Antibiotic-induced perturbations in microbial diversity during post-natal development alters amyloid pathology in an aged APPSWE/PS1ΔE9 murine model of Alzheimer’s disease

Abstract

Recent evidence suggests the commensal microbiome regulates host immunity and influences brain function; findings that have ramifications for neurodegenerative diseases. In the context of Alzheimer’s disease (AD), we previously reported that perturbations in microbial diversity induced by life-long combinatorial antibiotic (ABX) selection pressure in the APPSWE/PS1ΔE9 mouse model of amyloidosis is commensurate with reductions in amyloid-β (Aβ) plaque pathology and plaque-localised gliosis. Considering microbiota-host interactions, specifically during early post-natal development, are critical for immune- and neuro-development we now examine the impact of microbial community perturbations induced by acute ABX exposure exclusively during this period in APPSWE/PS1ΔE9 mice. We show that early post-natal (P) ABX treatment (P14-P21) results in long-term alterations of gut microbial genera (predominantly Lachnospiraceae and S24-7) and reduction in brain Aβ deposition in aged APPSWE/PS1ΔE9 mice. These mice exhibit elevated levels of blood- and brain-resident Foxp3+ T-regulatory cells and display an alteration in the inflammatory milieu of the serum and cerebrospinal fluid. Finally, we confirm that plaque-localised microglia and astrocytes are reduced in ABX-exposed mice. These findings suggest that ABX-induced microbial diversity perturbations during post-natal stages of development coincide with altered host immunity mechanisms and amyloidosis in a murine model of AD.

Microbiota-derived short chain fatty acids promote Aβ plaque deposition

“…Similar findings were obtained in 5xFAD and APPPS1 amyloidosis mouse models (Brandscheid et al, 2017;Harach et al, 2017). Other studies have identified that antibiotic treatment-induced changes in microbiota composition as well as microbial deficiency in GF animals was associated with reduced Ab pathology (Dodiya et al, 2019;Harach et al, 2017;Minter et al, 2017;Minter et al, 2016). This effect could result from reduced Ab production or increased clearance.…”

“…This effect could result from reduced Ab production or increased clearance. Interestingly, GF animals as well as antibiotic-mediated dysbiotic animals exhibited reduced microglial activation (Minter et al, 2017). While previous studies documented a link between the gut microbiome and Ab pathology, the underlying mechanisms and molecular mediators remain elusive.…”

Function of Akkermansia muciniphila in Obesity: Interactions With Lipid Metabolism, Immune Response and Gut Systems

“…The adverse effect of excessive A. muciniphila in Parkinson's disease is still unclear, but it has been reported that the reduction of SCFAs and the intestinal amyloid deposition evoked by the alteration of gut microbiota are associated with exacerbating cognitive deficits in Parkinson's disease . The gut microbiota has also been shown to have effects on Abeta amyloidosis through the modulation of host innate immunity in Parkinson's disease (Minter et al, 2017). It is admitted that a shift in microbiota can be influenced by various factors, including environment, species, and age.…”

Altered Bile Acid Profile Associates with Cognitive Impairment in Alzheimer’s Disease – An Emerging Role for Gut Microbiome

“…Recently, a role for the gut microbiome in motor dysfunction in Parkinson's disease has been highlighted [13] and several animal models of AD showed a possible role of gut bacteria in amyloid-beta (A) pathology [14,15]. The APP transgenic mouse model of AD had a drastically altered gut microbiome composition compared to wild-type mice [15].…”