Irritable bowel syndrome (IBS) and chronic normal transit constipation (CC) are prevalent intestinal disorders which are more common in women. In addition, female IBS patients experience more pain during low estrogen states, e.g. during the luteal phase of the menstrual period and post menopause. Until recently, there was no consensus about the pathophysiology of these disorders, no satisfactory long term treatments, and no reliable biomarkers for guiding treatment decisions. However, there is increasing evidence that disturbances at different levels of the brain-gut microbiome (BGM) axis play a central role in the pathophysiology of IBS and possibly CC. This proposal is based on the general hypothesis that female sex hormones and gut microbial metabolites play an important modulatory role on brain gut microbiome interactions, and that ascending arousal systems originating in the brainstem may in part responsible for the altered cognitive, affective and sensory processing function resulting in increased perception of visceral and other sensory signals, maladaptive coping, and comorbid anxiety characteristic for patient with functional GI disorders. Therefore, the overall goal of this proposal is to identify the sex-specific effect of gut microbial metabolites, and estrogen levels on ascending arousal pathways originating in distinct brainstem nuclei to change the activity and connectivity of brain networks involved in symptom generation. Using advanced brain imaging methods, gut microbiome analyses, and detailed clinical phenotyping, as well as state of the art statistical and bioinformatics tools, this proposal is addressing the hypothesis in 3 synergistic and closely related Projects, assisted by a Leadership Administrative Core and a Data Processing and Analysis Core. Project 1 aims to study the influence of natural low estrogen states and microbial metabolites on BGM interactions in female IBS patients with IBS and CC in the luteal phase, and after menopause. Project 2 aims to clearly identify the brainstem nuclei giving rise to ascending noradrenergic and serotonergic projections to limbic and cortical brain regions, determine the influence of gut microbial metabolites on these arousal systems and determine differences in these effects between male and female patients. Project 3 aims to evaluate the biological mechanisms within the BGM axis that mediate the clinical effectiveness of cognitive behavioral therapy (CBT) in male and female IBS patients, and identify possible predictors and mediators of outcome.The information garnered from this study could reveal novel insight into the involvement of different levels of the brain gut microbiome axis in IBS pathophysiology, and provide a powerful clinical tool for identifying the most effective therapeutic strategies for women and men with functional GI disorders.

Public Health Relevance

This SCORE proposals aims to gain a better understanding of the role of the gut microbiome and female sex hormones in the modulation of brain gut microbiome interactions in two of the most common disorders of the gastrointestinal tract, irritable bowel syndrome and chronic functional constipation. To achieve this goal it will study these interactions in 1) female patients during low estrogen states (perimenstrually, post menopausal); 2) by comparing these interactions between female and male patients and healthy control subjects and 3) by studying gut microbial and brain mechanisms underlying the effectiveness of cognitive behavioral therapy. Results obtained from the proposed studies are likely to lead to significant improvements in the treatment of these disorders.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZRG1)
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Hamilton, Frank A
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University of California Los Angeles
Internal Medicine/Medicine
Schools of Medicine
Los Angeles
United States
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