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International Journal of Molecular... Jan 2024The brain-gut axis has been identified as an important contributor to the physiopathology of Parkinson's disease. In this pathology, inflammation is thought to be driven... (Review)
Review
The brain-gut axis has been identified as an important contributor to the physiopathology of Parkinson's disease. In this pathology, inflammation is thought to be driven by the damage caused by aggregation of α-synuclein in the brain. Interestingly, the Braak's theory proposes that α-synuclein misfolding may originate in the gut and spread in a "prion-like" manner through the vagus nerve into the central nervous system. In the enteric nervous system, enteric glial cells are the most abundant cellular component. Several studies have evaluated their role in Parkinson's disease. Using samples obtained from patients, cell cultures, or animal models, the studies with specific antibodies to label enteric glial cells (GFAP, Sox-10, and S100β) seem to indicate that activation and reactive gliosis are associated to the neurodegeneration produced by Parkinson's disease in the enteric nervous system. Of interest, Toll-like receptors, which are expressed on enteric glial cells, participate in the triggering of immune/inflammatory responses, in the maintenance of intestinal barrier integrity and in the configuration of gut microbiota; thus, these receptors might contribute to Parkinson's disease. External factors like stress also seem to be relevant in its pathogenesis. Some authors have studied ways to reverse changes in EGCs with interventions such as administration of Tryptophan-2,3-dioxygenase inhibitors, nutraceuticals, or physical exercise. Some researchers point out that beyond being activated during the disease, enteric glial cells may contribute to the development of synucleinopathies. Thus, it is still necessary to further study these cells and their role in Parkinson's disease.
Topics: Animals; Humans; Parkinson Disease; alpha-Synuclein; Brain; Inflammation; Neuroglia; Enteric Nervous System
PubMed: 38279293
DOI: 10.3390/ijms25021294 -
Scientific Reports Jan 2024Achalasia is a rare esophageal motility disorder for which the etiology is not fully understood. Evidence suggests that autoimmune inflammatory infiltrates, possibly...
Achalasia is a rare esophageal motility disorder for which the etiology is not fully understood. Evidence suggests that autoimmune inflammatory infiltrates, possibly triggered by a viral infection, may lead to a degeneration of neurons within the myenteric plexus. While the infection is eventually resolved, genetically susceptible individuals may still be at risk of developing achalasia. This study aimed to determine whether immunological and physiological networks differ between male and female patients with achalasia. This cross-sectional study included 189 preoperative achalasia patients and 500 healthy blood donor volunteers. Demographic, clinical, laboratory, immunological, and tissue biomarkers were collected. Male and female participants were evaluated separately to determine the role of sex. Correlation matrices were constructed using bivariate relationships to generate complex inferential networks. These matrices were filtered based on their statistical significance to identify the most relevant relationships between variables. Network topology and node centrality were calculated using tools available in the R programming language. Previous occurrences of chickenpox, measles, and mumps infections have been proposed as potential risk factors for achalasia, with a stronger association observed in females. Principal component analysis (PCA) identified IL-22, Th2, and regulatory B lymphocytes as key variables contributing to the disease. The physiological network topology has the potential to inform whether a localized injury or illness is likely to produce systemic consequences and the resulting clinical presentation. Here we show that immunological involvement in achalasia appears localized in men because of their highly modular physiological network. In contrast, in women the disease becomes systemic because of their robust network with a larger number of inter-cluster linkages.
Topics: Humans; Female; Male; Esophageal Achalasia; Cross-Sectional Studies; Esophageal Motility Disorders; B-Lymphocytes, Regulatory; Blood Donors
PubMed: 38267468
DOI: 10.1038/s41598-024-52273-3 -
International Journal of Molecular... Jan 2024Recent discoveries have shown that enteric glial cells play an important role in different neurodegenerative disorders, such as Parkinson's disease (PD), which is...
Recent discoveries have shown that enteric glial cells play an important role in different neurodegenerative disorders, such as Parkinson's disease (PD), which is characterized by motor dysfunctions caused by the progressive loss of dopaminergic neurons in the substance nigra pars compacta and non-motor symptoms including gastrointestinal dysfunction. In this study, we investigated the modulatory effects of the flavonoid rutin on the behavior and myenteric plexuses in a PD animal model and the response of enteric glia. Adult male Wistar rats were submitted to stereotaxic injection with 6-hydroxydopamine or saline, and they were untreated or treated with rutin (10 mg/kg) for 14 days. The ileum was collected to analyze tissue reactivity and immunohistochemistry for neurons (HuC/HuD) and enteric glial cells (S100β) in the myenteric plexuses. Behavioral tests demonstrated that treatment with rutin improved the motor capacity of parkinsonian animals and improved intestinal transit without interfering with the cell population; rutin treatment modulated the reactivity of the ileal musculature through muscarinic activation, reducing relaxation through the signaling pathway of nitric oxide donors, and increased the longitudinal contractility of the colon musculature in parkinsonian animals. Rutin revealed modulatory activities on the myenteric plexus, bringing relevant answers regarding the effect of the flavonoid in this system and the potential application of PD adjuvant treatment.
Topics: Male; Rats; Animals; Rats, Wistar; Myenteric Plexus; Flavonoids; Rutin; Parkinson Disease; Disease Models, Animal; Dopaminergic Neurons
PubMed: 38256111
DOI: 10.3390/ijms25021037 -
International Journal of Biological... Mar 2024Oxidative stress-induced enteric neuropathy is an important factor in slow transit constipation (STC). Cistanche deserticola crude polysaccharides (CDCP) are natural...
Oxidative stress-induced enteric neuropathy is an important factor in slow transit constipation (STC). Cistanche deserticola crude polysaccharides (CDCP) are natural antioxidants with various biological activities. We prepared CDCP through water-extract and alcohol-precipitation methods. The structural characteristics of CDCP were analyzed by infrared spectroscopy and methylation analysis. The results showed that CDCP was primarily composed of (1 → 4)-linked glucans with minor amounts of pectic polysaccharides. Different doses of CDCP (100, 200, and 400 mg/kg) were administered to loperamide-induced STC mice to explore the therapeutic effects of CDCP. Compared with the untreated group, CDCP treatment significantly improved constipation symptoms, relevant gut-regulating peptides levels, colonic pathological damage, and colonic myenteric nerons injury. CDCP enhanced the antioxidant capacity by decreasing Malondialdehyde (MDA) content, increasing Superoxide Dismutase (SOD) activity and Reduced Glutathione (GSH) content. CDCP significantly reduced oxidative stress-induced injury by preserving mitochondrial function in the colonic myenteric plexus. Furthermore, the neuroprotective effects of CDCP might be associated with the Nrf2/Keap1 pathway. Thus, our findings first revealed the potential of CDCP to protect the colonic myenteric plexus against oxidative stress-induced damage in STC, establishing CDCP as promising candidates for natural medicine in the clinical management of STC.
Topics: Mice; Animals; Cistanche; Neuroprotective Agents; Kelch-Like ECH-Associated Protein 1; NF-E2-Related Factor 2; Constipation; Oxidative Stress; Antioxidants; Polysaccharides
PubMed: 38246435
DOI: 10.1016/j.ijbiomac.2024.129527 -
International Journal of Molecular... Dec 2023Bacteria in the gut microbiome play an intrinsic part in immune activation, intestinal permeability, enteric reflex, and entero-endocrine signaling. The gut microbiota... (Review)
Review
Bacteria in the gut microbiome play an intrinsic part in immune activation, intestinal permeability, enteric reflex, and entero-endocrine signaling. The gut microbiota communicates with the central nervous system (CNS) through the production of bile acids, short-chain fatty acids (SCFAs), glutamate (Glu), γ-aminobutyric acid (GABA), dopamine (DA), norepinephrine (NE), serotonin (5-HT), and histamine. A vast number of signals generated in the gastrointestinal tract (GIT) reach the brain via afferent fibers of the vagus nerve (VN). Signals from the CNS are returned to entero-epithelial cells (EES) via efferent VN fibers and communicate with 100 to 500 million neurons in the submucosa and myenteric plexus of the gut wall, which is referred to as the enteric nervous system (ENS). Intercommunications between the gut and CNS regulate mood, cognitive behavior, and neuropsychiatric disorders such as autism, depression, and schizophrenia. The modulation, development, and renewal of nerves in the ENS and changes in the gut microbiome alter the synthesis and degradation of neurotransmitters, ultimately influencing our mental health. The more we decipher the gut microbiome and understand its effect on neurotransmission, the closer we may get to developing novel therapeutic and psychobiotic compounds to improve cognitive functions and prevent mental disorders. In this review, the intricate control of entero-endocrine signaling and immune responses that keep the gut microbiome in a balanced state, and the influence that changing gut bacteria have on neuropsychiatric disorders, are discussed.
Topics: Humans; Mental Health; Gastrointestinal Microbiome; Central Nervous System; Enteric Nervous System; Glutamic Acid
PubMed: 38203207
DOI: 10.3390/ijms25010038 -
American Journal of Physiology.... May 2024The enteric nervous system (ENS) comprises millions of neurons and glia embedded in the wall of the gastrointestinal tract. It not only controls important functions of...
The enteric nervous system (ENS) comprises millions of neurons and glia embedded in the wall of the gastrointestinal tract. It not only controls important functions of the gut but also interacts with the immune system, gut microbiota, and the gut-brain axis, thereby playing a key role in the health and disease of the whole organism. Any disturbance of this intricate system is mirrored in an alteration of electrical functionality, making electrophysiological methods important tools for investigating ENS-related disorders. Microelectrode arrays (MEAs) provide an appropriate noninvasive approach to recording signals from multiple neurons or whole networks simultaneously. However, studying isolated cells of the ENS can be challenging, considering the limited time that these cells can be kept vital in vitro. Therefore, we developed an alternative approach cultivating cells on glass samples with spacers (fabricated by photolithography methods). The spacers allow the cells to grow upside down in a spatially confined environment while enabling acute consecutive recordings of multiple ENS cultures on the same MEA. Upside-down culture also shows beneficial effects on the growth and behavior of enteric neural cultures. The number of dead cells was significantly decreased, and neural networks showed a higher resemblance to the myenteric plexus ex vivo while producing more stable signals than cultures grown in the conventional way. Overall, our results indicate that the upside-down approach not only allows to investigate the impact of neurological diseases in vitro but could also offer insights into the growth and development of the ENS under conditions much closer to the in vivo environment. In this study, we devised a novel approach for culturing and electrophysiological recording of the enteric nervous system using custom-made glass substrates with spacers. This allows to turn cultures of isolated myenteric plexus upside down, enhancing the use of the microelectrode array technique by allowing recording of multiple cultures consecutively using only one chip. In addition, upside-down culture led to significant improvements in the culture conditions, resulting in a more in vivo-like growth.
Topics: Neurons; Enteric Nervous System; Myenteric Plexus; Submucous Plexus
PubMed: 38193168
DOI: 10.1152/ajpgi.00170.2023 -
American Journal of Physiology.... Mar 2024The enteric nervous system (ENS) functions largely independently of the central nervous system (CNS). Glutamate, the dominant neurotransmitter in the CNS and sensory...
The enteric nervous system (ENS) functions largely independently of the central nervous system (CNS). Glutamate, the dominant neurotransmitter in the CNS and sensory afferents, is not a primary neurotransmitter in the ENS. Only a fraction (∼2%) of myenteric neurons in the mouse distal colon and rectum (colorectum) are positive for vesicular glutamate transporter type 2 (VGLUT2), the structure and function of which remain undetermined. Here, we systematically characterized VGLUT2-positive enteric neurons (VGLUT2-ENs) through sparse labeling with adeno-associated virus, single-cell mRNA sequencing (scRNA-seq), and GCaMP6f calcium imaging. Our results reveal that the majority of VGLUT2-ENs (29 of 31, 93.5%) exhibited Dogiel type I morphology with a single aborally projecting axon; most axons (26 of 29, 89.7%) are between 4 and 10 mm long, each traversing 19 to 34 myenteric ganglia. These anatomical features exclude the VGLUT2-ENs from being intrinsic primary afferent or motor neurons. The scRNA-seq conducted on 52 VGLUT2-ENs suggests different expression profiles from conventional descending interneurons. Ex vivo GCaMP6f recordings from flattened colorectum indicate that almost all VGLUT2-EN (181 of 215, 84.2%) are indirectly activated by colorectal stretch via nicotinic cholinergic neural transmission. In conclusion, VGLUT2-ENs are a functionally unique group of enteric neurons with single aborally projecting long axons that traverse multiple myenteric ganglia and are activated indirectly by colorectal mechanical stretch. This knowledge will provide a solid foundation for subsequent studies on the potential interactions of VGLUT2-EN with extrinsic colorectal afferents via glutamatergic neurotransmission. We reveal that VGLUT2-positive enteric neurons (EN), although constituting a small fraction of total EN, are homogeneously expressed in the myenteric ganglia, with a slight concentration at the intermediate region between the colon and rectum. Through anatomic, molecular, and functional analyses, we demonstrated that VGLUT2-ENs are activated indirectly by noxious circumferential colorectal stretch via nicotinic cholinergic transmission, suggesting their participation in mechanical visceral nociception.
Topics: Mice; Animals; Immunohistochemistry; Motor Neurons; Neurotransmitter Agents; Cholinergic Agents; Colorectal Neoplasms; Myenteric Plexus
PubMed: 38193160
DOI: 10.1152/ajpgi.00200.2023 -
BMC Gastroenterology Jan 2024This study was designed to explore the expression changes of P2Y receptors in the distal colonic myenteric layer of rats. An opioid induced constipation(OIC) rat model...
This study was designed to explore the expression changes of P2Y receptors in the distal colonic myenteric layer of rats. An opioid induced constipation(OIC) rat model was generated by intraperitoneal (i.p) injection of loperamide. At 7 days post-treatment, the model rats were assessed by calculating the fecal water content and the gastrointestinal transit ratio. The immunofluorescence (IF)-based histochemical study was used to observe the distribution of P2Y receptors in the distal colonic myenteric plexus. Western blotting (WB) was performed to evaluate the expression changes of P2Y proteins in the myenteric layer, and the electrophysiological approaches were carried out to determine the regulatory roles of P2Y receptors on distal colonic motor function. IF showed that P2Y receptors are co-expressed MOR in the enteric nerve cells of the distal colonic myenteric plexus. Moreover, the WB revealed that the protein levels of P2Y were significantly decreased in the distal colonic myenteric layer of OIC rats. In vitro tension experiments exhibited that the P2Y receptor antagonist MRS2500 enhanced the spontaneous contraction amplitude, adding EM2 and β-FNA did not have any effect on MRS2500. Therefore, P2Y receptor expression could be associated with the occurrence of OIC in this rat model and the regulation of colonic motility by MOR may be related to the release of purine neurotransmitters such as ATP in the colonic nervous system.
Topics: Animals; Rats; Myenteric Plexus; Analgesics, Opioid; Opioid-Induced Constipation; Constipation; Blotting, Western
PubMed: 38191294
DOI: 10.1186/s12876-024-03119-9 -
Animals : An Open Access Journal From... Dec 2023In the expansive domain of neuropeptide investigation, spexin (SPX) has emerged as a captivating subject, exerting a significant impact on diverse physiological...
In the expansive domain of neuropeptide investigation, spexin (SPX) has emerged as a captivating subject, exerting a significant impact on diverse physiological processes. Initially identified in mice, SPX's distribution transcends various organs, suggesting its potential regulatory roles. Despite extensive research in smaller species, a notable gap exists in our comprehension of SPX in larger mammals, particularly ruminants. Our study meticulously explores the immunolocalization of SPX within the gastrointestinal organs of bovines, with a specific focus on the abomasum, jejunum, and colon. Tissue samples from Holstein-Friesian cattle underwent careful processing, and gene mRNA expression levels, particularly and , were assessed. Intriguingly, our findings revealed that expression was highest in the jejunum, signifying a potentially critical role in this digestive segment. Immunohistochemistry further unveiled distinct patterns of SPX immunoreactivity in each examined region-abomasum, jejunum, and colon-highlighting nuanced, region-specific responses. Notably, the abomasum and jejunum predominantly exhibited positive immunoreactivity in the submucosal plexus, while the colon, in contrast, demonstrated a higher degree of immunoreactivity in myenteric plexus neurons. Our investigation, grounded in the hypothesis of ubiquitous SPX distribution in ruminants, delves deeper into the intricate role of SPX within the enteric nervous system. This study meticulously explores the spatial distribution of SPX within the myenteric and submucosal plexuses, integral components of the enteric nervous system. These findings significantly enhance our understanding of SPX's potential roles in gastrointestinal regulation in bovines, providing a unique perspective on larger mammals and enriching our comprehension of this intriguing neuropeptide's significance in various physiological processes.
PubMed: 38136826
DOI: 10.3390/ani13243789 -
Biomolecules Dec 2023Oxygen level is a key regulator of organogenesis and its modification in postnatal life alters the maturation process of organs, including the intestine, which do not...
Oxygen level is a key regulator of organogenesis and its modification in postnatal life alters the maturation process of organs, including the intestine, which do not completely develop in utero. The β3-adrenoreceptor (β3-AR) is expressed in the colon and has an oxygen-dependent regulatory mechanism. This study shows the effects of the β3-AR agonist BRL37344 in a neonatal model of hyperoxia-driven colonic injury. For the first 14 days after birth, Sprague-Dawley rat pups were exposed to ambient oxygen levels (21%) or hyperoxia (85%) and treated daily with BRL37344 at 1, 3, 6 mg/kg or untreated. At the end of day 14, proximal colon samples were collected for analysis. Hyperoxia deeply influences the proximal colon development by reducing β3-AR-expressing cells (27%), colonic length (26%) and mucin production (47%), and altering the neuronal chemical coding in the myenteric plexus without changes in the neuron number. The administration of BRL37344 at 3 mg/kg, but not at 1 mg/kg, significantly prevented these alterations. Conversely, it was ineffective in preventing hyperoxia-induced body weight loss. BRL37344 at 6 mg/kg was toxic. These findings pave the way for β3-AR pharmacological targeting as a therapeutic option for diseases caused by hyperoxia-impaired development, typical prematurity disorders.
Topics: Rats; Animals; Ethanolamines; Hyperoxia; Rats, Sprague-Dawley; Adrenergic Agonists; Receptors, Adrenergic, beta-3; Oxygen
PubMed: 38136626
DOI: 10.3390/biom13121755