Prj-MSC-AD-microbiome

The complexity and multiplicity of Alzheimer's disease (AD) press for multi-target therapies. Mesenchymal stromal cells (MSCs) are promising candidates to improve AD symptoms, whether the therapeutic mechanism of MSCs involves regulation of gut microbes and microbiome-gut-brain axis (MGBA) has not been reported. In this study, three kinds of MSCs derived from umbilical cord (UCMSC), teeth pulp (SHED), and adipose tissue (ADSC) were isolated and injected into an APP/PS1 mouse model of AD. Compared to NaCl injection, all three MSCs injection could significantly alleviate behavioral disorders, reduce amyloid plaques and phosphorylated tau (p-tau) in the hippocampus and frontal cortex, and increase the number of neurons and Nissl bodies in brain regions of AD mice. By 16S rRNA sequencing, we uncovered that the the gut microbial imbalance in AD mice were partially restored after MSCs treatment, including the upregulation of neuro-protective Akkermansia, and the reduction of AD patients enriched Sphingomonas. Meanwhile, the inactivation of gut microbes using antibiotics could weaken the therapeutic effect of MSCs in AD mice, suggesting that MSCs exert therapeutic effects on AD partially via gut microbes. Furthermore function analysis of the differential gut microbes and targeted bile acids metabolism assays disclosed that MSCs treatment could dramatically increase bile acid profile. One of the main component of bile acids TCA was selected to supplement into AD mice by oral feeding, which also alleviated the symptoms of AD mice. However, the destruction of intestinal nerve cells with enterotoxin could greatly eliminate the therapeutic effect of either MSCs or TCA. Taken together, our data prove that MSCs exert therapeutic effects on AD mice mainly through the regulation of gut microbes and their associated metabolites via MGBA.