Irritable Bowel Syndrome (IBS), and other persistent visceral pain syndromes such as interstitial cystitis/painful bladder syndrome present a heterogeneous group of patients with often overlapping symptoms. We hypothesize that biologically determined subsets of IBS patients are composed of distinct clusters of biological and behavioral endophenotypes. Some of the involved endophenotypes show sex-related differences, biasing most of these syndromes towards female predominance. Our SCOR research during the past funding period has enabled us to generate a group of testable candidate endophenotypes, many with sex differences, that relate to important clinical characteristics in functional GI disorders. We propose to test the general hypothesis that distinct subgroups of patients can be identified in a population meeting IBS symptom criteria using a phenomics approach in three Aims.
In Aim A, we will prospectively perform comprehensive endophenotyping of 120 IBS patients (60 women). Multimodal brain imaging and psychophysiological techniqes, together with behavioral measures will be used to identify central endophenotypes related to stress hyperresponsiveness, pain sensitivity and cognitive modulation. These endophenotypes will be combined in a comprehensive data base with neuroendocrine (including HPA axis parameters studied in Project 1), and peripheral endophenotypes (including visceral adipose tissue [VAT] and adipokines, studied in Project 2).
In Aim B, we will use interventional phenotyping using a corticotropin releasing factor type 1 receptor (CRF-R1) antagonist in 60 female IBS patients to test the hypothesis that a subgroup of IBS patients with an upregulated CRF/CRF-R1 signaling system can be identified by their responsiveness to a selective CRF-R1 antagonist, while other subgroups show minimal or no response.
In Aim C we will apply advanced mathematical modeling techniques to identify patient subgroups from endophenotypes identified in Aims A and B to test the hypotheses that subgroups of IBS patients can be identified based on unique clusters of endophenotypes, that some of these endophenotypes are responsible for the greater female prevalence of IBS and related syndromes.

Public Health Relevance

Irritable bowel syndrome is a common disorder of considerable human and financial impact, with inadequate treatment options. Identification of objective and biologically based subgroups of irritable bowel syndrome patients is essential to improving the development of targeted, effective treatments for this disorder.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Specialized Center (P50)
Project #
5P50DK064539-13
Application #
8733659
Study Section
Special Emphasis Panel (ZRG1-EMNR-Q)
Project Start
Project End
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
13
Fiscal Year
2014
Total Cost
$217,956
Indirect Cost
$76,426
Name
University of California Los Angeles
Department
Type
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Labus, Jennifer S; Hollister, Emily B; Jacobs, Jonathan et al. (2017) Differences in gut microbial composition correlate with regional brain volumes in irritable bowel syndrome. Microbiome 5:49
Rolland-Fourcade, Claire; Denadai-Souza, Alexandre; Cirillo, Carla et al. (2017) Epithelial expression and function of trypsin-3 in irritable bowel syndrome. Gut 66:1767-1778
Walker, Claire-Dominique; Bath, Kevin G; Joels, Marian et al. (2017) Chronic early life stress induced by limited bedding and nesting (LBN) material in rodents: critical considerations of methodology, outcomes and translational potential. Stress 20:421-448
Wang, Lixin; Goebel-Stengel, Miriam; Yuan, Pu-Qing et al. (2017) Corticotropin-releasing factor overexpression in mice abrogates sex differences in body weight, visceral fat, and food intake response to a fast and alters levels of feeding regulatory hormones. Biol Sex Differ 8:2
Volkmann, Elizabeth R; Hoffmann-Vold, Anna-Maria; Chang, Yu-Ling et al. (2017) Systemic sclerosis is associated with specific alterations in gastrointestinal microbiota in two independent cohorts. BMJ Open Gastroenterol 4:e000134
Gupta, Arpana; Mayer, Emeran A; Acosta, Jonathan R et al. (2017) Early adverse life events are associated with altered brain network architecture in a sex- dependent manner. Neurobiol Stress 7:16-26
Gupta, Arpana; Mayer, Emeran A; Fling, Connor et al. (2017) Sex-based differences in brain alterations across chronic pain conditions. J Neurosci Res 95:604-616
Gupta, A; Mayer, E A; Hamadani, K et al. (2017) Sex differences in the influence of body mass index on anatomical architecture of brain networks. Int J Obes (Lond) 41:1185-1195
Khanna, Dinesh; Hays, Ron D; Shreiner, Andrew B et al. (2017) Responsiveness to Change and Minimally Important Differences of the Patient-Reported Outcomes Measurement Information System Gastrointestinal Symptoms Scales. Dig Dis Sci 62:1186-1192
Gupta, A; Cole, S; Labus, J S et al. (2017) Gene expression profiles in peripheral blood mononuclear cells correlate with salience network activity in chronic visceral pain: A pilot study. Neurogastroenterol Motil 29:

Showing the most recent 10 out of 205 publications