Understanding the Gut-Brain Axis and Its Therapeutic Implications for Neurodegenerative Disorders

Abstract

The gut-brain axis (GBA) is a complex bidirectional communication network connecting the gut and brain. It involves neural, immune, and endocrine communication pathways between the gastrointestinal (GI) tract and the central nervous system (CNS). Perturbations of the GBA have been reported in many neurodegenerative disorders (NDDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), among others, suggesting a possible role in disease pathogenesis. The gut microbiota is a pivotal component of the GBA, and alterations in its composition, known as gut dysbiosis, have been associated with GBA dysfunction and neurodegeneration. The gut microbiota might influence the homeostasis of the CNS by modulating the immune system and, more directly, regulating the production of molecules and metabolites that influence the nervous and endocrine systems, making it a potential therapeutic target. Preclinical trials manipulating microbial composition through dietary intervention, probiotic and prebiotic supplementation, and fecal microbial transplantation (FMT) have provided promising outcomes. However, its clear mechanism is not well understood, and the results are not always consistent. Here, we provide an overview of the major components and communication pathways of the GBA, as well as therapeutic approaches targeting the GBA to ameliorate NDDs.

Keywords: gut dysbiosis; gut microbiota; gut–brain axis; neurodegenerative disorders; probiotics.

Figure 1

Pathways involved in bidirectional communication within the gut–brain axis (GBA). They include neural, immune, and endocrine pathways. Neurotransmitters: dopamine, serotonin, norepinephrine, gamma-aminobutyric acid (GABA), etc. Cytokines: interleukin (IL)-1$\beta$, IL-6, IL-10, tumor necrosis factor-$\alpha$ (TNF-$\alpha$), etc. Nutrients and metabolites: short-chain fatty acids (SCFAs), amine compounds, vitamins, neuroprecursors, etc. ACTH: adrenocorticotropic hormone; HPA: hypothalamic-pituitary-adrenal; CRH: corticotrophin-releasing hormone. Created with BioRender.com.

Figure 2

Hallmarks in the pathophysiology of neurodegenerative disorders caused by gut dysbiosis. Gut dysbiosis tends to promote the generation of proinflammatory cytokines and toxic metabolites, which in turn disrupt the integrity of the intestinal barrier, commonly referred to as “leaky gut”, and leads to an increased systemic circulation of inflammatory factors, microbes, and microbial products, thereby inciting systemic inflammation. Furthermore, the inflammatory status disrupts the blood–brain barrier (BBB), facilitating the entry of toxic metabolites like lipopolysaccharides (LPS) and $\beta$-N-methylamino-L-alanine (BMAA) into the brain, resulting in neuroinflammation and oxidative stress. Chronic neuroinflammation fosters the aggregation of pathological proteins, disrupting neuronal function and ultimately causing neuronal loss. Additionally, gut dysbiosis-induced chronic inflammation and oxidative stress impair autophagic clearance processes in both the gut and the brain, resulting in proteolysis dysfunction. Created with BioRender.com.

Figure 3

Strategies to modify gut microbiota for neurodegenerative disorders treatment. They mainly include diet, prebiotics, probiotics, synbiotics, and fecal microbiota transplantation (FMT). These approaches primarily function by modifying microbial communities and producing microbial metabolites, such as neurotransmitters and SCFAs, to exert neuroprotective effects. The diet emphasizes the consumption of fruits, vegetables, legumes, and cereals. Prebiotics are compounds selectively utilized by beneficial gut microbes, promoting the growth of beneficial bacteria and the generation of their metabolic products. Probiotics are live, nonpathogenic microorganisms that confer health benefits when consumed in adequate amounts. Synbiotics are specialized formulations that combine prebiotics and probiotics, synergistically enhancing their viability and therapeutic effects. FMT aims to restore a healthy gut microbiome and enhance gut microbiota diversity and functionality by transferring rigorously screened donor fecal microbiota into the patient’s GI tract. Created with BioRender.com.