Modulation of the Gut Microbiota in Memory Impairment and Alzheimer's Disease via the Inhibition of the Parasympathetic Nervous System.

ABSTRACT

The gut microbiota has been demonstrated to play a critical role in maintaining cognitive function via the gut-brain axis, which may be related to the parasympathetic nervous system (PNS). However, the exact mechanism remains to be determined. We investigated that patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD) could exhibit an altered gut microbiota through the suppression of the PNS, compared to the healthy individuals, using the combined gut microbiota data from previous human studies. The hypothesis was validated in rats to suppress the PNS by scopolamine injections. The human fecal bacterial FASTA/Q files were selected and combined from four different AD studies (n = 410). All rats had a high-fat diet and treatments for six weeks. The MD rats had memory impairment by scopolamine injection (2 mg/kg body weight; MD, Control) or no memory impairment by saline injection. The scopolamine-injected rats had a donepezil intake as the positive group. In the optimal model generated from the XGboost analysis, Blautia luti, Pseudomonas mucidoiens, Escherichia marmotae, and Gemmiger formicillis showed a positive correlation with MCI while Escherichia fergusonii, Mycobacterium neglectum, and Lawsonibacter asaccharolyticus were positively correlated with AD in the participants with enterotype Bacteroides (ET-B, n = 369). The predominant bacteria in the AD group were negatively associated in the networking analysis with the bacteria in the healthy group of ET-B participants. From the animal study, the relative abundance of Bacteroides and Bilophilia was lower, and that of Escherichia, Blautia, and Clostridium was higher in the scopolamine-induced memory deficit (MD) group than in the normal group. These results suggest that MCI was associated with the PNS suppression and could progress to AD by exacerbating the gut dysbiosis. MCI increased Clostridium and Blautia, and its progression to AD elevated Escherichia and Pseudomonas. Therefore, the modulation of the PNS might be linked to an altered gut microbiota and brain function, potentially through the gut-brain axis.