Project Summary/Abstract Hepatic encephalopathy (HE) is a complication of cirrhosis characterized by cognitive, psychological, and motor dysfunction that is associated with decreased quality of life and poor survival. Unfortunately, current treatments for HE only have modest efficacy in preventing overt (or clinically apparent) HE episodes. Novel therapies are desperately needed to alleviate the burden of HE, and targeting the microbiome is a promising therapeutic pathway. HE is thought to result from translocation of bacterial products across a permeable intestinal epithelium, which bypass the dysfunctional liver and reach the brain. Dr. Bloom’s preliminary work shows that specific gut bacteria are associated with impaired intestinal barrier function and may influence HE. Despite this initial work, there is limited data regarding the most promising microbiome targets for HE treatment – a gap that Dr. Bloom plans to address in this proposal. Her central hypothesis is that microbiome-targeted therapies can treat and prevent HE. Her aims are to 1) identify host and microbiome features associated with future overt HE, and 2) compare mechanisms of microbiome-targeted therapies to treat minimal HE. In order to accomplish Aim 1, she will conduct a prospective cohort study that will enroll 150 patients with cirrhosis: 75 patients with a history of overt HE and 75 patients with no history of overt HE but at high risk. At baseline, she will collect microbiome and host data. She will then prospectively follow all patients for 6 months to identify interval overt HE, while collecting serial microbiome and host data. In order to accomplish Aim 2, she will conduct a pilot clinical trial in 60 patients with cirrhosis and minimal HE. She will randomize patients to 1) lactulose (standard of care), 2) polyethylene glycol (used as alternative to standard of care), or 3) potato starch. She will evaluate microbiome composition and function and cognitive function before, during, and after therapy. The primary outcome will be change in stool short-chain fatty acids with treatment. These proposed studies will identify host and microbiome features closely associated with HE and determine the impact of HE therapies in reversing HE-associated microbiome features. During the K23 award period, Dr. Bloom will acquire knowledge and skills in three core research domains: rigorous clinical trial design, microbiome sequencing analysis, and statistical modeling. She will achieve these training goals through hands-on mentorship, a Masters in Public Health, other formal didactics, several regular group meetings, and attending academic conferences. Dr. Bloom will specifically learn how to perform clinical trials of microbiome-targeted therapies, analyze metagenomic sequencing to interpret bacterial community composition and function, and develop multi-dimensional models that include multi-omics (microbiome and metabolome) and longitudinal data to better understand the pathogenesis of...