• Diabetes
• Diabetic neuropathy
• Enteric nervous system
• Enteric neuropathy
• Gastrointestinal
• Insulin resistance

• Humans
• Diabetic Neuropathies/etiology
• Diabetic Neuropathies/therapy
• Diabetic Neuropathies/diagnosis
• Diabetic Neuropathies/physiopathology
• Enteric Nervous System/physiopathology
• Gastrointestinal Diseases/physiopathology
• Gastrointestinal Diseases/therapy
• Gastrointestinal Diseases/diagnosis
• Gastrointestinal Diseases/etiology
• Gastrointestinal Motility
• Gastrointestinal Tract/innervation
• Gastrointestinal Tract/physiopathology
• Gastroparesis/therapy
• Gastroparesis/physiopathology
• Gastroparesis/diagnosis
• Gastroparesis/etiology
• Oxidative Stress
• Quality of Life

• Animals
• Mice
• Anal Canal/innervation
• Anal Canal/physiology
• Muscle Contraction/physiology
• Muscle, Smooth/physiology
• Myocytes, Smooth Muscle
• Anoctamin-1/physiology

• R01 HL139686 NHLBI NIH HHS
• R21 HD097458 NICHD NIH HHS

• diabetic dysmotility
• gastroparesis
• intestinal barrier dysfunction
• irritable bowel syndrome
• microRNAs

• Humans
• Mice
• Animals
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Irritable Bowel Syndrome
• Diabetes Mellitus
• Phenotype

• P01 DK041315 NIDDK NIH HHS
• P30 DK020595 NIDDK NIH HHS
• R01 DK103055 NIDDK NIH HHS
• R01 DK111848 NIDDK NIH HHS
• National Institute of Diabetes and Digestive and Kidney Diseases
• National Institutes of Health

The intestinal extracellular matrix (ECM) represents a complex network of proteins that not only forms a support structure for resident cells but also interacts closely with them by modulating their phenotypes and functions. More than 300 molecules have been identified, each of them with unique biochemical properties and exclusive biological functions. ECM components not only provide a scaffold for the tissue but also afford tensile strength and limit overstretch of the organ. The ECM holds water, ensures suitable hydration of the tissue, and participates in a selective barrier to the external environment. ECM-to-cells interaction is crucial for morphogenesis and cell differentiation, proliferation, and apoptosis. The ECM is a dynamic and multifunctional structure. The ECM is constantly renewed and remodeled by coordinated action among ECM-producing cells, degrading enzymes, and their specific inhibitors. During this process, several growth factors are released in the ECM, and they, in turn, modulate the deposition of new ECM. In this review, we describe the main components and functions of intestinal ECM and we discuss their role in maintaining the structure and function of the intestinal barrier. Achieving complete knowledge of the ECM world is an important goal to understand the mechanisms leading to the onset and the progression of several intestinal diseases related to alterations in ECM remodeling.

• MMPs
• TIMPs
• basement membrane
• bowel
• extracellular matrix
• interstitial matrix
• intestinal wall

• gastrointestinal tract
• interstitial cells of Cajal
• mathematical model
• slow waves

Chronic constipation is a gastrointestinal functional disease that seriously harms physical and mental health and impacts the quality of life of patients. Its incidence rate is 2%-27%. Slow transit constipation (STC) is a common type of chronic functional constipation, accounting for 10.3%-45.5% of such cases. Scholars have performed many studies on the pathogenesis of STC. These studies have indicated that the occurrence of STC may be related to multiple factors, such as dysfunction of the enteric nervous system, interstitial cells of Cajal (ICC) damage, and changes in neurotransmitters regulating intestinal peristalsis.

To investigate the role of Tenascin-X (TNX) in regulating the TGF-β/Smad signaling pathway in the pathogenesis of STC.

This study included an experimental group and a control group. The experimental group included 28 patients with severe colonic STC, and the control group included 18 patients with normal colon tissues. Immunohistochemistry (IHC) was used to detect c-Kit, a specific marker of the ICC. Western blot, immunofluorescence, and IHC were used to detect the localization and expression of TNX and TGF-β/Smad.

IHC showed that the number of ICC with positive c-Kit expression was significantly reduced in the colon of STC patients (22.17 ± 3.28 vs 28.69 ± 3.53, P < 0.05) and that the distribution was abnormal. Western blot results showed that c-Kit and Smad7 levels were significantly decreased in the colon of STC patients (c-kit: 0.462 ± 0.099 vs 0.783 ± 0.178, P < 0.01; Smad7: 0.626 ± 0.058 vs 0.799 ± 0.03, P < 0.01) and that TNX and Smad2/3 levels were higher in the STC group (TNX: 0.868 ± 0.028 vs 0.482 ± 0.032, P < 0.01). There was no significant difference in TGF-β between the two groups (0.476 ± 0.028 vs 0.511 ± 0.044, P = 0.272). Pearson correlation analysis showed that the TNX protein exhibited a strong correlation with Smad2/3 and Smad7 (P < 0.05, |R| > 0.8) and TGF-β (P < 0.05, |R| = 0.7).

The extracellular matrix protein TNX may activate the TGF-β/Smad signaling pathway by upregulating the Smad 2/3 signaling protein and thereby induce slight or complete epithelial stromal cell transformation, leading to an abnormal distribution and dysfunction of ICC in the diseased colon, which promotes the occurrence and development of STC.

• Slow transit constipation
• Tenascin-X
• Extracellular matrix glycoproteins
• TGF-β

• Adult
• Aged
• Blotting, Western
• Case-Control Studies
• Colon/metabolism
• Constipation/genetics
• Extracellular Matrix/metabolism
• Female
• Gastrointestinal Transit/genetics
• Humans
• Interstitial Cells of Cajal/metabolism
• Male
• Middle Aged
• Proto-Oncogene Proteins c-kit/metabolism
• Signal Transduction/genetics
• Smad Proteins/metabolism
• Tenascin/metabolism
• Transforming Growth Factor beta/metabolism

• immunological staining
• muscularis
• neurovascular markers
• pelvic organ prolapse

• Adult
• Aged
• Case-Control Studies
• Connective Tissue/pathology
• Female
• Humans
• Middle Aged
• Muscles/blood supply
• Muscles/innervation
• Muscles/pathology
• Pelvic Organ Prolapse/etiology
• Pelvic Organ Prolapse/pathology
• Vagina/blood supply
• Vagina/innervation
• Vagina/pathology

• RIA (Rilevante Interesse di Ateneo), Università degli Studi dell'Aquila

Gastrointestinal (GI) motility disorder is caused by excessive autophagy of the interstitial cells of Cajal (ICC). Chaihu Shugan Powder (CSP) is a traditional Chinese medicine with therapeutic benefits in GI motility disorders; however, the underlying mechanism of its therapeutic effect in GI disorders, especially autophagy of ICC, remains unclear. Thus, this study investigated the effects of CSP-contained serum on glutamate-induced autophagy in rat gastric ICC, exploring its underlying mechanism. In vitro cultured rat stomach ICC were identified by fluorescence microscopy and then stimulated with glutamate (5 mmol/L) for 3 h to establish the autophagy model. These cells were then treated with 10% CSP-containing serum or the autophagy inhibitor 3-methyladenine (3-MA; 5 mmol/L) for 24 h. The control group was cultured with only 10% serum containing physiological saline. The viability of ICC was measured by the CCK-8 assay. The ultrastructure and autophagosomes of ICC were observed using transmission electron microscopy. LC3 expression was detected by immunofluorescence, and LC3, Beclin1, Bcl2, and PI3KC3 expression was detected by western blot analysis. Transmission electron microscopy showed abundant endoplasmic reticulum, mitochondria, and other organelles in the control group, whereas the cells in the autophagy model control group had clear autophagic vacuoles, which were not apparent in both CSP and 3-MA groups. ICC viability was significantly increased by CSP and 3-MA interventions (P < 0.01), accompanied by a decrease in LC3 fluorescence (P < 0.01). Moreover, the expression levels of LC3II/I, Beclin1, and PI3KC3 were significantly decreased (all P < 0.01) with CSP and 3-MA treatment, while Bcl2 expression level was higher than that of the model group (P < 0.01). Thus, CSP can reduce autophagic damage by enhancing Bcl2 expression and downregulating the expression of LC3, Beclin1, and PI3KC3 to protect ICC. These results highlight the potential of CSP in the treatment of GI motility disorders.

• SEMA3F
• congenital
• pseudo-obstruction

Oriented smooth muscle layers in the intestine contract rhythmically due to the action of interstitial cells of Cajal (ICC) that serve as pacemakers of the intestine. Disruption of ICC networks has been reported in various intestinal motility disorders, which limit the quality and expectancy of life. A significant challenge in intestinal smooth muscle engineering is the rapid loss of function in cultured ICC and smooth muscle cells (SMC). Here we demonstrate a novel approach to maintain the function of both ICC and SMC in vitro. Primary intestinal SMC mixtures cultured on feeder cells seeded electrospun poly(3-caprolactone) scaffolds exhibited rhythmic contractions with directionality for over 10 weeks in vitro. The simplicity of this system should allow for wide usage in research on intestinal motility disorders and tissue engineering, and may prove to be a versatile platform for generating other types of functional SMC in vitro.

• abnormal differentiation
• excessive autophagy
• functional dyspepsia
• gastric dynamics
• myenteric interstitial cells of Cajal pathogenesis

This study assessed the efficacy and mechanism of action of Yangyin Runchang decoction (YRD) in the treatment of slow-transit constipation (STC). ICR mice were randomly divided into four groups (n = 10/group) and treated with saline (normal control; NC), atropine/diphenoxylate (model control; MC; 20 mg/kg), or atropine/diphenoxylate plus low-dose YRD (L-YRD; 29.6 g/kg) or high-dose YRD (H-YRD; 59.2 g/kg). Intestinal motility was assessed by evaluating feces and the intestinal transit rate (ITR). The serum level of stem cell factor (SCF) and changes in interstitial cells of Cajal (ICCs) were also evaluated. Additionally, the expression of SCF and c-kit and the intracellular Ca²⁺ concentration [Ca²⁺]_I were investigated. Fecal volume and ITR were greater in the L-YRD and H-YRD groups than in the MC group. The serum SCF level was lower in the MC group than in the NC group; this effect was ameliorated in the YRD-treated mice. Additionally, YRD-treated mice had more ICCs and elevated expression of c-kit and membrane-bound SCF, and YRD also increased [Ca²⁺]_I in vitro in isolated ICCs. YRD treatment in this STC mouse model was effective, possibly via the restoration of the SCF/c-kit pathway, increase in the ICC count, and enhancement of ICC function by increasing [Ca²⁺]_i.

• chemokine
• extracellular matrix
• fibroblast
• growth factor
• inflammatory bowel disease
• interleukin
• intestinal fibrosis
• myofibroblast

• chemokine
• extracellular matrix
• fibroblast
• growth factor
• inflammatory bowel disease
• interleukin
• intestinal fibrosis
• myofibroblast

• Animals
• Apoptosis
• Autophagy
• Cell Proliferation
• Cytokines/metabolism
• Fibroblasts/metabolism
• Fibroblasts/physiology
• Fibrosis
• Hematopoietic Stem Cells
• Humans
• Immune System/cytology
• Immune System/metabolism
• Inflammatory Bowel Diseases/complications
• Inflammatory Bowel Diseases/immunology
• Inflammatory Bowel Diseases/metabolism
• Intercellular Signaling Peptides and Proteins/metabolism
• Intestines/pathology
• Myocytes, Smooth Muscle/metabolism
• Myofibroblasts/metabolism
• Pericytes

• Aging
• Colon
• Interstitial cells of Cajal
• Nitric oxide synthase type I
• Rats, inbred F344

Patients with symptoms suggestive of gastroparesis exhibit several symptoms, such as epigastric pain, postprandial fullness, bloating and regurgitation. It is uncertain if such symptoms reflect underlying oesophageal motor disorder.

To examine whether patients with epigastric pain and postprandial distress syndrome suggestive of functional dyspepsia and/or gastroparesis also have concomitant oesophageal motility abnormalities and, if so, whether there are any associations between these disturbances.

In this retrospective cohort study, consecutive patients with functional gastrointestinal symptoms suggestive of gastric neuromuscular dysfunction (gastroparesis or functional dyspepsia) underwent clinical assessment, gastric scintigraphy, oesophageal high-resolution manometry and ambulatory pH monitoring using standard protocols.

We studied 61 patients with various functional upper gastrointestinal symptoms who underwent gastric scintigraphy, oesophageal high-resolution manometry and ambulatory pH monitoring. Forty-four patients exhibited gastroparesis by gastric scintigraphy. Oesophageal motility disorders were found in 68% and 42% of patients with or without scintigraphic evidence of gastroparesis respectively, suggesting of overlapping gastric and oesophageal neuromuscular disorder. Forty-three per cent of patients with gastroparesis had abnormal oesophageal acid exposure with mean % pH <4.0 of 7.5 in contrast to 38% of those symptomatic controls with normal gastric emptying, with mean %pH <4.0 of 5.4 (NS). Symptoms of epigastric pain, heartburn/regurgitation, bloating, nausea, vomiting, dysphagia, belching and weight loss could not distinguish patients with or without gastroparesis, although weight loss was significantly more prevalent and severe (p<0.002) in patients with gastroparesis. There was no relationship between oesophageal symptoms and motor or pH abnormalities in either groups.

Irrespective of gastric emptying delay by scintigraphy, patients with symptoms suggestive of gastric neuromuscular dysfunction have a high prevalence of oesophageal motor disorder and pathological oesophageal acid exposure that may contribute to their symptoms and may require therapy. High-resolution oesophageal manometry and pH monitoring are non-invasive and potentially useful in the assessment and management of these patients.

• functional bowel disorder
• motility disorders
• oesophageal disease

• anticholinergic drugs
• frequency domain
• gastrointestinal motility monitoring system
• interstitial cells of Cajal
• spatiotemporal analysis

Diabetic gastrointestinal dysfunction is a common complication in patients with diabetes mellitus. Most of the symptoms are related to impaired gastrointestinal function. The pathogenesis and etiology of diabetic gastroenteropathy are complex, involving the parasympathetic and sympathetic nervous systems, enteric neurons, smooth muscle cells, the network of interstitial cells of Cajal, cholinergic receptors and neuronal nitric oxide synthase. This article reviews the pathogenesis of diabetic gastrointestinal dysfunction.

• Diabetic gastrointestinal dysfunction
• Diabetic gastroparesis
• Diabetic enteropathy

• Diabetes mellitus
• Dysfunction
• Enteric nerves
• Gut microbiota
• Interstitial cells of Cajal
• Small and large bowel

• Animals
• Colon/physiopathology
• Diabetes Complications
• Diabetes Mellitus/physiopathology
• Enteric Nervous System
• Gastrointestinal Motility
• Humans
• Intestine, Small/physiopathology

• gastrointestinal motility
• human stomach
• resting membrane potentials
• slow wave potentials
• smooth muscle cell

• Brain injury
• estrogen
• estrogen receptor alpha agonist
• estrogen receptor beta agonist
• progesterone

Electroacupuncture (EA) is one of the techniques of acupuncture and is believed to be an effective alternative and complementary treatment in many disorders. The aims of this study were to investigate the effects and mechanisms of EA at acupoint Zusanli (ST36) on the plasticity of interstitial cells of Cajal (ICCs) in partial bowel obstruction.

A Sprague Dawley rat model of partial bowel obstruction was established and EA was conducted at Zusanli (ST36) and Yinglingquan (SP9) in test and control groups, respectively. Experiments were performed to study the effects and mechanisms of EA at Zusanli on intestinal myoelectric activity, distribution and alteration of ICCs, expression of inflammatory mediators, and c-Kit expression.

1) EA at Zusanli somewhat improved slow wave amplitude and frequency in the partial obstruction rats. 2) EA at Zusanli significantly stimulated the recovery of ICC networks and numbers. 3) the pro-inflammatory mediator TNF-α and NO activity were significantly reduced after EA at Zusanli, However, no significant changes were observed in the anti-inflammatory mediator IL-10 activity. 4) EA at Zusanli re-expressed c-Kit protein. However, EA at the control acupoint, SP9, significantly improved slow wave frequency and amplitude, but had no effect on ICC or inflammatory mediators.

We concluded that EA at Zusanli might have a therapeutic effect on ICC plasticity, and that this effect might be mediated via a decrease in pro-inflammatory mediators and through the c-Kit signaling pathway, but that the relationship between EA at different acupoints and myoelectric activity needs further study.

Fibrosis is a chronic and progressive process characterized by an excessive accumulation of extracellular matrix (ECM) leading to stiffening and/or scarring of the involved tissue. Intestinal fibrosis may develop in several different enteropathies, including inflammatory bowel disease. It develops through complex cell, extracellular matrix, cytokine and growth factor interactions. Distinct cell types are involved in intestinal fibrosis, such as resident mesenchymal cells (fibroblasts, myofibroblasts and smooth muscle cells) but also ECM-producing cells derived from epithelial and endothelial cells (through a process termed epithelial- and endothelial-mesenchymal transition), stellate cells, pericytes, local or bone marrow-derived stem cells. The most important soluble factors that regulate the activation of these cells include cytokines, chemokines, growth factors, components of the renin-angiotensin system, angiogenic factors, peroxisome proliferator-activated receptors, mammalian target of rapamycin, and products of oxidative stress. It soon becomes clear that although inflammation is responsible for triggering the onset of the fibrotic process, it only plays a minor role in the progression of this condition, as fibrosis may advance in a self-perpetuating fashion. Definition of the cellular and molecular mechanisms involved in intestinal fibrosis may provide the key to developing new therapeutic approaches.

• Inflammatory bowel disease
• Intestinal fibrosis
• Extracellular matrix
• Molecular mediators
• Myofibroblasts
• Inflammatory cells
• Epithelial cells
• Mesenchymal cells
• Endothelial cells

Inflammation and immune activation in the gut are usually accompanied by alteration of gastrointestinal (GI) motility. In infection, changes in motor function have been linked to host defense by enhancing the expulsion of the infectious agents. In this review, we describe the evidence for inflammation and immune activation in GI infection, inflammatory bowel disease, ileus, achalasia, eosinophilic esophagitis, microscopic colitis, celiac disease, pseudo-obstruction and functional GI disorders. We also describe the possible mechanisms by which inflammation and immune activation in the gut affect GI motility. GI motility disorder is a broad spectrum disturbance of GI physiology. Although several systems including central nerves, enteric nerves, interstitial cells of Cajal and smooth muscles contribute to a coordinated regulation of GI motility, smooth muscle probably plays the most important role. Thus, we focus on the relationship between activation of cytokines induced by adaptive immune response and alteration of GI smooth muscle contractility. Accumulated evidence has shown that Th1 and Th2 cytokines cause hypocontractility and hypercontractility of inflamed intestinal smooth muscle. Th1 cytokines downregulate CPI-17 and L-type Ca²⁺ channels and upregulate regulators of G protein signaling 4, which contributes to hypocontractility of inflamed intestinal smooth muscle. Conversely, Th2 cytokines cause hypercontractilty via signal transducer and activator of transcription 6 or mitogen-activated protein kinase signaling pathways. Th1 and Th2 cytokines have opposing effects on intestinal smooth muscle contraction via 5-hydroxytryptamine signaling. Understanding the immunological basis of altered GI motor function could lead to new therapeutic strategies for GI functional and inflammatory disorders.

• Cytokine
• Motility
• Inflammation
• Immunology

• Animals
• Diabetes Mellitus, Experimental/physiopathology
• Gastrointestinal Motility/physiology
• Interstitial Cells of Cajal/physiology
• Intestine, Small/physiology
• Intestine, Small/physiopathology
• Male
• Neuronal Plasticity/physiology
• Rats
• Rats, Wistar

• diabetes mellitus
• diabetic complications
• diabetic enteropathy
• iccs

• Animals
• Biological Clocks
• Humans
• Interstitial Cells of Cajal/physiology
• Kidney Pelvis/cytology
• Kidney Pelvis/physiology
• Ureter/cytology
• Ureter/physiology
• Urethra/cytology
• Urethra/physiology
• Urinary Bladder/cytology
• Urinary Bladder/physiology
• Urinary Bladder Diseases/pathology
• Urinary Bladder Diseases/physiopathology
• Urinary Tract/cytology

Interstitial cells of Cajal (ICC) are important players in the symphony of gut motility. They have a very significant physiological role orchestrating the normal peristaltic activity of the digestive system. They are the pacemaker cells in gastrointestinal (GI) muscles. Absence, reduction in number or altered integrity of the ICC network may have a dramatic effect on GI system motility. More understanding of ICC physiology will foster advances in physiology of gut motility which will help in a future breakthrough in the pharmacological interventions to restore normal motor function of GI tract. This mini review describes what is known about the physiologic function and role of ICCs in GI system motility and in a variety of GI system motility disorders.

• Interstitial cells of Cajal
• Gastrointestinal motility
• Peristalsis

• Adenoviridae/genetics
• Animals
• Basic Helix-Loop-Helix Transcription Factors/metabolism
• Cell Shape
• Colon/pathology
• Colon/ultrastructure
• Disease Models, Animal
• Gene Transfer Techniques
• HeLa Cells
• Humans
• Interstitial Cells of Cajal/pathology
• Interstitial Cells of Cajal/ultrastructure
• Leukemia/pathology
• Mice
• Mice, Inbred BALB C
• Proto-Oncogene Proteins c-kit/metabolism
• Recombination, Genetic
• Reproducibility of Results
• Staining and Labeling
• Stem Cells/metabolism

• colon
• constipation
• manometry
• scintigraphy
• marker studies