The pathological consequences of
type 2 diabetes mellitus (T2DM) also involve the central nervous system; indeed, T2DM patients suffer from learning and memory disabilities with a higher risk of developing
dementia. Although several factors have been proposed as possible contributors, how
neuroactive steroids and the gut microbiome impact brain pathophysiology in T2DM remain unexplored. On this basis, in male Zucker diabetic fatty (ZDF) rats, we studied whether T2DM alters memory abilities using the novel object recognition test,
neuroactive steroid levels by liquid chromatography-tandem mass spectrometry, hippocampal parameters using molecular assessments, and gut microbiome composition using 16S next-generation sequencing. Results obtained reveal that T2DM worsens memory abilities and that these are correlated with increased levels of
corticosterone in plasma and with a decrease in
allopregnanolone in the hippocampus, where
neuroinflammation, oxidative stress, and
mitochondrial dysfunction were reported. Interestingly, our analysis highlighted a small group of taxa strictly related to both memory impairment and
neuroactive steroid levels. Overall, the data underline an interesting role for
allopregnanolone and microbiota that may represent candidates for the development of therapeutic strategies.