Search Results (40)

The current opinion paper puts into perspective how altered microbiota transplanted from Alzheimer’s patients initiates the impairment of the microbiota–gut–brain axis of a healthy recipient, leading to impaired cognition primarily arising from the hippocampus, dysfunctional adult hippocampal neurogenesis, dysregulated systemic inflammation, long-term spatial memory impairment, or chronic pain with hippocampal involvement. This altered microbiota may induce acquired Piezo2 channelopathy on enterochromaffin cells, which, in turn, impairs the ultrafast long-range proton-based oscillatory synchronization to the hippocampus. Therefore, an intact microbiota–gut–brain axis could be responsible for the synchronization of ultradian and circadian rhythms, with the assistance of rhythmic bacteria within microbiota, to circadian regulation, and hippocampal learning and memory formation. Hippocampal ultradian clock encoding is proposed to be through a Piezo2-initiated proton-signaled manner via VGLUT3 allosteric transmission at a distance. Furthermore, this paper posits that these unaccounted-for ultrafast proton-based long-range oscillatory synchronizing ultradian axes may exist not only within the brain but also between the periphery and the brain in an analogous way, like in the case of this depicted microbiota–gut–brain axis. Accordingly, the irreversible Piezo2 channelopathy-induced loss of the Piezo2-initiated ultradian prefrontal–hippocampal axis leads to Alzheimer’s disease pathophysiology onset. Moreover, the same irreversible microdamage-induced loss of the Piezo2-initiated ultradian muscle spindle–hippocampal and cerebellum–hippocampal axes may lead to amyotrophic lateral sclerosis and Parkinson’s disease initiation, respectively. Full article

Stress may aggravate the development of inflammatory bowel disease and irritable bowel syndrome, in which the number of enterochromaffin (EC) cells and 5-hydroxytryptamine (5-HT) levels are abnormal, but the underlying mechanism remains largely unresolved. In this study, we discovered that restraint stress triggered the expression of Tph1, which led to 5-HT production. The 5-HT signaling then increased intestinal permeability, downregulated the expression of tight junction proteins, reduced the number of goblet cells and their ability to secrete mucin, promoted the expression of inflammatory cytokines, and ultimately damaged the intestinal mucosal barrier. Mechanistically, the 5-HT receptor HTR7 was highly expressed in the intestine. It interacted with 5-HT to initiate the Wnt/β-catenin signaling pathway, inducing an increase in intestinal EC cells and further promoting 5-HT secretion. Additionally, the activation of the Wnt/β-catenin signaling pathway could initiate the NF-κB signaling pathway and induce the expression of inflammatory cytokines. Blocking the 5-HT signal in mice inhibited the activation of the Wnt/β-catenin signal, thereby alleviating intestinal inflammation. Our findings revealed a novel role for 5-HT in intestinal inflammatory diseases and represent a potential new therapeutic target. Full article

The gut–brain axis represents an important bidirectional communication network, with the vagus nerve acting as a central conduit for peripheral signals from the various gut organs to the central nervous system. Among the molecular mediators involved, serotonin (5-HT), synthesized predominantly by enterochromaffin cells in the gut, plays a pivotal role. Gut-derived serotonin activates vagal afferent fibers, transmitting signals to the nucleus tractus solitarius (NTS) and modulating serotonergic neurons in the dorsal raphe nucleus (DRN) as well as the norepinephrinergic neurons in the locus coeruleus (LC). This interaction influences emotional regulation, stress responses, and immune modulation. Emerging evidence also highlights the role of microbial metabolites, particularly short-chain fatty acids (SCFAs), in enhancing serotonin synthesis and vagal activity, thereby shaping gut–brain communication. This review synthesizes the current knowledge on serotonin signaling, vagal nerve pathways, and central autonomic regulation, with an emphasis on their implications for neuropsychiatric and gastrointestinal disorders. By elucidating these pathways, novel therapeutic strategies targeting the gut–brain axis may be developed to improve mental and physical health outcomes. Full article

Background/Objectives: Neuroendocrine tumors (NETs) are heterogeneous malignancies arising from enterochromaffin cells that can arise from the gastrointestinal (GI) tract and pancreas. Surgical management is the cornerstone of treatment, with the optimal approach tailored by tumor grade, size, location, and presence of metastasis. This review discusses the current strategies for the surgical management of NETs of the gastroenteropancreatic tract. Methods: A review of the available literature was conducted to evaluate surgical approaches to NETs. Consensus guidelines were incorporated to synthesize evidence-based recommendations. Results: For gastric NETs, surgical approach depends on Rindi Classification, WHO grade, and tumor size, with endoscopic approaches favored for smaller and low-grade lesions. Small bowel NETs can be multifocal and thus often require a surgical approach with careful evaluation of the entire intestine. Pancreatic NETs are categorized as functional or non-functional, with enucleation or formal resection strategies based on size, location, functional status, and risk of malignancy. Colorectal NETs are primarily treated with transanal localized or formal surgical resection, depending on lesion size and depth of invasion or presence of lymph node involvement. Appendiceal NETs are either treated with appendectomy or right hemicolectomy, depending on the size, location, and invasiveness of the lesions. For metastatic NETs, cytoreduction, liver transplantation, and targeted therapies offer symptom relief and possible survival benefits. Conclusions: Surgical resection provides curative potential for localized NETs and symptom control in metastatic cases. Future research is essential to refine guidelines for intermediate-risk lesions and multifocal tumors, ensuring optimal outcomes for patients with gastroenteropancreatic NETs. Full article

The gastrointestinal (GI) tract is an organ actively involved in mechanical processes, where it detects forces via a mechanosensation mechanism. Mechanosensation relies on specialized cells termed mechanoreceptors, which convert mechanical forces into electrochemical signals via mechanosensors. The mechanosensitive Piezo1 and Piezo2 are widely expressed in various mechanosensitive cells that respond to GI mechanical forces by altering transmembrane ionic currents, such as epithelial cells, enterochromaffin cells, and intrinsic and extrinsic enteric neurons. This review highlights recent research advances on mechanosensitive Piezo channels in GI physiology and pathology. Specifically, the latest insights on the role of Piezo channels in the intestinal barrier, GI motility, and intestinal mechanosensation are summarized. Additionally, an overview of Piezo channels in the pathogenesis of GI disorders, including irritable bowel syndrome, inflammatory bowel disease, and GI cancers, is provided. Overall, the presence of mechanosensitive Piezo channels offers a promising new perspective for the treatment of various GI disorders. Full article

Background: Appendiceal neuroendocrine tumors (NETs) rank as the third most frequent neoplasm affecting the appendix, originating from enterochromaffin cells. This study aims to evaluate the influence of various prognostic factors on the mortality rates of patients diagnosed with NETs of the appendix. Methods: Conducted retrospectively, the study involved 3346 patients, utilizing data sourced from the Surveillance, Epidemiology, and End Results (SEER) database. Our analysis centered on investigating demographic characteristics, clinical features, overall mortality (OM), and cancer-specific mortality (CSM) among the cohort. Variables showing a p-value < 0.1 in the univariate Cox regression were incorporated into the multivariate Cox regression analysis. A Hazard Ratio (HR) > 1 indicated an unfavorable prognosis. Results: In the multivariate analysis, higher OM and CSM were observed in males, older age groups, tumors with distant metastasis, poorly differentiated tumors, and those who underwent chemotherapy. Non-Hispanic Black individuals showed elevated mortality rates. Conclusion: Delayed diagnosis may contribute to the increased mortality in this community. Improved access to healthcare and treatment is crucial for addressing these disparities. Larger prospective studies are needed to pinpoint the underlying causes of elevated mortality in non-Hispanic Black populations, and randomized controlled trials (RCTs) are warranted to evaluate therapies for advanced-stage appendix NETs. Full article

Gut microbes supporting body growth are known but the mechanisms are less well documented. Using the microbial tryptophan metabolite indole, known to regulate prokaryotic cell division and metabolic stress conditions, we mono-colonized germ-free (GF) mice with indole-producing wild-type Escherichia coli (E. coli) or tryptophanase-encoding tnaA knockout mutant indole-non-producing E. coli. Indole mutant E. coli mice showed multiorgan growth retardation and lower levels of glycogen, cholesterol, triglycerides, and glucose, resulting in an energy deficiency despite increased food intake. Detailed analysis revealed a malfunctioning intestine, enlarged cecum, and reduced numbers of enterochromaffin cells, correlating with a metabolic phenotype consisting of impaired gut motility, diminished digestion, and lower energy harvest. Furthermore, indole mutant mice displayed reduction in serum levels of tricarboxylic acid (TCA) cycle intermediates and lipids. In stark contrast, a massive increase in serum melatonin was observed—frequently associated with accelerated oxidative stress and mitochondrial dysfunction. This observational report discloses functional roles of microbe-derived indoles regulating multiple organ functions and extends our previous report of indole-linked regulation of adult neurogenesis. Since indoles decline by age, these results imply a correlation with age-linked organ decline and levels of indoles. Interestingly, increased levels of indole-3-acetic acid, a known indole metabolite, have been shown to correlate with younger biological age, further supporting a link between biological age and levels of microbe-derived indole metabolites. The results presented in this resource paper will be useful for the future design of food intervention studies to reduce accelerated age-linked organ decline. Full article

Background: Proton pump inhibitors (PPIs) are commonly prescribed long-acting drugs used to treat acid reflux, gastroesophageal reflux disease (GERD), and peptic ulcers. Recently, concerns have been raised about their safety, particularly due to the association between long-term PPI use and cancer development. Multiple comprehensive studies have consistently suggested a noteworthy link between prolonged PPI usage and an increased risk of developing gastric, esophageal, colorectal, and pancreatic cancers, yet the precise underlying mechanism remains elusive. Methods: First, we review the extensive body of research that investigates the intricate relationship between cancer and PPIs. Then, we predict PPI toxicity using the prodrug structures with the ProTox-II webserver. Finally, we predict the relative risk of cancer for each PPI, using PubMed citation counts of each drug and keywords related to cancer. Results: Our review indicates that prolonged PPI use (exceeding three months) is significantly associated with an elevated risk of cancer, while shorter-term usage (less than three months) appears to pose a comparatively lower risk. Our review encompasses various proposed mechanisms, such as pH and microbiome alterations, vitamin and mineral malabsorption, hypergastrinemia, and enterochromaffin-like cell proliferation, while ProTox-II also suggests aryl hydrocarbon receptor binding. Potentially, the PubMed citations count suggests that the PPIs omeprazole and lansoprazole are more associated with cancer than pantoprazole and esomeprazole. In comparison, the H2R blocker, famotidine, is potentially less associated with cancer than PPIs, and may serve as a safer alternative treatment for periods beyond 3 months. Conclusions: Despite the well-established cancer risk associated with PPIs, it is notable that these medications continue to be widely prescribed for periods longer than 3 months. Thus, it is of paramount importance for clinicians and patients to thoughtfully evaluate the potential risks and benefits of long-term PPI usage and explore alternative treatments before making informed decisions regarding their medical management. Full article

Serotonin (5-hydroxytryptamine, 5HT) homeostasis is essential for many physiological processes in the central nervous system and peripheral tissues. Hyperserotonemia, a measurable sign of 5HT homeostasis disruption, can be caused by 5HT-directed treatment of psychiatric and gastrointestinal diseases. Its impact on the long-term balance and function of 5HT in the peripheral compartment remains unresolved and requires further research due to possible effects on human health. We explored the effects of perinatal 5HT imbalance on the peripheral organs responsible for serotonin metabolism—the jejunum, a synthesis site, and the liver, a catabolism site—in adult rats. Hyperserotonemia was induced by subchronic treatment with serotonin precursor 5-hydroxytryptophan (5HTP) or serotonin degradation inhibitor tranylcypromine (TCP). The jejunum and liver were collected on postnatal day 70 and analyzed histomorphometrically. Relative mRNA levels of 5HT-regulating proteins were determined using qRT-PCR. Compared to controls, 5HTP- and TCP-treated rats had a reduced number of 5HT-producing cells and expression of the 5HT-synthesising enzyme in the jejunum, and an increased expression of 5HT-transporter accompanied by karyomegaly in hepatocytes, with these differences being more pronounced in the TCP-treated animals. Here, we report that perinatal 5HT disbalance induced long-term cellular and molecular changes in organs regulating 5HT-metabolism, which may have a negative impact on 5HT availability and function in the periphery. Our rat model demonstrates a link between the developmental abnormalities of serotonin homeostasis and 5HT-related changes in adult life and may be suitable for exploring the neurobiological substrates of vulnerability to behavioral and metabolic disorders, as well as for modeling the adverse effects of the prenatal exposure to 5HT enhancers in the human population. Full article

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. Full article

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. Full article

Proton pump inhibitor (PPI) treatment is responsible for substantial gastrin elevation secondary to reduced intragastric acidity. Due to the increasing global prevalence of PPI users, concerns have been raised about the clinical significance of continuous gastrin elevation and its potential long-term side effects. Hypergastrinemia secondary to PPIs has trophic effects on gastric mucosa, leading to enterochromaffin-like cell hyperplasia and gastric (fundic) polyp formation, and it is believed to provoke acid rebound following PPI withdrawal that induces PPI overutilization. Previous studies have found higher gastrin release following PPI therapy in females compared with males, and sex differences have also been demonstrated in pharmacokinetic parameters and dose requirements for acid reflux. It is conceivable that females might be at increased risk of PPI overuse, because they often receive higher milligram-per-kilogram doses. The prevalence of PPI use is more common among females, and the female sex is a risk factor for adverse drug reactions. This non-systematic review outlines the current knowledge of the impact of biological sex on the response to PPIs. The aim is to highlight the female sex as a potential risk factor that could be a step toward precision medicine and should be considered in future research on the response to PPI treatment. Full article

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. Full article

Nausea and vomiting are common gastrointestinal side effects of oxaliplatin chemotherapy used for the treatment of colorectal cancer. However, the mechanism underlying oxaliplatin-induced nausea and vomiting is unknown. The stomach is involved in the emetic reflex but no study investigated the effects of oxaliplatin treatment on the stomach. In this study, the in vivo effects of oxaliplatin treatment on eating behaviour, stomach content, intrinsic gastric neuronal population, extrinsic innervation to the stomach, levels of mucosal serotonin (5-hydroxytryptamine, 5-HT), and parasympathetic vagal efferent nerve activity were analysed. Chronic systemic oxaliplatin treatment in mice resulted in pica, indicated by increased kaolin consumption and a reduction in body weight. Oxaliplatin treatment significantly increased the stomach weight and content. The total number of myenteric and nitric oxide synthase-immunoreactive neurons as well as the density of sympathetic, parasympathetic, and sensory fibres in the stomach were decreased significantly with oxaliplatin treatment. Oxaliplatin treatment significantly increased the levels in mucosal 5-HT and the number of enterochromaffin-like cells. Chronic oxaliplatin treatment also caused a significant increase in the vagal efferent nerve activity. The findings of this study indicate that oxaliplatin exposure has adverse effects on multiple components of gastric innervation, which could be responsible for pica and gastric dysmotility. Full article

Serotonin (5-HT) is a neurotransmitter involved in many biophysiological processes in the brain and in the gastrointestinal tract. Electrochemical methods are commonly used to quantify 5-HT, but their reliability may suffer due to the time-dependent nature of adsorption-limited 5-HT detection, as well as electrode fouling over repeated measurements. Mathematical characterization and modeling of adsorption-based electrochemical signal generation would improve reliability of 5-HT measurement. Here, a model was developed to track 5-HT electrode adsorption and resulting current output by combining Langmuir adsorption kinetic equations and adsorption-limited electrochemical equations. 5-HT adsorption binding parameters were experimentally determined at a carbon-nanotube coated Au electrode: K_D = 7 × 10⁻⁷ M, k_on = 130 M⁻¹ s⁻¹, k_off = 9.1 × 10⁻⁵ s⁻¹. A computational model of 5-HT adsorption was then constructed, which could effectively predict 5-HT fouling over 50 measurements (R² = 0.9947), as well as predict electrode responses over varying concentrations and measurement times. The model aided in optimizing the measurement of 5-HT secreted from a model enterochromaffin cell line—RIN14B—minimizing measurement time. The presented model simplified and improved the characterization of 5-HT detection at the selected electrode. This could be applied to many other adsorption-limited electrochemical analytes and electrode types, contributing to the improvement of application-specific modeling and optimization processes. Full article