Distinct Patterns of Gene Expression Changes in the Colon and Striatum of Young Mice Overexpressing Alpha-Synuclein Support Parkinson's Disease as a Multi-System Process.

Background: Evidence supports a role for the gut-brain axis in Parkinson's disease (PD). Mice overexpressing human wild type α- synuclein (Thy1-haSyn) exhibit slow colonic transit prior to motor deficits, mirroring prodromal constipation in PD. Identifying molecular changes in the gut could provide both biomarkers for early diagnosis and gut-targeted therapies to prevent progression.

Experimental models of gut-first Parkinson's disease: A systematic review.

Background: There is strong support from studies in humans and in animal models that Parkinson's disease (PD) may begin in the gut. This brings about a unique opportunity for researchers in the field of neurogastroenterology to contribute to advancing the field and making contributions that could lead to the ability to diagnose and treat PD in the premotor stages. Lack of familiarity with some of the aspects of the experimental approaches used in these studies may present a barrier for neurogastroenterology researchers to enter the field.

Risk Factors for Abdominal Pain-Related Disorders of Gut-Brain Interaction in Adults and Children: A Systematic Review.

Background & Aims: Many studies have assessed risk factors of irritable bowel syndrome (IBS) and other abdominal pain-related disorders of gut-brain interaction (AP-DGBI); however, the role of these factors is unclear due to heterogeneous study designs. The aim of this systematic review was to extensively evaluate the literature and determine clinical risk and protective factors for the presence and persistence of AP-DGBI in children and adults.

Methods: A PubMed search identified studies investigating potential risk and protective factors for AP-DGBI in adults and children.

Latest Insights on the Pathogenesis of Irritable Bowel Syndrome.

The pathogenesis of irritable bowel syndrome is multifactorial and complex. Our understanding of its pathophysiology has evolved, but remains incompletely understood. Symptoms result from a dysregulation of brain-gut interactions.

The Colonic Mucosal MicroRNAs, MicroRNA-219a-5p, and MicroRNA-338-3p Are Downregulated in Irritable Bowel Syndrome and Are Associated With Barrier Function and MAPK Signaling.

Background & Aims: Alterations in microRNA (miRNA) and in the intestinal barrier are putative risk factors for irritable bowel syndrome (IBS). We aimed to identify differentially expressed colonic mucosal miRNAs, their targets in IBS compared to healthy controls (HCs), and putative downstream pathways.

Methods: Twenty-nine IBS patients (15 IBS with constipation [IBS-C], 14 IBS with diarrhea [IBS-D]), and 15 age-matched HCs underwent sigmoidoscopy with biopsies.

Importance of trauma-related fear in patients with irritable bowel syndrome and early adverse life events.

Background: Although early adverse life events (EALs) are prevalent among patients with irritable bowel syndrome (IBS), the impact of fear or dissociation experienced during the trauma has not been evaluated. We investigated the prevalence of fear at the time of trauma and its association with IBS status among individuals with early-life trauma before the age of 18.

Methods: Among participants with ≥1 EAL, association of fear and dissociation with IBS status was determined with logistic regression, and improvement in prediction of IBS over ETI score alone was determined with the likelihood ratio test.

Negative Events During Adulthood Are Associated With Symptom Severity and Altered Stress Response in Patients With Irritable Bowel Syndrome.

Background & Aims: Irritable bowel syndrome (IBS) is a stress-sensitive disorder associated with dysregulation of the hypothalamic-pituitary-adrenal axis. We studied the cumulative effect of events during adulthood on this pathway in patients with IBS.

Methods: We studied 129 patients with IBS, based on Rome III criteria (mean age 28.

Sigmoid colon mucosal gene expression supports alterations of neuronal signaling in irritable bowel syndrome with constipation.

Peripheral factors likely play a role in at least a subset of irritable bowel syndrome (IBS) patients. Few studies have investigated mucosal gene expression using an unbiased approach. Here, we performed mucosal gene profiling in a sex-balanced sample to identify relevant signaling pathways and gene networks and compare with publicly available profiling data from additional cohorts.

The effect of sex and irritable bowel syndrome on HPA axis response and peripheral glucocorticoid receptor expression.

Background And Aims: Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been reported in irritable bowel syndrome (IBS). Enhanced HPA axis response has been associated with reduced glucocorticoid receptor (GR) mediated negative feedback inhibition. We aimed to study the effects of IBS status, sex, or presence of early adverse life events (EAL) on the cortisol response to corticotropin-releasing factor (CRF) and adrenocorticotropic hormone (ACTH), and on GR mRNA expression in peripheral blood mononuclear cells (PBMCs).

Effects of linaclotide in patients with irritable bowel syndrome with constipation or chronic constipation: a meta-analysis.

Background & Aims: Linaclotide is a minimally absorbed, 14-amino acid peptide used to treat patients with irritable bowel syndrome with constipation (IBS-C) or chronic constipation (CC). We performed a meta-analysis to determine the efficacy of linaclotide, compared with placebo, for patients with IBS-C or CC.

Methods: MEDLINE, EMBASE, and the Cochrane central register of controlled trials were searched for randomized, placebo-controlled trials examining the effect of linaclotide in adults with IBS-C or CC.

Association between early adverse life events and irritable bowel syndrome.

Background & Aims: Although childhood and adult abuse are more prevalent among patients with irritable bowel syndrome (IBS) than healthy individuals (controls), other types of early adverse life events (EALs) have not been well characterized. We investigated whether different types of EALs, before age 18 years, are more prevalent among patients with IBS, and the effects of sex and nongastrointestinal symptoms on the relationship between EALs and IBS.

Methods: EALs were evaluated in 294 IBS patients (79% women) and 435 controls (77% women) using the Early Trauma Inventory Self-Report Form, which delineates subcategories of general trauma and physical, emotional, and sexual abuse.

Serum and colonic mucosal immune markers in irritable bowel syndrome.

Objectives: Low-grade colonic mucosal inflammation has been postulated to have an important role in the pathophysiology of irritable bowel syndrome (IBS). The objectives of this study were (i) to identify serum and tissue-based immunological and neuroendocrine markers associated with mucosal inflammation in male (M) and female (F) patients with non-post-infectious IBS (non-PI-IBS) compared with healthy controls and (ii) to assess possible correlations of such markers with IBS symptoms.

Methods: Sigmoid mucosal biopsies were obtained from 45 Rome II positive IBS patients without a history of PI-IBS (26 F, 35.

Childhood trauma is associated with hypothalamic-pituitary-adrenal axis responsiveness in irritable bowel syndrome.

Background & Aims: A history of early adverse life events (EALs) is associated with a poorer outcome and higher levels of distress in adult patients with functional gastrointestinal disorders. An EAL is thought to predispose individuals to develop a range of chronic illnesses by inducing persistent changes in the central stress response systems, including the hypothalamic-pituitary-adrenal (HPA) axis. We sought to determine if EALs affect the HPA axis response to a visceral stressor in irritable bowel syndrome (IBS) patients and healthy controls, and to determine if this is affected by sex or related to symptoms or quality of life.

Stress hormones and post-traumatic stress disorder in civilian trauma victims: a longitudinal study. Part I: HPA axis responses.

The aim of the study was to evaluate the association between post-traumatic disorder (PTSD) and hypothalamic-pituitary-adrenal (HPA) axis responses to the triggering trauma. A companion paper evaluates the adrenergic response and interactions between the two. We measured plasma and saliva cortisol, hourly urinary excretion of cortisol, plasma levels of adrenocorticotropin (ACTH), and the leukocyte glucocorticoid receptor (GR) density of 155 non-injured survivors of traumatic events (91 males and 64 females; 125 road traffic accidents, 19 terrorist attacks, 11 others).

Stress hormones and post-traumatic stress disorder in civilian trauma victims: a longitudinal study. Part II: the adrenergic response.

The aim of the study was to prospectively evaluate the association between the occurrence of post-traumatic stress disorder (PTSD) and the adrenergic response to the traumatic event, and additionally, to explore the link between PTSD and the initial norepinephrine:cortisol ratio. Plasma levels and urinary excretion of norepinephrine (NE) were measured in 155 survivors of traumatic events during their admission to a general hospital emergency room (ER) and at 10 d, 1 month and 5 months later. Symptoms of peri-traumatic dissociation, PTSD and depression were assessed in each follow-up session.

Irritable bowel syndrome: current approach to symptoms, evaluation, and treatment.

There are frequent advances in knowledge about the clinical presentation, pathophysiology, and treatment of irritable bowel syndrome. It is important for clinicians to be aware of available therapies and the supporting evidence for those therapies to increase patient satisfaction. This is best achieved with a collaborative and long-term clinician-patient relationship and mutual commitment to modify therapy and try new modalities until the greatest relief of symptoms and improvement in health-related quality of life is achieved.

Identification of a molecular recognition role for the activation loop phosphotyrosine of the SRC tyrosine kinase.

A human cDNA phage display library screen, using a phosphopeptide designed to mimic the activation loop phosphotyrosine of the Src tyrosine kinase, has identified the N-terminal SH2 domain of the p85 regulatory subunit of phosphatidyl inositol-3 kinase (PI3K) as an interacting recognition domain. Activation loop phosphorylation is known to play a conformational role in kinase activation, but is largely not thought to play a role in protein/protein recognition. Affinity chromatography and biochemical evaluation in mouse fibroblast cells has confirmed the dependence of this interaction on both the Src activation loop phosphotyrosine and the N-terminal SH2 domain of PI3K.

Two-dimensional diversity: screening human cDNA phage display libraries with a random diversity probe for the display cloning of phosphotyrosine binding domains.

A random phosphopeptide probe (bio-pYZZZ) has been used for the isolation and identification of multiple SH2 domains from human cDNA-displaying phage libraries. In addition, on-phage analysis and quantification of binding affinities for these phage-displayed proteins has shown them to be functional domains, retaining the same characteristics as in their native state.