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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 -
Journal of Diabetes Investigation Jul 2023A deficit of β-cells is a salient feature in both type 1 and type 2 diabetes mellitus. Due to the absolute lack of supplying β-cells for organ or cell...
A deficit of β-cells is a salient feature in both type 1 and type 2 diabetes mellitus. Due to the absolute lack of supplying β-cells for organ or cell transplantation, there is an urgent need to explore the efficient method to generate insulin-producing cells. Cell conversion of intestinal cryptic epithelial cells to insulin-producing β-like cells is a novel and promising therapeutic target. Activation of β-cell differentiation factors or modulation of terminally differentiated factors with forkhead homeobox O1 effectively induced such conversion, and suppressed hyperglycemia in streptozotocin-induced and non-obese diabetic (NOD) mice. Segi's cap, which was discovered >80 years ago, is composed of an aggregation of primitive granulated enteroendocrine cells, enterochromaffin cells, Paneth cells and goblet cells in the intestinal villi, and is only detected at the fetal stage. Its role has long been unknown, but the present study disclosed that it likely provides an underpin of newly generated β-like cells.
Topics: Animals; Mice; Diabetes Mellitus, Type 2; Mice, Inbred NOD; Intestinal Mucosa; Duodenum; Cell Differentiation; Insulins; Insulin; Insulin-Secreting Cells
PubMed: 37132053
DOI: 10.1111/jdi.14025 -
International Journal of Stem Cells Aug 2023The colonic epithelial layer is a complex structure consisting of multiple cell types that regulate various aspects of colonic physiology, yet the mechanisms underlying...
BACKGROUND AND OBJECTIVES
The colonic epithelial layer is a complex structure consisting of multiple cell types that regulate various aspects of colonic physiology, yet the mechanisms underlying epithelial cell differentiation during development remain unclear. Organoids have emerged as a promising model for investigating organogenesis, but achieving organ-like cell configurations within colonic organoids is challenging. Here, we investigated the biological significance of peripheral neurons in the formation of colonic organoids.
METHODS AND RESULTS
Colonic organoids were co-cultured with human embryonic stem cell (hESC)-derived peripheral neurons, resulting in the morphological maturation of columnar epithelial cells, as well as the presence of enterochromaffin cells. Substance P released from immature peripheral neurons played a critical role in the development of colonic epithelial cells. These findings highlight the vital role of inter-organ interactions in organoid development and provide insights into colonic epithelial cell differentiation mechanisms.
CONCLUSIONS
Our results suggest that the peripheral nervous system may have a significant role in the development of colonic epithelial cells, which could have important implications for future studies of organogenesis and disease modeling.
PubMed: 37385635
DOI: 10.15283/ijsc23026 -
Antioxidants (Basel, Switzerland) Dec 2023Melatonin (MT) has often been used to support good sleep quality, especially during the COVID-19 pandemic, as many have suffered from stress-related disrupted sleep... (Review)
Review
Melatonin (MT) has often been used to support good sleep quality, especially during the COVID-19 pandemic, as many have suffered from stress-related disrupted sleep patterns. It is less known that MT is an antioxidant, anti-inflammatory compound, and modulator of gut barrier dysfunction, which plays a significant role in many disease states. Furthermore, MT is produced at 400-500 times greater concentrations in intestinal enterochromaffin cells, supporting the role of MT in maintaining the functions of the intestines and gut-organ axes. Given this information, the focus of this article is to review the functions of MT and the molecular mechanisms by which it prevents alcohol-associated liver disease (ALD) and metabolic dysfunction-associated steatotic liver disease (MASLD), including its metabolism and interactions with mitochondria to exert its antioxidant and anti-inflammatory activities in the gut-liver axis. We detail various mechanisms by which MT acts as an antioxidant, anti-inflammatory compound, and modulator of intestinal barrier function to prevent the progression of ALD and MASLD via the gut-liver axis, with a focus on how these conditions are modeled in animal studies. Using the mechanisms of MT prevention and animal studies described, we suggest behavioral modifications and several exogenous sources of MT, including food and supplements. Further clinical research should be performed to develop the field of MT in preventing the progression of liver diseases via the gut-liver axis, so we mention a few considerations regarding MT supplementation in the context of clinical trials in order to advance this field of research.
PubMed: 38247468
DOI: 10.3390/antiox13010043 -
Foods (Basel, Switzerland) Nov 2023Constipation is a major health concern worldwide and requires effective and safe treatment options. In this study, we selected ten strains of two species of lactobacilli...
Constipation is a major health concern worldwide and requires effective and safe treatment options. In this study, we selected ten strains of two species of lactobacilli to identify whether they were effective against constipation induced by loperamide administration in BALB/c mice. Monitoring of constipation-related indicators indicated that () mainly acted on the whole intestinal peristalsis to relieve constipation. Furthermore, through the detection of biological, chemical, mechanical, and immune barriers in mice, it was discovered that changed the relative abundance of bacteria related to the levels of acetic acid and 5-hydroxytryptamine (5-HT) (such as by increasing the relative abundance of and , and reducing the relative abundance of , , , and ), increased the concentration of acetic acid in the intestine, which stimulated enterochromaffin cells, promoted 5-HT synthesis in the colon, enhanced intestinal motility, and relieved constipation. In conclusion, this study provides a theoretical foundation for the development of personalized products for the treatment of constipation.
PubMed: 38002233
DOI: 10.3390/foods12224176 -
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 -
Neuroscience Bulletin Nov 2023
Topics: Humans; Enterochromaffin Cells
PubMed: 37458959
DOI: 10.1007/s12264-023-01090-1 -
World Journal of Gastrointestinal... Aug 2023The molecular changes present in gastric neuroendocrine tumors (NETs) include a loss of heterozygosity or mutation of , gene mutation, heterozygous mutation, and gene...
BACKGROUND
The molecular changes present in gastric neuroendocrine tumors (NETs) include a loss of heterozygosity or mutation of , gene mutation, heterozygous mutation, and gene missense mutation. We identified and are the first to report a case of type 1 histamine-producing enterochromaffin-like cell NETs (ECL-cell NETs) with a gene germline mutation.
CASE SUMMARY
The patient had a history of iron-deficient anemia for 5 years, and gastroscopic examination indicated multiple gastric tumors. Then, the patient underwent distal gastrectomy. Microscopically, multifocal tumor cells were found in the mucosa and submucosa; tumor cells were organoid and arranged in nests and cords, and the stroma was rich in sinusoids. The surrounding gastric mucosa showed atrophy with mild intestinal metaplasia or pseudopyloric gland metaplasia. Neuroendocrine cells could be seen with diffuse linear, nodular, and adenomatous hyperplasia. Immunohistochemically, the tumor cells diffusely expressed cytokeratin, chromogranin, synaptophysin, and CD56. Whole-genome high-throughput molecular sequencing revealed a pathogenic germline mutation in the gene, a heterozygous germline frameshift mutation in exon 11, c.6443_6444del (p.S2148Yfs*2). The final diagnosis was gastric type 1 ECL-cell NETs with a gene germline mutation, accompanied by autoimmune gastritis.
CONCLUSION
This is the first report of a case of type 1 gastric ECL-cell NETs with a pathogenic germline mutation of the gene. The findings of this report will expand the germline mutation spectrum of gastric NETs and increase the understanding of the molecular changes present in these tumors for their improved diagnosis in the future.
PubMed: 37663942
DOI: 10.4251/wjgo.v15.i8.1497 -
BMC Microbiology Jan 2024Colorectal cancer (CRC) is a prevalent malignant malignancy affecting the gastrointestinal tract that is usually treated clinically with chemotherapeutic agents, whereas...
BACKGROUND
Colorectal cancer (CRC) is a prevalent malignant malignancy affecting the gastrointestinal tract that is usually treated clinically with chemotherapeutic agents, whereas chemotherapeutic agents can cause severe gastrointestinal toxicity, which brings great pain to patients. Therefore, finding effective adjuvant agents for chemotherapy is crucial.
METHODS
In this study, a CRC mouse model was successfully constructed using AOM/DSS, and the treatment was carried out by probiotic Bifidobacterium longum SX-1326 (B. longum SX-1326) in combination with irinotecan. Combining with various techniques of modern biomedical research, such as Hematoxylin and Eosin (H&E), Immunohistochemistry (IHC), Western blotting and 16S rDNA sequencing, we intend to elucidate the effect and mechanism of B. longum SX-1326 in improving the anticancer efficacy and reducing the side effects on the different levels of molecules, animals, and bacteria.
RESULTS
Our results showed that B. longum SX-1326 enhanced the expression of Cleaved Caspase-3 (M vs. U = p < 0.01) and down-regulated the expression level of B-cell lymphoma-2 (Bcl-2) through up-regulation of the p53 signaling pathway in CRC mice, which resulted in an adjuvant effect on the treatment of CRC with irinotecan. Moreover, B. longum SX-1326 was also able to regulate the gut-brain-axis (GBA) by restoring damaged enterochromaffin cells, reducing the release of 5-hydroxytryptamine (5-HT) in brain tissue (I vs. U = 89.26 vs. 75.03, p < 0.05), and further alleviating the adverse effects of nausea and vomiting. In addition, B. longum SX-1326 reversed dysbiosis in CRC model mice by increasing the levels of Dehalobacterium, Ruminnococcus, and Mucispirillum. And further alleviated colorectal inflammation by downregulating the TLR4/MyD88/NF-κB signaling pathway.
CONCLUSIONS
In conclusion, our work reveals that B. longum SX-1326 has a favorable effect in adjuvant irinotecan for CRC and amelioration of post-chemotherapy side effects, and also provides the theoretical basis and data for finding a safe and efficient chemotherapeutic adjuvant.
Topics: Animals; Humans; Mice; Bifidobacterium longum; Brain-Gut Axis; Gastrointestinal Microbiome; Irinotecan; Signal Transduction; Tumor Suppressor Protein p53
PubMed: 38172689
DOI: 10.1186/s12866-023-03152-w -
The Turkish Journal of Gastroenterology... Feb 2024Neuroendocrine cell hyperplasia is a non-neoplastic proliferation of enterochromaffin-like cells and is considered a premalignant lesion because of their potential to...
BACKGROUND/AIMS
Neuroendocrine cell hyperplasia is a non-neoplastic proliferation of enterochromaffin-like cells and is considered a premalignant lesion because of their potential to progress to neuroendocrine tumor. In this study, we aimed to evaluate the demographic and clinical features, laboratory, radiological and endoscopic findings, gastric biopsy histopathological features, follow-up frequency, and histopathological findings of patients diagnosed with gastric neuroendocrine cell hyperplasia as well as to investigate the factors that play a role in the development of neuroendocrine tumors on the basis of neuroendocrine cell hyperplasia.
MATERIALS AND METHODS
The study has been conducted in 2 centers with 282 patients that were grouped as those with and without neuroendocrine tumor. Individuals with control endoscopy were separated as those with regression of neuroendocrine cell hyperplasia and those without regression, and the determined parameters were evaluated between the groups.
RESULTS
The most common histological subtype of neuroendocrine cell hyperplasia was linear+micronodular (50.4%). Neuroendocrine tumor developed in 4.3% (12/282) of the patients with neuroendocrine cell hyperplasia after a mean of 36 months. The presence of polyps as confirmed via endoscopy and dysplasia as confirmed via histopathological examination was significantly higher in favor of the group with neuroendocrine tumor (P = .01). In patients with neuroendocrine cell hyperplasia regressed and patients in whom it did not regress were examined, the rate of asymptomatic patients and increased sedimentation rate were found in favor of the group that did not regress (P = .02 and P = .02), but no difference was found in other parameters.
CONCLUSION
Neuroendocrine tumor development rate was found to be 4.3% in the background of neuroendocrine cell hyperplasia. Two factors predicting progression from neuroendocrine cell hyperplasia to neuroendocrine tumor can be elaborated as the presence of polypoid appearance due to neuroendocrine cell hyperplasia as confirmed via endoscopy and dysplasia as confirmed via histopathological examination.
Topics: Humans; Hyperplasia; Neuroendocrine Cells; Neuroendocrine Tumors; Gastroscopy; Biopsy; Polyps; Stomach Neoplasms
PubMed: 38454240
DOI: 10.5152/tjg.2024.22681