Unlocking the Potential of Microbial Bile Acids: Expanding the Libraries to Discover Thousands of Novel Compounds

In a groundbreaking study published in Nature, titled "Reverse metabolomics for the discovery of chemical structures from humans," researchers from Bileomix and collaborating institutions have made a significant advancement in the field of bile acid research by expanding the libraries to discover thousands of novel microbial bile acids.

Building upon their previous work, which identified novel microbial bile acids conjugated with amino acids such as phenylalanine, tyrosine, and leucine, the researchers employed a cutting-edge approach called reverse metabolomics. This innovative strategy involves searching tandem mass spectrometry (MS/MS) spectra of newly synthesized compounds in public metabolomics datasets to uncover phenotypic associations.

By broadly synthesizing and exploring multiple classes of metabolites in humans, including N-acyl amides, fatty acid esters of hydroxy fatty acids, bile acid esters, and conjugated bile acids, the researchers were able to significantly expand the libraries of known bile acids. This expansion led to the discovery of an astounding number of novel microbial bile acids, numbering in the thousands.

The study focused on bile amidates, which are bile acids conjugated with amino acids. While glycine and taurine conjugates are the most frequently observed, the researchers proposed that these microbial-conjugated bile acids are part of a much larger class of bile acid amidates that includes other naturally occurring amino acids, both proteinogenic and non-proteinogenic. By performing combinatorial amide coupling reactions between various bile acids and amino acids, the researchers collected MS/MS data for each combination, leading to the identification of an unprecedented number of novel bile acid conjugates.

The implications of this discovery are far-reaching, as these novel microbial bile acids may play crucial roles in human health and disease. The study found that some of these conjugated bile acids were associated with inflammatory bowel disease (IBD), with validation using four distinct human IBD cohorts showing that cholic acids conjugated to specific amino acids were increased in Crohn's disease. Furthermore, several of these compounds and related structures were found to affect pathways associated with IBD, such as interferon-γ production in CD4+ T cells and agonism of the pregnane X receptor.

The researchers also investigated the microbial production of these bile amidates, revealing that bacteria belonging to the Bifidobacterium, Clostridium, and Enterococcus genera were capable of producing these compounds. This finding highlights the complex interplay between the gut microbiome and host metabolism, opening up new avenues for the development of targeted therapies and diagnostic tools.

The reverse metabolomics approach employed in this study demonstrates the power of leveraging public metabolomics data and advanced analytical techniques to discover new molecules from human and animal ecosystems. By expanding the libraries of known bile acids and identifying thousands of novel microbial bile acids, Bileomix and its collaborators have paved the way for a deeper understanding of the role these compounds play in human health and disease.

As research continues to unravel the complexities of the human metabolome and the influence of the gut microbiome, the discovery of these novel microbial bile acids by the Bileomix team serves as a testament to the vast potential that lies within this field. The implications for the development of new diagnostic tools, therapeutic interventions, and a greater understanding of the intricate relationship between the gut microbiome and human health are truly exciting.