Contribution of Gut Microbiota to Immunological Changes in Alzheimer's Disease

Abstract

Emerging evidence suggests that both central and peripheral immunological processes play an important role in the pathogenesis of Alzheimer's disease (AD), but regulatory mechanisms remain unknown. The gut microbiota and its key metabolites are known to affect neuroinflammation by modulating the activity of peripheral and brain-resident immune cells, yet an overview on how the gut microbiota contribute to immunological alterations in AD is lacking. In this review, we discuss current literature on microbiota composition in AD patients and relevant animal models. Next, we highlight how microbiota and their metabolites may contribute to peripheral and central immunological changes in AD. Finally, we offer a future perspective on the translation of these findings into clinical practice by targeting gut microbiota to modulate inflammation in AD. Since we find that gut microbiota alterations in AD can induce peripheral and central immunological changes via the release of microbial metabolites, we propose that modulating their composition may alter ongoing inflammation and could therefore be a promising future strategy to fight progression of AD.

Keywords: Alzheimer’s disease; gut microbiota; immune cells; microbial metabolites; neuroinflammation; therapeutic intervention.

Figure 1

Schematic representation of the impact of a misbalanced gut microbiota on host immunity. A balanced composition of gut microbiota with a high diversity of commensal bacteria carrying out essential microbial functions supports healthy immune responses (left). During microbiota misbalance (right), excessive proinflammatory cytokines and bacterial toxins (e.g., lipopolysaccharide) can lead to disruption of gut permeability and blood–brain barrier (BBB) integrity. Distorted immune responses in the brain can further accelerate and worsen AD-associated pathology such as Aβ and tau accumulation.

Figure 2

Microbial taxa are altered in AD mouse models compared to WT mice. Phylogenetic representation at phylum, family and genus level of microbial taxa described by three or more animal studies. Animal studies are represented that either compare microbiota composition between AD and WT mice at certain age point(s), or that examine alterations with increasing age in AD mice compared to WT. Arrows indicate an increase or decrease in abundance of a certain taxa in AD mouse models compared to WT. * indicates a result was observed in AD mice with increasing age, but not in WT. F or M show a change that was only seen in females or males respectively, if both were included in one study. Presence or excretion of toxin lipopolysaccharide (LPS; yellow) and metabolites polysaccharide A (PSA; green) and butyrate (red) is indicated, as well as the used animal model and sex of the animals used per study.

Figure 3

Microbial taxa are altered in AD patients compared to control subjects. Phylogenetic representation at phylum, family, genus and species level of microbial taxa in human studies. Arrows indicate an increase or decrease in abundance of a certain taxa in AD patients compared to healthy controls. * depict changes associated with amyloid pathology in cognitively impaired patients. Presence or excretion of toxin lipopolysaccharide (LPS; yellow) and metabolites polysaccharide A (PSA; green) and butyrate (red) is indicated.

Figure 4

Schematic representation of the effects of microbial metabolites and toxins on peripheral and central immunity and blood-brain barrier function. Impact of microbial metabolites and toxins, that were changed in AD patients and in relevant animal models, on peripheral and central immune cells, cytokine secretion and blood-brain barrier (BBB) function are showed. Red arrow heads indicate a pro-inflammatory effect or loss of BBB integrity, green arrow heads indicate tolerogenic effects and improvements in BBB function.

Figure 5

Therapeutic strategies targeting the gut microbiota and metabolites modulate AD-associated pathology. Associations are shown between therapeutic interventions that modulate gut microbiota composition and/or function and AD-associated pathologies such as tau and Aβ accumulation, oxidative stress and neuroinflammation, neuronal loss, synaptic plasticity and cognitive function.