From Postbiotic to Prodrug: Chemical Strategies to Widen the Therapeutic Potential of Butyric Acid.

Abstract

Postbiotics, particularly Short-Chain Fatty Acids (SCFAs), have recently emerged as safe and measurable alternatives to live probiotics. Postbiotics are metabolites produced through the gut microbial fermentation of dietary fibers and primarily comprise acetate, propionate, and butyrate, which together account for approximately 90% of the total SCFAs produced. Among these, butyrate has been the most extensively investigated because of its broad therapeutic potential in a wide range of gastrointestinal, neurological, cardiovascular, metabolic, and immunological disorders. The therapeutic effects of butyric acid are primarily attributed to the inhibition of Histone Deacetylase (HDAC) and activation of G Protein-Coupled Receptors (GPCRs), thereby modulating gene expression, immune responses, and intestinal barrier integrity. Despite its promising pharmacological profile, the clinical application of free butyric acid is limited by its unpleasant odor and taste, poor gastrointestinal stability, and rapid systemic metabolism. To overcome these limitations, various chemical modification strategies have been explored. Conjugation of the free carboxylic acid group of butyric acid with diverse promoieties, including fatty acids, amino acids, monosaccharides, polyhydric alcohols, and polymers, through esterification or amidation, has led to the development of several butyric acid prodrugs. These prodrugs undergo enzymatic hydrolysis, often mediated by pancreatic lipases, to release active butyrate in a controlled manner. Such modifications not only improve the organoleptic and pharmacokinetic properties of butyric acid but also, in some cases, enable sitespecific, sustained, and targeted drug delivery. Preclinical studies have demonstrated that butyrate prodrugs exhibit superior therapeutic efficacy compared with free butyric acid in various oncological, neuromuscular, cardiovascular, metabolic, and inflammatory disorders. Furthermore, formulation- based approaches, including nanoparticle-based delivery systems, have been employed to further enhance bioavailability and therapeutic performance. Notably, a few butyrate prodrugs, such as tributyrin and AN-9, are currently undergoing clinical evaluation, highlighting their translational potential. This review summarizes recent advances in the design and therapeutic applications of butyric acid prodrugs, with particular emphasis on their potential as next-generation postbiotic-based therapeutics.