What question did this study set out to answer?

The study aims to explore how Akkermansia muciniphila influences microglial lipid metabolism and inflammation after acute ischemic stroke.

February 2, 2026

Abstract DP232: From Gut to Brain: Akkermansia muciniphila Modulates Microglial Lipid Metabolism and Inflammation to Enhance Post-Stroke Recovery

Key Points

The study aims to explore how Akkermansia muciniphila influences microglial lipid metabolism and inflammation after acute ischemic stroke.
Male mice underwent permanent middle cerebral artery occlusion (pMCAO) and were treated with AKK or vehicle.
Neurological recovery was assessed using Rotarod and Foot Fault tests.
Single-cell RNA sequencing profiled brain immune cell responses to treatment.
Immunofluorescence and immunohistochemistry evaluated microglial phenotypes and lipid accumulation.
Metabolomics and pathway analysis identified key metabolites and pathways affected by AKK.
Microglia were identified as the main cell type affected by AIS and responsive to AKK, showing changes in phenotypes with 73 genes upregulated and 27 downregulated.
AKK treatment reduced harmful foam cell-like microglia, enhanced M2 polarization, and restored PSAP/GPR37/ERK signaling.
Isorhamnetin was discovered as a key metabolite inversely correlated with neurological deficits, while beneficial sphingomyelins were restored in AKK-treated mice.

Abstract

Introduction: Acute ischemic stroke (AIS) is increasingly recognized as a systemic disorder in which gut microbiota dysbiosis drives neuroinflammation via the brain–gut axis. Akkermansia muciniphila (AKK), a commensal bacterium comprising ~3% of the human gut microbiota, has been linked to improved neurological recovery; however, its molecular mechanisms is unknown. We investigated how AKK modulates microglial lipid metabolism, signaling pathways, and inflammatory phenotypes after AIS. Methods: Male mice underwent permanent middle cerebral artery occlusion (pMCAO) and received AKK or vehicle. Neurological outcomes were assessed by Rotarod and Foot Fault tests. Single-cell RNA sequencing (scRNA-seq) profiled brain immune cell heterogeneity. Microglial phenotypes and lipid accumulation were evaluated by immunofluorescence, immunohistochemistry, and BODIPY staining. RT-qPCR quantified pro-inflammatory cytokines, and Western blot measured PSAP, GPR37, GPR37L, and p-ERK. Untargeted plasma metabolomics with KEGG pathway analysis identified AKK-modulated metabolites and lipid pathways. Results: scRNA-seq identified microglia as the principal AIS-affected cell type responsive to AKK, comprising four subclusters: disease-associated microglia (DAM), H-microglia (homeostatic), ATM (tissue-resident macrophage–like), and foam cells. In AKK-treated mice, 73 genes were upregulated and 27 downregulated in microglia, with enrichment of lipid transport/metabolism (Apoe, Apoc4) and “Lipid and atherosclerosis” plus NF-κB/TNF signaling pathways. pMCAO markedly increased foam cell–like microglia and lipid accumulation; AKK reduced these cells, restored PSAP/GPR37/ERK signaling, decreased total Iba1+ microglia, and enhanced M2 polarization (↑lba1+/CD206+). Metabolomics identified isorhamnetin as a key AKK-induced metabolite inversely correlated with neurological deficits. AKK restored beneficial sphingomyelins, improved glycerophospholipid/sphingolipid metabolism, reduced pro-inflammatory trimethylamine N-oxide, and enriched lysosome-related pathways. Conclusion: AKK confers neuroprotection after AIS by increasing isorhamnetin, activating PSAP/GPR37/ERK signaling, and reprogramming microglia from pro-inflammatory foam cells toward a reparative M2 phenotype, while restoring phospholipid homeostasis and reducing harmful microbial metabolites. This work defines a novel gut microbe–metabolite–signaling axis in AIS and highlights AKK as a promising, translational therapeutic strategy.

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