Modulation of the Gut Microbiota in Memory Impairment and Alzheimer’s Disease via the Inhibition of the Parasympathetic Nervous System Original paper

What was studied?

This original research article investigated how modulation of the parasympathetic nervous system influences gut microbiota signatures associated with mild cognitive impairment and Alzheimer’s disease. The work integrates human microbiome datasets and an animal model to determine whether parasympathetic inhibition contributes to gut dysbiosis that characterizes progressive memory impairment. The authors combined 410 human fecal FASTA/Q datasets across four independent studies and performed enterotyping, taxonomic profiling, and machine-learning modeling. Using these combined data, they examined whether Bacteroides-dominant enterotypes show reproducible bacterial signatures distinguishing healthy aging, mild cognitive impairment, and Alzheimer’s disease. They then validated the mechanistic hypothesis in rats by inhibiting parasympathetic signaling with scopolamine—an anticholinergic compound known to induce memory impairment—while measuring changes in gut microbiota composition. This dual-approach design enabled the researchers to analyze a broad set of microbial taxa while determining whether the parasympathetic system itself shapes these microbial shifts.

Who was studied?

Human data were obtained from older adults aged 60–85 years across studies conducted in Singapore, China, and Turkey. From the combined 410 human participants, most were categorized into a Bacteroides enterotype (n=369), which became the primary analytical subgroup. This group included 125 healthy individuals, 141 with mild cognitive impairment, and 103 with Alzheimer’s disease. An animal arm included thirty male Sprague Dawley rats fed a high-fat diet to emulate a human Bacteroides-dominant enterotype. Rats were assigned to memory-deficient, positive-control (donepezil-treated), or normal groups and assessed for spatial and short-term memory while undergoing parasympathetic suppression with scopolamine.

Most important findings

Across human datasets, progression from health to mild cognitive impairment to Alzheimer’s disease corresponded with declining Bacteroidaceae and increasing Proteobacteria members such as Escherichia and Pseudomonas. Mild cognitive impairment showed distinct elevations in Blautia, Faecalibacterium, and Streptococcus, while Alzheimer’s disease consistently featured increased Escherichia fergusonii, Pseudomonas syringae, and Mycobacterium neglectum. Machine-learning models using species-level data achieved strong discrimination (ROC ~0.94), highlighting taxa with predictive value: Blautia luti and Escherichia marmotae for mild cognitive impairment, and Escherichia fergusonii and Lawsonibacter asaccharolyticus for Alzheimer’s disease. Network analyses showed Alzheimer’s associated bacteria formed tightly correlated clusters negatively linked to health-associated taxa, suggesting weakened microbial resilience during disease progression. In scopolamine-treated rats, parasympathetic inhibition reproduced human-like dysbiosis: Bacteroides decreased while Clostridium, Escherichia, and Blautia increased, mirroring transitions observed from mild cognitive impairment to Alzheimer’s disease.

Key implications

These findings position parasympathetic suppression as a mechanistic driver of gut dysbiosis linked to memory decline. The data support a model wherein early increases in Blautia and certain butyrate-producing genera mark mild cognitive impairment, while overgrowth of Proteobacteria—especially Escherichia and Pseudomonas—accompanies or accelerates progression to Alzheimer’s disease. Identifying microbial signatures tied to parasympathetic activity suggests therapeutic opportunities: enhancing vagal tone, modifying bile acid signaling, or targeting specific harmful taxa may stabilize the gut–brain axis. This work strengthens the rationale for including microbiome diagnostics in evaluating cognitive impairment trajectories.

Citation

Park S, Wu X. Modulation of the gut microbiota in memory impairment and Alzheimer’s disease via the inhibition of the parasympathetic nervous system.Int J Mol Sci. 2022;23(21):13574. doi:10.3390/ijms232113574