Indole lactic acid derived from Akkermansia muciniphila activates the aryl hydrocarbon receptor to inhibit ferroptosis in ischemic stroke

Abstract

Ischemic stroke concurrent with gut microbiome dysbiosis induces intestinal damage, which exacerbates cerebral infarction. Probiotic or prebiotic interventions that reverse gut microbiome dysbiosis can promote recovery after ischemic stroke. Akkermansia muciniphila (AKK) safeguards intestinal health and is a promising probiotic; however, its role in ischemic stroke remains unclear. In this study, we found that live AKK, but not pasteurized AKK, mitigated ischemic-stroke-induced neurological injury, reduced cerebral infarction, and enhanced both blood-brain and intestinal barrier integrity. Moreover, the AKK supernatant reduced intestinal and cerebral injury, demonstrating efficacy comparable to that of live AKK. Metabolomic analysis revealed that the AKK supernatant was significantly enriched in indole lactic acid (ILA), a tryptophan metabolite. ILA levels were elevated in the serum and brains of pseudo-germ-free stroke rats administered AKK. Exogenous gavage with ILA mitigated ischemic-stroke-induced brain and intestinal damage. Mechanistically, ILA activated the aryl hydrocarbon receptor (AhR) and the nuclear transcription factor Nrf2, leading to the upregulation of SLC7A11 and GPX4 protein expression. This attenuated lipid peroxidation and intracellular iron accumulation triggered by ischemic stroke. Notably, intervention with the AhR inhibitor CH223191 abrogated the protective effects of ILA in ischemic stroke rats. These findings suggest that the therapeutic efficacy of AKK in ischemic stroke is at least partially attributable to ILA-mediated ferroptosis inhibition via AhR activation. AKK was selectively enriched by Puerariae lobatae Radix-resistant starch (PRS), promoting ILA generation more effectively than inulin and β-glucan. AKK and PRS synergistically alleviated ischemic-stroke-induced impairments, outperforming monomicrobial or prebiotic treatment alone. These findings reveal the unique mechanisms of AKK in ischemic stroke and provide a viable strategy for the clinical treatment of ischemic stroke through a novel synbiotic combination.