Gut dysbiosis, defective autophagy and altered immune responses in neurodegenerative diseases: Tales of a vicious cycle

Sep 18, 2021Pharmacology & therapeutics

Imbalanced Gut Bacteria, Faulty Cell Cleaning, and Changed Immunity in Brain Diseases: A Harmful Cycle

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Abstract

Alterations in gut microbiota composition, known as gut dysbiosis, are linked to neurodegenerative diseases (NDDs).

Gut dysbiosis involves an increase in harmful microorganisms and a decrease in beneficial ones.
Gastrointestinal symptoms often appear years before neurological symptoms in neurodegenerative diseases.
Disruption of the intestinal barrier allows harmful substances to enter the bloodstream, affecting brain function.
Chronic inflammation in the brain may lead to the buildup of toxic proteins that harm nerve cells.
There is evidence suggesting gut dysbiosis may worsen the spread of protein-related diseases from the nervous system's periphery to the brain.
Potential treatments include dietary changes and probiotic strategies aimed at restoring healthy gut microbiota.

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The human microbiota comprises trillions of symbiotic microorganisms and is involved in regulating gastrointestinal (GI), immune, nervous system and metabolic homeostasis. Recent observations suggest a bidirectional communication between the gut microbiota and the brain via immune, circulatory and neural pathways, termed the Gut-Brain Axis (GBA). Alterations in gut microbiota composition, such as seen with an increased number of pathobionts and a decreased number of symbionts, termed gut dysbiosis or microbial intestinal dysbiosis, plays a prominent role in the pathogenesis of central nervous system (CNS)-related disorders. Clinical reports confirm that GI symptoms often precede neurological symptoms several years before the development of neurodegenerative diseases (NDDs). Pathologically, gut dysbiosis disrupts the integrity of the intestinal barrier leading to ingress of pathobionts and toxic metabolites into the systemic circulation causing GBA dysregulation. Subsequently, chronic neuroinflammation via dysregulated immune activation triggers the accumulation of neurotoxic misfolded proteins in and around CNS cells resulting in neuronal death. Emerging evidence links gut dysbiosis to the aggravation and/or spread of proteinopathies from the peripheral nervous system to the CNS and defective autophagy-mediated proteinopathies. This review summarizes the current understanding of the role of gut microbiota in NDDs, and highlights a vicious cycle of gut dysbiosis, immune-mediated chronic neuroinflammation, impaired autophagy and proteinopathies, which contributes to the development of neurodegeneration in Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis and frontotemporal lobar degeneration. We also discuss novel therapeutic strategies targeting the modulation of gut dysbiosis through prebiotics, probiotics, synbiotics or dietary interventions, and faecal microbial transplantation (FMT) in the management of NDDs.

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Gut dysbiosis, defective autophagy and altered immune responses in neurodegenerative diseases: Tales of a vicious cycle

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