Gut microbiota-derived indole-3-propionic acid preserves dorsal hippocampal catecholamines to prevent post-stroke cognitive impairment

ABSTRACT Gut dysbiosis has been increasingly implicated in post-stroke cognitive impairment (PSCI); however, the causal contribution and therapeutic potential of gut microbiota-derived metabolites remain unclear. This study aimed to identify key microbiota-derived metabolites involved in PSCI and elucidate their underlying mechanisms. We found that both PSCI patients and middle cerebral artery occlusion (MCAO) mice exhibited distinct gut microbial alterations, characterized by a marked reduction in tryptophan-metabolizing bacteria and indole-3-propionic acid (IPA), a gut microbiota-derived tryptophan metabolite. Exogenous IPA administration alleviated PSCI-like phenotypes in MCAO mice. Mechanistically, IPA preserved tyrosine hydroxylase-positive (Th + ) fibers and catecholamine levels in the dorsal hippocampus. Further analyses showed that IPA binds to the adaptor protein Ywhab, promotes ERK activation, and enhances neuronal survival, thereby counteracting neuronal apoptosis-associated inflammation, and subsequent Th + fiber degeneration. These findings identify IPA as a gut microbiota-derived neuromodulator that mitigates PSCI by preserving dorsal hippocampal catecholaminergic transmission. IPA may therefore serve as a therapeutic candidate for PSCI. IMPORTANCE The advance of the present work lies in defining a mechanistic link between microbiota-derived IPA deficiency and post-stroke cognitive dysfunction rather than acute ischemic injury alone. We show that circulating IPA is persistently reduced in patients who develop PSCI and in MCAO mice and that early IPA supplementation improves post-stroke memory by preserving dorsal hippocampal TH-positive fibers and catecholamine availability. Mechanistically, we identify Ywhab as an IPA-binding protein and demonstrate that modulation of the Ywhab-ERK pathway promotes neuronal survival, limits secondary neuroinflammation, and preserves catecholaminergic projections. Importantly, Ywhab knockdown reproduced several protective effects of IPA, including reduced neuronal apoptosis and microglial activation, preservation of TH-positive fibers, and improved cognitive performance. These findings nominate Ywhab as a potential therapeutic target for PSCI and distinguish the present study from previous reports describing only the general neuroprotective effects of IPA.