Biochemistry and Biophysics Reports · Nov 13, 2026
Indole-3-propionic acid attenuates O-GlcNAc-associated oxidative stress and DNA damage responses to preserve intestinal stem cell homeostasis
By Na HJ, Jeon EY, Park JS et al.
Intestinal stem cell (ISC) homeostasis progressively declines during aging, leading to impaired intestinal renewal and dysfunction. Aberrant O-linked β-N-acetylglucosamine (O-GlcNAc) modification and persistent DNA damage response (DDR) activation are emerging as key causes of aging and age-related diseases. Indole-3-propionic acid (IPA), a tryptophan metabolite produced by the gut microbiota, exhibits antioxidant and cytoprotective activities; however, its role in age-associated ISC dysfunction has not been defined. In this study, we examined the effects of IPA in Drosophila models of physiological aging, pharmacological O-GlcNAc elevation, and genetic OGA depletion. IPA suppressed ISC hyperproliferation while attenuating DDR activation, as evidenced by reduced γH2AVD and pS/TQ levels in aged and Thiamet G-treated flies. In parallel, IPA decreased excessive O-GlcNAcylation and intracellular reactive oxygen species (ROS) accumulation under both conditions. To assess whether these protective effects were mediated through O-GlcNAc signaling, we evaluated OGA knockdown flies and found that IPA effectively rescued OGA depletion-induced ISC hyperproliferation, excessive O-GlcNAcylation, ROS accumulation, and DDR activation. At the tissue level, IPA improved intestinal morphology and restored epithelial barrier function. IPA may contribute to the preservation of intestinal homeostasis by attenuating changes associated with O-GlcNAcylation, ROS accumulation, and DDR activation, thereby maintaining ISC function during aging. Our study identifies microbiota-derived IPA as a potential nutritional intervention for promoting healthy intestinal aging associated with the modulation of O-GlcNAc-related stress responses.