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Neurobiology of Disease Oct 2015Lewy pathology affects the gastrointestinal tract in Parkinson's disease (PD) and recent reports suggest a link between the disorder and gut inflammation. In this study,...
Lewy pathology affects the gastrointestinal tract in Parkinson's disease (PD) and recent reports suggest a link between the disorder and gut inflammation. In this study, we investigated enteric neuroprotection and macrophage immunomodulation by 17β-estradiol (E2) and the G protein-coupled estrogen receptor 1 (GPER1) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse PD model. We found that both E2 and the GPER1 agonist G1 are protective against the loss of dopamine myenteric neurons and inhibited enteric macrophage infiltration in MPTP-treated mice. Coadministration of GPER1 antagonist G15, while completely blocking the neuroprotective and anti-inflammatory effects of G1 also partially prevented those of E2. Interestingly, we found that E2 and G1 treatments could directly alter MPTP-mediated immune responses independently from neurodegenerative processes. Analyses of monocyte/macrophage NF-κB and iNOS activation and FACs immunophenotype indicated that 1-methyl-4-phenylpyridinium (MPP(+)) treatment induces a strong immune response in monocytes, comparable to that of canonical challenge by lipopolysaccharide. In these cells, G1 and E2 treatment are equally potent in promoting a shift toward an anti-inflammatory "M2" immunophenotype reducing MPP(+)-induced NF-κB and iNOS activation. Moreover, G15 also antagonized the immunomodulatory effects of G1 in MPP(+)-treated macrophages. Together these data provide the first evidence for the role of GPER1 in enteric immunomodulation and neuroprotection. Considering increasing recognition for myenteric pathology as an early biomarker for PD, these findings provide a valuable contribution for better understanding and targeting of future therapeutic strategies.
Topics: Animals; Benzodioxoles; Dopaminergic Neurons; Estradiol; Immunomodulation; Mice; Myenteric Plexus; NF-kappa B; Neuroprotection; Neuroprotective Agents; Nitric Oxide Synthase Type II; Parkinsonian Disorders; Quinolines; Receptors, Estrogen; Receptors, G-Protein-Coupled
PubMed: 26051538
DOI: 10.1016/j.nbd.2015.05.017 -
Digestion 2018The gut microbiome has been developing and making adaption all the time, which is consistent with their host from the initial colonization at birth or earlier. Emerging... (Review)
Review
BACKGROUND
The gut microbiome has been developing and making adaption all the time, which is consistent with their host from the initial colonization at birth or earlier. Emerging evidence is showing that dysbiosis is involved in various diseases associated with immune, metabolism, infection, nervous system, social behaviors, and psychopathology, etc., maybe via modulating gut barrier, microbiome-gut-brain axis, or some metabolites like short-chain fatty acids (SCFAs).
SUMMARY
In the review, we will conclude the recent researches related to the influence of microbiome on local structure, function, regulation, metabolism of gut, and systematic modulation to the host, as well as some affective factors such as diet or antibiotics. Key Messages: It is a reasonable hypothesis that the balance of bioactive factors or cells and the opposites such as the regulatory T/helper T17 balance and interleukin (IL)-10/IL-17 balance plays a vital role in homeostasis of immunity system. Meanwhile, the link between gut microbiome and immune system via microbiota-derived metabolite SCFAs involved in multi-function of the host locally and systematically has been revealed. We hope to contribute to the microbiome-targeted treatment and prevention of some diseases.
Topics: Anti-Bacterial Agents; Diet; Dysbiosis; Fatty Acids, Volatile; Gastrointestinal Diseases; Gastrointestinal Microbiome; Humans; Immunity; Intestinal Mucosa; Myenteric Plexus; Permeability; T-Lymphocytes
PubMed: 29310114
DOI: 10.1159/000484687 -
International Journal of Surgical... May 2021Gastrointestinal inflammatory neuropathy, namely, eosinophilic myenteric ganglioneuronitis (EMG) and lymphocytic ganglioneuronitis (LG), is a form of chronic intestinal...
Gastrointestinal inflammatory neuropathy, namely, eosinophilic myenteric ganglioneuronitis (EMG) and lymphocytic ganglioneuronitis (LG), is a form of chronic intestinal pseudo-obstruction and results from the infiltration of the myenteric plexus by eosinophils and lymphocytes, respectively. The literature related to the clinicopathological features of adult inflammatory neuropathy is scarce. We aim to elucidate the clinical and histological details of 7 cases of inflammatory neuropathy (EMG, n = 4, and LG, n = 3) and compare the features of EMG and LG retrospectively. There was no difference between these two entities in terms of clinical, hematological, or biochemical parameters. Histologically, almost all cases (n = 6/7) showed accompanying elements of ganglion cell vacuolization, mesenchymopathy, and partial/complete desmosis in addition to the disease-defining pathology. Besides, all cases of EMG showed infiltration of the inner circular muscle of muscularis propria by eosinophils. Two cases of LG showed additional muscular pathology pertaining to the muscularis propria. Inflammatory infiltration of the myenteric plexus is pathognomonic for the diagnosis of gastrointestinal inflammatory neuropathy although additional features in the form of ganglion cell vacuolization, reduction in the number of ganglia, desmosis, mesenchymopathy, and inflammation of the muscularis propria (eosinophils in EMG) can be seen. The pathologists need proper awareness along with judicious use of special and immunostains for clinching the diagnosis.
Topics: Adult; Aged; Aged, 80 and over; Chronic Disease; Eosinophilia; Female; Humans; Inflammation; Intestinal Pseudo-Obstruction; Intestines; Lymphocytes; Male; Middle Aged; Myenteric Plexus; Peripheral Nervous System Diseases; Retrospective Studies
PubMed: 32964744
DOI: 10.1177/1066896920960515 -
Neurogastroenterology and Motility Dec 2022Alterations in gastrointestinal (GI) function and the gut-brain axis are associated with progression and pathology of Alzheimer's Disease (AD). Studies in AD animal...
BACKGROUND
Alterations in gastrointestinal (GI) function and the gut-brain axis are associated with progression and pathology of Alzheimer's Disease (AD). Studies in AD animal models show that changes in the gut microbiome and inflammatory markers can contribute to AD development in the central nervous system (CNS). Amyloid-beta (Aβ) accumulation is a major AD pathology causing synaptic dysfunction and neuronal death. Current knowledge of the pathophysiology of AD in enteric neurons is limited, and whether Aβ accumulation directly disrupts enteric neuron function is unknown.
METHODS
In 6-month-old 5xFAD (transgenic AD) and wildtype (WT) male and female mice, GI function was assessed by colonic transit in vivo; propulsive motility and GI smooth muscle contractions ex vivo; electrochemical detection of enteric nitric oxide release in vitro, and changes in myenteric neuromuscular transmission using smooth muscle intracellular recordings. Expression of Aβ in the brain and colonic myenteric plexus in these mice was determined by immunohistochemistry staining and ELISA assay.
KEY RESULTS
At 6 months, 5xFAD mice did not show significant changes in GI motility or synaptic neurotransmission in the small intestine or colon. 5xFAD mice, but not WT mice, showed abundant Aβ accumulation in the brain. Aβ accumulation was undetectable in the colonic myenteric plexus of 5xFAD mice.
CONCLUSIONS
5xFAD AD mice are not a robust model to study amyloidosis in the gut as these mice do not mimic myenteric neuronal dysfunction in AD patients with GI dysmotility. An AD animal model with enteric amyloidosis is required for further study.
Topics: Female; Male; Animals; Mice; Amyloidosis; Synaptic Transmission; Neurons; Submucous Plexus; Myenteric Plexus; Disease Models, Animal
PubMed: 36458522
DOI: 10.1111/nmo.14439 -
Journal of Histotechnology Sep 2021The neural crest cell-derived enteric nervous system (ENS) is the intrinsic innervation of the gastrointestinal tract (GIT) which consists of neurons and enteric glia...
The neural crest cell-derived enteric nervous system (ENS) is the intrinsic innervation of the gastrointestinal tract (GIT) which consists of neurons and enteric glia cells in the myenteric ganglia and forming plexus. The ENS consists mainly of submucosal and myenteric plexuses. It has various functions on the GIT, which include control of local blood flow, motility, mucosal transport, secretions, immune modulation as well as endocrine functions and coordinated contractile activity of smooth muscle. The knowledge on the development of the innervations at different segments of the gut in humans from 11 to 26 weeks of gestation (WG) may help in understanding the pathophysiology of various congenital diseases affecting the ENS. The aim of this study is to determine the morphology of the myenteric plexus in the esophagus, ascending colon and sigmoid colon at various weeks of gestation. Tissue samples from 10 naturally terminated fetuses aged 11-26 WG were processed for hematoxylin and eosin staining and immunohistochemistry assay. The neurons, enteric glia, the smooth muscle were visualized using PGP9.5, Vimentin and S-100 antibodies. The number of neurons and enteric glial cells appeared lowest in the esophagus than the ascending and sigmoid colon. The myenteric ganglion was closely apposed to each other, forming a continuous arch along the entire circumference of gut sections of ascending and sigmoid colon but the myenteric ganglia in the esophagus was thinly populated and widely spread in the fetus at 13 WG. As the fetal gastrointestinal tract grew in diameter and length, the myenteric ganglia became discernible.
Topics: Enteric Nervous System; Fetus; Humans; Myenteric Plexus; Neuroglia
PubMed: 33441042
DOI: 10.1080/01478885.2020.1862604 -
The Journal of Comparative Neurology Dec 2022Quantitative data of biological systems provide valuable baseline information for understanding pathology, experimental perturbations, and computational modeling. In...
Quantitative data of biological systems provide valuable baseline information for understanding pathology, experimental perturbations, and computational modeling. In mouse colon, calcitonin gene-related peptide (CGRP) is expressed by myenteric neurons with multiaxonal (Dogiel type II) morphology, characteristic of intrinsic primary afferent neurons (IPANs). Analogous neurons in other species and gut regions represent 5-35% of myenteric neurons. We aimed to quantify proportions of CGRP-immunopositive (CGRP+) myenteric neurons. Colchicine-treated wholemount preparations of proximal, mid, and distal colon were labeled for HuC/D, CGRP, nitric oxide synthase (NOS), and peripherin (Per). The pan-neuronal markers (Hu+/Per+) co-labeled 94% of neurons. Hu+/Per- neurons comprised ∼6%, but Hu-/Per+ cells were rare. Thus, quantification was based on Hu+ myenteric neurons (8576 total; 1225 ± 239 per animal, n = 7). CGRP+ cell bodies were significantly larger than the average of all Hu+ neurons (329 ± 13 vs. 261 ± 12 μm , p < .0001). CGRP+ neurons comprised 19% ± 3% of myenteric neurons without significant regional variation. NOS+ neurons comprised 42% ± 2% of myenteric neurons overall, representing a lower proportion in proximal colon, compared to mid and distal colon (38% ± 2%, 44% ± 2%, and 44% ± 3%, respectively). Peripherin immunolabeling revealed cell body and axonal morphology in some myenteric neurons. Whether all CGRP+ neurons were multiaxonal could not be addressed using peripherin immunolabeling. However, of 118 putatively multiaxonal neurons first identified based on peripherin immunoreactivity, all were CGRP+ (n = 4). In conclusion, CGRP+ myenteric neurons in mouse colon were comprehensively quantified, occurring within a range expected of a putative IPAN marker. All Per+ multiaxonal neurons, characteristic of Dogiel type II/IPAN morphology, were CGRP+.
Topics: Mice; Animals; Calcitonin Gene-Related Peptide; Myenteric Plexus; Peripherins; Neurons; Colon; Nitric Oxide Synthase; Colchicine
PubMed: 36043843
DOI: 10.1002/cne.25403 -
The Journal of Physiology Oct 2022
Topics: Gastrointestinal Motility; Myenteric Plexus
PubMed: 35980322
DOI: 10.1113/JP283624 -
Proceedings of the National Academy of... Oct 2021Glia in the central nervous system exert precise spatial and temporal regulation over neural circuitry on a synapse-specific basis, but it is unclear if peripheral glia...
Glia in the central nervous system exert precise spatial and temporal regulation over neural circuitry on a synapse-specific basis, but it is unclear if peripheral glia share this exquisite capacity to sense and modulate circuit activity. In the enteric nervous system (ENS), glia control gastrointestinal motility through bidirectional communication with surrounding neurons. We combined glial chemogenetics with genetically encoded calcium indicators expressed in enteric neurons and glia to study network-level activity in the intact myenteric plexus of the proximal colon. Stimulation of neural fiber tracts projecting in aboral, oral, and circumferential directions activated distinct populations of enteric glia. The majority of glia responded to both oral and aboral stimulation and circumferential pathways, while smaller subpopulations were activated only by ascending and descending pathways. Cholinergic signaling functionally specifies glia to the descending circuitry, and this network plays an important role in repressing the activity of descending neural pathways, with some degree of cross-inhibition imposed upon the ascending pathway. Glial recruitment by purinergic signaling functions to enhance activity within ascending circuit pathways and constrain activity within descending networks. Pharmacological manipulation of glial purinergic and cholinergic signaling differentially altered neuronal responses in these circuits in a sex-dependent manner. Collectively, our findings establish that the balance between purinergic and cholinergic signaling may differentially control specific circuit activity through selective signaling between networks of enteric neurons and glia. Thus, enteric glia regulate the ENS circuitry in a network-specific manner, providing profound insights into the functional breadth and versatility of peripheral glia.
Topics: Animals; Cell Communication; Enteric Nervous System; Female; Gastrointestinal Motility; Male; Mice; Myenteric Plexus; Neuroglia; Neurons; Signal Transduction
PubMed: 34593632
DOI: 10.1073/pnas.2025938118 -
Cellular and Molecular Neurobiology Jan 2023The close interaction between the enteric nervous system, microbiome, and brain in vertebrates is an emerging topic of recent studies. Different species such as rat,...
The close interaction between the enteric nervous system, microbiome, and brain in vertebrates is an emerging topic of recent studies. Different species such as rat, mouse, and human are currently being used for this purpose, among others. The transferability of protocols for tissue isolation and sample collection is not always straightforward. Thus, the present work presents a new protocol for isolation and sample collection of rat myenteric plexus cells for in vivo as well as in vitro studies. With the methods and chemicals described in detail, a wide variety of investigations can be performed with regard to normal physiological as well as pathological processes in the postnatal developing enteric nervous system. The fast and efficient preparation of the intestine as the first step is particularly important. We have developed and described a LIENS chamber to obtain optimal tissue quality during intestinal freezing. Cryosections of the flat, snap-frozen intestine can then be prepared for histological examination of the various wall layers of the intestine, e.g. by immunohistochemistry. In addition, these cryosections are suitable for the preparation of defined regions, as shown here using the ganglia of the mesenteric plexus. This specific tissue was obtained by laser microdissection, making the presented methodology also suitable for subsequent analyses that require high quality (specificity) of the samples. Furthermore, we present here a fully modernized protocol for the cultivation of myenteric neurons from the rat intestine, which is suitable for a variety of in vitro studies.
Topics: Rats; Mice; Humans; Animals; Myenteric Plexus; Enteric Nervous System; Immunohistochemistry; Neurons; Intestine, Small
PubMed: 34932174
DOI: 10.1007/s10571-021-01181-5 -
Anatomical Record (Hoboken, N.J. : 2007) Apr 2018Duchenne-like muscular dystrophy (canine dystrophinopathy) is a hereditary degenerative disease characterized by muscle changes similar to those described for Duchenne...
Duchenne-like muscular dystrophy (canine dystrophinopathy) is a hereditary degenerative disease characterized by muscle changes similar to those described for Duchenne muscular dystrophy (DMD) and by alterations in the smooth muscles of the gastrointestinal tract. Some authors have suggested that these abnormalities may be associated with intestinal motility. This study analyzed the nitrergic and cholinergic neurons and P2X7 receptor expression in the myenteric plexus of the ileum and distal colon of dogs with muscular dystrophy. Immunohistochemical techniques were used to detect nitric oxide synthase (NOS) and acetylcholine transferase (ChAT) expression and to label all HuC/D- and P2X7 receptor-immunoreactive (IR) neurons. Transmission electron microscopy and basic histology were performed for further analysis. The results showed that nitrergic neurons exhibited a Dogiel type I morphology in the ileum and distal colon. The neuronal profile results showed that there were fewer NOS-, ChAT-, and HuC/D-IR neurons in the ileum than in the distal colon in the dystrophic (DT) dogs. Additionally, there were more NOS-, ChAT- and HuC/D-IR neurons per ganglion in the distal colon than in the ileum. The P2X7 receptor-expressing neurons colocalized with nitrergic and cholinergic neurons. Transmission and light microscopy revealed collagen between the muscle fibers, between the circular and longitudinal muscle layers and within the myenteric ganglia of dogs with muscular dystrophy. These findings provide a morphological description of the myenteric neurons in the ileum and distal colon of these DT dogs and may contribute to a better understanding of the gastrointestinal disorders found in patients with DMD. Anat Rec, 301:673-685, 2018. © 2017 Wiley Periodicals, Inc.
Topics: Animals; Choline O-Acetyltransferase; Colon; Dog Diseases; Dogs; Ileum; Muscular Dystrophy, Animal; Myenteric Plexus; Neurons; Nitric Oxide Synthase; Receptors, Purinergic P2X7
PubMed: 29059716
DOI: 10.1002/ar.23708