Exploring the effect of gut microbiome on Alzheimer's disease

Abstract

Alzheimer's disease (AD) is the most widespread and irreversible form of dementia and accounts for more than half of dementia cases. The most significant risk factors for AD are aging-related exacerbations, degradation of anatomical pathways, environmental variables and mitochondrial dysfunction. Finding a decisive therapeutic solution is a major current issue. Nuanced interactions between major neuropathological mechanisms in AD in patients and microbiome have recently gained rising attention. The presence of bacterial amyloid in the gut triggers the immune system, resulting in increased immune feedbacks and endogenous neuronal amyloid within the CNS. Also, early clinical research revealed that changing the microbiome with beneficial bacteria or probiotics could affect brain function in AD. New approaches focus on the possible neuroprotective action of disease-modifying medications in AD. In the present review, we discuss the impact of the gut microbiota on the brain and review emerging research that suggests a disruption in the microbiota-brain axis can affect AD by mediating neuroinflammation. Such novel methods could help the development of novel therapeutics for AD.

Keywords: Alzheimer's disease; Gut-brain axis; Microbiome; Neurodegenerative disorders.

Graphical abstract

Fig. 1

In the realm of gut-brain-microbiome interaction, various impacts stemming from the gut microbiome can exert a significant influence on a wide array of diseases, with dietary choices potentially exacerbating certain conditions such as diabetes, obesity, heart failure, colorectal cancer, and neurological disorders. These effects underscore the intricate interplay between the gut, brain, and microbiome, highlighting the multifaceted nature of the gut-brain axis and its implications for overall health outcomes. Understanding the nuanced relationships between the gut microbiome and disease pathogenesis is crucial for developing targeted interventions that can modulate these interactions and potentially mitigate the risk of developing associated health conditions.

Fig. 2

Innate immune cells in the CNS, primarily microglia and astrocytes, produce various pro-inflammatory cytokines such as IL-1, IL-6, IL-18, and TNF. These cells also release chemokines, including CCL1, CCL5, and CXCL1, along with small-molecule messengers like prostaglandins, nitric oxide (NO), and reactive oxygen species. Reactive microglia have been shown to internalize amyloid plaques, linking them to Alzheimer's disease. Various species of Aβ aggregates can induce glial activation and the production of pro-inflammatory cytokines IL-1, IL-6, IL-8, and TNF. Additionally, TGF-β, an anti-inflammatory cytokine, and chemokines such as MCP1 and macrophage inflammatory protein 1, may contribute to neuronal death and dysfunction.

Fig. 3

TLRs are crucial components of the innate immune system as they are responsible for recognizing pathogens derived from microbes and triggering the inflammatory cascade, thereby playing a significant role in immune responses. Additionally, these TLRs have been identified in the brain, particularly in microglial cells, and have been implicated in the pathogenesis of Alzheimer's disease. The immunological implications of TLR activation include a reduction in microbiome diversity, which in turn leads to an increase in pro-inflammatory cytokines through the activation of macrophage and dendritic cells. The interplay between the innate immune responses and the microbiome's side effects via TLR activation in Alzheimer's disease underscores the complexity of the immune system's involvement in neurodegenerative disorders. Understanding the mechanisms by which TLRs contribute to the development and progression of AD is essential for the development of targeted therapies that can modulate immune responses without compromising the delicate balance of the microbiome. Further research into the intricate interactions between TLRs, the microbiome, and neuroinflammation may provide valuable insights into potential therapeutic strategies for Alzheimer's disease.

Fig. 4

An overview of tauopathy modulation via gut-brain-axis. A) The induction of neuroinflammation by the gut microbiota. 1) diminished Firmicutes and Bifidobacterium in line with increased Bacteroidetes levels are examples of gut microbiota alterations. 2) gut microbiota alterations lead to enhanced permeability of gut lining. 3,4) The enhanced permeability ends in enhanced gut and systemic inflammation. 5) Systemic inflammation causes brain inflammation. B) Nitric oxide pathway is a key regulator of brain damage following inflammation. C) The mentioned damages could end in tauopathy.