Gut Microbes Linked to Alzheimer’s Disease

Researchers examined the available information on the function of the gut microbes in the pathophysiology of Alzheimer’s disease (AD) in a review that was recently published in Nutrients.

Overview
Reduced synapses, neurofibrillary tangles, and an accumulation of amyloid-β are the outcomes of AD, the leading cause of dementia globally.

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Research indicates connections between the brain’s central nervous system (CNS) and the gastrointestinal tract’s enteric nerve system (ENS).

While the role of microbes in AD pathogenesis may increase the range of available therapies, it is unknown how characteristics of the gastrointestinal tract affect cognitive function. Extant literature is constrained by small sample sizes and lifestyle factors.

About the Study
Researchers talked about changes in gut microbiota in AD patients in this review. In May 2024, they conducted a non-restrictive search of the PubMed database for English publications published in the preceding six years, without regard to publication type or research design.

2,259 records were found in PubMed, 12 by hand search, 381 records were examined, and 113 full-text records were evaluated for eligibility. The team included 61 records in the review after eliminating those that did not assess the research outcome.

Gut-brain-microbiome (MGB) axis

Peripheral intestine function is linked to the emotional and cognitive regions of the brain through the microbiota, gut, and brain axis.

The brain is bidirectionally connected to gastrointestinal tissues, the ENS, and the gut microbiome through the sympathetic and parasympathetic nervous system, the hypothalamic-pituitary-adrenal (HPA) axis, vagal nerves, cytokines, hormones, and metabolic signals.

Vagal nerves transmit impulses to corticothalamic brain areas from the brainstem, which connects the stomach. In response to neurotransmitters that are generated from the brain, gut bacteria produce substances that affect central-type neurons via lymphatic pathways.

Trimethylamine N-oxide (TMAO) and short-chain-type fatty acid molecules (SCFAs, propionate, butyrate, and acetate) are examples of bacterial metabolites that might change central nervous system homeostasis. Cognitive processes like learning and reward-related behavior can be changed by SCFAs. TMAO increases Aβ buildup in the brain via stimulating β-secretase activity.

Fusobacterium nucleatum can cause neuroinflammation by lowering the blood-brain barrier’s (BBB) permeability. Lipopolysaccharides (LPS) derived from bacteria cause neurons to release substances that facilitate inflammation and the immune system.

A gram-negative bacterium LPS predominates in AD inflammation of the brain and intestines. These neurotoxins bind to neurons in AD brains and activate transcription of nuclear factor kappa B (NF-kB) in human glial and neuronal cells.

Paroxetine, sertraline, fluoxetine, and other antidepressant selective serotonin reuptake inhibitors (SSRIs) have shown antibacterial action against Gram-positive bacteria such Enterococcus and Staphylococcus.

Tricyclic antidepressants (TCAs) have the ability to stop the growth of Yersinia enterocolitica and Escherichia coli, two harmful gut microorganisms.

gastrointestinal disorders and Alzheimer’s disease correlations

Microbiome imbalance or gut dysbiosis is linked to AD neurodegeneration. Pro-inflammatory bacteria such Bacteroidetes, Faecalibacterium prausnitzii, Desulfovibrio, Eubacterium rectale, Porphyromonas gingivalis, and Lactobacillus rhamnosus are more prevalent in AD patients.

On the other hand, Firmicutes and Clostridium sensu stricto 1 numbers are lower in AD patients. By reestablishing the balance of gut microbiota, combinations of vancomycin, ampicillin, metronidazole, neomycin, and amphotericin-B can lower the numbers of Bacteroidetes and Firmicutes and ameliorate AD.

By altering BBB permeability, elevating amyloidosis, and facilitating bacterial lipopolysaccharide (LPS) invasion of the central nervous system via oropharyngeal olfactory pathways, gut dysbiosis contributes to AD by impairing cognition.

Research has demonstrated a connection between intestinal microflora-related issues such gastritis, peptic ulcers, GERD, Helicobacter pylori infections, and inflammatory bowel disease (IBD) and Alzheimer’s disease.

By raising amyloid precursor protein (APP) expression, lowering ApoeE2 levels, increasing apolipoprotein E4 (ApoeE4), and upregulating the expression of neurodegeneration-risk genes like 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 predispose to the onset of Alzheimer’s disease (AD).

Neuroinflammation is also caused by H. pylori infections, which raise levels of inflammatory cytokines such TNF-α, interleukin-8 (IL-8), and C-reactive protein (CRP).

Systemic inflammation brought on by periodontitis is accompanied by increased levels of neutrophils and pro-inflammatory cytokines, which may lead to the formation of beta-amyloid plaque in the brain.

The identification of molecular patterns of damage-associated (DAMPs) and pathogen-associated molecular patterns (PAMPs), such as high mobility group box 1 (HMGB1) or H. pylori LPS, that elicit an inflammatory response in the central nervous system (CNS), is facilitated by the activation of toll-like receptor 4 (TRL-4).

Neurotoxic amyloid beta proteins can be produced from APP by upregulating cathepsin B expression. TNF-α blockers and immunosuppressants can reduce inflammation and the risk of AD in IBD patients. H. pylori infection raises the risk of AD in people over 50 by 11%, according to studies.

In summary
The results indicate that AD is a complex illness affecting the digestive system, with significant changes in the gut microbiota observed in AD patients.

Through synaptic dysfunction and the microbiota-gut-brain connection, the microbiome affects CNS function. Periodontitis and H. pylori infection may be associated with AD, although more research is required to confirm these results.

Future research ought to examine the connection between aberrant microbiota and neurodegenerative diseases.

For more information: Correlation between Alzheimer’s Disease and Gastrointestinal Tract Disorders, Nutrients, https://doi.org/10.3390/nu16142366