Metabolite mimicry identifies butyrate analogs with select protective functions in the intestinal mucosa.
AI summary
75% confidenceThe study utilized metabolite mimicry to identify butyrate analogs that overcome the limitations of rapid metabolism and differential cellular responses in the intestinal mucosa. The identified analog, 3-chlorobutyrate (3-Cl BA), acts as a potent HDAC inhibitor that enhances barrier formation and wound healing without stabilizing HIF or serving as metabolic fuel.
Generated by MESSAI extraction pipeline · review against source PDF
No 3D model is mapped to this paper yet. Parameter ranges above still place reported values on the literature distribution.
Abstract
Microbial-derived short-chain fatty acids regulate a variety of pathways in the healthy colonic mucosa. In particular, butyrate serves as the primary energy source for colonocytes and regulates gene transcription by stabilizing the transcription factor hypoxia-inducible-factors (HIF) and functioning as a histone deacetylase (HDAC) inhibitor. A limitation of butyrate as a therapeutic is its rapid metabolism in differentiated colonocytes. Furthermore, intestinal stem cells (ISCs) respond differently to butyrate, preferentially using glucose for energy procurement. To address these limitations, we explored metabolite-mimicry to discover compounds with potent or selective biological responses within the butyrate pathway(s). We discovered an analog, 3-chlorobutyrate (3-Cl BA), that significantly enhances epithelial barrier formation and wound healing in vitro. Mechanistically, we revealed that 3-Cl BA is a potent HDAC inhibitor. Furthermore, unlike butyrate, 3-Cl BA does not stabilize HIF and it is not used as metabolic fuel. In vivo studies in a DSS-colitis model revealed that contrary to butyrate, 3-Cl BA is protective. Studies in stem-like colonoids demonstrated that only butyrate inhibits ISC proliferation and differentiation. Furthermore, it was recently reported that HIF stabilization inhibits ISCs activity. Given the fact that butyrate but not 3-Cl BA stabilizes HIF, we surmised that 3-Cl BA would circumvent these detrimental functional consequences. We demonstrate here that pharmacologic HIF stabilization inhibits colonoid differentiation and that genetic loss of HIF significantly promotes ISC differentiation. This study reveals a promising butyrate analog protective in colitis and demonstrates the advantages of metabolite-mimicry to dissect selective biological functions from major metabolites in the gut.
Key findings
- 3-chlorobutyrate (3-Cl BA) significantly enhances epithelial barrier formation and wound healing in vitro compared to butyrate.
- Unlike butyrate, 3-Cl BA does not stabilize hypoxia-inducible-factors (HIF) and is not utilized as metabolic fuel by colonocytes.
- In vivo studies demonstrated that 3-Cl BA provides protective effects in a DSS-colitis model, whereas butyrate did not show the same level of protection.