Inulin alleviates vascular cognitive impairment by restoring prefrontal GABAergic function via microbiota-SCFA-GPR41/43 axis.

Authors

Zhiying Zou, Junxiu Xi, Juan Li, Bo Lian, Cairui Fan, Haichao Cao, Weiping Liu, Shengxi Wu, Qianfa Long, Yue Hei

Published in

Microbiome. Jul 15, 2026. Epub Jul 15, 2026.

Abstract

Vascular cognitive impairment (VCI) impairs medial prefrontal cortex (mPFC) function, a cognitive hub reliant on intact GABAergic transmission. Although prebiotics may counteract VCI by remodeling the gut microbiota, the underlying mechanisms remain unclear. This study investigated whether the prebiotic inulin could improve VCI by restoring mPFC GABAergic function via the gut-brain axis.
In a mouse model of VCI induced by bilateral carotid artery stenosis (BCAS), inulin supplementation ameliorated cognitive deficits and anxiety-like behaviors and reshaped the gut microbiota, particularly enriching SCFA-producing genera such as Ruminococcaceae. Antibiotic depletion abolished inulin's cognitive and intestinal barrier benefits, confirming microbiota dependence. In the mPFC, inulin reversed VCI-induced reductions in GABAergic synaptic transmission and GABA levels, which positively correlated with elevated colon short-chain fatty acid (SCFA) levels. Mechanistically, these effects were linked to the upregulation of SCFA receptors GPR41/43 and presynaptic restoration. Critically, shRNA-mediated knockdown of GPR41/43 abolished the behavioral and GABAergic benefits of SCFA supplementation, confirming the necessity of this signaling axis. Furthermore, to show the role of GABAergic function as inulin's final common pathway, pharmacological blockade of GABAergic signaling with bicuculline eliminated inulin's cognitive and anti-inflammatory benefits.
Inulin alleviates VCI by elevating gut-derived SCFAs, which activate neuronal GPR41/43 in the mPFC to restore GABAergic function. These findings delineate a clear gut-mPFC pathway and support the therapeutic potential of inulin as an intervention targeting the microbiota-SCFA-GABA axis in cognitive disorders. Video Abstract.

PMID:
42458594
Bibliographic data and abstract were imported from PubMed on 16 Jul 2026.

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