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Frontiers in Physiology 2023A rhythmic expression of clock genes occurs within the cells of multiple organs and tissues throughout the body, termed "peripheral clocks." Peripheral clocks are... (Review)
Review
A rhythmic expression of clock genes occurs within the cells of multiple organs and tissues throughout the body, termed "peripheral clocks." Peripheral clocks are subject to entrainment by a multitude of factors, many of which are directly or indirectly controlled by the light-entrainable clock located in the suprachiasmatic nucleus of the hypothalamus. Peripheral clocks occur in the gastrointestinal tract, notably the epithelia whose functions include regulation of absorption, permeability, and secretion of hormones; and in the myenteric plexus, which is the intrinsic neural network principally responsible for the coordination of muscular activity in the gut. This review focuses on the physiological circadian variation of major colonic functions and their entraining mechanisms, including colonic motility, absorption, hormone secretion, permeability, and pain signalling. Pathophysiological states such as irritable bowel syndrome and ulcerative colitis and their interactions with circadian rhythmicity are also described. Finally, the classic circadian hormone melatonin is discussed, which is expressed in the gut in greater quantities than the pineal gland, and whose exogenous use has been of therapeutic interest in treating colonic pathophysiological states, including those exacerbated by chronic circadian disruption.
PubMed: 37711458
DOI: 10.3389/fphys.2023.1239278 -
Seminars in Neurology Aug 2023Nervous system disorders may be accompanied by gastrointestinal (GI) dysfunction. Brain lesions may be responsible for GI problems such as decreased peristalsis (e.g.,... (Review)
Review
Nervous system disorders may be accompanied by gastrointestinal (GI) dysfunction. Brain lesions may be responsible for GI problems such as decreased peristalsis (e.g., lesions in the basal ganglia, pontine defecation center/Barrington's nucleus), decreased abdominal strain (e.g., lesions in the parabrachial nucleus), hiccupping and vomiting (e.g., lesions in the area postrema), and appetite loss (e.g., lesions in the hypothalamus). Decreased peristalsis also may be caused by lesions of the spinal long tracts or the intermediolateral nucleus projecting to the myenteric plexus. This review addresses GI dysfunction caused by multiple sclerosis, neuromyelitis optica spectrum disorder, and myelin oligodendrocyte glycoprotein-associated disorder. Neuro-associated GI dysfunction may develop concurrently with brain or spinal cord dysfunction or may predate it. Collaboration between gastroenterologists and neurologists is highly desirable when caring for patients with GI dysfunction related to nervous system disorders, particularly since patients with these symptoms may visit a gastroenterologist prior to the establishment of a neurological diagnosis.
Topics: Humans; Multiple Sclerosis; Gastrointestinal Diseases; Myelin-Oligodendrocyte Glycoprotein; Basal Ganglia; Brain
PubMed: 37703888
DOI: 10.1055/s-0043-1771462 -
The Journal of Comparative Neurology Nov 2023Nociceptive afferent axons innervate the stomach and send signals to the brain and spinal cord. Peripheral nociceptive afferents can be detected with a variety of...
Nociceptive afferent axons innervate the stomach and send signals to the brain and spinal cord. Peripheral nociceptive afferents can be detected with a variety of markers (e.g., substance P [SP] and calcitonin gene-related peptide [CGRP]). We recently examined the topographical organization and morphology of SP-immunoreactive (SP-IR) axons in the whole mouse stomach muscular layer. However, the distribution and morphological structure of CGRP-IR axons remain unclear. We used immunohistochemistry labeling and applied a combination of imaging techniques, including confocal and Zeiss Imager M2 microscopy, Neurolucida 360 tracing, and integration of axon tracing data into a 3D stomach scaffold to characterize CGRP-IR axons and terminals in the whole mouse stomach muscular layers. We found that: (1) CGRP-IR axons formed extensive terminal networks in both ventral and dorsal stomachs. (2) CGRP-IR axons densely innervated the blood vessels. (3) CGRP-IR axons ran in parallel with the longitudinal and circular muscles. Some axons ran at angles through the muscular layers. (4) They also formed varicose terminal contacts with individual myenteric ganglion neurons. (5) CGRP-IR occurred in DiI-labeled gastric-projecting neurons in the dorsal root and vagal nodose ganglia, indicating CGRP-IR axons were visceral afferent axons. (6) CGRP-IR axons did not colocalize with tyrosine hydroxylase or vesicular acetylcholine transporter axons in the stomach, indicating CGRP-IR axons were not visceral efferent axons. (7) CGRP-IR axons were traced and integrated into a 3D stomach scaffold. For the first time, we provided a topographical distribution map of CGRP-IR axon innervation of the whole stomach muscular layers at the cellular/axonal/varicosity scale.
Topics: Animals; Mice; Calcitonin Gene-Related Peptide; Stomach; Axons; Neurons; Nerve Fibers
PubMed: 37694767
DOI: 10.1002/cne.25519 -
Frontiers in Neuroscience 2023The central and peripheral nervous systems provide cholinergic innervation in the colon. The ability to assess their neuroanatomical distinctions is still a challenge....
INTRODUCTION
The central and peripheral nervous systems provide cholinergic innervation in the colon. The ability to assess their neuroanatomical distinctions is still a challenge. The pig is regarded as a relevant translational model due to the close similarity of its enteric nervous system (ENS) with that of human. Opioid-induced constipation is one of the most common side effects of opioid therapy.
METHODS
We developed an approach to differentiate the central and peripheral cholinergic innervation of the pig colon using double immunolabeling with a novel mouse anti-human peripheral type of choline acetyltransferase (hpChAT) antibody combined with a rabbit anti-common type of ChAT (cChAT) antibody, a reliable marker of cholinergic neurons in the central nervous system. We examined their spatial configurations in 3D images of the ENS generated from CLARITY-cleared colonic segments. The density was quantitated computationally using Imaris 9.7. We assessed changes in the distal colon induced by daily oral treatment for 4 weeks with the μ opioid receptor agonist, loperamide (0.4 or 3 mg/kg).
RESULTS
The double labeling showed strong cChAT immunoreactive (ir) fibers in the cervical vagus nerve and neuronal somata and fibers in the ventral horn of the sacral (S2) cord while hpChAT immunoreactivity was visualized only in the ENS but not in the vagus or sacral neural structures indicating the selectivity of these two antibodies. In the colonic myenteric plexus, dense hpChAT-ir neurons and fibers and varicose cChAT-ir fibers surrounding hpChAT-ir neurons were simultaneously visualized in 3D. The density of cChAT-ir varicose fibers in the outer submucosal plexus of both males and females were higher in the transverse and distal colon than in the proximal colon and in the myenteric plexus compared to the outer submucosal plexus and there was no cChAT innervation in the inner submucosal plexus. The density of hpChAT in the ENS showed no segmental or plexus differences in both sexes. Loperamide at the highest dose significantly decreased the density hpChAT-ir fibers + somata in the myenteric plexus of the distal colon.
DISCUSSION
These data showed the distinct density of central cholinergic innervation between myenteric and submucosal plexuses among colonic segments and the localization of cChAT-ir fibers around peripheral hpChAT neurons in 3D. The reduction of cholinergic myenteric innervation by chronic opiate treatment points to target altered prokinetic cholinergic pathway to counteract opiate constipation.
PubMed: 37650102
DOI: 10.3389/fnins.2023.1204233 -
British Journal of Pharmacology Feb 2024Glial cell-derived neurotrophic factor (GDNF) maintains gut homeostasis. Dopamine promotes GDNF release in astrocytes. We investigated the regulation by dopamine of...
BACKGROUND AND PURPOSE
Glial cell-derived neurotrophic factor (GDNF) maintains gut homeostasis. Dopamine promotes GDNF release in astrocytes. We investigated the regulation by dopamine of colonic GDNF secretion.
EXPERIMENTAL APPROACH
D receptor knockout (D R ) mice, adeno-associated viral 9-short hairpin RNA carrying D receptor (AAV9-shD R)-treated mice, 6-hydroxydopamine treated (6-OHDA) rats and primary enteric glial cells (EGCs) culture were used. Incubation fluid from colonic submucosal plexus and longitudinal muscle myenteric plexus were collected for GDNF and ACh measurements.
KEY RESULTS
D receptor-immunoreactivity (IR), but not D receptor-IR, was observed on EGCs. Both D receptor-IR and D receptor-IR were co-localized on cholinergic neurons. Low concentrations of dopamine induced colonic GDNF secretion in a concentration-dependent manner, which was mimicked by the D receptor agonist SKF38393, inhibited by TTX and atropine and eliminated in D R mice. SKF38393-induced colonic ACh release was absent in D R mice. High concentrations of dopamine suppressed colonic GDNF secretion, which was mimicked by the D receptor agonist quinpirole, and absent in AAV-shD R-treated mice. Quinpirole decreased GDNF secretion by reducing intracellular Ca levels in primary cultured EGCs. Carbachol ( ACh analogue) promoted the release of GDNF. Quinpirole inhibited colonic ACh release, which was eliminated in the AAV9-shD R-treated mice. 6-OHDA treated rats with low ACh and high dopamine content showed decreased GDNF content and increased mucosal permeability in the colon.
CONCLUSION AND IMPLICATIONS
Low concentrations of dopamine promote colonic GDNF secretion via D receptors on cholinergic neurons, whereas high concentrations of dopamine inhibit GDNF secretion via D receptors on EGCs and/or cholinergic neurons.
Topics: Rats; Mice; Animals; Dopamine; Glial Cell Line-Derived Neurotrophic Factor; Quinpirole; Oxidopamine; 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Receptors, Dopamine D1; Receptors, Dopamine D2; Cholinergic Agents
PubMed: 37614042
DOI: 10.1111/bph.16226 -
Microbiological Research Nov 2023The gut microbiota plays a critical role in the appropriate development and maintenance of the enteric nervous system (ENS). Esophageal achalasia (EA) is a rare motility...
OBJECTIVE
The gut microbiota plays a critical role in the appropriate development and maintenance of the enteric nervous system (ENS). Esophageal achalasia (EA) is a rare motility disorder characterized by the selective degeneration of inhibitory neurons in the esophageal myenteric plexus. This study aimed to evaluate the composition of the esophageal microbiota in achalasia and explore the potential microbial mechanisms involved in its pathogenesis.
DESIGN
The lower esophageal mucosal microbiota was analyzed in patients with achalasia and control participants using 16 S rRNA sequencing. The association between the esophageal microbiota and achalasia was validated by inducing esophageal dysbiosis in C57BL/10 J and C57BL/10ScNJ (TLR4KO) mice via chronic exposure to ampicillin sodium in their drinking water.
RESULTS
The esophageal microbiota in EA patients had lower diversity and a predominance of Gram-negative bacteria (Type II microbiota) compared to that in the healthy controls. Additionally, the relative abundance of Rhodobacter decreased significantly in patients with achalasia, which correlated with an enrichment of lipopolysaccharide (LPS) biosynthesis based on the COG database. Antibiotic-treated mice showed an esophageal microbiota characterized by increased abundance of Gram-negative bacteria (Type II microbiome), decreased abundance of Rhodobacter, and enriched LPS biosynthesis. Compared to the control and TLR4KO mice, the antibiotic-treated wild-type mice had higher LES resting pressure, increased LES contraction rate after carbachol stimulation, and decreased relaxation response to L-arginine. Moreover, the number of myenteric neurons decreased, while the number of lamina propria macrophages (LpMs) increased after antibiotic exposure. Furthermore, the TLR4-MYD88-NF-κB pathway was up-regulated, and the production of TNF-α, IL-1β, and IL-6 increased in the antibiotic-treated mice.
CONCLUSIONS
Patients with achalasia exhibit esophageal dysbiosis, which may induce aberrant esophageal motility.
Topics: Mice; Animals; Esophageal Achalasia; Lipopolysaccharides; Dysbiosis; Mice, Inbred C57BL; Neurons; Gastrointestinal Microbiome; Anti-Bacterial Agents
PubMed: 37574627
DOI: 10.1016/j.micres.2023.127470 -
Journal of Crohn's & Colitis Jan 2024Pain is a cardinal symptom in inflammatory bowel disease [IBD]. An important structure in the transduction of pain signalling is the myenteric plexus [MP]. Nevertheless,...
BACKGROUND AND AIMS
Pain is a cardinal symptom in inflammatory bowel disease [IBD]. An important structure in the transduction of pain signalling is the myenteric plexus [MP]. Nevertheless, IBD-associated infiltration of the MP by immune cells lacks in-depth characterisation. Herein, we decipher intra- and periganglionic immune cell infiltrations in Crohn´s disease [CD] and ulcerative colitis [UC] and provide a comparison with murine models of colitis.
METHODS
Full wall specimens of surgical colon resections served to examine immune cell populations by either conventional immuno-histochemistry or immunofluorescence followed by either bright field or confocal microscopy. Results were compared with equivalent examinations in various murine models of intestinal inflammation.
RESULTS
Whereas the MP morphology was not significantly altered in IBD, we identified intraganglionic IBD-specific B cell- and monocyte-dominant cell infiltrations in CD. In contrast, UC-MPs were infiltrated by CD8+ T cells and revealed a higher extent of ganglionic cell apoptosis. With regard to the murine models of intestinal inflammation, the chronic dextran sulphate sodium [DSS]-induced colitis model reflected CD [and to a lesser extent UC] best, as it also showed increased monocytic infiltration as well as a modest B cell and CD8+ T cell infiltration.
CONCLUSIONS
In CD, MPs were infiltrated by B cells and monocytes. In UC, mostly CD8+ cytotoxic T cells were found. The chronic DSS-induced colitis in the mouse model reflected best the MP-immune cell infiltrations representative for IBD.
Topics: Animals; Mice; Colitis, Ulcerative; Crohn Disease; Myenteric Plexus; Inflammatory Bowel Diseases; Colitis; Neurotransmitter Agents; Pain; Inflammation
PubMed: 37565754
DOI: 10.1093/ecco-jcc/jjad122 -
Nature Communications Aug 2023Achalasia is a rare motility disorder of the esophagus caused by the gradual degeneration of myenteric neurons. Immune-mediated ganglionitis has been proposed to...
Achalasia is a rare motility disorder of the esophagus caused by the gradual degeneration of myenteric neurons. Immune-mediated ganglionitis has been proposed to underlie the loss of myenteric neurons. Here, we measure the immune cell transcriptional profile of paired lower esophageal sphincter (LES) tissue and blood samples in achalasia and controls using single-cell RNA sequencing (scRNA-seq). In achalasia, we identify a pattern of expanded immune cells and a specific transcriptional phenotype, especially in LES tissue. We show C1QC macrophages and tissue-resident memory T cells (T), especially ZNF683 CD8 T and XCL1 CD4 T, are significantly expanded and localized surrounding the myenteric plexus in the LES tissue of achalasia. C1QC macrophages are transcriptionally similar to microglia of the central nervous system and have a neurodegenerative dysfunctional phenotype in achalasia. T also expresses transcripts of dysregulated immune responses in achalasia. Moreover, inflammation increases with disease progression since immune cells are more activated in type I compared with type II achalasia. Thus, we profile the immune cell transcriptional landscape and identify C1QC macrophages and T as disease-associated immune cell subsets in achalasia.
Topics: Humans; Esophageal Achalasia; Esophageal Sphincter, Lower; Neurons; Inflammation; Macrophages
PubMed: 37542039
DOI: 10.1038/s41467-023-39750-5 -
Revista Espanola de Enfermedades... Jun 2024We are grateful our case has aroused such interest from our Turkish colleagues, and we thank them for their kind reply. Sigmoid volvulus (SV) is the third leading cause...
We are grateful our case has aroused such interest from our Turkish colleagues, and we thank them for their kind reply. Sigmoid volvulus (SV) is the third leading cause of colonic obstruction in the world. Is it widely known there is a progressive aging of the population. Prevention with lifestyle habits and early treatment of cardiovascular risk factors has led to an increase of pluripatologic chronic conditions. A higher incidence of neurodegenerative diseases is also a proven fact. Their intestinalinvolvementcan be ina direct form, withneuronal destruction in myenteric plexus leading to chronic constipation, and alsodue to secondary drug effects (laxatives causing fecal overloading, increased intracolonic pressure, dolichocolon…), all favouringweakness in colonic wall, and therefore the appearance of sigmoid volvulus. We don´t have specific data about SV incidence and recurrence in our centre.However, literature reviews show recurrence is the norm in the majority of cases after colonic decompression. Data reported from our colleagues in Turkey represents a single centre cohort and a broad spectrum over time (from 1960s until now), so recurrence rate should not be generalized to global population. The continuous improvement in endoscopic procedures since their beginning might have despair results of colonic decompression and need of surgery among years. Nowadays we have more sophisticated and high-resolution endoscopes, as well as better trained endoscopists with more advanced therapeutic techniques. This might overlap with surgical development of less invasive techniques, lower rates of complication and shorter postoperative recovery. We suggest the authors to examin in their database the different outcomes through decades in their cohort since we believe medical/endoscopic/surgical approach has changed from 1960s until now. Finally, we agree elective surgery must be the final treatment in SV cases with American Society of Anesthesiologists (ASA) scores 1-3. Endoscopic or laparoscopic colopexychoice for ASA > 3 patients should be made based on each centre´s experience. We believe endoscopic approach with endoscopic colostomy or sigmoidopexy might be the first approach for fragile patients since it is an easily performed technique, with low rate of complications and acceptable long-term results preventing a recurrence of SV. Further studies are needed to compare minimally invasive surgery to endoscopic approach.
Topics: Humans; Intestinal Volvulus; Sigmoid Diseases; Decompression, Surgical; Recurrence
PubMed: 37539528
DOI: 10.17235/reed.2023.9880/2023 -
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