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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.

May 6, 2021 @ 2pm EST

Dissecting 2-aminoacrylate global stress outcomes in Salmonella enterica using 1H-NMR Metabolomics


Speakers

Goncolo Gouveia

University of Georgia

Andrew Borchert

National Renewable Energy Laboratory

The reactive intermediate deaminase, RidA, is conserved across all domains of life and neutralizes reactive enamine species through deamination. When Salmonella enterica ridA mutants are grown in minimal medium, 2-aminoacrylate (2AA) accumulates, damages several pyridoxal 5′-phosphate (PLP)-dependent enzymes, and elicits an observable growth defect. Genetic studies suggested that damage to serine hydroxymethyltransferase (GlyA), and the resultant depletion of 5,10-methelenetetrahydrofolate (5,10-mTHF), was responsible for the observed growth defect. However, the global metabolic consequences resultant of 2AA stress and the downstream effects stemming from GlyA damage by 2AA remains relatively unexplored. Untargeted proton nuclear magnetic resonance (1H NMR) metabolomics helped determine the metabolic state of an S. enterica ridA mutant. The data supported the conclusion that metabolic changes in a ridA mutant were due to the IlvA-dependent generation of 2AA, and that the majority of these changes were a consequence of damage to GlyA. While many of the metabolic differences for a ridA mutant could be explained, changes in some metabolites were not easily modeled, suggesting that additional levels of metabolic complexity remain to be unraveled. This study demonstrates the utility in implementing nutrient supplementation and genetic perturbation into metabolomics workflows as a means to disentangle complex metabolic outcomes stemming from a general metabolic stress, connecting metabolic outputs to physiological phenomena and establishing causal relationships. Overall, these sorts of metabolomics experiments show great potential as a complement to classical reductionist approaches to cost-effectively accelerate the rate of progress in expanding our global understanding of metabolic network structure and cellular physiology.


April 1, 2021 @ 2pm EST

Using metabolomics data as insight into the biochemical signatures of chronic exhaustion (ME/CFS and similar diseases)


Speakers

Oliver Fiehn

University of California, Davis

Ian Lipkin

Columbia University

The pathogenesis of ME/CFS, a disease characterized by fatigue, cognitive dysfunction, sleep disturbances, orthostatic intolerance, fever, gut intestinal complications, and lymphadenopathy, is poorly understood. We have previously reported biomarker discovery and topological analysis of plasma metabolomic, fecal bacterial metagenomic, and clinical data from  ME/CFS patients and matched healthy controls. We have now replicated and extended our initial findings and found signatures that may provide insights into the pathogenesis of ME/CFS and its subtypes, with possible implications for other diseases such as long-covid patients that present with similar symptoms.


March 4, 2021 @ 2pm EST

Understanding the chemical biology of the gut-liver axis with metabolomics


Speakers

Andrew Neish

Emory University

Ken Liu

Emory University

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

Speakers

Jennifer Kyle

Pacific Northwest National Laboratory

Fikadu Tafesse

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.