Molecular characterization of ascites fluid to identify drivers of infection in patients with decompensated cirrhosis

University Of California, San Francisco, San Francisco CA

Investigators

Abstract

Project Summary In patients with liver cirrhosis, infection is directly responsible for 30-50% of all deaths. The most common infection in patients with cirrhosis is spontaneous bacterial peritonitis (SBP), an infection that develops in excess abdominal fluid, known as ascites fluid. SBP accounts for ~25% of infections in hospitalized patients with cirrhosis, and results in a 4-fold increase in mortality. An improved understanding of the microbial and host features in cirrhotic ascites that drive the susceptibility to SBP is central to improving outcomes. The objective of this proposal is to apply a two-pronged, unbiased approach to develop a foundational metagenomic, meta- transcriptomic, and serological atlas of ascites, to test the hypothesis that patients with cirrhosis have a unique host and microbial signature that can identify those at greatest risk of SBP and mortality. These objectives will be addressed in Aim 1 through the application of metagenomic next generation sequencing (mNGS) and meta-transcriptomics to the study of ascites fluid, to determine whether these gene signatures can predict poor outcomes in cirrhosis, specifically SBP and mortality. These objectives will be further carried out in Aim 2 by employing a customized phage display library of peptides (representing a broad array of intestinal bacteria) to identify the ascites antimicrobial antibody repertoire. These experiments will establish a foundational dataset to determine the bacterial composition of ascites, parallel host response, and impact on outcomes in patients with cirrhosis. Accomplishing these specific aims will yield a comprehensive atlas of ascites microbial and serological composition, uncovering novel host and microbial attributes with the potential to predict outcomes and inform interventions. The candidate’s long-term career development goal is to be an independent physician scientist focused on uncovering the mechanisms of increased infection risk in patients with cirrhosis. The proposed career development plan will help the candidate master molecular and analytic approaches required to identify mechanisms of disease directly in patients with cirrhosis, and develop into an intendent scientist, generating results that can be used to develop tailored prevention strategies, improved diagnostics, and targeted therapeutics.