Gut-Brain Axis

The microbiota-gut-brain axis is a bidirectional communication network between gut microbes and their host, in which the microbiota and the brain communicate with each other via various routes. ^[1] The human gastrointestinal tract harbors approximately 100 trillion microorganisms comprising viruses, bacteria, fungi, and archaea, whose profound genetic and metabolic capabilities underlie their involvement in nearly every facet of human biology from health maintenance and development to aging and disease. ^[2]

The microbiota and the brain communicate via various routes including the immune system, tryptophan metabolism, the vagus nerve, and the enteric nervous system, involving microbial metabolites such as short-chain fatty acids, branched chain amino acids, and peptidoglycans. ^[1] Short-chain fatty acids, the main metabolites produced in the colon by bacterial fermentation of dietary fibers, are speculated to play a key role in neuro-immunoendocrine regulation within microbiota-gut-brain interactions. ^[3] The vagus nerve senses microbiota metabolites through its afferents and transfers this gut information to the central nervous system, and a cholinergic anti-inflammatory pathway through its fibers can dampen peripheral inflammation and decrease intestinal permeability. ^[4] Barriers including the gut epithelial barrier, the blood-brain barrier, and the blood-cerebrospinal fluid barrier are ideally positioned to receive and communicate gut microbial signals, constituting a gateway for gut-microbiota-brain communication. ^[5]

Microbial diversity diminishes with aging, and all components of the microbiota-gut-brain axis undergo age-related alterations that can be influenced by or even driven by the gut microbiota. ^[6] Bidirectional communication between the gut microbiome and the central nervous system makes the microbiota-gut-brain axis an important regulator of glial functions and an actionable target to ameliorate the development and progression of neurodegenerative diseases. ^[7] Increased permeability of the gut and blood-brain barrier induced by microbiota dysbiosis may mediate or affect Alzheimer's disease pathogenesis and other neurodegenerative disorders, especially those associated with aging. ^[8]

Leveraging an increased understanding of how gut-brain interactions regulate immunity has the potential to usher in a new era of precision neuropsychiatric clinical interventions for psychiatric, neurodevelopmental, and neurological disorders. ^[9] Diet is one of the major factors shaping gut microbiota composition across the lifespan, and microbiota-targeted whole-dietary strategies are being explored to improve brain and mental health, though additional evidence from clinical cohorts is required. ^[10] Microbiota-based therapies under investigation for the gut-brain axis include the use of prebiotics, probiotics, and fecal microbiota transplantation. ^[11]