In a recent study published within the journal Mechanisms of Ageing and Development, researchers explore the preventive and therapeutic potential of gut microbiome (GM) modulation in reducing the chance 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 proposals. Image Credit: mi_viri / Shutterstock.com

Gut dysbiosis and AD

GM dysbiosis arises resulting from elevated levels of pathogenic or pro-inflammatory bacterial organisms that produce neurotoxins, accompanied by a discount in protective or anti-inflammatory bacterial organisms that produce neurological compounds, including norepinephrine and tryptophan.

This microbial imbalance may end up in cognitive impairments, elevated levels of enterotoxins, lipopolysaccharides, trimethylamine N-oxide (TMAO), pro-inflammatory chemokines and cytokines, increased amyloid fiber deposition, in addition to reduced anti-inflammatory chemokine and cytokine levels and short-chain fatty acid (SCFAs).

Gut dysbiosis may also result in 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 end in “leaky gut” formation, with enhanced gut permeability that facilitates the transfer of harmful substances derived from pathogenic gut microbes.

Intestinal inflammation for prolonged periods results in disruption of blood-brain barrier (BBB) and the following transfer of intestine-derived molecules to brain tissues through the vagus nerve. The circulation of those compounds within the brain could subsequently increase amyloid loads, amyloid plaque formation, neurofibrillary tangling, astrocyte and microglial activation, which may contribute to neuronal loss, the activation of neurodegenerative processes, and cognitive decline in AD.

AD is related to elevated levels of Lactobacillaceae, Clostridium clostridioforme, Streptococcus salivarius, Proteobacteria, Gammaproteobacteria, Enterobacteriales, Enterobacteriaceae, Bacteroidetes, Tenericutes, Bacteroidaceae, Gemellaceae, Rikenellaceae, Escherichia, and Shigella.

Moreover, 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 amongst AD patients.

The connection between gut dysbiosis and AD is bi-directional, with gut microbial imbalance observed through the initial stages of AD and, conversely, AD pathophysiological mechanisms, corresponding to the activation of microglia and Aβ assimilation, shown to disrupt the intestinal microbiome balance.

Type 2 diabetes mellitus is a commonly observed comorbid condition amongst AD patients. Moreover, immunological dysfunction and impaired glucose, amyloid, and insulin metabolism have been observed amongst diabetic and AD patients.

AD and diabetes also share altered levels of assorted intestinal microbes, corresponding to Firmicutes, Bacteroidetes, and Actinobacteria, with alpha and beta diversity alterations. As well as, a reduced abundance of SCFA-producing bacteria and increased production of microbial metabolites, corresponding to GABA, have been observed in these two diseases.

Gut microbiome modulation in AD management

The intestinal microbiota may be altered through weight-reduction plan modifications, probiotic and prebiotic supplementation, and certain therapies corresponding to fecal microbiota transplantation (FMT). Other approaches, corresponding to precision medicine, is also used, wherein the microbiota of diabetic patients is sequenced before treatment.

The Mediterranean weight-reduction plan has also been related to 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 may also regulate neuronal growth.

Agathobaculum butyriciproducens SR79, a bacterial organism that produces butyrate, reportedly enhances cognitive function. The every day intake of probiotics including Lactobacillus fermentum, Lactobacillus acidophilus, and Lacktobacillus casei facilitate the restoration of the gut microbial balance and aid in the upkeep of intestinal homeostasis. Prebiotic supplements, corresponding to sodium oligomannate, have demonstrated BBB penetrability, in addition to the power to bind to Aβ molecules and forestall the conversion of Aβ fibrils into plaques.

Prebiotics and probiotics may 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 within the brain, tau phosphorylation, and Aβ-40,-42 expression. Moreover, changes within the intestinal microbiota composition and increased SCFA levels correlated with enhanced synaptic plasticity and associated cognitive, and memory function, in addition to spatial improvements.

It has been hypothesized that FMT could regulate AD pathophysiological pathways by decreasing intestinal inflammation and oxidative stress. Moreover, this treatment approach could facilitate the transfer of pathogenic gut microbes that activate neuroinflammatory mechanisms.

Conclusions

Intestinal microbiota balance is vital to the traditional functioning of the human body. AD patients are related to distinct microbial signatures, with a rise in pathogenic bacteria and reduced levels of helpful bacteria. Thus, the restoration of the microbiota could reduce neurodegeneration and improve cognitive function amongst AD patients.

Furthermore, distinctive gut microbial profiles could aid in the chance estimation of AD. Gut microbiome restoration by weight-reduction plan modifications, probiotic supplementations, and FMT could also improve cognition and, in consequence, offer potential therapeutic strategies for the treatment of AD.

Journal reference:

• 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 proposals. Mechanisms of Ageing and Development. doi:10.1016/j.mad.2023.111787