhibits the proton pump in gastric parietal cells and has been approved for the treatment of acid-related diseases in Korea. This study aimed to evaluate the carcinogenic potential of tegoprazan in Sprague-Dawley rats and CD-1 mice. Tegoprazan was administered daily by oral gavage to rats for up to 94 weeks and mice for up to 104 weeks. Evidence of carcinogenic potential of tegoprazan was identified in rats only and was limited to benign and/or malignant neuroendocrine cell tumors at exposures >7-fold of the recommended human dose. Glandular stomach findings were considered secondary to the expected pharmacology of tegoprazan, characterized by their location in the fundic and body regions of the stomach. Overall, tegoprazan induced gastric enterochromaffin-like (ECL) cell tumors in SD rats, but did not produce any treatment-related statistically significant increase in the incidence of neoplasms relevant to humans when administered to SD rats and CD-1 mice by gavage at doses up to 300 and 150 mg/kg/day, respectively. Gastric ECL cell tumors are thought to be induced by the exaggerated indirect pharmacological effect of tegoprazan, similar to that reported for proton pump inhibitors (PPIs) and other P-CABs.
Topics: Rats; Mice; Humans; Animals; Rats, Sprague-Dawley; Mice, Inbred ICR; Imidazoles; Stomach Neoplasms; Carcinogens
PubMed: 37295487
DOI: 10.1016/j.yrtph.2023.105424 -
Gastroenterology Oct 2023
Topics: Humans; Enterochromaffin Cells; Duodenum; Serotonin
PubMed: 37178735
DOI: 10.1053/j.gastro.2023.05.008 -
Journal of Neuroendocrinology Nov 2023Throughout the 20th Century, regulatory peptide discovery advanced from the identification of gut hormones to the extraction and characterization of hypothalamic... (Review)
Review
Throughout the 20th Century, regulatory peptide discovery advanced from the identification of gut hormones to the extraction and characterization of hypothalamic hypophysiotropic factors, and to the isolation and cloning of multiple brain neuropeptides. These discoveries were followed by the discovery of G-protein-coupled and other membrane receptors for these peptides. Subsequently, the systems physiology associated with some of these multiple regulatory peptides and receptors has been comprehensively elucidated and has led to improved therapeutics and diagnostics and their approval by the US Food and Drug Administration. In light of this wealth of information and further potential, it is truly a time of renaissance for regulatory peptides. In this perspective, we review what we have learned from the pioneers in exemplified fields of gut peptides, such as cholecystokinin, enterochromaffin-like-cell peptides, and glucagon, from the trailblazing studies on the key stress hormone, corticotropin-releasing factor, as well as from more recently characterized relaxin-family peptides and receptors. The historical viewpoints are based on our understanding of these topics in light of the earliest phases of research and on subsequent studies and the evolution of knowledge, aiming to sharpen our vision of the current state-of-the-art and those studies that should be prioritized in the future.
Topics: Neuropeptides; Corticotropin-Releasing Hormone; Cholecystokinin; Relaxin; Glucagon
PubMed: 37053148
DOI: 10.1111/jne.13251 -
Neurogastroenterology and Motility Aug 2023Enterochromaffin (EC) cell-derived 5-hydroxytryptamine (5-HT) is a mediator of toxin-induced reflexes, initiating emesis via vagal and central 5-HT receptors. The amine...
BACKGROUND
Enterochromaffin (EC) cell-derived 5-hydroxytryptamine (5-HT) is a mediator of toxin-induced reflexes, initiating emesis via vagal and central 5-HT receptors. The amine is also involved in gastrointestinal (GI) reflexes that are prosecretory and promotile, and recently 5-HT's roles in chemosensation in the distal bowel have been described. We set out to establish the efficacy of 5-HT signaling, local 5-HT levels and pharmacology in discrete regions of the mouse small and large intestine. We also investigated the inter-relationships between incretin hormones, glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) and endogenous 5-HT in mucosal and motility assays.
METHODS
Adult mouse GI mucosae were mounted in Ussing chambers and area-specific studies were performed to establish the 5-HT and 5-HT pharmacology, the sidedness of responses, and the inter-relationships between incretins and endogenous 5-HT. Natural fecal pellet transit in vitro and full-length GI transit in vivo were also measured.
KEY RESULTS
We observed the greatest level of tonic and exogenous 5-HT-induced ion transport and highest levels of 5-HT in ascending colon mucosa. Here both 5-HT and 5-HT receptors were involved but elsewhere in the GI tract epithelial basolateral 5-HT receptors mediate 5-HT's prosecretory effect. Exendin-4 and GIP induced 5-HT release in the ascending colon, while L cell-derived PYY also contributed to GIP mucosal effects in the descending colon. Both peptides slowed colonic transit.
CONCLUSIONS & INFERENCES
We provide functional evidence for paracrine interplay between 5-HT, GLP-1 and GIP, particularly in the colonic mucosal region. Basolateral epithelial 5-HT receptors mediated both 5-HT and incretin mucosal responses in healthy colon.
Topics: Mice; Animals; Serotonin; Incretins; Gastric Inhibitory Polypeptide; Colon; Intestinal Mucosa; Glucagon-Like Peptide 1
PubMed: 37010838
DOI: 10.1111/nmo.14589