The Triple Alliance: Microbiome, Mitochondria, and Metabolites in the Context of Age-Related Cognitive Decline and Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is a progressive, age-related neurodegenerative disorder that affects a large proportion of the older population. It currently lacks effective treatments, placing a heavy burden on patients, families, health care systems, and society. This is mainly due to our limited comprehension of the pathophysiology of AD progression, as well as the lack of effective drug targets and intervention timing to address the underlying pathology. AD is a multifactorial condition, and emerging evidence suggests that abnormalities in the gut microbiota play a significant role as environmental and multifaceted contributors to AD, although the exact mechanisms are yet to be fully explored. Changes in the composition of microbiota influence host neuronal health through their metabolites. These metabolites regulate intestinal epithelia, blood-brain barrier permeability, and neuroinflammation by affecting mitochondrial function. The decline in the proportion of beneficial microbes and their essential metabolites during aging and AD is directly linked to poor mitochondrial function, although the specific mechanisms remain unclear. In this review, we discuss recent developments in understanding the impact of the microbiome and its metabolites on various cell types, their influence on the integrity of the gut and blood-brain barriers, systemic and brain inflammation, and cell-specific effects in AD pathology. This information is expected to pave the way for a new understanding of the interactions between microbiota and mitochondria in AD, providing a foundation for the development of novel treatments for AD.

Keywords: Alzheimer’s disease; Metabolites; Microbiome; Mitochondria.

Figure 1.

(A) The diagram illustrates the neurovascular unit that constitutes the blood-brain barrier (BBB). It includes pericytes and astrocytes, which play crucial roles in the structure and function of the BBB. (B) The diagram depicts the main pathways through which chemicals and substances enter the central nervous system. (a) It highlights how tight connections between endothelial cells prevent the penetration of polar medicines and water-soluble chemicals. (b) The endothelium contains transporters or carriers for amino acids, nucleosides, and other chemicals. (c) Lipid-soluble drugs including nanoparticles can diffuse through endothelial membranes, providing a pathway for their traversal. (d) Plasma proteins, including albumin, have weak transportation; however, cationization can enhance their absorption through processes like endocytosis and transcytosis.

Figure 2.

The consequences of AD on the gut–brain axis can have several effects. The gut and the brain are connected through a complex and effective communication system. Here are some potential consequences of AD on the gut–brain axis: (1) intestinal epithelial dysfunction: in a healthy state, the intestinal epithelium maintains its integrity through tight junctions between cells. However, during gut dysbiosis (an imbalance in the gut microbiota), these tight junctions can become compromised, leading to increased intestinal permeability or “leaky gut.” The decrease in gut microbiota diversity during gut dysbiosis allows proinflammatory bacteria or their toxic byproducts to proliferate, triggering immune system activation and resulting in inflammation. (2) Systemic inflammation: with a leaky gut, bacteria, and their byproducts can enter the body, triggering the release of cytokines into the systemic circulation. These cytokines promote inflammation throughout the body, including the brain. (3) Impact on amyloid-beta (Aβ) and tau: certain bacteria can produce amyloids that may be taken up or leaked from the gut into circulation and reach the brain. The systemic inflammation and cytokine release caused by the leaky gut also promote the production of Aβ and tau in the brain. (4) BBB permeability: systemic inflammatory cytokines can disrupt the tight junctions in the blood-brain barriers (BBBs), leading to the leakage of Aβ originating from the gut into the brain, or vice versa. These events trigger neuroinflammatory responses in astrocytes and microglia, contributing to neurodegeneration and the worsening of AD pathology. (5) Mitochondrial dysfunction: mitochondrial dysfunction can occur at various levels, including intestinal epithelial cells, leading to reduced tight junctions, immune cells producing inflammatory cytokines, BBB cells developing leakiness, astrocytes, and microglia causing neuroinflammation, and neurons experiencing dysfunction or degeneration. Overall, this exacerbates the progression of AD (36).

Figure 3.

The triple alliance of microbiome, metabolite, and mitochondria plays a significant role in AD pathology: (1) microbiome-metabolite impact on mitochondria: microbiome metabolites can affect mitochondria in both beneficial and detrimental ways. For instance, certain microbial metabolites like TMAO and LPS may cause abnormalities in the mitochondria, impair electron transport chain (ETC) function, and increase the accumulation of reactive oxygen species (ROS). On the other hand, metabolites like short-chain fatty acids (SCFAs) and bile acids (BA) can prevent ROS formation and improve ETC function. During aging, hereditary changes occur in ETC genes, leading to ROS generation. (2) Abnormalities in ETC genes and mtDNA alterations: mitochondrial dysfunction can originate from the downregulation of ETC-related genes due to mtDNA alterations. (3) Mitochondrial dysfunction: Underactivity of mitochondrial bioenergetics leads to mitochondrial dysfunction. (4) Development of AD pathology: mitochondrial dysfunction contributes to the development of AD by facilitating the formation of Aβ, removing programmed cell death of weakened cells (senescence), and promoting the formation of neurofibrillary tangles (142).