Adiponectin Regulated by Indole-3-Acetic Acid in Paneth Cells Controls Renewal and Differentiation of Gut Stem Cells

The intestinal epithelium is tightly regulated by intestinal stem cells (ISCs), but the precise mechanisms governing their differentiation remain incompletely understood. We here demonstrate that adiponectin secreted by Paneth cells (PCs) suppresses ISC renewal and differentiation via adiponectin receptor 1 (adipoR1). Genetic ablation of adiponectin in gut epithelial cells (adip^{fl/fl-Villi-Cre} mice) enhanced crypt cell renewal and differentiation. Single-cell RNA sequencing (scRNA-seq) revealed a significant increase in the enrichment of ISCs and transit-amplifying (TA) cells in adip^{fl/fl-Villi-Cre} mice compared to control adip^fl/fl mice. Furthermore, adip^{fl/fl/-Villi-Cre} mice exhibited accelerated regeneration of intestinal epithelial cells following irradiation or dextran sulfate sodium (DSS)-induced injury. Intestinal organoids derived from adip^{fl/fl-Villi-Cre} mice also displayed markedly faster growth than those from adip^fl/fl mice. Consistent with these findings, adipoR1 knockout (KO) mice exhibited elongated crypt structures, further supporting adiponectin's inhibitory role in ISC proliferation. Notably, gut microbiota-derived indole-3-acetic acid (IAA) downregulated adiponectin expression, thereby promoting ISC renewal and proliferation. This was corroborated by in vitro organoid cultures, where IAA treatment accelerated development. Thus, our findings reveal that adiponectin modulated by microbial IAA serves as a critical regulator of ISC dynamics, ensuring epithelial homeostasis.