Therapeutic Potential of Microbiota Modulation in Alzheimer's Disease: A Review of Preclinical Studies

Abstract

Alzheimer's disease (AD) is the most common neurodegenerative disease, yet it currently lacks effective treatment due to its complex etiology. The pathological changes in AD have been linked to the neurotoxic immune responses following aggregation of Aβ and phosphorylated tau. The gut microbiota (GM) is increasingly studied for modulating neuroinflammation in neurodegenerative diseases and in vivo studies emerge for AD. This critical review selected 7 empirical preclinical studies from 2019 onwards assessing therapy approaches targeting GM modulating microglia neuroinflammation in AD mouse models. Results from probiotics, fecal microbiota transplantation, and drugs were compared and contrasted, including for cognition, neuroinflammation, and toxic aggregation of proteins. Studies consistently reported significant amelioration or prevention of cognitive deficits, decrease in microglial activation, and lower levels of pro-inflammatory cytokines, compared to AD mouse models. However, there were differences across papers for the brain regions affected, and changes in astrocytes were inconsistent. Aβ plaques deposition significantly decreased in all papers, apart from Byur dMar Nyer lNga Ril Bu (BdNlRB) treatment. Tau phosphorylation significantly declined in 5 studies. Effects in microbial diversity following treatment varied across studies. Findings are encouraging regarding the efficacy of study but information on the effect size is limited. Potentially, GM reverses GM derived abnormalities, decreasing neuroinflammation, which reduces AD toxic aggregations of proteins in the brain, resulting in cognitive improvements. Results support the hypothesis of AD being a multifactorial disease and the potential synergies through multi-target approaches. The use of AD mice models limits conclusions around effectiveness, as human translation is challenging.

Keywords: Alzheimer’s disease; brain-gut axis; dysbiosis; fecal microbiota transplantation; microglia; neurodegenerative diseases; probiotics; therapeutics.

Fig. 1

Microbiota-gut-brain axis involvement in AD pathogenesis. The gut microbiota disturbances (changes in bacteria diversity) lead to an increase in gut barrier permeability that may cause release of molecules in systemic circulation (including proinflammatory cytokines) and an increase in the BBB permeability. This may in turn activate microglia (changing their morphology) and lead to an accumulation of Aβ. The neuroinflammation and neurodegeneration that follow are characteristic of AD. SCFA, short chain fatty acids; IL, interleukin; TNF, tumor necrosis factor; BBB, blood-brain barrier.