This proposal is based on extensive preclinical and clinical evidence supporting complex interactions between alterations in the stress response system reactivity, visceral adipose tissue (VAT), and brain structural and functional changes that might be related to gastrointestinal symptoms and IBS pathophysiology. Using an interdisciplinary translational approach, we will test the hypothesis that increased VAT related to hyperactivity of the HPA axis, is associated with changes in brain morphometry with sex related differences in these alterations. We will adress the following specific aims:
Aim A will correlate changes between visceral adiposity, HPA axis activity and regional brain morphology in a rodent model of chronic unpredictable stress in adult male and female rats.
Aim B will characterize the role of visceral fat products in stress-induced changes in the HPA axis and brain structural and functional changes in male and female rodents.
Aim C will study sex differences in the correlation between HPA overactivity, VAT and adipokines in CRF-OE mice as a model of chronic alterations of stress, genetically driven by CRF since early life, Aim D will correlate HPA axis with VAT accumulation and circulating adipokines to regional brain structural and resting state functional changes in male and female IBS patients. We will employ several novel methodologies and state-of-the-art technologies in many aspects of this application, including rodent brain MRI, multimodal brain imaging in humans, and quantitative MRI-or CT based VAT assessment methods in rodents and humans. Transgenic animals will be used to test the specific role of adipokines and of the CRF/CRFR1 signaling pathways in this system. The use of rodent models and human studies in this project are complementary and related to project 1 which characterizes HPA axis dysregulation in IBS patients and to Project 3 which uses multimodal brain imaging, advanced mathematical modeling/systems biological approaches to identify IBS patients subtypes based on distinct endophenotype clusters. The results of the proposed preclinical and clinical studies should be able to unequivocally address the main hypotheses on the pathophysiological role of excessive VAT accumulation and brain changes and relationship to IBS.
Understanding the pathophysiological role of excessive VAT accumulation and brain changes in IBS patients would fundamentally change current concepts about proinflammatory mechanisms and their relationship to stress in IBS pathophysiology and therapy. VAT accumulation associated with chronic psychological stress, and its risk factors, could become a major target for novel therapeutic interventions in IBS and other FGIDs.
|Bonfiglio, Ferdinando; Zheng, Tenghao; Garcia-Etxebarria, Koldo et al. (2018) Female-Specific Association Between Variants on Chromosome 9 and Self-Reported Diagnosis of Irritable Bowel Syndrome. Gastroenterology 155:168-179|
|Park, S H; Naliboff, B D; Shih, W et al. (2018) Resilience is decreased in irritable bowel syndrome and associated with symptoms and cortisol response. Neurogastroenterol Motil 30:|
|Martin, Clair R; Osadchiy, Vadim; Kalani, Amir et al. (2018) The Brain-Gut-Microbiome Axis. Cell Mol Gastroenterol Hepatol 6:133-148|
|Addante, Raymond; Naliboff, Bruce; Shih, Wendy et al. (2018) Predictors of Health-related Quality of Life in Irritable Bowel Syndrome Patients Compared With Healthy Individuals. J Clin Gastroenterol :|
|Gupta, Arpana; Woodworth, Davis C; Ellingson, Benjamin M et al. (2018) Disease-Related Microstructural Differences in the Brain in Women With Provoked Vestibulodynia. J Pain 19:528.e1-528.e15|
|Gupta, Arpana; Mayer, Emeran A; Labus, Jennifer S et al. (2018) Sex Commonalities and Differences in Obesity-Related Alterations in Intrinsic Brain Activity and Connectivity. Obesity (Silver Spring) 26:340-350|
|Tache, Yvette; Larauche, Muriel; Yuan, Pu-Qing et al. (2018) Brain and Gut CRF Signaling: Biological Actions and Role in the Gastrointestinal Tract. Curr Mol Pharmacol 11:51-71|
|Hoffman, Jill M; Sideri, Aristea; Ruiz, Jonathan J et al. (2018) Mesenteric Adipose-derived Stromal Cells From Crohn's Disease Patients Induce Protective Effects in Colonic Epithelial Cells and Mice With Colitis. Cell Mol Gastroenterol Hepatol 6:1-16|
|Fang, Kai; Law, Ivy Ka Man; Padua, David et al. (2018) MicroRNA-31-3p Is Involved in Substance P (SP)-Associated Inflammation in Human Colonic Epithelial Cells and Experimental Colitis. Am J Pathol 188:586-599|
|Henström, Maria; Diekmann, Lena; Bonfiglio, Ferdinando et al. (2018) Functional variants in the sucrase-isomaltase gene associate with increased risk of irritable bowel syndrome. Gut 67:263-270|
Showing the most recent 10 out of 219 publications