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Microbial bile acid conjugation has a previously unrecognized drug-activating function, with conjugates of 5-aminosalicylic acid (5-ASA) and bile acids detected in individuals treated with 5-ASA. These conjugates, such as cholyl-5-ASA, are formed by gut bacteria and have enhanced therapeutic effects. The discovery of these conjugates reveals a new mechanism of drug activation and potential therapeutic targets.

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Abstract

Microbially modified bile acids shape host physiology by regulating nutrient absorption, glucose homeostasis, circadian rhythms and thermoregulation. Here we identify a previously unrecognized drug-activating function of microbial bile acid conjugation. By systematically mining human LC-MS/MS datasets across public repositories and linking uncharacterized bile acid spectra to health-associated metadata, we discovered conjugates of the 75-year-old anti-inflammatory drug 5-aminosalicylic acid (5-ASA) with primary and secondary bile acids, including cholic, deoxycholic and lithocholic acids. These bile acid-drug conjugates were detected specifically in individuals treated with 5-ASA or its prodrugs. Multiple gut bacteria, including members of the Bacteroidota and Bacillota, generated cholyl-5-ASA in vitro, and bile salt hydrolase-associated transaminase activity was required for conjugate formation. In a mouse model of colitis, cholyl-5-ASA was associated with reduced intestinal inflammatory pathology and showed markedly enhanced activation of PPAR-g; in cell-based reporter assays compared with 5-ASA alone. Consistent with this activity, cholyl-5-ASA elicited selective immunophenotypic changes in CD4+; T cells in vitro, including increased Foxp3+ regulatory T cells. Together with prior evidence that 5-ASA efficacy depends on the microbiome, these findings support a model in which microbial bile acid conjugation represents a key activation step for 5-ASA therapy. More broadly, this work demonstrates how pan-repository metabolomics can uncover previously unrecognized microbiome-dependent chemical functions with direct therapeutic relevance.

Key findings

  • Conjugates of 5-ASA with primary and secondary bile acids were detected in individuals treated with 5-ASA
  • Gut bacteria, including Bacteroidota and Bacillota, generate cholyl-5-ASA in vitro
  • Cholyl-5-ASA has enhanced therapeutic effects, including reduced intestinal inflammatory pathology and activation of PPAR-g

Keywords

Lithocholic acidBile acidDeoxycholic acidBiochemistryFunction (biology)Cholic acid

Identifiers

DOI
10.64898/2026.03.03.709330
Journal
bioRxiv (Cold Spring Harbor Laboratory)
Year
2026