The impact of host gut microbiota on microglia in Alzheimer’s disease : : a study in the 5xFAD transgenic murine model

Abstract: The human body is colonized with trillions of myriad microorganisms. In particular, the human gut harbors the largest human microbial ecosystem, which provides vital nutrients and metabolites to maintain host physiological functions. The gut microbiota and its essential impact on the development and functionality of a wide variety of host organs, including the central nervous system (CNS), has received considerable attention. Numerous human CNS diseases, including Alzheimer's disease (AD), have been linked to gut microbiota dysbiosis. Therefore, the gut microbiota represents an attractive target for the development of novel therapeutic interventions. Clinically, AD manifests in overall deterioration of mental and cognitive function. Neuropathologically, among others AD is characterized by the accumulation of extracellular amyloid-β (Aβ) plaques in the brain parenchyma. Interestingly, some AD patients displayed altered gut microbiota diversity. In a transgenic AD mouse model, raised under germ-free (GF) conditions, attenuated Aβ pathology has been observed. However, the underlying cellular mechanisms remained unsolved. Recently, in healthy GF-housed mice the impact of gut microbiota on microglial functionality, the resident innate immune cells of the CNS parenchyma, has been uncovered. This observation confirmed the existing crosstalk across the microbiota-gut-brain axis.
The current study sought to provide novel insights into the gut microbiota - microglia interaction during the course of AD by using the well-established 5x familial AD (5xFAD) transgenic murine model. Rearing 5xFAD mice under a GF environment, having a constitutive lack of commensal microbes, enhanced microglial numbers, microglial Aβ phagocytic rates and altered gene expression profile in the early disease stage. These effects were concomitantly associated with mitigated Aβ burden and dampened disease progression. Contrary, antibiotics-induced microbiota eradication was not sufficient to influence microglial Aβ phagocytic functions. However, alleviated Aβ burden was observed, indicating different underlying mechanisms. In the progressed disease stage, enhanced microglial Aβ phagocytosis in GF-housed 5xFAD mice was no longer evident, supported the notion that microglia become dysfunctional and inefficient as disease progresses. Nevertheless, in the progressed disease stage, AD-related pathology remained attenuated in GF-housed 5xFAD mice. Interestingly, in the early disease stage, changes in microglial metabolism were uncovered in a gut microbiota-dependent manner, but it remained unsolved to what extent these changes might affect microglial response and impact the disease progression. Altering microglial metabolic fitness could serve as a potential therapeutic target to improve microglia-mediated Aβ clearance. Finally, the gut microbiota-derived short-chain-fatty acid acetate was identified as the key metabolite that reached the brain, influenced microglial phagocytosis and Aβ pathology in the early disease stage, shed light on the impact of certain microbially produced molecules on the functionality of microglia.
Taken together, in the current study novel insights into the gut microbiota - microglia relationship under pathophysiological conditions were obtained. Thus, providing further avenues of research for the development of new therapeutic interventions in the fight against Alzheimer’s disease and other incurable CNS disorders

Object Details

• Location: Deutsche Nationalbibliothek Frankfurt am Main
• Extent: Online-Ressource
• Language: Englisch
• Notes: Universität Freiburg, Dissertation, 2021

Classification and Topics

• Keyword: Microglia ; Impact

Contributors, Places and Time

• Event: Veröffentlichung
• (where): Freiburg
• (who): Universität
• (when): 2021
• Creator: Mezö, Charlotte
• Contributor: Prinz, Marco ; Erny, Daniel ; Albert-Ludwigs-Universität Freiburg. Fakultät für Biologie

Further information

• DOI: 10.6094/UNIFR/222376
• URN: urn:nbn:de:bsz:25-freidok-2223768
• Rights: Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Last update: 25.03.2025, 1:46 PM CET