The human gastrointestinal tract harbors a diverse microbial community that profoundly influences various aspects of health and function, including aging, development, disease prevention, and overall well-being.
There is vital bidirectional communication between GI microbes and the human central nervous system (CNS). This phenomenon is known as the microbiota-gut-brain axis (MGBA).
This complex axis regulates glial function and influences neurological health and the risk of neurodegeneration. The gut microbiota contains nearly 150 times more genes than the human genome and consists of fungi, viruses, archaea, and at least 2,000 identified bacterial species. Disruption of GI microbiome function and balance, known as dysbiosis, can compromise health and is considered a notable hallmark of aging.
The bidirectional communication between the gut microbiome and the brain is mediated by the immune system, vagus nerve, enteric nervous system, neuroendocrine system, and circulatory system. Alterations in gut microbiota have been linked to the development of autism spectrum disorders, anxiety, depressive-like behavior, impaired physical performance, and motivation, as well as neurodegenerative diseases.
The microglia are the primary innate immune cells in the central nervous system and are the glial cells most susceptible to alterations in the gut microbiome. Normally, the gut microbiome regulates microglial maturation and activation via the release of short-chain fatty acids.
Animal research suggests that changes in the gut microbiome can contribute to pathology by altering microglial activation and function. Human research confirms early microbiome alterations in preclinical Alzheimer's disease and prodromal Parkinson’s.
Microglia regulate:
Microglial activation and neuroinflammation are hallmarks of neurodegenerative disease. Microglia are the primary responders to beta-amyloid plaque and the primary cell type that expresses Alzheimer's genes. They have also been implicated in the pathogenesis of Parkinson’s. Glial dysfunction, neuroinflammation, and impaired intestinal barrier integrity are implicated in the development of amyotrophic lateral sclerosis (ALS) in human and animal research.
The phagocytic activity of microglia becomes dysfunctional with aging and in neurogenerative diseases, leading to the accumulation of toxic compounds and cognitive decline. Neuronal loss and neurodegeneration occur when overactive microglia phagocytize viable neurons that are stressed.
Aging induces microglial activation by activating the cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) signaling pathway. Misfolded proteins and protein aggregates induce microglial activation by impairing microglial autophagy. Stage-1 DAM represents a transitory and functional subtype with a higher capacity of phagocytosis initiated by a TREM2-independent mechanism, whereas stage-2 DAM represents a dysfunctional state initiated by a TREM2-dependent mechanism. The microglial spleen tyrosine kinase (SYK) signaling provides metabolic support to facilitate microglial transition into stage-2 DAM. Maladaptive microglial-T-cell signaling drives neurodegeneration by releasing neurotoxic factors. Microglial activation creates a feed-forward vicious cycle that aggravates neurodegeneration as activated microglia contribute to the propagation of protein aggregates into unaffected brain regions.
a Short-chain fatty acids (SCFAs) exert their neuroprotective effects by acting as endogenous ligands for G-protein-coupled receptors (GPCRs) and modulating gene expression by inhibiting histone deacetylases (HDACs). b Trimethylamine N-oxide (TMAO) promotes microglial activation, neuroinflammation, Aβ and tau pathology. c Neuroprotective bile acids (BAs), including UDCA and TUDCA, inhibit neuroinflammation via direct and indirect pathways. In the direct pathway, UDCA and TUDCA activate the nuclear receptor Farnesoid X receptor (FXR) and membrane receptor Takeda G-protein-coupled receptor 5 (TGR5) found in microglia and neurons. In the indirect pathway, UDCA and TUDCA provide signals to the central nervous system indirectly via intestinal TGR5-dependent glucagon-like peptide-1 (GLP-1) pathway and intestinal FXR-dependent fibroblast growth factor 15 or 19 (FGF15/19) pathway. d Tryptophan and indole derivatives activate microglial aryl hydrocarbon receptor (AHR) signaling to inhibit microglial activation and neuroinflammation. e Polyunsaturated fatty acids (PUFAs): omega-3 fatty acids exhibit neuroprotective effects in Alzheimer’s disease, whereas omega-6 fatty acid arachidonic acid and its pro-inflammatory metabolites induce microglial activation.
a Short-chain fatty acids (SCFAs) exert their neuroprotective effects by acting as endogenous ligands for G-protein-coupled receptors (GPCRs) and modulating gene expression by inhibiting histone deacetylases (HDACs). b Neuroprotective bile acids (BAs), including UDCA and TUDCA, inhibit neuroinflammation via direct and indirect pathways. In the direct pathway, UDCA and TUDCA activate the nuclear receptor Farnesoid X receptor (FXR) and membrane receptor Takeda G-protein-coupled receptor 5 (TGR5) found in microglia and neurons. In the indirect pathway, UDCA and TUDCA provide signals to the central nervous system indirectly via intestinal TGR5-dependent glucagon-like peptide-1 (GLP-1) pathway and intestinal FXR-dependent fibroblast growth factor 15 or 19 (FGF15/19) pathway. c Trimethylamine N-oxide (TMAO) promotes microglial activation and neuroinflammation. However, contradictory findings have been reported regarding the roles of TMAO in PD. d Tryptophan and indole derivatives activate microglial aryl hydrocarbon receptor (AHR) signaling to inhibit microglial activation and neuroinflammation. e Branched-chain amino acids (BCAAs) promote anti-inflammatory microglial phenotypes.
GI bacteria ferment non-digestible fibers to produce short-chain fatty acids (SCFAs), which are saturated fatty acids with 1-6 carbon atoms. Butyrate, acetate, and propionate are the primary SCFAs found in humans and make up ~95% of the SCFA pool. SCFAs are associated with
Mild cognitive impairment and Alzheimer’s are associated with a reduction in SCFA-producing bacteria and decreased SCFA levels. Lower fecal SCFA levels have been associated with increased beta amyloid in subjects with mild cognitive impairment.
However, the role and influence of SCFAs in Alzheimer’s and Parkinson’s is unclear, and studies have yielded conflicting results.
The intestinal barrier, composed of the mucus layer, epithelial barrier, and gut vascular barrier, protects the host from external hazards and also regulates the microbiome-gut-brain axis. Unfavorable changes in the gut microbiome and intestinal barrier impairment have been seen with mild cognitive impairment, Alzheimer’s, Parkinson’s, and ALS. Restoration and maintenance of the intestinal barrier may be therapeutic in neurodegenerative states.
a High-fiber diets contribute to a healthy gut microbiome and enhance intestinal barrier integrity by increasing SCFAs-producing species, and fiber-degrading species and promoting resistance to perturbations. Indole and its derivatives improve intestinal barrier integrity by activating epithelial aryl hydrocarbon receptors (AHR). b Low-fiber diets, aging and sleep deprivation contribute to dysbiosis and disrupt intestinal barrier integrity by reducing SCFAs-producing species and fiber-degrading species while increasing mucin-degrading species. Low-fiber diets induce mucosal and systemic immune depression by impairing the metabolic fitness of CD4+ T cells.
a SCFAs and p-cresol glucuronide improve BBB integrity and prevent glial activation. b Elevated levels of trimethylamine-N-oxide (TMAO) has been reported in the plasma and cerebrospinal fluid of individuals with mild cognitive impairment, Alzheimer’s disease (AD) and Parkinson’s disease (PD). TMAO is detrimental to BBB integrity and induces glial activation.
Animal research has demonstrated the beneficial effects of pre- and probiotics on cognitive function, intestinal barrier integrity, the blood-brain barrier, neurotransmitter restoration, and the resolution of intestinal inflammation.
Fecal microbiota transplant (FMT), the transfer of a healthy donor’s microbial ecosystem into a recipient’s gastrointestinal tract, is a promising therapy that can help correct gastrointestinal dysbiosis and alleviate associated neurodegeneration.
Further human research is needed to confirm that prebiotics, probiotics, and fecal microbiota transplantation (FMT) can increase beneficial gut microbes, reduce harmful microbes, help restore gut microbial balance, and reduce the risk of neurodegeneration.
Loh, Jian Sheng et al. “Microbiota-gut-brain axis and its therapeutic applications in neurodegenerative diseases.” Signal transduction and targeted therapy vol. 9,1 37. 16 Feb. 2024, doi:10.1038/s41392-024-01743-1 This article is licensed under a Creative Commons Attribution 4.0 International License