In a recent review published in Nutrients, researchers reviewed existing data on the role of the gut microbiome in Alzheimer’s disease (AD) pathogenesis.
Study: Correlation between Alzheimer’s Disease and Gastrointestinal Tract Disorders. Image Credit: Joyisjoyful/Shutterstock.com
Introduction
AD, the primary dementia cause worldwide, results in amyloid-β buildup, reduced synapses, and neurofibrillary tangles.
Studies report links between the central nervous system (CNS) of the brain and the enteric nervous system (ENS) of the gastrointestinal tract.
Microbial participation in AD pathogenesis might broaden the therapy options; however, the effects of gastrointestinal tract features on cognition are unclear. Small sample sizes and lifestyle factors limit existing research.
About the review
In the present review, researchers discussed gut microbial alterations in AD patients. They searched the PubMed database in May 2024 for English articles published within the previous six years without study design or publication type restrictions.
They identified 2,259 records in PubMed and 12 by manual searching, screened 381, and assessed 113 full-text ones for eligibility. After excluding records that did not evaluate the research outcome, the team included 61 in the review.
Microbiome-gut-brain (MGB) axis
The microbiome-gut-brain axis connects peripheral intestinal function to the brain’s emotional and cognitive centers.
The sympathetic and parasympathetic nerves, the hypothalamic-pituitary-adrenal (HPA) axis, vagal nerves, cytokines, hormones, and metabolic signals connect the brain to gastrointestinal tissues, the ENS, and the gut microbiome in a bidirectional manner.
Vagal nerves link the stomach and the brainstem, sending impulses to corticothalamic brain regions. Gut bacteria respond to neurotransmitters released from the brain, producing chemicals that impact central-type neurons through lymphatics.
Bacterial metabolites, such as short-chain-type fatty acid molecules (SCFAs, propionate, butyrate, and acetate) and trimethylamine N-oxide (TMAO), can alter CNS homeostasis. SCFAs can alter cognitive functions such as learning and reward-related behavior. TMAO enhances β-secretase activities, increasing Aβ accumulation in the brain.
Fusobacterium nucleatum can induce neuroinflammation by reducing the permeability of the blood-brain barrier (BBB). The bacterial lipopolysaccharides (LPS) induce neurons to produce chemicals that support the inflammatory process and immunological response.
AD inflammation in the brain and intestines is gram-negative bacterial LPS-predominant. These neurotoxins attach to neurons in AD brains and stimulate nuclear factor kappa B (NF-kB) transcription in human neuronal and glial cells.
Antidepressant selective-serotonin reuptake inhibitors (SSRIs), paroxetine, sertraline, and fluoxetine have demonstrated antimicrobial activity against Gram-positive bacteria such as Enterococcus and Staphylococcus.
Tricyclic antidepressants (TCAs) can prevent the growth of pathogenic gut microbes, such as Escherichia coli and Yersinia enterocolitica.
Associations between Alzheimer’s disease and gastrointestinal diseases
AD neurodegeneration involves gut dysbiosis or a microbiome imbalance. AD patients have increased abundances of pro-inflammatory microbes such as Bacteroidetes, Faecalibacterium prausnitzii, Desulfovibrio, Eubacterium rectale, Porphyromonas gingivalis, and Lactobacillus rhamnosus.
In contrast, AD patients have lower Firmicutes and Clostridium sensu stricto 1 counts. Combinations of vancomycin, ampicillin, metronidazole, neomycin, and amphotericin-B can reduce Bacteroidetesand Firmicutes counts and improve AD by restoring gut microbial balance.
Gut dysbiosis contributes to AD by modifying BBB permeability, increasing amyloidosis, and causing CNS invasion by bacterial lipopolysaccharides (LPS) through oropharyngeal olfactory pathways, leading to cognitive impairment.
Studies have revealed a link between Alzheimer’s disease and intestinal microflora-related concerns such as Helicobacter pylori infections, gastritis, peptic ulcers, gastroesophageal reflux disease (GERD), and inflammatory bowel disease (IBD).
H. pylori infections predispose to AD onset by increasing apolipoprotein E4 (ApoeE4) and decreasing ApoeE2 levels, increasing amyloid precursor protein (APP) expression, and increasing the expression of neurodegeneration risk genes such as Myc box-dependent-interacting protein 1 (BIN1), clusterin (Clu), ATP-binding cassette sub-family A member 7 (ABCA7), and cluster of differentiation 33 (CD33).
H. pylori infections also increase the levels of inflammatory cytokines such as C-reactive protein (CRP), interleukin-8 (IL-8), and tumor necrosis factor-alpha (TNF-α), inducing neuroinflammation.
Periodontitis produces systemic inflammation with elevated levels of pro-inflammatory cytokines and neutrophils, which may result in beta-amyloid plaque development in the brain.
Toll-like receptor 4 (TRL-4) activation in AD identifies molecular patterns of damage-associated (DAMPs) and pathogen-associated molecular patterns (PAMPs), like high mobility group box 1 (HMGB1) or H. pylori LPS, that cause an inflammatory response in the CNS.
Increased cathepsin B expression can break APP into neurotoxic amyloid beta proteins. Immunosuppressants and TNF-α blockers can lower inflammation and AD risk among IBD patients. Studies show that H. pylori infection increases AD risk by 11% among individuals aged above 50 years.
Conclusion
Based on the findings, AD is a complicated disorder that affects the digestive system, with considerable gut microbiota alterations in AD patients.
The microbiome influences CNS function via the microbiota-gut-brain link and synaptic dysfunction. H. pylori infection and periodontitis may be linked to AD, although further study is needed to corroborate these findings.
Future studies should explore the relationship between microbiota abnormalities and neurodegenerative illnesses.
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