Triple-Omics Analysis Unveiled the Neuroprotective Mechanisms of Akkermansia muciniphila in an Environmental Exposure-Linked Mouse Model of Alzheimer’s Disease

ABSTRACT Cadmium (Cd) is an emerging environmental risk factor for cognitive decline and Alzheimer’s disease, and few interventions limit its effects on the brain. Akkermansia muciniphila , a human gut commensal, is neuroprotective through mechanisms that remain unclear. Building on our finding that A. muciniphila prevented Cd-induced memory deficits without reducing brain Cd burden (Wang et al., 2026a), we tested whether it reprograms Cd-disrupted hippocampal RNA regulation. Male C57BL/6J mice received A. muciniphila (1×10⁹ CFU, oral gavage, 5 days/week) before and throughout 9 weeks of 3 mg/L CdCl₂ exposure; hippocampi were analyzed by RNA-seq, m⁶A epitranscriptomic profiling, and rMATS-based alternative-splicing analysis. Cd disrupted hippocampal neuropeptide signaling, neuronal excitability, and synaptic plasticity. Co-exposure with A. muciniphila reversed signatures enriched for Nrf2-centered cytoprotective signaling and opposed m⁶A and splicing changes across more than a thousand genes, largely without changes in total mRNA abundance. Restored events converged on machinery governing local translation, calcium-dependent plasticity, and synaptic transmission. Projected onto predicted protein structures, most introduced a premature termination codon predicted to trigger nonsense-mediated decay or edited short loop and linker segments rather than rebuilding folded domains, regulation largely invisible to gene-level expression analysis. Among these, paired events amplifying semaphorin-plexin signaling, an axis linked to oligodendrocyte injury and memory consolidation, were reversed. These findings identify restoration of hippocampal transcript fate and splice-isoform selection as a mechanism potentially underlying A. muciniphila -mediated protection against Cd neurotoxicity, and establish post-transcriptional RNA regulation as a gut-brain target for mitigating environmentally driven neurotoxicity. IMPACT STATEMENT Cadmium is a widespread environmental contaminant associated with cognitive decline and Alzheimer’s disease, and few interventions are available to limit its effects on the brain. This study shows that supplementation with the gut commensal Akkermansia muciniphila reverses Cd-induced changes in hippocampal m⁶A methylation and splice-isoform selection, largely without altering total transcript abundance. These results identify post-transcriptional RNA regulation as a gut-brain target for mitigating environmentally driven neurotoxicity, and show that conventional gene-expression analysis alone would miss most of the protective response.

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