Gut-Brain Axis as a Pathological and Therapeutic Target for Neurodegenerative Disorders

Abstract

Human lifestyle and dietary behaviors contribute to disease onset and progression. Neurodegenerative diseases (NDDs), considered multifactorial disorders, have been associated with changes in the gut microbiome. NDDs display pathologies that alter brain functions with a tendency to worsen over time. NDDs are a worldwide health problem; in the US alone, 12 million Americans will suffer from NDDs by 2030. While etiology may vary, the gut microbiome serves as a key element underlying NDD development and prognosis. In particular, an inflammation-associated microbiome plagues NDDs. Conversely, sequestration of this inflammatory microbiome by a correction in the dysbiotic state of the gut may render therapeutic effects on NDDs. To this end, treatment with short-chain fatty acid-producing bacteria, the main metabolites responsible for maintaining gut homeostasis, ameliorates the inflammatory microbiome. This intimate pathological link between the gut and NDDs suggests that the gut-brain axis (GBA) acts as an underexplored area for developing therapies for NDDs. Traditionally, the classification of NDDs depends on their clinical presentation, mostly manifesting as extrapyramidal and pyramidal movement disorders, with neuropathological evaluation at autopsy as the gold standard for diagnosis. In this review, we highlight the evolving notion that GBA stands as an equally sensitive pathological marker of NDDs, particularly in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and chronic stroke. Additionally, GBA represents a potent therapeutic target for treating NDDs.

Keywords: epigenetics; microbiome; neurodegeneration; neurological disorders; stem cells.

Figure 1

ALS and GBA. A dysfunctional gut accompanies the progression of ALS, with increased bacteria, including E. coli and enterobacteriaceae, leading to upregulation of damaging reactive oxygen species (ROS) and eventually contributing to motor neuron death, which is a hallmark pathological manifestation of the disease.

Figure 2

AD and GBA. A leaky gut may allow the transport of bacterial amyloids from the intestines to the brain, where aberrant aggregation of amyloid β (Aβ) occurs, forming Aβ plaques implicated in AD pathology and symptoms.

Figure 3

PD and GBA. Prior to dopaminergic depletion in the brain and even before the manifestation of PD symptoms, preclinical and clinical evidence indicates a dysregulated gut characterized by downregulated short-chain fatty acid bacteria but upregulated lipopolysaccharide bacteria, resulting in abnormal accumulation of α-synuclein in the gut that subsequently aggregates in the brain and causes dopaminergic degeneration, a PD pathological hallmark.

Figure 4

Stroke and GBA. Following the initial primary injury of ischemic injury (acute phase), the gut mounts an inflammatory response, resulting in the production of deleterious pro-inflammatory microbiomes, which, when uncontrolled over time (chronic phase), leads to detrimental inflammation that damages the neurovascular unit, thereby exacerbating stroke outcomes.