The NIH Human Microbiome Project (HMP) has revolutionized our perspective on humanmicrobe
interactions and provided a tremendous impetus for research in order to obtain a much
deeper understanding of how microbes impact human health. The gut microorganisms of the
HMP Reference Genomes and the Human Gastrointestinal Bacteria Culture Collection contain
961 species representing 142 genera. Yet, relatively little is known about these specific gut
microbes. Herein we will test the hypothesis that tungsten (W), a metal almost never considered
in biological systems, is essential for the health of the human gut microbiome. Our bioinformatics
analyses reveal that a large number of these gut microbes contain genes encoding diverse
members of the W-containing oxidoreductase (WOR) family of enzymes. Only a very few WOR
enzymes have been previously characterized, mainly from exotic thermophilic microbes. The
overall goal of the proposed research is to show that other members of the WOR family have
essential functions in the gut microbiome. In preliminary studies, we have shown that some gut
microbes take up trace amounts of W and their W-containing WORs remove reactive and
potentially toxic aldehydes found in the gut, which are generated from cooked foods and
microbiome metabolism. Other W-containing WORs proposed to catalyze other as yet unknown
reactions. In the proposed research we will purify ten novel phylogenetically distinct WORs by
W-monitored (using ICP-MS) anaerobic chromatography. Their catalytic activities and
physiological substrates will be determined by an enzyme-induced metabolomics approach (using
LC-MS). In addition, we propose that some of these WORs are electron bifurcating enzymes that
simultaneously couple exergonic and endergonic reactions, a recently discovered mechanism of
energy conservation in biological systems. Kinetic, spectroscopic and structural (using cryoEM)
analyses of this subset of W-enzymes will be used to investigate the nature of the bifurcation
reactions and what their functions are in the gut microbiome. Using genome-based metabolic
reconstructions, the physiological functions of the various WORs will be ascertained and we will
determine the effects of W on the metabolism of the gut microbes, including on their resistance to
gut- and cooking-related aldehydes.
It is now clear that, in addition to facilitating digestion, the gut microbiome plays roles in a
surprisingly extensive range of human conditions, including in Parkinson’s, schizophrenia,
osteoarthritis and in cardiovascular, liver and immune-deficiency diseases. The results of the this
research will provide a completely new perspective on the primary metabolisms of the key
microbes in our gastrointestinal tract and the proposed essential role of tungsten, a metal that was
thought to be seldom used in biological systems.
Interested? Email Mike Adams (adamsm@uga.edu), University of Georgia