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Alongside such direct interactions, the microbial orchestration of the BA landscapethrough a cascade of enzymatic modifications including deconjugation by bile salt hydrolases (BSH) (113, 114), various epimerizations and oxidations by hydroxysteroid dehydrogenases (HSDHs) (115), as well as 5-reduction leading to allo-bile acids (Allo-BAs) (116)generates a diverse pool of secondary and modified BAs whose altered structures confer distinct signaling capacities, enabling them to interact with host receptors and profoundly influence the TIME (100), and medications (117), highlighting a complex interplay

Moreover, upon LPS stimulation, ATF2 promotes IL-23 secretion in macrophages, which then induces pathogenic Th17 cell expansion in autoimmune disorders, such as multiple sclerosis, inflammatory bowel disease and rheumatoid arthritis (201)

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The process of validating biomarkers and identifying affinity reagents such as experimental substrate profiling, phage display, or aptamer selection via systematic evolution of ligands by exponential enrichment is effective but can be labor-intensive, expensive in a lab, and challenging

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