Impact of Gut Microbiome Manipulation in 5xFAD Mice on Alzheimer’s Disease-Like Pathology

Abstract

The gut brain axis seems to modulate various psychiatric and neurological disorders such as Alzheimer’s disease (AD). Growing evidence has led to the assumption that the gut microbiome might contribute to or even present the nucleus of origin for these diseases. In this regard, modifiers of the microbial composition might provide attractive new therapeutics. Aim of our study was to elucidate the effect of a rigorously changed gut microbiome on pathological hallmarks of AD. 5xFAD model mice were treated by antibiotics or probiotics (L. acidophilus and L. rhamnosus) for 14 weeks. Pathogenesis was measured by nest building capability and plaque deposition. The gut microbiome was affected as expected: antibiotics significantly reduced viable commensals, while probiotics transiently increased Lactobacillaceae. Nesting score, however, was only improved in antibiotics-treated mice. These animals additionally displayed reduced plaque load in the hippocampus. While various physiological parameters were not affected, blood sugar was reduced and serum glucagon level significantly elevated in the antibiotics-treated animals together with a reduction in the receptor for advanced glycation end products RAGE—the inward transporter of Aβ peptides of the brain. Assumedly, the beneficial effect of the antibiotics was based on their anti-diabetic potential.

A Systematic Review on the Effects of Different Types of Probiotics in Animal Alzheimer's Disease Studies

“…An increase in certain bacterial phyla was observed upon probiotic administration (i.e., Actinobacteria, Verrucomicrobia, Bacteroidetes ) ( 50 , 56 ). At the family level, an increase in Peptococcaceae, Ruminococcaceae, Prevotellaceae , S24-7, and Lactobacillaceae was found compared to control group animals ( 49 , 52 , 55 – 58 , 62 ). An increase in Acetatifactor, Millionella, Alloprevotella, Parabacteroides, Bifidobacterium, Lactobacillus and Bacteroidales was observed compared to AD controls at the genus level ( 47 , 51 – 53 , 61 ).…”

microRNA-146a-5p, Neurotropic Viral Infection and Prion Disease (PrD)

“…miRNA-146a's role and significance in viral-induced encephalopathies and prion disease appear to be expanding. Several attractive and all-encompassing recently proposed theories suggest: (i) that there is a contribution of prions and misfolded proteins in human degenerative diseases that include AD and AMD and other miRNA-146a-associated neurological disorders [56,75,108]; and (ii) that there may be a gastrointestinal (GI)-tract-sourced contribution of microbes or microbial neurotoxins to AD and related neurodegenerative disorders that critically involve miRNA-146a-mediated immunological and/or pro-inflammatory signaling components [108][109][110][111]…”

Impact of the Age of Cecal Material Transfer Donors on Alzheimer’s Disease Pathology in 5xFAD Mice

“…Early post-natal antibiotics treatment (P14-P21) resulted not only in long-term alterations of gut microbial genera but also in reduction of brain Aβ deposits and neuroinflammation in aged APPSWE/PS1∆E9 mice. Several publications revealed that antibiotics such as vancomycin, bacitracin, and metronidazole might affect metabolic homeostasis-especially brain insulin sensitivity-in different mouse strains [56][57][58][59]. This might be highly relevant for the observed effects in AD mouse models as a diabetic phenotype contributes to pathogenesis and C57Bl6 mice, often used as disease models, are prodiabetic-in particular, males are prone to obesity.…”