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Phenotypic high-throughput screening identifies modulators of gut microbial choline metabolism
Amelia Y M Woo1, Walter J Sandoval-Espinola1, Maud Bollenbach1
1Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, USA.
Mbio
|February 23, 2026
Summary
Researchers discovered new ways to lower trimethylamine-N-oxide (TMAO) levels by targeting gut bacteria
Area of Science:
- Microbiology
- Metabolic Engineering
- Drug Discovery
Background:
- Gut microbial metabolism of choline to trimethylamine (TMA) is linked to diseases.
- Impaired TMA oxidation causes trimethylaminuria (TMAU); high TMAO correlates with cardiometabolic disease.
- Inhibiting this pathway offers therapeutic potential.
Purpose of the Study:
- To identify novel small molecules that modulate anaerobic microbial choline metabolism.
- To discover inhibitors with distinct chemical scaffolds.
- To lower trimethylamine-N-oxide (TMAO) levels in vivo.
Main Methods:
- Utilized a growth-based phenotypic high-throughput screen.
- Employed medicinal chemistry for inhibitor optimization.
- Tested compounds in gnotobiotic mice.
Main Results:
- Identified novel chemical scaffolds targeting choline metabolism.
- Developed optimized compounds that effectively lower serum TMAO levels.
- Demonstrated that these compounds do not significantly alter gut microbiome composition.
Conclusions:
- Phenotypic screening is a viable strategy for discovering inhibitors of microbial metabolic activities.
- Novel inhibitors targeting gut microbial choline metabolism can be developed.
- This approach accelerates microbiome research and disease understanding.
