The long-term goal of the proposed research is to better understand the pathophysiology of irritable bowel syndrome (IBS), in the hope to develop more effective treatments. Despite the high prevalence and high human and economic costs of IBS, the disorder is poorly understood, and existing treatment options remain unsatisfactory. IBS is a disorder of altered brain-gut interactions, characterized by enhanced stress-sensitivity, frequent overlap with other disorders of chronic pain and discomfort, familial predisposition, and greater prevalence in women. Both peripheral and central abnormalities have been demonstrated. Centrally, it is characterized by enhanced perception of gut stimuli resulting in abdominal pain and discomfort. Altered bowel habits may be related to altered central and/or peripheral neural responses regulating intestinal motility and secretion. The current proposal uses cutting edge brain imaging, genetic and mathematical techniques to characterize distinct brain networks (intermediate brain phenotypes) concerned with the processing of visceral afferent information, with the modulation of visceral pain perception, and with determining arousal and stress sensitivity, and possible associations of these intermediate phenotypes with polymorphisms in several candidate genes. This goal will be accomplished by studying 300 Caucasian subjects (200 IBS patients, 100 healthy controls, 50% women) in 3 Specific Aims:
In Aim A, by using fMRI combined with advanced analysis techniques, we will characterize alterations in the activity and connectivity of distinct brain networks concerned with pain processing, pain modulation, and arousal/emotional regulation in patients and controls. We will look for possible associations between functional network responses and selected candidate gene polymorphisms, for gene-gene, gene-early life event, and gene-sex interactions in shaping network responses.
In Aim B, we will analyze all brain structural MRI images from Aim A using voxel-based morphometry for structural differences between IBS patients and controls, and search for possible associations of such regional brain volume changes and candidate genes.
In Aim C, we will study perceptual and autonomic responses to somatic pain stimuli, and correlate these (as well as visceral pain responses obtained in Aim A) with intermediate brain phenotypes, as well as with genetic polymorphisms.

Public Health Relevance

A better understanding of brain circuits which underlie predominant symptoms, and associated genetic traits will enhance our understanding of IBS pathophysiology, and greatly facilitate the development of better treatments for these common GI disorders.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Clinical and Integrative Gastrointestinal Pathobiology Study Section (CIGP)
Program Officer
Hamilton, Frank A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Los Angeles
Internal Medicine/Medicine
Schools of Medicine
Los Angeles
United States
Zip Code
Mayer, Emeran A; Knight, Rob; Mazmanian, Sarkis K et al. (2014) Gut microbes and the brain: paradigm shift in neuroscience. J Neurosci 34:15490-6
Mayer, Emeran A; Savidge, Tor; Shulman, Robert J (2014) Brain-gut microbiome interactions and functional bowel disorders. Gastroenterology 146:1500-12
Labus, Jennifer S; Dinov, Ivo D; Jiang, Zhiguo et al. (2014) Irritable bowel syndrome in female patients is associated with alterations in structural brain networks. Pain 155:137-49
Gupta, Arpana; Kilpatrick, Lisa; Labus, Jennifer et al. (2014) Early adverse life events and resting state neural networks in patients with chronic abdominal pain: evidence for sex differences. Psychosom Med 76:404-12
Hong, Jui-Yang; Kilpatrick, Lisa A; Labus, Jennifer S et al. (2014) Sex and disease-related alterations of anterior insula functional connectivity in chronic abdominal pain. J Neurosci 34:14252-9
Kilpatrick, Lisa A; Coveleskie, Kristen; Connolly, Lynn et al. (2014) Influence of sucrose ingestion on brainstem and hypothalamic intrinsic oscillations in lean and obese women. Gastroenterology 146:1212-21
Mayer, Emeran A; Padua, David; Tillisch, Kirsten (2014) Altered brain-gut axis in autism: comorbidity or causative mechanisms? Bioessays 36:933-9
Hong, Jui-Yang; Labus, Jennifer S; Jiang, Zhiguo et al. (2014) Regional neuroplastic brain changes in patients with chronic inflammatory and non-inflammatory visceral pain. PLoS One 9:e84564
Grasberger, Helmut; Chang, Lin; Shih, Wendy et al. (2013) Identification of a functional TPH1 polymorphism associated with irritable bowel syndrome bowel habit subtypes. Am J Gastroenterol 108:1766-74
Hong, Jui-Yang; Kilpatrick, Lisa A; Labus, Jennifer et al. (2013) Patients with chronic visceral pain show sex-related alterations in intrinsic oscillations of the resting brain. J Neurosci 33:11994-2002

Showing the most recent 10 out of 74 publications