ABSTRACT Cognitive Behavioral Therapy (CBT) is the most well researched and most effective treatment for IBS that targets the brain-gut-microbiome (BGM) axis, and preliminary data show that this therapeutic effect is associated with a reduction of brainstem connectivity with other brain networks and a change in relative abundance of Bacteroides taxa. The increased prevalence of IBS in women, the higher rate of comorbid non- GI pain conditions, as well as the higher prevalence in female IBS of increased sensitivity to a variety of internal and external stimuli (multisensory sensitivity) suggest the presence of important sex differences in some of these BGM mechanisms. Research performed by the UCLA SCOR during previous funding has established an increased responsiveness of the CRF-Locus Coeruleus system in female IBS subjects, suggesting that this noradrenergic brainstem system plays an important role in IBS pathophysiology. In addition, our earlier research has begun to identify clinical, functional and cortical brain mechanisms that may underlie these sex effects. Based on these preliminary data, the overall goal of this Project is to use CBT as a probe to study the relationship between specific disease-related alterations of the brain, brainstem, the gut microbiome, and symptomatic outcome, and identify the role of sex differences in these relationships. We will study male and female IBS patients before and after CBT or usual care using the advanced neuroimaging and microbiome technologies of the overall SCOR to test the following: Aim A. will identify sex differences in the impact of CBT on the connectivity between brainstem nuclei and brain networks and between these networks at rest and after provocation. Aim B. will identify sex differences in the impact of CBT on gut microbiome parameters and Aim C will identify clinical, brain and gut microbiome predictors of CBT outcomes.