Enterochromaffin Research Articles

NY-ESO-1-specific T cell receptor-engineered T cells and Tranilast, a TRPV2 antagonist bivalent treatment enhances the killing of esophageal cancer: a dual-targeted cancer therapeutic route

BackgroundEsophageal cancer (EC) is a global canker notorious for causing high mortality due to its relentless incidence rate, convoluted with unyielding recurrence and metastasis. However, these intricacies of EC are associated with an immoderate expression of NY-ESO-1 antigen, presenting a lifeline for adoptive T cell therapy. We hypothesized that naturally isolated higher-affinity T cell receptors (TCRs) that bind to NY-ESO-1 would allow T lymphocytes to target EC with a pronounced antitumor response efficacy. Also, targeting TRPV2, which is associated with tumorigenesis in EC, creates an avenue for dual-targeted therapy. We exploited the dual-targeting antitumor efficacy against EC.MethodsWe isolated antigen-specific TCRs (asTCRs) from a naive library constructed with TCRs obtained from enriched cytotoxic T lymphocytes. The robustness of our asTCRs and their TCR-T cell derivatives, Tranilast (TRPV2 inhibitor), and their bivalent treatment were evaluated with prospective cross-reactive human-peptide variants and tumor cells.ResultsOur study demonstrated that our naive unenhanced asTCRs and their TCR-Ts perpetuated their cognate HLA-A*02:01/NY-ESO-1(157–165) specificity, killing varying EC cells with higher cytotoxicity compared to the known affinity-enhanced TCR (TCRe) and its wild-type (TCR0) which targets the same NY-ESO-1 antigen. Furthermore, the TCR-Ts and Tranilast bivalent treatment showed superior EC killing compared to any of their monovalent treatments of either TCR-T or Tranilast.ConclusionOur findings suggest that dual-targeted immunotherapy may have a superior antitumor effect. Our study presents a technique to evolve novel, robust, timely therapeutic strategies and interventions for EC and other malignancies.

Xiao Cheng Qi Decoction, an Ancient Chinese Herbal Mixture, Relieves Loperamide-Induced Slow-Transit Constipation in Mice: An Action Mediated by Gut Microbiota.

Xiao Cheng Qi (XCQ) decoction, an ancient Chinese herbal mixture, has been used in treating slow-transit constipation (STC) for years. The underlying action mechanism in relieving the clinical symptoms is unclear. Several lines of evidence point to a strong link between constipation and gut microbiota. Short-chain fatty acids (SCFAs) and microbial metabolites have been shown to affect 5-HT synthesis by activating the GPR43 receptor localized on intestinal enterochromaffin cells, since 5-HT receptors are known to influence colonic peristalsis. The objective of this study was to evaluate the efficacy of XCQ in alleviating clinical symptoms in a mouse model of STC induced by loperamide. The application of loperamide leads to a decrease in intestinal transport and fecal water, which is used to establish the animal model of STC. In addition, the relationship between constipation and gut microbiota was determined. The herbal materials, composed of Rhei Radix et Rhizoma (Rhizomes of Rheum palmatum L., Polygonaceae) 55.2 g, Magnoliae Officinalis Cortex (Barks of Magnolia officinalis Rehd. et Wils, Magnoliaceae) 27.6 g, and Aurantii Fructus Immaturus (Fruitlet of Citrus aurantium L., Rutaceae) 36.0 g, were extracted with water to prepare the XCQ decoction. The constipated mice were induced with loperamide (10 mg/kg/day), and then treated with an oral dose of XCQ herbal extract (2.0, 4.0, and 8.0 g/kg/day) two times a day. Mosapride was administered as a positive drug. In loperamide-induced STC mice, the therapeutic parameters of XCQ-treated mice were determined, i.e., (i) symptoms of constipation, composition of gut microbiota, and amount of short-chain fatty acids in feces; (ii) plasma level of 5-HT; and (iii) expressions of the GPR43 and 5-HT4 receptor in colon. XCQ ameliorated the constipation symptoms of loperamide-induced STC mice. In gut microbiota, the treatment of XCQ in STC mice increased the relative abundances of Lactobacillus, Prevotellaceae_UCG_001, Prevotellaceae_NK3B31_group, Muribaculaceae, and Roseburia in feces and decreased the relative abundances of Desulfovibrio, Tuzzerella, and Lachnospiraceae_ NK4A136_group. The levels of SCFAs in stools from the STC group were significantly lower than those the control group, and were greatly elevated via treatment with XCQ. Compared with the STC group, XCQ increased the plasma level of 5-HT and the colonic expressions of the GPR43 and 5-HT4 receptor, significantly. The underlying mechanism of XCQ in anti-constipation could be related to the modulation of gut microbiota, the increase in SCFAs, the increase in plasma 5-HT, and the colonic expressions of the GPR43 and 5-HT4 receptor. Our results indicate that XCQ is a potent natural product that could be a therapeutic strategy for constipation.

Synthesis of New Isoindolines Derived from L‐Α‐Amino Acids and their Selectivity on Cancer Cell Lines

AbstractIsoindolines are essential from the point of view of synthesis and their biological properties, so this work is focused on the synthesis of new isoindolines derived from the following L‐α‐amino acids, aspartic acid (1), arginine (2), glutamic acid (3‐5), serine (6), and lysine (7). All compounds were characterized by 1H and 13C NMR, infrared, and high‐resolution mass spectrometry. In addition, the synthesized compounds were screened to investigate their antiproliferative activities against five human cancer cell lines, A549, U373, MDA‐MB‐231, MCF‐7, and HeLa, as well as on primary cell culture healthy, MGC, EC, and Vero cells lines. All tested compounds exhibited activity against cancer cell lines at mM concentrations. Notably, compounds 6 derived from Ser, and 7 derived from Lys exhibited remarkable effects on the A549 and U373. The IC50 values for these compounds were determined to be 0.001 and 0.007 mM, respectively. These findings indicate a significantly higher potency of compounds 6 and 7 than the other tested compounds. Among the tested compounds, only compound 5 displayed significant cytotoxic activity against the Vero cell line.

Role of CD1d and iNKT cells in regulating intestinal inflammation.

Invariant natural killer T (iNKT) cells, a subset of unconventional T cells that recognize glycolipid antigens in a CD1d-dependent manner, are crucial in regulating diverse immune responses such as autoimmunity. By engaging with CD1d-expressing non-immune cells (such as intestinal epithelial cells and enterochromaffin cells) and immune cells (such as type 3 innate lymphoid cells, B cells, monocytes and macrophages), iNKT cells contribute to the maintenance of immune homeostasis in the intestine. In this review, we discuss the impact of iNKT cells and CD1d in the regulation of intestinal inflammation, examining both cellular and molecular factors with the potential to influence the functions of iNKT cells in inflammatory bowel diseases such as Crohn's disease and ulcerative colitis.

Bifidobacterium longum SX-1326 ameliorates gastrointestinal toxicity after irinotecan chemotherapy via modulating the P53 signaling pathway and brain-gut axis

BackgroundColorectal 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.MethodsIn 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.ResultsOur 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.ConclusionsIn 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.

Shatianyu (Citrus grandis L. Osbeck) whole fruit alleviated loperamide-induced constipation via enhancing gut microbiota-mediated intestinal serotonin secretion and mucosal barrier homeostasis.

This study aims to explore the effects of Shatianyu (Citrus grandis L. Osbeck) whole fruit powder (SWFP) enriched in flavonoids and dietary fiber on loperamide-induced constipation after a 4-week administration in the diet, together with possible microbiota-mediated mechanisms. The SWFP intervention shortened the first defecation time and increased defecation frequency; it also increased the serum serotonin (5-HT) level and decreased the LPS level in constipation mice. SWFP promoted the development of colonic enterochromaffin cells (ECs) and upregulated the expression of 5-HT synthetic rate-limiting enzyme (Tph1) in ECs. Furthermore, SWFP downregulated the expression of colonic TLR-4, TNF-α and IL-1β and upregulated the expression of tight junction proteins. Besides promoting 5-HT secretion in ECs, butyrate was proved to play a positive role in enhancing intestinal barrier homeostasis through FFAR2/3. Notably, SWFP increased both the fecal butyrate contents and colonic FFAR3 expression in a dose-related manner. Likewise, SWFP enriched butyrate-production related microbes, such as Ruminococcus_torques_group, Ruminococcus, Dubosiella and Parasutterella. Thus, SWFP might alleviate constipation by regulating the microbiota to produce butyrate, thereby enhancing colonic 5-HT secretion and the FFAR3-mediated anti-inflammatory pathway.

A microfluidic chip for sustained oxygen gradient formation in the intestine ex vivo.

The oxygen gradient across the intestine influences intestinal physiology and the microbial environment of the microbiome. The microbiome releases metabolites that communicate with enterochromaffin cells, neuronal cells, and resident immune cells to facilitate the bidirectional communication across the gut-brain axis. Measuring communication between various cell types within the intestine could provide essential information about key regulators of gut and brain health; however, the microbial environment of the intestine is heavily dependent on the physiological oxygen gradient that exists across the intestinal wall. Likewise, there exist a need for methods which enable real-time monitoring of intestinal signaling ex vivo yet this remains challenging due to the inability to adequately culture intestinal tissue ex vivo while also exposing the appropriate locations of the intestine for probe insertion and monitoring. Here, we designed and fabricated a 3D printed microfluidic device to maintain the oxygen gradient across precision cut murine intestinal slices with the capability to couple to external neurochemical recording techniques. The gradient is maintained from outlets below while allowing access to the slice from above for detection with fast scan cyclic voltammetry (FSCV) and carbon-fiber microelectrodes. A series of 11 outlet ports were designed to lay underneath the slice which were connected to channels to deliver oxygenated vs. deoxygenated media. Outlet ports were designed in an oval shape where deoxygenated media was delivered to the center of the slice and oxygenated media is delivered to the outer portion of the slice to mimic the location of oxygen across the intestine. An oxygen sensitive fluorescent dye, tris(2,2'-bipyridyl)dichlororuthenium(II), was used to characterize the tunability of the gradient. Viability of the tissue was confirmed by both fluorescence microscopy and FSCV. Additionally, we measured simultaneous serotonin and melatonin signaling with FSCV in the intestine for the first time. Overall, this chip provides a significant advance in our ability to culture intestinal slices ex vivo with the added benefit of direct access for measurements and imaging.

Circ_0003855 involvement of esophageal cancer progression through miR-622/FLOT1.

To confirm the relationship between Circ_0003855 and EC, we purchased the Human esophageal carcinoma cell line Eca109 and normal human esophageal epithelial cells HEEC, and the expression levels of Circ_0003855, miR-622, and FLOT1 were detected. The results show that Circ_0003855 and FLOT1 were highly expressed in Eca109 cells, while miR-622 was lowly expressed (p < 0.05). Subsequently, Circ_0003855 small interfering RNA (si-Circ_0003855) and its negative control (si-NC) were used to detect changes in cellular biological behaviors. We found that the activity of Eca109 cells was reduced after interfering with the expression of Circ_0003855, and miR-622 expression was elevated, while FLOT1 was decreased (p < 0.05). Additionally, si-Circ_0003855 and miR-622 inhibitor sequence (miR-622-inhibition) were co-transfected into cells with miR-622-inhibition alone, and untreated Eca109 cells were used as a control to detect the expression of FLOT1. Co-transfection of si-Circ_0003855 and miR-622-inhibition showed no significant difference in FLOT1 expression compared to the control cells (p > 0.05). Synthesizing the results of these experiments above, we believe that interfering with the expression of Circ_0003855 can inhibit the activity of EC cells, and its mechanism is related to miR-622 and FLOT1.

BRONCHIAL CARCINOID TUMOR MIMICKING PULMONARY ARTERY ANEURYSM

Neuroendocrine tumor, also called APUDomas&#x0D; histopathologically, is a broad-spectrum disease. It&#x0D; is a heterogeneous group of malignancies derived&#x0D; from embryonic neural crest tissue from any part of&#x0D; the body. It originates from Kulchitsky cells in the&#x0D; lung and is a group of malignancies ranging from low&#x0D; grade to high grade.

Endoscopy in the Diagnosis and Management of Gastrointestinal Neuroendocrine Tumors

Abstract Gastrointestinal neuroendocrine tumors (GI NETs) are considered rare neoplasms that arise from enterochromaffin cells which form a part of the neuroendocrine cell system present throughout the GI tract. Although considered a rare tumor, its prevalence has increased significantly in recent years owing to the increase in the number of endoscopic evaluations, advanced imaging modalities, and greater detection of the entity by pathologists. The role of an endoscopist remains pivotal in diagnosing and managing GI NETs, ranging from tumor detection, sampling, characterization, and staging which forms the basis of oncological evaluation, particularly of those involving the stomach, duodenum, and colorectum. Endoscopic therapy can provide curative resection of tumors and surveillance scopies in a minimally invasive fashion owing to lesser patient morbidity. Our review aims to provide an overview of the role of the gastroenterologist in diagnosing and managing GI NETs.

Melatonin Prevents Alcohol- and Metabolic Dysfunction- Associated Steatotic Liver Disease by Mitigating Gut Dysbiosis, Intestinal Barrier Dysfunction, and Endotoxemia.

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.

The olfactory receptor Olfr78 promotes differentiation of enterochromaffin cells in the mouse colon

The gastrointestinal epithelium constitutes a chemosensory system for microbiota-derived metabolites such as short-chain fatty acids (SCFA). Here, we investigate the spatial distribution of Olfr78, one of the SCFA receptors, in the mouse intestine and study the transcriptome of colon enteroendocrine cells expressing Olfr78. The receptor is predominantly detected in the enterochromaffin and L subtypes in the proximal and distal colon, respectively. Using the Olfr78-GFP and VilCre/Olfr78flox transgenic mouse lines, we show that loss of epithelial Olfr78 results in impaired enterochromaffin cell differentiation, blocking cells in an undefined secretory lineage state. This is accompanied by a reduced defense response to bacteria in colon crypts and slight dysbiosis. Using organoid cultures, we further show that maintenance of enterochromaffin cells involves activation of the Olfr78 receptor via the SCFA ligand acetate. Taken together, our work provides evidence that Olfr78 contributes to colon homeostasis by promoting enterochromaffin cell differentiation.

Serotonin production of the developing gastrointestinal tract of human embryos in 6th gestation week

Background: Local regulation of gastrointestinal tract digestion is performed by a large number of hormones produced by the mucosal enteroendocrine cells. Some of the earliest differentiating cells in the gastrointestinal tract are enteroendocrine cells. Serotonin-producing cells - EC cells are found mostly in the stomach and duodenum. Aim: The aim of our study is to establish the presence and to make morphological and morphofunctional characteristic of ЕС cells in the developing gastrointestinal tract of a human. Materials and methods: Our study was performed with biopsy specimen from human stomach and duodenum and fragments of gastrointestinal tract of human embryos 6th gestation week, studied by immunohistochemical, electron microscopy and morphometric methods. Results: EC cells have already been differentiated in the 6th gestation week. Embryonic EC cells had identical characteristics with those of adults. They were in two morphofunctional conditions: stage of increased synthesis and stage of relative secretory rest. Conclusion: In the early embryonic period - 6th gestation week EC cells have already been differentiated. The occurrence of EC cells with hormonal production prior to the definitive differentiation of tissues presupposes participation of serotonin in the digestive tube histogenetic processes.

LncRNA FIRRE regulated endometrial cancer radiotherapy sensitivity via the miR-199b-5p/SIRT1/BECN1 axis-mediated autophagy

BackgroundEndometrial cancer (EC) poses a serious threat to women's health. Radiotherapy has been widely used for EC treatment. However, the mechanism of FIRRE in EC development and radioresistance remains unknown. MethodsMTT and colony formation assays determined cell proliferation. The degree of autophagy was tested by the measurement of autophagy-related genes and immunofluorescence staining of LC3. Molecular interactions were demonstrated via luciferase reporter assay, RIP, and Co-IP. The FIRRE role's was analyzed by in vivo xenograft tumor model. ResultsFIRRE and SIRT1 were upregulated in EC tumor tissues, whereas miR-199b-5p was reduced. FIRRE knockdown increased EC cell radiotherapy sensitivity by sponging miR-199b-5p and inhibiting autophagy. SIRT1 was targeted and negatively regulated by miR-199b-5p. SIRT1 could otherwise deacetylate BECN1 protein and participate in FIRRE-mediated autophagy. Silencing FIRRE increased sensitivity of EC radiotherapy in vivo. ConclusionFIRRE reduced EC cell radiotherapy sensitivity by stimulating autophagy via miR-199b-5p/SIRT1/BECN1 axis.

OLANZAPINE FOR NAUSEA AND VOMITING IN VARIOUS ETIOLOGIES : A REVIEW

Nausea is an unpleasant response followed by the risk of vomiting that results rapid forced ejection of gastric substance from the stomach upwards and out of the mouth. The Gastrointestinal tract, vestibular system, and thalamus are the sites that cause this event. Serotonin type 3 (5-HT3), Mu, neurokinin-1 (NK-1), kappa opioids, dopamine type 2 (D2) are CTZ receptors that cause emesis. 5-HT3 antagonists, antihistamines, and phenothiazines are common antiemetic agents. Olanzapine is an atypical antipsychotic second-generation medication with antiemetic properties. This article review used a classical method to identify studies related to the mechanism and efficacy of olanzapine as an antiemetic. The journal article related to olanzapine in nausea and vomiting that published on 2002 until 2022 for critical appraisal. The purpose of this literature review is to provide a review of antiemetics, especially olanzapine as a therapy option, as well as to evaluate the mechanism and efficacy of olanzapine. The activity of olanzapine with several receptors associated with nausea and vomiting suggests that it may have antiemetic activity. Olanzapine inhibits the 5-HT2C receptor, which is located near small intestine enterochromaffin cells and is required for the emetic response. In CINV therapy, research suggests combining olanzapine 10 mg with a 5-HT3 antagonist, NK-1 antagonist, dexamethasone. There is a lack of data in literature on the use of olanzapine in hyperemesis gravidarum. From the review we concluded that olanzapine can be considered for use as a therapy for the treatment of nausea and vomiting.

Self-Assembled Acid-Responsive Nanosystem for Synergistic Anti-Angiogenic/Photothermal/Ferroptosis Therapy against Esophageal Cancer.

Esophageal cancer (EC) treatment via anti-angiogenic therapy faces challenges due to non-cytotoxicity and non-specific biodistribution of the anti-angiogenic agents. Hence, the quest for a synergistic treatment modality and a targeted delivery approach to effectively address EC has become imperative. In this study, an acid-responsive release nanosystem (Bev-IR820@FeIII TA) that involves the conjugation of bevacizumab, an anti-angiogenic monoclonal antibody, with TA and Fe3+ to form a metal-phenolic network, followed by loading with the near-infrared photothermal agent (IR820) to achieve combinational therapy, is designed. The construction of Bev-IR820@FeIII TA can be realized through a facile self-assembly process. The Bev-IR820@FeIII TA exhibits tumor-targeting capabilities and synergistic therapeutic effects, encompassing anti-angiogenic therapy, photothermal therapy (PTT), and ferroptosis therapy (FT). Bev-IR820@FeIII TA exhibits remarkable proficiency in delivering drugs to EC tissue through its pH-responsive release properties. Consequently, bevacizumab exerts its therapeutic effects by obstructing tumor angiogenesis, thereby impeding tumor growth. Meanwhile, PTT facilitates localized thermal ablation at the tumor site, directly eradicating EC cells. FT synergistically collaborates with PTT, giving rise to the formation of a reactive oxygen species (ROS) storm, subsequently culminating in the demise of EC cells. In summary, this amalgamated treatment modality carries substantial promise for synergistically impeding EC progression and showcases auspicious prospects for future EC treatment.

A Novel Flp Reporter Mouse Shows That TRPA1 Expression Is Largely Limited to Sensory Neuron Subsets.

Transient receptor potential ankyrin 1 (TRPA1) is a polymodal cation channel that is activated by electrophilic irritants, oxidative stress, cold temperature, and GPCR signaling. TRPA1 expression has been primarily identified in subsets of nociceptive sensory afferents and is considered a target for future analgesics. Nevertheless, TRPA1 has been implicated in other cell types including keratinocytes, epithelium, enterochromaffin cells, endothelium, astrocytes, and CNS neurons. Here, we developed a knock-in mouse that expresses the recombinase FlpO in TRPA1-expressing cells. We crossed the TRPA1Flp mouse with the R26ai65f mouse that expresses tdTomato in a Flp-sensitive manner. We found tdTomato expression correlated well with TRPA1 mRNA expression and sensitivity to TRPA1 agonists in subsets of TRPV1 (transient receptor potential vanilloid receptor type 1)-expressing neurons in the vagal ganglia and dorsal root ganglia (DRGs), although tdTomato expression efficiency was limited in DRG. We observed tdTomato-expressing afferent fibers centrally (in the medulla and spinal cord) and peripherally in the esophagus, gut, airways, bladder, and skin. Furthermore, chemogenetic activation of TRPA1-expressing nerves in the paw evoked flinching behavior. tdTomato expression was very limited in other cell types. We found tdTomato in subepithelial cells in the gut mucosa but not in enterochromaffin cells. tdTomato was also observed in supporting cells within the cochlea, but not in hair cells. Lastly, tdTomato was occasionally observed in neurons in the somatomotor cortex and the piriform area, but not in astrocytes or vascular endothelium. Thus, this novel mouse strain may be useful for mapping and manipulating TRPA1-expressing cells and deciphering the role of TRPA1 in physiological and pathophysiological processes.

RET Signaling Persists in the Adult Intestine and Stimulates Motility by Limiting PYY Release From Enteroendocrine Cells

RET tyrosine kinase is necessary for enteric nervous system development. Loss-of-function RET mutations cause Hirschsprung disease (HSCR), in which infants are born with aganglionic bowel. Despite surgical correction, patients with HSCR often experience chronic defecatory dysfunction and enterocolitis, suggesting that RET is important after development. To test this hypothesis, we determined the location of postnatal RET and its significance in gastrointestinal (GI) motility. RetCFP/+ mice and human transcriptional profiling data were studied to identify the enteric neuronal and epithelial cells that express RET. To determine whether RET regulates gut motility invivo, genetic, and pharmacologic approaches were used to disrupt RET in all RET-expressing cells, a subset of enteric neurons, or intestinal epithelial cells. Distinct subsets of enteric neurons and enteroendocrine cells expressed RET in the adult intestine. RET disruption in the epithelium, rather than in enteric neurons, slowed GI motility selectively in male mice. RET kinase inhibition phenocopied this effect. Most RET+ epithelial cells were either enterochromaffin cells that release serotonin or L-cells that release peptide YY (PYY) and glucagon-like peptide 1 (GLP-1), both of which can alter motility. RET kinase inhibition exaggerated PYY and GLP-1 release in a nutrient-dependent manner without altering serotonin secretion in mice and human organoids. PYY receptor blockade rescued dysmotility in mice lacking epithelial RET. RET signaling normally limits nutrient-dependent peptide release from L-cells and this activity is necessary for normal intestinal motility in male mice. These effects could contribute to dysmotility in HSCR, which predominantly affects males, and uncovers a mechanism that could be targeted to treat post-prandial GI dysfunction.

Astragaloside IV improves slow transit constipation by regulating gut microbiota and enterochromaffin cells

Astragaloside IV improves slow transit constipation by regulating gut microbiota and enterochromaffin cells

Lactobacillus paracasei Relieves Constipation by Acting on the Acetic Acid-5-HT-Intestinal Motility Pathway.

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 Lactobacillus paracasei (L. paracasei) 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 L. paracasei 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 Odoribacter and Clostridium, and reducing the relative abundance of Mucispirillum, Ruminococcus, Coprobacillus, and Dorea), 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.