Lactobacillus casei Zhang modulates hippocampal metabolism and cognition in T2DM rats: a microbiota-gut-brain axis...

The gut plays a pivotal role in metabolic disorders, providing a tractable target for type 2 diabetes mellitus (T2DM) prevention. Although Lactobacillus casei Zhang (LCZ) demonstrates cognitive benefits in T2DM, the mechanism by which LCZ modulates the gut microbiota to ameliorate cognition decline remains unelucidated. Therefore, we investigated the protective effects of LCZ against diabetic encephalopathy via the microbiota-gut-brain axis. Forty-two male Sprague-Dawley rats were randomly assigned to three groups (n=14/group): saline control (CON), T2DM group, and T2DM prevented with LCZ (T2DM+LCZ). Cognitive function was assessed by novel object recognition and Y-maze tests. Hippocampal metabolism was analyzed via ¹H NMR-based metabolomics. Gut microbiota composition was determined by 16S rRNA sequencing, and fecal short-chain fatty acid (SCFA) levels were quantified using targeted metabolomics. Compared with CON, T2DM rats exhibited significant increases in fasting blood glucose and insulin resistance, cognitive deficits, hippocampal metabolism disruption, elevated hippocampal inflammation, altered gut microbiota composition, and reduced SCFA. LCZ intervention (T2DM+LCZ group) effectively mitigated these T2DM-induced alterations, significantly lowering fasting blood glucose and insulin resistance, improving cognitive function, attenuating hippocampal inflammation, normalizing hippocampal metabolites, and restoring gut microbiota composition and SCFA levels. Crucially, no significant differences in most metrics were observed between the T2DM+LCZ and CON groups. Our findings demonstrate that LCZ alleviates T2DM-induced cognitive impairment by modulating the microbiota-gut-brain axis. Specifically, LCZ administration restores SCFA production and partially remodeled brain metabolism, highlighting its therapeutic promise for preventing diabetic encephalopathy.