LeeAnne B. Sherwin

Neuroimaging the brain-gut axis in patients with irritable bowel syndrome

AIM To summarize and synthesize current literature on neuroimaging the brain-gut axis in patients with irritable bowel syndrome (IBS). METHODS A database search for relevant literature was conducted using PubMed, Scopus and Embase in February 2015. Date filters were applied from the year 2009 and onward, and studies were limited to those written in the English language and those performed upon human subjects. The initial search yielded 797 articles, out of which 38 were pulled for full text review and 27 were included for study analysis. Investigations were reviewed to determine study design, methodology and results, and data points were placed in tabular format to facilitate analysis of study findings across disparate investigations. RESULTS Analysis of study data resulted in the abstraction of four key themes: Neurohormonal differences, anatomic measurements of brain structure and connectivity, differences in functional responsiveness of the brain during rectal distention, and confounding/correlating patient factors. Studies in this review noted alterations of glutamate in the left hippocampus (HIPP), commonalities across IBS subjects in terms of brain oscillation patterns, cortical thickness/gray matter volume differences, and neuroanatomical regions with increased activation in patients with IBS: Anterior cingulate cortex, mid cingulate cortex, amygdala, anterior insula, posterior insula and prefrontal cortex. A striking finding among interventions was the substantial influence that patient variables (e.g., sex, psychological and disease related factors) had upon the identification of neuroanatomical differences in structure and connectivity. CONCLUSION The field of neuroimaging can provide insight into underlying physiological differences that distinguish patients with IBS from a healthy population.

Effect of Illness Representations and Catastrophizing on Quality of Life in Adults With Irritable Bowel Syndrome

There is limited understanding of the influence of psychosocial factors on irritable bowel syndrome (IBS), which contributes to management difficulties and ineffective long-term treatment. The goal of the current study was to assess the effect illness representations and coping had on health-related quality of life (HRQOL) in adults with IBS. Self-report data were collected from 101 adults with IBS. Illness representations were measured with the Revised Illness Perception Questionnaire; catastrophizing was measured with the catastrophizing subscale of the Coping Strategies Questionnaire; and HRQOL was measured using the IBS-Quality of Life Measure. Participants perceived their IBS to be a chronic, cyclical condition with negative consequences, moderate symptomatology, and strong negative emotional impact. Their quality of life was poor and catastrophic thinking was noted to be used. Therefore, integrating illness beliefs and coping style into the management of IBS may improve well-being and minimize suffering. [Journal of Psychosocial Nursing and Mental Health Services, 54(9), 44-53.].

The microbiome of the oral mucosa in irritable bowel syndrome

abstract Irritable bowel syndrome (IBS) is a poorly understood disorder characterized by persistent symptoms, including visceral pain. Studies have demonstrated oral microbiome differences in inflammatory bowel diseases suggesting the potential of the oral microbiome in the study of non-oral conditions. In this exploratory study we examine whether differences exist in the oral microbiome of IBS participants and healthy controls, and whether the oral microbiome relates to symptom severity. The oral buccal mucosal microbiome of 38 participants was characterized using PhyloChip microarrays. The severity of visceral pain was assessed by orally administering a gastrointestinal test solution. Participants self-reported their induced visceral pain. Pain severity was highest in IBS participants (P = 0.0002), particularly IBS-overweight participants (P = 0.02), and was robustly correlated to the abundance of 60 OTUs, 4 genera, 5 families and 4 orders of bacteria (r2 > 0.4, P < 0.001). IBS-overweight participants showed decreased richness in the phylum Bacteroidetes (P = 0.007) and the genus Bacillus (P = 0.008). Analysis of β-diversity found significant separation of the IBS-overweight group (P < 0.05). Our oral microbial results are concordant with described fecal and colonic microbiome-IBS and -weight associations. Having IBS and being overweight, rather than IBS-subtypes, was the most important factor in describing the severity of visceral pain and variation in the microbiome. Pain severity was strongly correlated to the abundance of many taxa, suggesting the potential of the oral microbiome in diagnosis and patient phenotyping. The oral microbiome has potential as a source of microbial information in IBS.

Altered vasoactive intestinal peptides expression in irritable bowel syndrome patients and rats with trinitrobenzene sulfonic acid-induced colitis.

AIM To investigate the vasoactive intestinal peptides (VIP) expression in irritable bowel syndrome (IBS) and trinitrobenzene sulfonic acid (TNBS) induced colitis. METHODS The VIP gene expression and protein plasma levels were measured in adult participants (45.8% male) who met Rome III criteria for IBS for longer than 6 mo and in a rat model of colitis as induced by TNBS. Plasma and colons were collected from naïve and inflamed rats. Markers assessing inflammation (i.e., weight changes and myeloperoxidase levels) were assessed on days 2, 7, 14 and 28 and compared to controls. Visceral hypersensitivity of the rats was assessed with colo-rectal distension and mechanical threshold testing on hind paws. IBS patients (n = 12) were age, gender, race, and BMI-matched with healthy controls (n = 12). Peripheral whole blood and plasma from fasting participants was collected and VIP plasma levels were assayed using a VIP peptide-enzyme immunoassay. Human gene expression of VIP was analyzed using a custom PCR array. RESULTS TNBS induced colitis in the rats was confirmed with weight loss (13.7 ± 3.2 g) and increased myeloperoxidase activity. Visceral hypersensitivity to colo-rectal distension was increased in TNBS treated rats up to 21 d and resolved by day 28. Somatic hypersensitivity was also increased up to 14 d post TNBS induction of colitis. The expression of an inflammatory marker myeloperoxidase was significantly elevated in the intracellular granules of neutrophils in rat models following TNBS treatment compared to naïve rats. This confirmed the induction of inflammation in rats following TNBS treatment. VIP plasma concentration was significantly increased in rats following TNBS treatment as compared to naïve animals (P < 0.05). Likewise, the VIP gene expression from peripheral whole blood was significantly upregulated by 2.91-fold in IBS patients when compared to controls (P < 0.00001; 95%CI). VIP plasma protein was not significantly different when compared with controls (P = 0.193). CONCLUSION Alterations in VIP expression may play a role in IBS. Therefore, a better understanding of the physiology of VIP could lead to new therapeutics.

Gender and Weight Influence Quality of Life in Irritable Bowel Syndrome

Irritable bowel syndrome (IBS) is a common gastrointestinal disorder characterized by abdominal pain and bowel dysfunction in the absence of structural abnormality. Diagnosis can be challenging and often leads to extensive medical tests, non-effective therapeutic modalities, and reduced quality of life (QOL). Identifying factors associated with dysfunction have the potential to enhance outcomes. Participants with IBS (n = 41) and healthy volunteers (n = 74) were recruited into this cross-sectional, descriptive, natural history protocol at the National Institute of Health, Clinical Center. Demographic characteristics were self-reported. QOL was assessed with the Irritable Bowel Syndrome Quality of Life (IBS-QOL) questionnaire. Statistical analysis included descriptive statistics, factorial ANOVA, and multiple regression. Individuals with IBS reported lower QOL scores across all QOL-subscales compared to healthy controls. Normal-weight women and overweight men with IBS reported the greatest QOL impairment. Body fat percent had confounding effects on the relationship between IBS and QOL. The disparity between QOL scores in participants with IBS by both gender and weight groups may reflect different social pressures perceived by normal and overweight women and men. These findings enhance the recognition of the disparities in patients with chronic symptoms and thereby lead to personalized assessment and interventions to improve their QOL.

The Gastrointestinal Pain Pointer: A Valid and Innovative Method to Assess Gastrointestinal Symptoms.

Abdominal pain is a chronic condition experienced by approximately 20% of individuals in the United States. The purpose of the study was to assess the validity of the Gastrointestinal Pain Pointer as a measure of abdominal pain intensity. A prospective longitudinal time-series study design was utilized. The sample included 93 outpatients (58.1% female). Participants met Rome III criteria for irritable bowel syndrome (n = 32) or were healthy controls (n = 61). The Gastrointestinal Pain Pointer, a new electronic pain assessment tool, was used to assess self-reported abdominal pain intensity among participants before and after ingestion of an intestinal permeability test solution across 11 time points over a 5-hour time period. The results were compared with the Short-Form McGill Pain Questionnaire. The Gastrointestinal Pain Pointer was found to be valid in the assessment of abdominal pain intensity. The tool is a novel and valid measure of abdominal pain intensity that enhances the ability for clinicians to better quantify, in real time, patient-related pain outcomes for both clinical care and research.

Colon Epithelial MicroRNA Network in Fatty Liver

Background & Aims Intestinal barrier alterations are associated with fatty liver (FL) and metabolic syndrome (MetS), but microRNA (miR) signaling pathways in MetS-FL pathogenesis remain unclear. This study investigates an epithelial-focused miR network in colorectal cell models based on the previously reported MetS-FL miR trio of hsa-miR-142-3p, hsa-miR-18b, and hsa-miR-890. Methods Each miR mimic construct of MetS-FL miR trio was transfected into human colorectal cells, CRL-1790 or Caco-2. Global miRNome changes posttransfection were profiled (nCounter® Human v3 miRNA, NanoString Technologies). Changes in barrier (transepithelial electrical resistance, TEER) and epithelial cell junction structure (Occludin and Zona Occludens-1/ZO-1 immunofluorescence staining-confocal microscopy) were examined pre- and posttransfection in Caco-2 cell monolayers. A signaling network was constructed from the MetS-FL miR trio, MetS-FL miR-induced colorectal miRNome changes, ZO-1, and Occludin. Results Transfection of CRL-1790 cells with each MetS-FL miR mimic led to global changes in the cellular miRNome profile, with 288 miRs being altered in expression by more than twofold. Eleven miRs with known cytoskeletal and metabolic roles were commonly altered in expression by all three miR mimics. Transfection of Caco-2 cell monolayers with each MetS-FL miR mimic induced barrier-associated TEER variations and led to structural modifications of ZO-1 and Occludin within epithelial cell junctions. Pathway analysis incorporating the MetS-FL miR trio, eleven common target miRs, ZO-1, and Occludin revealed a signaling network centered on TNF and AKT2, which highlights injury, inflammation, and hyperplasia. Conclusions Colon-specific changes in epithelial barriers, cell junction structure, and a miRNome signaling network are described from functional studies of a MetS-FL miR trio signature.

Data supporting the effects of lysozyme on mRNA and protein expression in a colonic epithelial scratch wound model

Colonic epithelial health is implicated in a host of gastrointestinal (GI) diseases and disorders. Lysozyme is suspected to play a role in the ability of the epithelium to recover from injury (Abey et al., in press; Gallo, 2012; Rubio, 2014) [1], [2], [3]. Disrupted repair mechanisms may lead to delayed or ineffective recovery and disruptions to epithelial biology resulting in GI symptoms and altered barrier function (Peterson and Artis, 2014) [4]. The effect of lysozyme on the transcriptomic and proteomic profile of healthy colonic epithelial cells was investigated. Epithelial cells in culture were scratch wounded and treated with lysozyme. mRNA and protein profiles were simultaneously quantified in the same sample using a digital counting technology. Gene and protein expressions altered by the presence or absence of lysozyme are described in this article. Extensive statistical and bioinformatic analysis, and interpretation of the results can be found in “Lysozyme association with circulating RNA, extracellular vesicles, and chronic stress” (Abey et al., in press) [1].

Mo2040 Experimentally Induced Visceral Pain, Variation in the Microbiome, and Host Gene Expression in Irritable Bowel Syndrome

Male Wistar rats were exposed to 1 hour of water avoidance stress (WA) each day over a 10 day period (12 stressed and 12 controls). Visceral hypersensitivity was determined using colorectal distension and electromyographic recording. Animals were sacrificed at the end of the experimental protocol and colonic tissue was dissected out. The colonic epithelium was mechanically separated and DNA and RNA was isolated. Hypervariable bacterial 16S RNA regions were amplified (V3 and V4) and sequenced on an IonTorrent PGM. Host colonic epithelial mRNA (13 stressed and 12 controls) was hybridized to Affymetrix GeneChip® Rat Gene 2.0 ST Arrays for whole genome gene expression determination. Results: WA animals showed increased bacterial richness compared to healthy controls (HC). Proteobacteria and Actinobacteria were significantly enriched inWA animals. 2991 bacterial operational taxonomic units (OTUs) were significantly differentially expressed. Of these 61% were over expressed in WA animals. All differentially expressed OTUs belonging to the families Rikenellaceae and Porphyromonadaceae (20% of OTUs) were down regulated inWA animals. Almost all differentially expressed OTUs belonging to the families Weeksellaceae, S24-7, Comamonadaceae, Lachnospiraceae, Moraxellaceae and Pseudomonadaceae (39% of OTUs) were over expressed in WA animals. Using a novel analytical methodology (maximum parsimony analysis) 32 changes in gene expression which are implicated or associated with inflammation were identified. Genes that showed the most uniform change in expression included Anxa5, Csnk2a1, Ddx19a, Hnf1a, Hoxc4, Igfbp7, Kcnh2, Map6d1, RT-M6-2, Stard10 and Vtcn1. Discussion: Bacterial richness showed the opposite of what is generally observed in disease conditions. WA animals were characterized by bacterial over expression. Specifically, families which contain butyrate producing taxa are over expressed. Although butyrate is essential for colonic mucosal health it is known to cause concentration dependent colonic hypersensitivity in rats. The expression of the proinflammatory gene Vtcn1 can be modulated by butyrate suggesting a functional link with changes in microbial expression. Microbial dysbiosis in chronically stressed animals is associated with gene expression changes in the colonic mucosa which implicate inflammatory pathways. Possible relationships between the identified genes and specific bacterial groups and species remain to be further elucidated and offer a rich source of future research.

Sa1185 Dysbiosis of the Mucosa-Adherent Microbiome in Patients With Irritable Bowel Syndrome

Background: Functional Gastrointestinal Disorders (FGIDs) are identified by the dominant presenting symptoms: functional heartburn (FH), irritable bowel syndrome (IBS), dyspepsia, etc. This nomenclature assumes an organ-specific origin of symptoms rather than symptoms associated with a common pathophysiology such as visceral hypersensitivity. The symptoms reported in most FGIDs overlap more than one gastrointestinal (GI) organ. FH patients report abdominal cramping, bloating and nausea with their FH symptoms. This study tested the primary hypothesis that there is a correlation of MPT in the esophagus and rectum in FH patients. Secondary aims evaluated correlations with IPT and PT. Methods:. This study explored objective sensory endpoints of initial perception threshold (IPT), pain threshold (PT), and maximum pain threshold (MPT) in the esophagus and rectum of FH subjects to determine whether visceral hypersensitivity is a generalized or organ specific observation Fourteen women with FH participated in this study. Each subject underwent a training sensory study protocol session including step volume and pressure ramp balloon barostat distention of the esophagus and rectum. A data collection visit occurred within 7-14 days to collect data on balloon volume and pressure measurements at IPT, PT, and MPT with esophageal and rectal barostat distention. The relationship of sensation and pain to volume, pressure, and compliance was analyzed. Results: The correlation between esophageal and rectal IPT balloon volume scores was highly and significantly correlated (r = 0.61, p = 0.02). The correlation between esophageal and rectal PT balloon volume scores was highly and significantly correlated (r = 0.6, p = 0.02). The correlation between esophageal and rectal MPT balloon volume scores was not correlated (r = 0.35, p = 0.26). In contrast to volume, the pressure endpoints were not significantly correlated. Conclusions: 1. In this study, there was weak correlation for the relationship of rectal and esophageal volume scores at MPT (Primary Aim). Findings revealed a strong positive correlation for the relationship of rectal and esophageal volume and pressure scores to IPT and PT (Secondary Aims). The lack of MPT correlation may provide insight into the organ specific stratification of FGIDs through identification of the most sensitive organ. 2. In this study, volume was superior to pressure in assessing changes in visceral sensitivity in FGID patients. 3. The correlation of visceral sensitivity in the esophagus and rectum in patients with FH supports the hypothesis that visceral sensory changes in FGIDs are not organ specific. 4. Visceral hypersensitivity throughout the GI tract may explain the overlapping symptoms in FGID patients suggesting visceral sensitivity may occur in two separate areas of the GI tract simultaneously.