In a recent study published in the journal Mechanisms of Ageing and Development, researchers explore the preventive and therapeutic potential of gut microbiome (GM) modulation in reducing the risk of and improving the symptoms of Alzheimer’s disease (AD).
Study: Gut-brain axis through the lens of gut microbiota and their relationships with Alzheimer’s disease pathology: review and recommendations. Image Credit: mi_viri / Shutterstock.com
Gut dysbiosis and AD
GM dysbiosis arises due to elevated levels of pathogenic or pro-inflammatory bacterial organisms that produce neurotoxins, accompanied by a reduction in protective or anti-inflammatory bacterial organisms that produce neurological compounds, including norepinephrine and tryptophan.
This microbial imbalance can result in cognitive impairments, elevated levels of enterotoxins, lipopolysaccharides, trimethylamine N-oxide (TMAO), pro-inflammatory chemokines and cytokines, increased amyloid fiber deposition, as well as reduced anti-inflammatory chemokine and cytokine levels and short-chain fatty acid (SCFAs).
Gut dysbiosis can also lead to the increased production of major neurotransmitters like gamma-aminobutyric acid (GABA), butyrate, 5-hydroxytryptamine, and dopamine, with subsequent cleavage of junctional proteins like E-cadherin, tight junction disruption, and chronic gut inflammation. These events could result in “leaky gut” formation, with enhanced gut permeability that facilitates the transfer of harmful substances derived from pathogenic gut microbes.
Intestinal inflammation for extended periods leads to disruption of blood-brain barrier (BBB) and the subsequent transfer of intestine-derived molecules to brain tissues through the vagus nerve. The circulation of these compounds in the brain could subsequently increase amyloid loads, amyloid plaque formation, neurofibrillary tangling, astrocyte and microglial activation, which can contribute to neuronal loss, the activation of neurodegenerative processes, and cognitive decline in AD.
AD is associated with elevated levels of Lactobacillaceae, Clostridium clostridioforme, Streptococcus salivarius, Proteobacteria, Gammaproteobacteria, Enterobacteriales, Enterobacteriaceae, Bacteroidetes, Tenericutes, Bacteroidaceae, Gemellaceae, Rikenellaceae, Escherichia, and Shigella.
Furthermore, reduced levels of Firmicutes, Peptostreptococcaceae, Clostridiaceae, Bifidibacteriaceae, Turicibacteriaceae, Mogibacteriaceae, Ruminococcaceae, Verrucomicrobia, Allobaculum, Akkermansia, Actinobacteria, Bacillus fragilis, Bacteroids fragilis, Eubacterium rectale, Eubacterium hallii, Bifidobacterium, and Faecalibacterium prausnitzii have been reported among AD patients.
The relationship between gut dysbiosis and AD is bi-directional, with gut microbial imbalance observed during the initial stages of AD and, conversely, AD pathophysiological mechanisms, such as the activation of microglia and Aβ assimilation, shown to disrupt the intestinal microbiome balance.
Type 2 diabetes mellitus is a commonly observed comorbid condition among AD patients. Furthermore, immunological dysfunction and impaired glucose, amyloid, and insulin metabolism have been observed among diabetic and AD patients.
AD and diabetes also share altered levels of various intestinal microbes, such as Firmicutes, Bacteroidetes, and Actinobacteria, with alpha and beta diversity alterations. In addition, a reduced abundance of SCFA-producing bacteria and increased production of microbial metabolites, such as GABA, have been observed in these two diseases.
Gut microbiome modulation in AD management
The intestinal microbiota can be altered through diet modifications, probiotic and prebiotic supplementation, and certain therapies such as fecal microbiota transplantation (FMT). Other approaches, such as precision medicine, could also be used, wherein the microbiota of diabetic patients is sequenced before treatment.
The Mediterranean diet has also been associated with greater Firmicutes/Bacteroidetes ratios and lowered pro-inflammatory chemokines and cytokine levels, with subsequent cognitive improvements. In mice, fat and caloric limitations reportedly reduce the abundance of Eubacterium rectale and Bifidobacterium species, neurological inflammation, and Aβ plaques, thereby improving neurovascular and cognitive functions. Reduced lipopolysaccharides and increased intake of SCFAs like sodium butyrate can also regulate neuronal growth.
Agathobaculum butyriciproducens SR79, a bacterial organism that produces butyrate, reportedly enhances cognitive function. The daily intake of probiotics including Lactobacillus fermentum, Lactobacillus acidophilus, and Lacktobacillus casei facilitate the restoration of the gut microbial balance and aid in the maintenance of intestinal homeostasis. Prebiotic supplements, such as sodium oligomannate, have demonstrated BBB penetrability, as well as the ability to bind to Aβ molecules and prevent the conversion of Aβ fibrils into plaques.
Prebiotics and probiotics can also improve intestinal integrity and reverse the leaky gut phenomenon, thus reducing the transfer of pathogenic microbe-derived neuromodulators and their associated neurological inflammation.
FMT to treat AD
FMT refers to fecal infusions from healthy donors to the gastrointestinal tracts of diseased individuals for GM modulation. FMT is an emerging therapy for AD and has been used successfully for Clostridium difficile infections, with cure rates of about 90%.
The transfer of gut microbes from healthy individuals to mice with AD has successfully reduced tau and amyloid pathologies. FMT in mice also lowered Aβ accumulation and amyloid pathology in the brain, tau phosphorylation, and Aβ-40,-42 expression. Furthermore, changes in the intestinal microbiota composition and increased SCFA levels correlated with enhanced synaptic plasticity and associated cognitive, and memory function, as well as spatial improvements.
It has been hypothesized that FMT could regulate AD pathophysiological pathways by decreasing intestinal inflammation and oxidative stress. Additionally, this treatment approach could facilitate the transfer of pathogenic gut microbes that activate neuroinflammatory mechanisms.
Intestinal microbiota balance is key to the normal functioning of the human body. AD patients are associated with distinct microbial signatures, with an increase in pathogenic bacteria and reduced levels of beneficial bacteria. Thus, the restoration of the microbiota could reduce neurodegeneration and improve cognitive function among AD patients.
Moreover, distinctive gut microbial profiles could aid in the risk estimation of AD. Gut microbiome restoration by diet modifications, probiotic supplementations, and FMT could also improve cognition and, as a result, offer potential therapeutic strategies for the treatment of AD.
- Krishaa, L., Ng, T. K. S., Wee H. .N., & Ching, J. (2023). Gut-brain axis through the lens of gut microbiota and their relationships with Alzheimer’s disease pathology: review and recommendations. Mechanisms of Ageing and Development. doi:10.1016/j.mad.2023.111787