Gary Siuzdak, Ph.D., from the Scripps Research Institute, highlighted exciting technologies that he says will advance the field of metabolomics and a wide range of scientific findings, at a NIEHS conference on December 7. Metabolomics is the large-scale study of chemical reactions involving metabolites, which are small molecules that play important roles in cells, tissues, and organisms.
Role of metabolites in health and disease
According to Siuzdak, research in this area initially focused on identifying metabolites that serve as biological signs of disease, which scientists call biomarkers. However, metabolomics has become a more comprehensive tool for understanding how metabolites themselves can influence health and disease.
“The most important area where metabolomics can be applied is the search for active metabolites that affect physiology,” said Siuzdak. “For example, metabolites can impact and even improve the way we respond to drugs or to exposure to toxic agents.”
Enable scientific discovery
Siuzdak has developed data analysis platforms – called XCMS and METLIN – which allow scientists to discover how metabolites can alter critical biological processes, and the tools have been cited in more than 10,000 science projects, he noted.
“Thanks to XCMS and METLIN, which now contain detailed data on 860,000 molecular standards, the Scripps Center for Metabolomics has strengthened research around the world, in various disciplines, ”said Siuzdak, director of the center.
“The continued development of databases such as METLIN is critical to the success of the field of metabolomics,” noted David Crizer, Ph.D., chemist in the NIEHS division of the National Toxicology Program. He is a member of the institute’s Metabolomics Cross-Divisional Group, which hosted the Siuzdak conference (see box).
Identify key molecules
METLIN is designed to help scientists identify molecules in organisms, whether they are metabolites, toxicological agents or other chemical entities, according to Siuzdak. He noted that the database encompasses over 350 chemical classes and that there are now over 50,000 registered users in 132 countries.
“Our goal is to identify as many metabolites and other chemical entities as possible, and given advances in other areas of biology, this data is long overdue,” said Siuzdak.
“We find metabolites that were previously unknown, quite regularly,” he added. “The more complete METLIN, the better our chances of identifying all the molecules in the long term. To this end, I am constantly looking for ways to facilitate the growth of the platform.
Of particular interest to Siuzdak is a metabolite called indole-3-propionic acid (IPA). IPA is a metabolite derived from the human gut originally identified by its laboratory in a 2009 article in the Proceedings of the National Academy of Sciences, and it has since been examined in thousands of studies. Researchers have found that it is a multifunctional molecule that can help immune function, among other things.
“In retrospect, it makes sense that a metabolite derived from a gut microbe could modulate the immune system, which is probably why it still generates so much excitement,” he said.
IPA could be particularly relevant when it comes to autoimmune diseases, Siuzdak added.
“For example, most people who die from COVID-19 do not succumb to the virus but to an overactive immune response that causes them to develop respiratory illnesses,” he said. “A metabolite that modulates this effect could be very beneficial,” noted Siuzdak.
“Overall, we are pursuing a primary goal in the development of METLIN, which is to use experimental data generated from molecular standards to help identify these key and physiologically relevant molecules,” he said.
Quote: Wikoff WR, Anfora AT, Liu J, Schultz PG, Lesley SA, Peters EC, Siuzdak G. 2009. Metabolomic analysis reveals important effects of intestinal microflora on blood metabolites of mammals. Proc Natl Acad Sci USA 106 (10): 3698-3703.
(John Yewell is a contract writer for the NIEHS Office of Communications and Public Liaison.)