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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 -
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 -
Journal of Integrative Neuroscience Feb 2024Recently, the hypothesis that pathological α-Synuclein propagates from the gut to the brain has gained attention. Although results from animal studies support this...
BACKGROUND
Recently, the hypothesis that pathological α-Synuclein propagates from the gut to the brain has gained attention. Although results from animal studies support this hypothesis, the specific mechanism remains unclear. This study focused on the intestinal fatty acid-binding protein (FABP2), which is one of the subtypes of fatty acid binding proteins localizing in the gut, with the hypothesis that FABP2 is involved in the gut-to-brain propagation of α-synuclein. The aim of this study was to clarify the pathological significance of FABP2 in the pathogenesis and progression of synucleinopathy.
METHODS
We examined the relationship between FABP2 and α-Synuclein in the uptake of α-Synuclein into enteric neurons using primary cultured neurons derived from mouse small intestinal myenteric plexus. We also quantified disease-related protein concentrations in the plasma of patients with synucleinopathy and related diseases, and analyzed the relationship between plasma FABP2 level and progression of the disease.
RESULTS
Experiments on α-Synuclein uptake in primary cultured enteric neurons showed that following uptake, α-Synuclein was concentrated in areas where FABP2 was localized. Moreover, analysis of the plasma protein levels of patients with Parkinson's disease revealed that the plasma FABP2 and α-Synuclein levels fluctuate with disease duration. The FABP2/α-Synuclein ratio fluctuated more markedly than either FABP2 or α-Synuclein alone, depending on the duration of disease, indicating a higher discriminant ability of early Parkinson's disease patients from healthy patients.
CONCLUSIONS
These results suggest that FABP2 potentially contributes to the pathogenesis and progression of α-synucleinopathies. Thus, FABP2 is an important molecule that has the potential to elucidate the consistent mechanisms that lead from the prodromal phase to the onset and subsequent progression of synucleinopathies.
Topics: Animals; Humans; Mice; alpha-Synuclein; Fatty Acid-Binding Proteins; Neurons; Parkinson Disease; Synucleinopathies
PubMed: 38419457
DOI: 10.31083/j.jin2302044 -
Arthritis & Rheumatology (Hoboken, N.J.) Jan 2024Autoantibodies are clinically useful in phenotyping patients with systemic sclerosis (SSc). Gastrointestinal (GI) function is regulated by the enteric nervous system...
OBJECTIVE
Autoantibodies are clinically useful in phenotyping patients with systemic sclerosis (SSc). Gastrointestinal (GI) function is regulated by the enteric nervous system (ENS) and commonly impaired in SSc, suggesting that the SSc autoimmune response may target ENS antigens. We sought to identify novel anti-ENS autoantibodies with an aim to clinically phenotype SSc GI dysfunction.
METHODS
Serum from a patient with SSc with GI dysfunction but without defined SSc-associated autoantibodies was used for autoantibody discovery. Immunoprecipitations performed with murine myenteric plexus lysates were on-bead digested, and autoantigens were identified by mass spectrometry. Prevalence was determined, and clinical features associated with novel autoantibodies were evaluated in a SSc cohort using regression analyses. The expression of gephyrin in human GI tract tissue was examined by immunohistochemistry.
RESULTS
We identified gephyrin as a novel SSc autoantigen. Anti-gephyrin antibodies were present in 9% of patients with SSc (16/188) and absent in healthy controls (0/46). Anti-gephyrin antibody-positive patients had higher constipation scores (1.00 vs 0.50, P = 0.02) and were more likely to have severe constipation and severe distention/bloating (46% vs 15%, P = 0.005; 54% vs 25%, P = 0.023, respectively). Anti-gephyrin antibody levels were significantly higher among patients with severe constipation (0.04 vs 0.00; P = 0.001) and severe distention and bloating (0.03 vs 0.004; P = 0.010). Severe constipation was associated with anti-gephyrin antibodies even in the adjusted model. Importantly, gephyrin was expressed in the ENS, which regulates gut motility.
CONCLUSION
Gephyrin is a novel ENS autoantigen that is expressed in human myenteric ganglia. Anti-gephyrin autoantibodies are associated with the presence and severity of constipation in patients with SSc.
Topics: Membrane Proteins; Autoantigens; Scleroderma, Systemic; Autoantibodies; Gastrointestinal Tract; Humans; Animals; Mice; Neurons; Enteric Nervous System
PubMed: 37530745
DOI: 10.1002/art.42667 -
International Journal of Molecular... Jun 2024The influence of accelerated electrons on neuronal structures is scarcely explored compared to gamma and X-rays. This study aims to investigate the effects of...
The influence of accelerated electrons on neuronal structures is scarcely explored compared to gamma and X-rays. This study aims to investigate the effects of accelerated electron radiation on some pivotal neurotransmitter circuits (cholinergic and serotonergic) of rats' myenteric plexus. Male Wistar rats were irradiated with an electron beam (9 MeV, 5 Gy) generated by a multimodality linear accelerator. The contractile activity of isolated smooth muscle samples from the gastric corpus was measured. Furthermore, an electrical stimulation (200 μs, 20 Hz, 50 s, 60 V) was performed on the samples and an assessment of the cholinergic and serotonergic circuits was made. Five days after irradiation, the recorded mechanical responses were biphasic-contraction/relaxation in controls and contraction/contraction in irradiated samples. The nature of the contractile phase of control samples was cholinergic with serotonin involvement. The relaxation phase involved ACh-induced nitric oxide release from gastric neurons. There was a significant increase in serotonergic involvement during the first and second contractile phases of the irradiated samples, along with a diminished role of acetylcholine in the first phase. This study demonstrates an increased involvement of serotonergic neurotransmitter circuits in the gastric myenteric plexus caused by radiation with accelerated electrons.
Topics: Animals; Myenteric Plexus; Male; Rats; Rats, Wistar; Stomach; Electrons; Muscle, Smooth; Serotonin; Muscle Contraction; Acetylcholine; Nitric Oxide
PubMed: 38928511
DOI: 10.3390/ijms25126807 -
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 -
Acta Histochemica Apr 2024Cancer-induced cachexia is associated with systemic inflammation and gastrointestinal dysfunction. How changes to cells of the enteric nervous system contribute to gut...
Cancer-induced cachexia is associated with systemic inflammation and gastrointestinal dysfunction. How changes to cells of the enteric nervous system contribute to gut dysfunction in tumor development and cancer cachexia is unknown. Here, we tested the hypothesis that changes to enteric glia, a type of peripheral glia that surround enteric neurons and regulate gut homeostasis, are associated with tumor development and that supplementing with the antioxidant L-glutathione is protective against the changes induced. Immunohistochemistry for neurons, enteric glial cells and immune cells was performed in whole-mount preparations and frozen histological sections of the jejunum from 20 Wistar rats, distributed in 4 groups: control, tumor of Walker-256, control administered with 1 % L-glutathione, and tumor of Walker-256 administered with 1 % L-glutathione. Morphoquantitative analyses were made using Image-Pro® Plus 4.5 and ImageJ® 1.43° software. Tumor development significantly reduced neuronal and glial cell populations in the myenteric and submucosal plexuses and enlarged glial cell body area in the submucosal plexus. In contrast, tumors increased glia in the jejunal mucosa and this effect was accompanied by B-lymphocyte recruitment. GSH-supplemented diet was not sufficient to protect against changes to neurons and glia in the submucosal plexus but was partially protective in the myenteric plexus. L-glutathione had no effect on physiological parameters of cachexia but was sufficient to preserve enteric glial cell density in the myenteric plexus. These results suggest that changes to both enteric neurons and glia likely contribute to the gastrointestinal effects of tumor development and that oxidative stress contributes to these effects in the enteric nervous system.
PubMed: 38422841
DOI: 10.1016/j.acthis.2024.152146 -
Current Medicinal Chemistry Oct 2023The Enteric Nervous System (ENS) is described as a division of the Peripheral Nervous System (PNS), located within the gut wall and it is formed by two main plexuses:...
The Enteric Nervous System (ENS) is described as a division of the Peripheral Nervous System (PNS), located within the gut wall and it is formed by two main plexuses: the myenteric plexus (Auerbach's) and the submucosal plexus (Meissner's). The contribution of the ENS to the pathophysiology of various neurological diseases such as Parkinson's or Alzheimer's disease has been described in the literature, while some other studies have found a connection between epilepsy and the gastrointestinal tract. The above could be explained by cholinergic neurons and neurotransmission systems in the myenteric and submucosal plexuses, regulating the vagal excitability effect. It is also understandable, as the discharges arising in the amygdala are transmitted to the intestine through projections the dorsal motor nucleus of the vagus, giving rise to efferent fibers that stimulate the gastrointestinal tract and consequently the symptoms at this level. Therefore, this review's main objective is to argue in favor of the existing relationship of the ENS with the Central Nervous System (CNS) as a facilitator of epileptogenic or ictogenic mechanisms. The gut microbiota also participates in this interaction; however, it depends on many individual factors of each human being. The link between the ENS and the CNS is a poorly studied epileptogenic site with a big impact on one of the most prevalent neurological conditions such as epilepsy.
PubMed: 37855342
DOI: 10.2174/0109298673260479231010044020 -
Biomolecules Oct 2023No standard diagnostic method or surgical treatment for congenital isolated hypoganglionosis (CIHG) has been established. This study aimed to analyze the clinical...
No standard diagnostic method or surgical treatment for congenital isolated hypoganglionosis (CIHG) has been established. This study aimed to analyze the clinical outcomes of patients with CIHG and identify the best surgical interventions provided thus far. Data on surgical interventions in 19 patients were collected between 1992 and 2020, including the type of enterostomy, type of revision, and length of the intestines. Ganglion cells in the myenteric plexus were enumerated using Hu C/D staining. The ratio of the length of the small intestine to its height was defined as the intestinal ratio (IR). The outcomes were assessed using the stoma output, growth parameters including the body mass index (BMI), and parenteral nutrition (PN) dependency. All patients required a diverting enterostomy. The IR ranged from 0.51 to 1.75 after multiple non-transplant surgeries. The stoma types were tube-stoma, end-stoma, Santulli-type, and Bishop-Koop (BK)-type. Patients with Santulli- or BK-type stomas had better BMIs and less PN dependency in terms of volume than those with end-stomas or tube-stomas. Two patients with BK-type stomas were off PN, and three who underwent an intestinal transplantation (Itx) achieved enteral autonomy. The management of CIHG involves a precise diagnosis using Hu C/D staining, neonatal enterostomy, and stoma revision using the adjusted IR and Itx if other treatments do not enable enteral autonomy.
Topics: Infant, Newborn; Humans; Cohort Studies; Retrospective Studies; Intestines; Enterostomy; Surgical Stomas
PubMed: 37892242
DOI: 10.3390/biom13101560 -
Anatomical Record (Hoboken, N.J. : 2007) Sep 2023Neurons, expressing neuronal nitric oxide synthase (nNOS) in the enteric ganglia are inhibitory motor neurons or interneurons. The aim of the study was to identify the...
Neurons, expressing neuronal nitric oxide synthase (nNOS) in the enteric ganglia are inhibitory motor neurons or interneurons. The aim of the study was to identify the percentage, cross-sectional area of nNOS-immunoreactive (IR) neurons and their colocalization with choline acetyltransferase (ChAT), vasoactive intestinal polypeptide (VIP), and neuropeptide Y in the intramural ganglia of the myenteric (MP) and submucous plexus (SP) of the small intestine (SI) and large intestine (LI) of rats of different age groups using immunohistochemical methods. In the intramural ganglia of the MP, the largest percentage of nNOS-IR neurons was detected in newborn rats in the LI (81 ± 0.9%) and SI (48 ± 4.1%). Subsequently, it decreased in ontogenesis up to 60 days of life (26 ± 0.9% LI, 29 ± 3.2% SI), and did not change until senescence. In the SP, abundant nNOS-IR neurons were also detected in newborns (82 ± 7.0% SI, 85 ± 3.2% LI), while their percentage decreased significantly in the next 20 days. Furthermore, a very small number of nNOS-IR neurons was detected in 30-day- and 2-month-old animals, but they again appeared in large numbers in aged rats. In the MP, the highest percentage of nNOS+/ChAT+ neurons was in 1-day-old, 10-day-old, and 2-year-old rats. In the SP, the largest number of nNOS-IR neurons colocalized ChAT regardless of age. In the MP of all rats, many nNOS-IR neurons colocalized VIP, and the maximal percentage of nNOS+/VIP+ neurons was found in 2-year-old rats, minimal-in newborns. In conclusion, nNOS expression in neurons of the gut is decreased in early postnatal ontogenesis and subsequently increased in aged rats.
Topics: Animals; Rats; Nitric Oxide Synthase Type I; Neurons; Vasoactive Intestinal Peptide; Myenteric Plexus; Intestine, Small
PubMed: 35500072
DOI: 10.1002/ar.24947