Akkermansia muciniphila Modulates Central Nervous System Autoimmune Response and Cognitive Impairment by Inhibiting Hippocampal NLRP3-Mediated Neuroinflammation.

Background: Numerous studies have demonstrated the significant role of Akkermansia muciniphila (A. muciniphila) in enhancing host immune responses and metabolic functions. However, its increased presence in multiple sclerosis (MS) patients has led to a focus on the relationships between A. muciniphila and diseases, with the underlying mechanisms remaining unknown.

Method: Solochrome cyanin, hematoxylin-eosin staining (H&E) and immunofluorescence staining were used to assess demyelination and inflammation. Gut microbiota changes were examined by 16S rRNA sequencing. Intracellular cytokine levels were assessed by flow cytometry. Cognitive impairment was evaluated using four behavioral tests. Intestinal barrier function and pyrin domain-containing protein 3 (NLRP3)-mediated neuroinflammation were evaluated by immunoblotting.

Results: We found that treatment with an appropriate dose of A. muciniphila (5.0 × 10 CFU/mL) reduced neuropathology and disease severity in experimental autoimmune encephalomyelitis (EAE) mice. In addition, A. muciniphila supplementation increased the diversity and abundance of intestinal microbiota while decreasing the Firmicutes/Bacteroidetes ratio. Moreover, it improved intestinal barrier function and attenuated Th17 responses in the gut, central nervous system (CNS), and lymphoid tissues, without affecting Treg response in the lymphoid tissue. Furthermore, A. muciniphila administration partly regulated cognitive impairment and hippocampal NLRP3-mediated neuroinflammation.

Conclusion: Our results suggest that A. muciniphila holds promise as a probiotic for treating NLRP3-associated inflammatory disorders and cognitive impairment, including MS.