Indole-3-aldehyde Alleviates High-Fat Diet-Induced Gut Barrier Disruption by Increasing Intestinal Stem Cell Expansion

High-fat diet (HFD) feeding is known to cause intestinal barrier disruption, thereby triggering severe intestinal inflammatory disease. Indole-3-aldehyde (IAld) has emerged as a potential candidate for mitigating inflammatory responses and maintaining intestinal homeostasis. However, the role of IAld in the HFD-related intestinal disruption remains unclear. In this study, 48 7 week-old male C57BL/6J mice were assigned to four groups: the normal chow diet (NCD) group received a NCD; the HFD group was fed an HFD; the HFD + IAld200 group was supplemented with 200 mg/kg IAld in the HFD; and the HFD + IAld600 group was supplemented with 600 mg/kg IAld in the HFD. The results showed that dietary IAld supplementation ameliorated fat accumulation and metabolic disorders, which are associated with reduced intestinal permeability. This reduction potentially led to decreased systemic inflammation and enhanced intestinal barrier function in HFD-fed mice. Furthermore, we found that IAld promoted intestinal stem cell (ISC) proliferation by activating aryl hydrocarbon receptors (AHRs) in vivo and ex vivo. These findings suggest that IAld restores the HFD-induced intestinal barrier disruption by promoting AHR-mediated ISC proliferation.