Harnessing Metabolic Machinery of Gut Bacteria for Metabolic Dysfunction-Associated Steatohepatitis

About This Grant

Project Summary/Abstract Metabolic dysfunction-associated steatohepatitis (MASH) is a growing public health concern in industrialized nations, with an estimated cost of $1.66 trillion in the U.S. by 2039. Despite its prevalence, therapeutic strategies remain limited due to an incomplete understanding of its pathogenesis. Emerging evidence suggests that the gut microbiota plays a critical role in modulating metabolic and inflammatory processes in MASH through the production of microbiota-dependent metabolites (MDMs). Therefore, a promising approach is to augment therapeutic MDMs in the gut by reintroducing their producers. However, current microbiome-based interventions, such as fecal microbiota transplantation (FMT), have been largely ineffective in ameliorating MASH due to critical gaps in identifying potent MDM-producing bacterial strains and elucidating the mechanisms that enable their durable engraftment in the gut. My long-term goal is to develop rationally designed microbiome therapeutics for MASH and other metabolic diseases by leading a multidisciplinary research program. This proposal aims to establish a foundational strategy to combat liver inflammation in MASH by leveraging bacterial strains with high MDM-producing capacity, focusing on Clostridia isolated from the Hadza hunter-gatherers. The Hadza harbor a highly distinct gut microbiome enriched with bacterial strains that efficiently utilize dietary polysaccharides and synthesize health-promoting MDMs, presenting promising therapeutic potential. Aim 1 will identify Hadza-derived Clostridia that produce anti-inflammatory MDMs. Aim 2 will investigate the mechanisms enabling their stable MDM production in the gut, with a focus on their polysaccharide-utilizing machinery that facilitates engraftment. Aim 3 will determine their immune and therapeutic effects in diet-induced MASH models. The successful completion of this study will enhance our understanding of gut bacterial metabolism in MASH and establish a rational framework for developing targeted microbiome therapeutics beyond current FMT approaches. Additionally, this K99/R00 award will provide essential training in both scientific and career development, facilitating my transition to becoming an interdisciplinary independent researcher. My training will be supported by a distinguished mentoring team with expertise in microbiome science (Dr. Justin Sonnenburg, primary mentor), liver biology (Dr. Natalie Torok, co-mentor), metabolomics (Dr. Michael Fischbach, advisor), gut ecology (Dr. Kerwyn Casey Huang, advisor), and immune profiling (Dr. Holden Maecker, advisor). Stanford University, a renowned institution in biomedical research, provides extensive resources, state-of-the-art equipment, and unparalleled opportunities to support my training. In summary, this K99/R00 proposal will equip me with the necessary skills to launch an independent research program in microbiome therapeutics for MASH and other metabolic diseases. The research findings will provide key insights into the role of microbiota in MASH and establish the groundwork for translational strategies aimed at improving metabolic and liver health.