Neuroprotective effects of mesenchymal stromal cells in mouse models of Alzheimer’s Disease: The Mediating role of gut microbes and their metabolites via the Microbiome-Gut-Brain axis

Aug 27, 2024Brain, behavior, and immunity

Protective effects of stem cells in mouse Alzheimer's models linked to gut microbes and their byproducts through the gut-brain connection

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Abstract

Administration of mesenchymal stromal cells (MSCs) led to a significant reduction in behavioral disturbances and amyloid plaques in an Alzheimer’s disease mouse model.

Three types of MSCs—derived from umbilical cord, dental pulp, and adipose tissue—were evaluated for their effects on Alzheimer’s disease symptoms.
MSCs treatment resulted in increased neuronal count and Nissl body density in the brains of Alzheimer's-afflicted mice.
Partial restoration of gut microbial balance was observed post-MSC treatment, with an increase in the neuroprotective bacterium Akkermansia.
Antibiotic treatment that disrupted gut microbiota reduced the efficacy of MSCs in alleviating Alzheimer’s symptoms.
Bile acid profiling indicated a significant increase in bile acid variety following MSC therapy, with taurocholic acid showing potential to reduce symptoms.
Disruption of intestinal neuronal integrity diminished the benefits of both MSCs and taurocholic acid treatments.

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The intricacy and multifaceted nature of Alzheimer's disease (AD) necessitate therapies that target multiple aspects of the disease. Mesenchymal stromal cells (MSCs) emerge as potential agents to mitigate AD symptoms; however, whether their therapeutic efficacy involves modulation of gut microbiota and the microbiome-gut-brain axis (MGBA) remains unexplored. In this study, we evaluated the effects of three distinct MSCs types-derived from the umbilical cord (UCMSC), dental pulp (SHED), and adipose tissue (ADSC)-in an APP/PS1 mouse model of AD. In comparison to saline control, MSCs administration resulted in a significant reduction of behavioral disturbances, amyloid plaques, and phosphorylated tau in the hippocampus and frontal cortex, accompanied by an increase in neuronal count and Nissl body density across AD-afflicted brain regions. Through 16S rRNA gene sequencing, we identified partial restoration of gut microbial balance in AD mice post-MSCs treatment, evidenced by the elevation of neuroprotective Akkermansia and reduction of the AD-associated Sphingomonas. To examine whether gut microbiota involved in MSCs efficacy in treating AD, SHED with better anti-inflammatory and gut microbiota recovery effects among three MSCs, and another AD model 5 × FAD mice with earlier and more pathological proteins in brain than APP/PS1, were selected for further studies. Antibiotic-mediated gut microbial inactivation attenuated MSCs efficacy in 5 × FAD mice, implicating the involvement of gut microbiota in the therapeutic mechanism. Functional analysis of altered gut microbiota and targeted bile acid metabolism profiling revealed a significant enhancement in bile acid variety following MSCs therapy. A chief bile acid constituent, taurocholic acid (TCA), was orally administered to AD mice and similarly abated AD symptoms. Nonetheless, the disruption of intestinal neuronal integrity with enterotoxin abrogated the ameliorative impact of both MSCs and TCA treatments. Collectively, our findings substantiate that MSCs confer therapeutic benefits in AD within a paradigm that primarily involves regulation of gut microbiota and their metabolites through the MGBA.

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Neuroprotective effects of mesenchymal stromal cells in mouse models of Alzheimer’s Disease: The Mediating role of gut microbes and their metabolites via the Microbiome-Gut-Brain axis

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