Faecalibacterium prausnitzii attenuates diabetes-associated affective disorders by suppressing neuroinflammation through the SCFAs/FFAR3/NF-κB/NLRP3 pathway.

BACKGROUND

Diabetes-associated affective disorders are a global health burden tightly linked to the gut microbiota. The depletion of Faecalibacterium prausnitzii (F. prausnitzii) is a shared feature of diabetes and depression, yet its therapeutic potential and mechanisms remain unclear.

METHODS

We first analyzed the microbial composition of populations with type 2 diabetes mellitus (T2DM) and major depressive disorder (MDD) using the GMrepo database to potential probiotic candidates. We then investigated whether supplementation with this probiotic could ameliorate anxiety- and depression-like behaviors in a T2DM mouse model. Utilizing integrated multi-omics analysis, we assessed alterations in gut microbiota profiles and fecal short-chain fatty acid (SCFA) levels, combined with molecular biology experiments to evaluate the impact on neuroinflammation, intestinal barrier integrity, HPA axis activity, and monoamine neurotransmitter levels. Finally, the molecular mechanisms underlying this anti-neuroinflammatory effect were further explored.

RESULTS

We identified a marked depletion of F. prausnitzii in individuals with T2DM and in those with MDD. Administration of F. prausnitzii to T2DM mice ameliorated anxiety and depression-like behaviors, reversed gut dysbiosis, and elevated butyric and valeric acids levels. These improvements were coupled with enhanced intestinal barrier integrity, normalized HPA axis activity, and restored monoamine neurotransmitter levels. Moreover, the anti-neuroinflammatory effects elicited by F. prausnitzii-derived butyric acids and valeric acids appeared to be associated with the FFAR3/NF-κB/NLRP3 pathway.

CONCLUSIONS

Our findings suggest that SCFA-induced FFAR3 pathway may contribute to the anxiolytic- and antidepressant-like effects of F. prausnitzii, highlighting its potential as a microbiome-based strategy for managing diabetes-associated affective disorders.