Targeting of microbe-derived metabolites to improve human health: The next frontier for drug discovery

Abstract

Recent advances in metabolomic and genome mining approaches have uncovered a poorly understood metabolome that originates solely or in part from bacterial enzyme sources. Whether living on exposed surfaces or within our intestinal tract, our microbial inhabitants produce a remarkably diverse set of natural products and small molecule metabolites that can impact human health and disease. Highlighted here, the gut microbe-derived metabolite trimethylamine N-oxide has been causally linked to the development of cardiovascular diseases. Recent studies reveal drugging this pathway can inhibit atherosclerosis development in mice. Building on this example, we discuss challenges and untapped potential of targeting bacterial enzymology for improvements in human health.

Keywords: atherosclerosis; cardiovascular disease; drug discovery; metabolomics; microbiome.

Figure 1.

Small molecule metabolites originating from the human microbiome. Diverse bacterial ecosystems present in the oral cavity, upper and lower gastrointestinal tract, skin surface, lungs, and almost every exposed orifice studied possess the enzymatic machinery to generate chemically diverse and biologically active metabolites that impact host health and disease. Collectively, human microbiota represent a major contributor to the chemical diversity in the human metaorganism, and many known bacterial metabolites have dedicated host receptor systems that allow for microbe-host cross-talk that modulates human health and disease.

Figure 2.

Drugging the gut microbial TMAO pathway for the treatment of prevention of cardiometabolic disease. Dietary consumption of choline, phosphatidylcholine (PC), carnitine, γ-butyrobetaine, and likely other methylamine-containing source nutrient gut microbes provides substrate for gut bacterial production of TMA through the collective actions of several TMA lyase enzymes. Bacteria expressing the YeaW/X enzyme complex can sequentially convert l-carnitine to γ-butyrobetaine and then γ-butyrobetaine to TMA. TMA can be generated from another l-carnitine TMA lyase enzyme complex known as CntA/B. Choline and phosphatidylcholine can be used by the CutC/D enzyme complex to generate a substantial pool of TMA. Once generated from these distinct sources, TMA enters the portal circulation where it is ultimately delivered to the host liver. The host flavin-containing monooxygenase (FMO) family of enzymes, especially FMO3, can then convert TMA to TMAO. TMAO can then promote atherosclerosis, thrombosis, heart failure, kidney disease, and insulin resistance via tissue- or cell type-specific reprogramming. Inhibition and choline and l-carnitine TMA lyase activity by DMB can blunt atherosclerosis progression in mice. The TMAO pathway represents one of the first pathways where small molecule inhibitors targeting microbial enzymes can benefit host disease.