A review of the preclinical and clinical studies on the role of the gut microbiome in aging and neurodegenerative diseases and its modulation

Abstract

As the world population ages, the burden of age-related health problems grows, creating a greater demand for new novel interventions for healthy aging. Advancing aging is related to a loss of beneficial mutualistic microbes in the gut microbiota caused by extrinsic and intrinsic factors such as diet, sedentary lifestyle, sleep deprivation, circadian rhythms, and oxidative stress, which emerge as essential elements in controlling and prolonging life expectancy of healthy aging. This condition is known as gut dysbiosis, and it affects normal brain function via the brain-gut microbiota (BGM) axis, which is a bidirectional link between the gastrointestinal tract (GIT) and the central nervous system (CNS) that leads to the emergence of brain disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD). Here, we reviewed the role of the gut microbiome in aging and neurodegenerative diseases, as well as provided a comprehensive review of recent findings from preclinical and clinical studies to present an up-to-date overview of recent advances in developing strategies to modulate the intestinal microbiome by probiotic administration, dietary intervention, fecal microbiota transplantation (FMT), and physical activity to address the aging process and prevent neurodegenerative diseases. The findings of this review will provide researchers in the fields of aging and the gut microbiome design innovative studies that leverage results from preclinical and clinical studies to better understand the nuances of aging, gut microbiome, and neurodegenerative diseases.

Keywords: aging; brain-gut-microbiota axis; gut microbiome; interventions; neurodegenerative diseases.

FIGURE 1

Schematic representation of the premise behind the Free Radical Theory of Aging (FRTA). Oxygen toxicity is the basis of FRTA. By-radical molecular oxygen can generate partially depleted molecules and ROS (Balaban et al., 2005). ROS are primarily produced during oxidative phosphorylation in the mitochondria, but they are also produced by other exogenous and endogenous factors such as ultraviolet light, air pollution, etc. Catalase, vitamin A, SOD, and other antioxidants can detoxify ROS within the cell (Davies, 2000). When these antioxidants are depleted, ROS accumulates, disrupting the cell’s normal redox state and resulting in oxidative stress. ROS-induced oxidative stress causes overproduction of MDA and HNE, which act as a second messenger of oxidative stress and a major bioactive marker of lipid peroxidation (Barrera, 2012). Additionally, oxidative stress causes protein degradation or proteolysis via the ubiquitin-proteosome pathway (Cooper, 2000). Moreover, oxidative stress also causes DNA base modification via γH2AX, a molecular marker of DNA damage and repair (Mah et al., 2010). Despite mechanisms for repairing oxidatively damaged biomolecules, several damages remain. According to FRTA, oxidative stress causes aging, physiological decline, and age-related disorders (Selman et al., 2012). ROS, reactive oxygen species; SOD, superoxide dismutase; GPx, glutathione peroxidase; MDA, malondialdehyde; HNE, 4-hydroxynonenal; γH2AX, phosphorylated histone H2AX. This figure was created with Canva.com.

FIGURE 2

The mechanism underlying the effect of the gut microbiome on the etiology of neurodegenerative diseases. GIT is composed of a diverse group of microbes, and its composition changes significantly with age. These alterations are termed “gut dysbiosis,” which leads to increased leaky gut, causing translocation of bacteria (a process known as atopobiosis) into the bloodstream (König et al., 2016). Reduced numbers of beneficial microbes that produce SCFAs such as Firmicutes and Actinobacteria is unable to inhibit HDAC activity and LPS-induced inflammation. On the other hand, gut microbes such as Bacteroidetes are able to excrete an abundance of LPS, which stimulates the TLR4 receptor by interacting with CD14 and MD-2 proteins, triggering an inflammatory response (Zhao et al., 2015). Furthermore, Proteobacteria produce an abundance of bacterial amyloids such as curli peptide, and binding of curli peptide to TLR2 activates macrophages, which secrete pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β (Rapsinski et al., 2015), and activation of T-lymphocytes induces the production of pro-inflammatory interleukins such as IL-17A and IL-22 by Th17 cells (Nishimori et al., 2012). These cytokines are able to penetrate the BBB, increase production of ROS, and promote oxidative stress, leading to neuroinflammation and neurodegeneration (Zhan et al., 2018). These cytokines also activate TLR2/1 and NFκB signaling pathways in microglia and astrocytes, which stimulates the transcription of pro-inflammatory miRNAs, activates neuroinflammatory mediators, and inhibits phagocytosis in microglial cells (Zhao and Lukiw, 2018), leading to the progression of neurodegenerative diseases. [AD: increased Aβ plaques and P-tau tangles; PD: increases α-synuclein aggregates in Lewy bodies and Lewy neurites, and impairment and loss of melanated dopaminergic neurons in the substantia nigra; ALS: increases SOD1, FUS, and TDP-43 aggregates; TDP: increases P-tau tangles, TDP-43 and FUS aggregates]. Additionally, several microbes may signal through their metabolites to promote the synthesis and release of neurotransmitters, which are involved in the transport of chemical signals from nerve cells to the target cell, such as muscle or gland. Gut dysbiosis may also decrease synthesis and secretion of neurotrophic factors such as GABA, BDNF, and NMDA receptors, leading to neurodegeneration (Askarova et al., 2020). Aβ, amyloid-beta; BBB, blood-brain barrier; BDNF, brain-derived neurotrophic factor; CD14, cluster of differentiation 14; FFARs, free fatty acids receptors; FOXP3, forkhead box P3; FUS, fused in sarcoma; GABA, gamma-aminobutyric acid; GIT, gastrointestinal tract; HDAC, histone deacetylase; IL, interleukin; LPS, lipopolysaccharide; NF-κB, nuclear factor-κB; MD-2, myeloid differentiation factor-2; NMDA receptor, N-methyl-D-aspartate receptor; SCFAs, short-chain fatty acids; SOD1, superoxide dismutase 1 gene; TDP-43, TAR DNA-binding protein 43; TGF-β, transforming growth factor-β; Th, T helper; TLR, tall-like receptor; TNF-α, tumor necrosis factor alpha; Treg, regulatory T cells. This figure was created with BioRender.com.