Metabolomics Consortium Collaborative Webinar Series
This webinar series highlights the collaborative projects of metabolomics research investigators and their biomedical collaborators with the intention of engaging scientists within other NIH institutes, as well as presenting case studies to the consortium of successful metabolomics partnerships.
March 4, 2021 @ 2pm EST
Understanding the chemical biology of the gut-liver axis with metabolomics
The vast number of microbes (10 to 100 trillion) that comprise the mammalian microbiota serves numerous beneficial functions for the host that includes stimulation of immune development and competitive exclusion of pathogenic microorganisms. Exogenously administered viable bacteria –probiotics- can dampen inflammation, improve barrier function and promote reparative responses in vitro, and have shown promise as therapy in inflammatory and developmental disorders of the intestinal tract. Abnormalities of the microbiota are associated with inflammatory bowel disease (IBD) and other allergic, systemic immune, and infectious disorders (e.g., asthma, juvenile-onset diabetes, multiple sclerosis) and metabolic disorders (adult-onset diabetes, nonalcoholic steatohepatitis, and obesity). Thus, there is an increasing need to understand the mechanistic basis for microbiota in human disease. High throughput sequencing platforms allow species-level identification of complex communities associated with clinical phenotypes but do not provide insight into mechanisms by which bacteria can influence physiological and pathological processes. Advances in metabolomic analyses have enabled considerable progress in the study of host-microbial interactions. In our collaborations, we identified a small molecule activator of the Nrf2 liver antioxidant system, 5-methoxyindoleacetic acid, is produced by human commensal bacteria and protects against oxidative stress (1). In an ongoing untargeted LC-MS analysis of hepatic tissue in germ-free and conventionalized animals, we identified delta-valerobetaine (VB) as the top microbial metabolite present in liver and liver mitochondria. VB was found to decrease cellular carnitine, inhibit mitochondrial fatty acid oxidation, and increased central adiposity in mice. VB was also found to be elevated with obesity in humans. These studies illustrate the considerable value of metabolomics to complement genetic and molecular methods to address mechanisms underlying human health and disease.
February 3, 2021 @ 2pm EST
A global lipid map defines a network essential for Zika virus replication
Pacific Northwest National Laboratory
Oregon Health and Science University
Zika virus (ZIKV), an arbovirus of global concern, remodels intracellular membranes to form replication sites. How ZIKV dysregulates lipid networks to allow this, and consequences for disease, is poorly understood. Here, we perform comprehensive lipidomics using liquid chromatography tandem mass spectrometry to create a lipid network map during ZIKV infection. We find that ZIKV significantly alters host lipid composition, with the most striking changes seen within subclasses of sphingolipids. Ectopic expression of ZIKV NS4B protein results in similar changes, demonstrating a role for NS4B in modulating sphingolipid pathways. Disruption of sphingolipid biosynthesis in various cell types, including human neural progenitor cells, blocks ZIKV infection. Additionally, the sphingolipid ceramide redistributes to ZIKV replication sites, and increasing ceramide levels by multiple pathways sensitizes cells to ZIKV infection. Thus, we identify a sphingolipid metabolic network with a critical role in ZIKV replication and show that ceramide flux is a key mediator of ZIKV infection.