Synergistic depletion of gut microbial consortia, but not individual antibiotics, reduces amyloidosis in APPPS1-21 Alzheimer’s transgenic mice

Abstract

In preceding efforts, we demonstrated that antibiotic (ABX) cocktail-mediated perturbations of the gut microbiome in two independent transgenic lines, termed APPSWE/PS1ΔE9 and APPPS1-21, leads to a reduction in Aβ deposition in male mice. To determine whether these observed reductions of cerebral Aβ amyloidosis are specific to any individual antibiotic or require the synergistic effects of several antibiotics, we treated male APPPS1-21 transgenic mice with either individual ABX or an ABX cocktail and assessed amyloid deposition. Specifically, mice were subject to oral gavage with high dose kanamycin, gentamicin, colistin, metronidazole, vancomycin, individually or in a combination (ABX cocktail) from postnatal days (PND) 14 to 21, followed by ad libitum, low-dose individual ABX or ABX cocktail in the drinking water until the time of sacrifice. A control group was subject to gavage with water from PND 14 to 21 and received drinking water till the time of sacrifice. At the time of sacrifice, all groups showed distinct cecal microbiota profiles with the highest differences between control and ABX cocktail-treated animals. Surprisingly, only the ABX cocktail significantly reduced brain Aβ amyloidosis compared to vehicle-treated animals. In parallel studies, and to assess the potential exposure of ABX to the brain, we quantified the levels of each ABX in the brain by liquid chromatography-mass spectrometry (LC-MS) at PND 22 or at 7 weeks of age. With the exception of metronidazole (which was observed at less than 3% relative to the spiked control brains), we were unable to detect the other individual ABX in brain homogenates. Our findings suggest that synergistic alterations of gut microbial consortia, rather than individual antimicrobial agents, underlie the observed reductions in brain amyloidosis.

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

“…The antibiotics treatment regimen differed from the here used one (containing 1 mg/mL vancomycin, 1 mg/mL cefoxitin, 1 mg/mL gentamicin and 1 mg/mL metronidazol for two months). As an investigation in APP/PS1 mice demonstrated, however, a single administered antibiotic drug is not effective, but rather a mixture is [ 63 ]. This study also reported that only minor amounts of the administered drugs could be found in brain parenchyma.…”

Roles and Mechanisms of Gut Microbiota in Patients With Alzheimer’s Disease

“…Another study in APP/PS1 transgenic mice has found that the gut microbiota alterations with enrichment of inflammation-related bacterial taxa including Escherichia-Shigella, Desulfovibrio, Akkermansia, and Blautia precede the development of key pathological features of AD, including amyloidosis and plaquelocalized neuroinflammation (Chen Y. et al, 2020). Dodiya et al (2020) also found that synergistic alterations in the gut microbial consortia, rather than individual antimicrobial agents, underlie the observed reductions in brain amyloidosis in APPPS1-21 AD transgenic mice. Sun et al (2020c) used a novel dementia mouse model to study the influence of gut Aβ on CNS histopathology and function.…”

Modulation of Glial Function in Health, Aging, and Neurodegenerative Disease

“…These findings are congruent with previous studies that administered an antibiotic cocktail to transgenic APP/PS1 AD mice and showed a reduction in Aβ plaque pathology and plaque-associated microgliosis as well as increased cytokine and chemokine circulation (Minter et al, 2016 , 2017 ; Harach et al, 2017 ; Dodiya et al, 2019 ). Though recent literature notes that the reduced plaque deposition trends previously established in two transgenic APP/PS1 mice were only replicable when administered an antibiotic cocktail and that individual antibiotic did not affect cerebral Aβ amyloidosis (Dodiya et al, 2020 ). AD pathology was also curtailed in 5xFAD mice through the dietary supplementation of β-hydroxybutyrate (BHB), a ketone body produced during ketogenesis, which reduced Aβ plaque formation, microgliosis, and Asc speck formation (Shippy et al, 2020 ).…”