Mechanistic Insights Into Gut Microbiome Dysbiosis-Mediated Neuroimmune Dysregulation and Protein Misfolding and Clearance in the Pathogenesis of Chronic Neurodegenerative Disorders

Abstract

The human gut microbiota is a complex, dynamic, and highly diverse community of microorganisms. Beginning as early as in utero fetal development and continuing through birth to late-stage adulthood, the crosstalk between the gut microbiome and brain is essential for modulating various metabolic, neurodevelopmental, and immune-related pathways. Conversely, microbial dysbiosis - defined as alterations in richness and relative abundances - of the gut is implicated in the pathogenesis of several chronic neurological and neurodegenerative disorders. Evidence from large-population cohort studies suggests that individuals with neurodegenerative conditions have an altered gut microbial composition as well as microbial and serum metabolomic profiles distinct from those in the healthy population. Dysbiosis is also linked to psychiatric and gastrointestinal complications - comorbidities often associated with the prodromal phase of Parkinson's disease (PD) and Alzheimer's disease (AD). Studies have identified potential mediators that link gut dysbiosis and neurological disorders. Recent findings have also elucidated the potential mechanisms of disease pathology in the enteric nervous system prior to the onset of neurodegeneration. This review highlights the functional pathways and mechanisms, particularly gut microbe-induced chronic inflammation, protein misfolding, propagation of disease-specific pathology, defective protein clearance, and autoimmune dysregulation, linking gut microbial dysbiosis and neurodegeneration. In addition, we also discuss how pathogenic transformation of microbial composition leads to increased endotoxin production and fewer beneficial metabolites, both of which could trigger immune cell activation and enteric neuronal dysfunction. These can further disrupt intestinal barrier permeability, aggravate the systemic pro-inflammatory state, impair blood-brain barrier permeability and recruit immune mediators leading to neuroinflammation and neurodegeneration. Continued biomedical advances in understanding the microbiota-gut-brain axis will extend the frontier of neurodegenerative disorders and enable the utilization of novel diagnostic and therapeutic strategies to mitigate the pathological burden of these diseases.

Keywords: Alzheimer’s and Parkinson’s diseases; gut inflammation; gut metabolome; gut microbiota; microbiome; neurodegeneration; neuroinflammation; protein aggregation.

FIGURE 1

Microbiome-gut-brain axis and neurodegenerative disease. Several risk factors have been associated with the etiology of microbial dysbiosis and neurodegenerative disorders. The balance between normobiosis and dysbiosis within the gut microbiome is preserved by the presence or absence of high-abundant species (Lachnospiracea, Clostridiaceae, Ruminococcaceae, Eubacterium, Butyriciccocaceae, Lactobacillus, Bifidobacterium, Faecalibacterium, Roseburia, and Bacteroides) and low-abundant species (Enterobacteriaceae, Alistipes, and Akkermansia). In the presence of beneficial microbes, homeostatic mechanisms such as neuropeptide synthesis, promotion of intestinal barrier integrity and immune cell regulatory functions are maintained. Higher abundances of microbes are associated with dysbiosis, degrade mucin, dysregulate intestinal barrier, and enable pathogenic microbes and their metabolites and endotoxins to infiltrate, promoting local immune cell recruitment and triggering systemic inflammation.

FIGURE 2

Microbial dysbiosis-mediated fibril formation. (A) Distinct microbes secrete metabolites that can directly and/or indirectly modulate fibril formation. (B) Endotoxin and LPS micelles can interact with amyloid monomeric protein triggering oligomerization and aggregation. (C) Pathogenic bacteria with csgA/B operon produce amyloid curli proteins, which can participate in cross-seeding, fibrillization and aggregation.

FIGURE 3

Microbial dysbiosis-modulated protein mechanisms and autoimmune functions. (A) Microbe-mediated generation of protein aggregates reduces autophagic flux and thereby dysregulates the autophagosomal-lysosomal pathway. (B) Enteric infection triggers peripheral immune recruitment into the CNS by gaining access across the blood–brain barrier, thereby triggering an autoimmune attack on subsets of neurons (e.g., dopaminergic neurons).