The gut microbiome and Alzheimer’s: the missing link to new treatments?

By Grace Brook

After decades of dementia research, we the public remain in the dark about effective treatments whilst cases are rising rapidly due to the UK’s aging population.

The London School of Economics and Political Science has projected an increase of 81% in dementia cases amongst people aged 65 and over from the year 2019 to 2040. However, the largest increase of 109% is set to happen for severe cases of dementia by 2040.

This will undoubtedly cause the largest impact on the livelihood of the patient and those around them, as well as a colossal pressure on social care. Dementia, in all forms, can cause memory loss, changes in behaviour and issues with critical thinking and problem solving.

Alzheimer’s disease (AD) is progressive, starting with short term memory loss and difficulties with reasoning and perception. When focussing in on AD, we are referring to the neural connections lost in the brain due to the formation of amyloid plaques and intracellular neurofibrillary tangles.

In 2017, a team at the University of Wisconsin found that the gut microbiome of AD patients had decreased diversity compared to non-patients

Amyloid plaques occur due to the deposition of amyloid-β protein in the grey matter of the brain which can lead to swollen axons and dendrites of neurons. Neurofibrillary tangles consist of the protein tau, causing a lack of communication between neurons and eventually cell death.

Whilst these features of damaged brain function are hallmark traits of Alzheimer’s, we must ask ourselves how these relate to the gut microbiome. The gut-brain axis describes the communication that occurs between these areas of the body. Within the gut of a healthy adult is a vastly diverse microbiome from the age of maturity at 3 years old.

In 2017, a team at the University of Wisconsin found that the gut microbiome of AD patients had decreased diversity compared to non-patients. This study specified the bacterial species that decreased and increased in numbers within these patients, including decreased Firmicutes and Bifidobacterium with increased Bacteroidetes. Whilst this knowledge permits us to understand the condition more, it supplies no insight as to whether the microbiome reduced diversity is the direct cause of AD.

With a lack of diversity and common gut microbiome alterations in the elderly, this aids in our explanation of the prevalence of AD. We must take into consideration overall health and that with advanced age one is more likely to take multiple medications and use antibiotics regularly, which can contribute to reduced gut microbiota.

Dysbiosis, used to describe an imbalance within the gut microbiome, can lead to the release of cortisol which can cause reduced intestinal barrier integrity. This leads to the intestinal and blood-brain barrier permeability increasing. Reactive oxygen species present in neurons and microglia are therefore greater and cause the oxidative stress that is present in AD.

Consequently, these findings suggest that disturbance of the gut microbiota can cause the oxidative stress seen in AD, providing evidence of dysbiosis causing neurodegeneration. In mouse models, amyloid-β deposits in the brain increase inflammation via the release of pro-inflammatory cytokines by microglia. A specific proinflammatory cytokine, IL-1β, increases the rate of tau hyperphosphorylation and leads to the neurofibrillary tangles in AD. One can say that the presence of a single hallmark trait of AD, amyloid plaques, can lead to the increase of another trait, neurofibrillary tangles.

Paraprobiotics have proven effective in human trials

With the knowledge that the gut microbiota can cause or at least exacerbate AD and other neurodegenerative disorders, this opens new possibilities for therapeutics. Epigenetic changes to DNA can be regulated by the metabolites of the gut microbiota.

Most importantly, this can help determine the efficacy of therapeutics used for neurodegenerative disorders. Probiotics, thought to be a suitable therapeutic for AD, can cause a myriad of side effects including sepsis. Many may consider this high risk, moderate reward.

On the other hand, paraprobiotics may appeal to more patients. Paraprobiotics have proven effective in human trials without the risk of side effects due to an absence of living organisms in the treatment. Peptidoglycan derived from gut microbiota bacterial cell walls has been shown to modulate the host’s immune system and pass into the brain to modulate brain development and behaviour. Paraprobiotics containing peptidoglycan could therefore prove effective at reducing the symptoms of AD without the harmful side effects of probiotics.

At the forefront of research should be the greatest consideration for the health of the patient. Therapeutics, such as paraprobiotics, can alleviate and possibly delay neurodegeneration in AD without harmful side effects. This can bestow a more fulfilling life for a greater number of years. With further progression in research, the way we perceive AD can hopefully change and we can attempt to prevent AD from overshadowing the later years of one’s life.

Image: CDC via Unsplash

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