Pathophysiology Of Gastrointestinal Diseases Research Articles

Decoding spatiotemporal transcriptional dynamics and epithelial fibroblast crosstalk during gastroesophageal junction development through single cell analysis

The gastroesophageal squamocolumnar junction (GE-SCJ) is a critical tissue interface between the esophagus and stomach, with significant relevance in the pathophysiology of gastrointestinal diseases. Despite this, the molecular mechanisms underlying GE-SCJ development remain unclear. Using single-cell transcriptomics, organoids, and spatial analysis, we examine the cellular heterogeneity and spatiotemporal dynamics of GE-SCJ development from embryonic to adult mice. We identify distinct transcriptional states and signaling pathways in the epithelial and mesenchymal compartments of the esophagus and stomach during development. Fibroblast-epithelial interactions are mediated by various signaling pathways, including WNT, BMP, TGF-β, FGF, EGF, and PDGF. Our results suggest that fibroblasts predominantly send FGF and TGF-β signals to the epithelia, while epithelial cells mainly send PDGF and EGF signals to fibroblasts. We observe differences in the ligands and receptors involved in cell-cell communication between the esophagus and stomach. Our findings provide insights into the molecular mechanisms underlying GE-SCJ development and fibroblast-epithelial crosstalk involved, paving the way to elucidate mechanisms during adaptive metaplasia development and carcinogenesis.

The importance of the microbiome and metabolome in health and disease of dogs and cats

The canine intestinal tract harbors a highly complex microbial ecosystem. Various studies have reported changes in microbial communities in acute and chronic gastrointestinal diseases, especially in inflammatory bowel disease (IBD) and acute diarrhea. Most commonly observed are decreases in the bacterial phyla Firmicutes (i.e., Lachnospiraceae, Ruminococcaceae, Faecalibacterium) and Bacteroidetes, with concurrent increases in Proteobacteria (i.e. Escherichia coli). Due to the importance of microbial and host derived metabolites for intestinal health, it is important to better understand the functional consequences of microbial dysbiosis. Novel approaches such as shotgun sequencing of DNA allow describing the functional changes in the bacterial metagenome in gastrointestinal disease. Furthermore, wide scale and untargeted measurements of metabolic products derived by the host and the microbiota in intestinal samples allow a better understanding of the functional alterations that occur in gastrointestinal disease. For example, changes in bile acid metabolism, short-chain fatty acid concentrations, and tryptophan pathways have recently been reported in humans and dogs. Also, metabolites associated with the pentose phosphate pathway were reported to be differentially expressed in gastrointestinal inflammation and indicate the presence of oxidative stress in dogs with IBD. Of interest is that these changes did not correlate with clinical activity, suggesting the presence of ongoing inflammation. Better understanding of the interactions of microbial-derived metabolites and the host will yield insights into the pathophysiology of gastrointestinal diseases and may be a new avenue for therapeutic approaches. Furthermore, some of these metabolic pathways can be used for monitoring of therapy success.

Quiet but powerful: the role of the enteric nervous system in the pathophysiology of gastrointestinal disease (214.1)

The enteric nervous system (ENS) is large, complex, and uniquely able to function independently of the CNS. The ENS is also essential and, when defective, causes disorders of gastrointestinal (GI) motility, secretion, inflammation, and/or infection. Although the ENS is neural crest‐ and the CNS is neural tube‐derived, many developmental processes and molecules are common to both systems. Disruptions of GI function thus frequently occur together with cognitive/behavioral abnormalities as components of disorders (such as Parkinson's and autism) that affect both ENS and CNS. Serotonin (5‐HT) is a molecule that both gut and CNS express. Enteric 5‐HT is stored in enteroendocrine (EC) cells and neurons and participates in peristaltic reflexes, secretion, crypt cell proliferation, GI inflammation, neurotransmission, ENS development, and neurogenesis. EC cell and neuronal 5‐HT biosynthesis depend, respectively on tryptophan hydroxylase 1 (TPH1) and TPH2. A high affinity 5‐HT transporter (SERT) inactivates both mucosal and neuronal 5‐HT. Selective deletion of the TPH’s has enabled roles of EC cell and neuronal 5‐HT to be distinguished. Studies of mice that lack SERT, or which express SERT mutations associated with human disorders, confirm that enteric 5‐HT is multifunctional and link 5‐HT to the pathogenesis of GI manifestations of autism and functional GI disease.

Role of Ghrelin in the Pathophysiology of Gastrointestinal Disease

Ghrelin is a 28-amino-acid peptide that plays multiple roles in humans and other mammals. The functions of ghrelin include food intake regulation, gastrointestinal (GI) motility, and acid secretion by the GI tract. Many GI disorders involving infection, inflammation, and malignancy are also correlated with altered ghrelin production and secretion. Although suppressed ghrelin responses have already been observed in various GI disorders, such as chronic gastritis, Helicobacter pylori infection, irritable bowel syndrome, functional dyspepsia, and cachexia, elevated ghrelin responses have also been reported in celiac disease and inflammatory bowel disease. Moreover, we recently reported that decreased fasting and postprandial ghrelin levels were observed in female patients with functional dyspepsia compared with healthy subjects. These alterations of ghrelin responses were significantly correlated with meal-related symptoms (bloating and early satiation) in female functional dyspepsia patients. We therefore support the notion that abnormal ghrelin responses may play important roles in various GI disorders. Furthermore, human clinical trials and animal studies involving the administration of ghrelin or its receptor agonists have shown promising improvements in gastroparesis, anorexia, and cancer. This review summarizes the impact of ghrelin, its family of peptides, and its receptors on GI diseases and proposes ghrelin modulation as a potential therapy.

The most important diagnostic modalities for Helicobacter pylori, now and in the future

CURRENT DIAGNOSTIC METHODS: Helicobacter pylori infection plays a central role in the pathophysiology of gastrointestinal disease, and its accurate diagnosis and successful eradication is crucial in a wide range of different circumstances. Currently, serology is recommended for initial screening, followed by histology and/or culture to confirm the diagnosis before treatment. Since H. pylori is developing greater resistance to certain antibiotics, culture is becoming increasingly important in some populations to test for susceptibility to antibiotics. To confirm eradication after treatment, the urea breath test is used. This test is presently the best non-invasive test to determine eradication. NEW APPROACHES: Considerable efforts are being made to improve diagnostic methods, and a host of new or improved approaches can be expected in the near future. For general screening, tests are being developed that use whole blood and can be used by general practitioners to give rapid results in a cost-effective manner. The evidence so far suggests that these new 'office' tests are not as accurate as laboratory tests, but they are nevertheless important for general diagnostic purposes. Serological tests for cagA antibodies and immunoblot tests are also under development. New biopsy-based tests include the development of a true rapid urease test which will give accurate results in 1 h. Polymerase chain reaction/DNA enzyme immunoassay detection is another field receiving attention. Non-invasive direct tests of the future are likely to include the use of the polymerase chain reaction in faeces. This paper reviews current diagnostic modalities for H. pylori and gives an overview of expected future developments.

Nanomedicine in GI

Recent advances in nanotechnology offer new hope for disease detection, prevention, and treatment. Nanomedicine is a rapidly evolving field wherein targeted therapeutic approaches using nanotechnology based on the pathophysiology of gastrointestinal diseases are being developed. Nanoparticle vectors capable of delivering drugs specifically and exclusively to regions of the gastrointestinal tract affected by disease for a prolonged period of time are likely to significantly reduce the side effects of existing otherwise effective treatments. This review aims at integrating various applications of the most recently developed nanomaterials that have tremendous potential for the detection and treatment of gastrointestinal diseases.

Glial Cell–Derived Neurotrophic Factor Enhances Synaptic Communication and 5-Hydroxytryptamine 3a Receptor Expression in Enteric Neurons

Glial cell-derived neurotrophic factor (GDNF) is essential for the development of the enteric nervous system during embryogenesis. We have observed the presence of Gdnf transcripts in the gastrointestinal tract of adult mice, and its early up-regulation after inflammation. We therefore investigated the effects of GDNF on enteric neuronal function in vitro. Primary neuronal cultures were established from isolated myenteric plexi, and characterized by immunostaining and Ca(2+) imaging. Gene expression of several ion channels was analyzed by quantitative polymerase chain reaction (PCR) and the electrophysiologic properties of the neurons were studied by patch clamp. GDNF enhanced synaptogenesis and intercellular communication in primary myenteric neuronal cultures. Expression profiling revealed that GDNF exposure results in an up-regulation of Htr3a expression in the cultures and a similar increase was observed in inflamed colonic tissue where Gdnf expression was also increased. The increased Htr3a expression was accompanied by a functional increase in the response of neurons to acute challenge with 5-hydroxytryptamine (5-HT). GDNF treatment also caused inhibition of delayed rectifying voltage-gated potassium (Kv) currents, which correlated with the up-regulation of Htr3a and 5-HT-induced responses. Furthermore, pharmacologic blockade of Kv channels mimicked the effect of GDNF by increasing Htr3a expression as well as enhancing 5-HT-induced responses in the cultured myenteric neurons. GDNF promotes synaptic communication in cultured myenteric neurons. It also up-regulates 5-HT(3a)-receptor expression via modulation of Kv channel activity. Up-regulation of Gdnf after gastrointestinal inflammation might play an important role in the pathophysiology of gastrointestinal diseases.

Neuropeptides, Mesenteric Fat, and Intestinal Inflammation

The ability of fat tissue cells to produce proinflammatory cytokines and the concept that obesity represents a low-grade inflammatory response have been well documented during the past decade. The effects of fat-mediated inflammation on metabolic pathologies have also been drawing increasing interest. However, very little is known on the potential effects of adipose tissue in the pathophysiology of gastrointestinal diseases with an inflammatory component, such as inflammatory bowel disease (IBD). The development of large fat masses around the inflamed intestine during Crohn's disease makes this tissue a candidate for more intense investigation in studies aiming to gain insights into the pathogenesis and progress of the disease. Furthermore, neuropeptides act in many cases in a proinflammatory manner and are shown to participate in the pathogenesis of intestinal inflammation in animal models of IBD. However, the potential of these molecules to interact with fat cells in the context of IBD has not been investigated. In this review the authors' most recent data related to the effects of neuropeptides on noninflammatory fat tissue components are described. In addition, a discussion to associate neuropeptide-induced, adipose tissue-mediated responses with the generation of intestinal inflammatory conditions such as Crohn's disease is included.

GASTROINTESTINAL ENDOCANNABINOID SYSTEM: MULTIFACETED ROLES IN THE HEALTHY AND INFLAMED INTESTINE

1. The endogenous cannabinoid (endocannabinoid) system is emerging as a key modulator of intestinal physiology, influencing motility, secretion, epithelial integrity and immune function in the gut, in addition to influencing satiety and emesis. 2. Accumulating evidence suggests that the endocannabinoid system may play a pivotal role in the pathophysiology of gastrointestinal disease, particularly in the light of recent studies demonstrating an effect of endocannabinoids on the development of experimental inflammation and linkages with functional clinical disorders characterized by altered motility. 3. The predominant endocannabinoids, anandamide and 2-arachidonoylglycerol, not only mediate their effects via two recognized cannabinoid receptor subtypes, namely CB(1) and CB(2), but emerging evidence now shows they are also substrates for cyclo-oxygenase (COX)-2, generating a distinct and novel class of prostaglandin ethanolamides (prostamides) and prostaglandin glycerol esters. These compounds are bioactive and may mediate an array of biological effects distinct to those of conventional prostanoids. 4. The effects of prostamides on gastrointestinal motility, secretion, sensation and immune function have not been characterized extensively. Prostamides may play an important role in gastrointestinal inflammation, particularly given the enhanced expression of both COX-2 and endocannabinoids that occurs in the inflamed gut. 5. Further preclinical studies are needed to determine the therapeutic potential of drugs targeting the endocannabinoid system in functional and inflammatory gut disorders, to assist with the determination of feasibility for clinical translation.

Neurotrophin regulation of development of vagal innervation of the gastrointestinal tract

Despite the importance of vagal sensory innervation of the gastrointestinal (GI) tract, little is known about its development. Moreover, there has been little investigation of potential roles of altered vagal development in the pathophysiology of GI diseases with a neurodevelopmental origin, such as irritable bowel syndrome, or in eating disorders, including obesities resulting from abnormal hormonal or nutritional pre- and post-natal environments. Therefore, we are investigating genetic controls of vagal development and exploring conditional gene targeting strategies for examining the effects of altered vagal development on GI function and feeding.

Interstitial Cells of Cajal and their Role in Veterinary Gastrointestinal Pathologies

This study highlights the importance of interstitial cells of Cajal (ICs) in gastrointestinal disease. Human research is already considering IC pathologies but in veterinary research IC pathologies are rarely studied. Nevertheless, recent studies of ICs show a growing interest in the pathophysiology of gastrointestinal diseases and emphasize the consideration of this cell type in the pathophysiology of veterinary gastrointestinal malfunctions.

Genetic polymorphisms of human flavin-containing monooxygenase 3: implications for drug metabolism and clinical perspectives.

Flavin-containing monooxygenase 3 (FMO3) is a hepatic microsomal enzyme that oxidizes a host of drugs, xenobiotics and other chemicals. Numerous variants in the gene encoding FMO3 have been identified, some of which result in altered enzymatic activity and, consequently, altered substrate metabolism. Studies also implicate individual and ethnic differences in the frequency of FMO3 polymorphisms. In addition, new variants continue to be identified with potentially important clinical implications. For example, the role of FMO3 variants in the pathophysiology of gastrointestinal diseases is an evolving area of research. Two commonly occurring polymorphisms of FMO3, E158K and E308G, have been associated with a reduction in polyp burden in patients with familial adenomatous polyposis who were treated with sulindac sulfide, an FMO3 substrate. These findings suggest a potential role for prospective genotyping of common FMO3 polymorphisms in the treatment of disease states that involve the use of drugs metabolized by FMO3. This review summarizes the current state of research on the genetic polymorphisms of FMO3, with a focus on their clinical implications in gastrointestinal diseases.

Pathophysiology of Gastrointestinal Diseases.

Pathophysiology of Gastrointestinal Diseases. Get access Chopra S., and May R. J., (eds.) Pathophysiology of Gastrointestinal Diseases.2nd ed. Boston: Little Brown & Co. 1989. Price $37.50. John Craig, M.D. PH.D. John Craig, M.D. PH.D. St. Luke Hospital Pasadena, California Search for other works by this author on: Oxford Academic Google Scholar American Journal of Clinical Pathology, Volume 95, Issue 6, 1 June 1991, Pages 898–899, https://doi.org/10.1093/ajcp/95.6.898a Published: 01 June 1991

Alimentary Tract Roentgenology.

In the six years since Margulis and Burhenne's Alimentary Tract Roentgenology was first printed, it has established itself as a basic reference for all practicing radiologists, radiology residents and other physicians involved in the diseases of the gastrointestinal tract. During this interval new techniques and new concepts have been developed, new insights into the pathophysiology of gastrointestinal disease have been formed, and the role of the radiologist in the diagnosis and overall management of gastrointestinal disease has substantially expanded. These changes are reflected in the second edition of Alimentary Tract Roentgenology which became available in the fall of 1973. The new text is approximately 500 pages longer, the number of illustrations is more than double while avoiding duplication of content, and the index has been expanded from 15 to 42 pages, greatly enhancing the usefulness of the text as a rapid reference source. Two new chapters on physiology provide clear, concise, and up-to-date information on the normal mechanisms involved in digestion and absorption. Emphasis on the radiographic correlation with pathophysiology is initiated here and continued throughout much of the new material. Sections dealing with pathology have now been integrated into each separate anatomical division, thereby increasing its exposure and utilization, while serving to emphasize the close relationship that must exist between the two diagnostic methods. New chapters dealing with abdominal trauma and motility disorders of the esophagus fill a void which had detracted from the overall value of the first edition. The chapter on colonic polyps has been brought up-to-date with a concise discussion of the polyposis syndromes. A major addition to the section on the liver and biliary tract is Arthur Clemett's new chapter, in which he uniquely combines cholangiography, arteriography and portography, isotope scanning, barium contrast and plain film studies to clearly portray a host of congenital, inflammatory, vascular, and neoplastic abnormalities of the liver and biliary tree. Burhenne's chapter on the biliary tract includes a discussion on the removal of retained common duct stones, a technique of immense clinical value. Its recognition and inclusion in this text will assist greatly in the widespread application of this exciting technique. The increased use of arteriography in the abdomen is reflected in the expanded chapter devoted to this topic. The illustrations are excellent and the bibliography is current. In summary, this new edition of Alimentary Tract Roentgenology has substantially increased in value over the original text as an inclusive reference work on the radiology of gastrointestinal disease. It belongs in every radiologist's library.