PROJECT SUMMARY/ABSTRACT Mindfulness-Based Intervention (MBI) training programs have been shown to reduce stress and improve a broad range of stress-related disease outcomes in initial randomized controlled trials (RCTs). For example, there is initial evidence from small RCTs that MBIs reduce symptoms in Irritable Bowel Syndrome (IBS) patients. Yet we know little about the underlying active treatment mechanisms of mindfulness training. Guided by a theoretical and conceptual model of the active treatment elements of MBIs, called Monitor and Acceptance Theory (MAT), we recently showed in two published dismantling MBI RCTs that acceptance skills training is critical for driving stress reduction effects in healthy stressed community adults. Specifically, standard MBI programs with attention monitoring and acceptance skills training were superior in reducing stress relative to parallel MBI programs that did not include acceptance skills training (or to control groups) at post-treatment. We observed consistent stress reduction effects across intervention delivery approaches in these two dismantling trials, using either a 2-week remote smartphone MBI or with an 8-week group-based Mindfulness-Based Stress Reduction (MBSR) MBI treatment approach. Here we propose the first translational trial of this mechanistic account, examining whether acceptance skills training drives stress resilience and improved symptom outcomes in IBS patients. In the largest and most well-controlled RCT of MBI training in IBS to-date (N=325), we will evaluate whether a smartphone MBI program (with attention monitoring and acceptance skills training; Monitor+Accept, MA-MBI) reduces daily life stress and IBS symptoms at post-treatment and two-month follow-up, relative to a matched MBI program with acceptance skills training removed (training in attention monitoring skills only; Monitor Only, MO-MBI) or to an active stress management training control group (Coping Control, CC). Participants will not only provide clinician and patient assessed measures of IBS symptoms at the three time points, but they will also provide sensitive experience sampling assessments (using Ecological Momentary Assessment) of their stress and symptoms in daily life at each time point. Finally, as an exploratory aim, participants will provide stool samples at baseline and post-intervention to provide the first ever test of whether MBIs can alter the gut microbiome in IBS. Guided by a conceptual model, the proposed study will experimentally evaluate whether acceptance skills training is a key ingredient for stress reduction and health benefits in IBS patients, and will provide an important mechanistically-focused evaluation of the active treatment elements of MBIs for at risk stressed patient populations. We believe that this trial not only can help identify a new accessible and scalable evidence-based treatment for IBS patients, but the mechanistic focus will also help the field advance more effective and ef...