Multi-omics profiling implicates gut microbiota-sphingolipid interplay in the neuroprotective effects of semaglutide on diabetic cognitive impairment

Background The gut microbiome is a critical regulator of host health, but how it mediates the therapeutic effects of drugs targeting neurodegenerative diseases like diabetic cognitive impairment (DCI) is unclear. Here, we investigated whether the neuroprotective effects of the GLP-1 agonist semaglutide (SE) are linked to its modulation of the gut-brain axis. Methods We used an integrative multi-omics approach in a mouse model of DCI. We combined fecal shotgun metagenomics and targeted bile acid profiling with cerebral proteomics and metabolomics to characterize the gut-brain crosstalk following a 12-week SE treatment. Animal behavior, neuronal survival and synaptic integrity were assessed to confirm therapeutic efficacy. Results SE treatment reversed cognitive deficits, rescued hippocampal neuronal loss, and restored synaptic integrity in diabetic mice. At the ecosystem level, metagenomics revealed that SE treatment profoundly remodeled the gut microbiota, enhancing microbial α-diversity, enriched beneficial genera ( Bacteroides , Barnesiella ), and depleted the pro-inflammatory genus Desulfovibrio . This microbial shift was associated with normalized fecal and cerebral bile acid profiles. Mechanistically, our analysis implicated a dysregulated sphingolipid pathway in the DCI brain, characterized by the upregulation of the transporter ATP-binding cassette transporter A2 (ABCA2) and the enzymes sphingosine-1-phosphate phosphatase 1 (SGPP1) and ceramide synthase 2 (CERS2). SE treatment dynamically modulated this pathway: it downregulated ABCA2 in a potentially weight-independent manner and SGPP1 in a weight-dependent fashion, linked to the normalization of cerebral bile acid profiles. In contrast, CERS2, a robust marker of disease severity, was not altered by SE. Conclusion Our study uncovers a novel “gut microbiota–bile acid–sphingolipid” axis in DCI and suggests that SE acts via a dual mechanism. It drives a weight-dependent restoration of the gut-brain axis, normalizing microbial and bile acid profiles to regulate SGPP1, while also exerting weight-independent effects, potentially through direct modulation of targets like ABCA2. This work highlights the gut microbiome as a key component in the therapeutic action of SE and reveals the multifaceted nature of its neuroprotective effects.