Gut bugs & the brain

Alzheimer’s disease (AD) is increasingly being recognized as a multifactorial condition causing neurodegeneration, as well as progressively destroying memory, thinking skills, and the ability to perform daily tasks. Many treatments have been trialed – and many have failed: so, what if we focused on the gut?

Although it may initially sound far-fetched to focus on the gut for a brain condition, the two are in constant communication. The gut has its own nervous system and uses many of the same chemical messengers as the brain, while also communicating with it through the immune system.

This matters for conditions like Alzheimer’s, in which reaching the brain for detection or treatment is notoriously difficult, especially as the blood-brain barrier blocks most drugs. The gut, by contrast, is much easier to access: it can be sampled non-invasively and altered through diet or probiotics.

Alzheimer’s disease is classically characterized by the accumulation of a protein known as beta-amyloid and tau neurofibrillary tangles. For decades, the amyloid cascade hypothesis has reigned as the central dogma of Alzheimer’s disease research, gaining the vast majority of scientific attention and funding.

It was proposed almost 34 years ago and has produced only modest clinical benefit. There is a long history of clinical trials that cleared amyloid plaques without halting cognitive decline. Today, researchers are widening their perspective, zooming out from a purely amyloid-centric view to investigate what seems to be a more complex, multifactorial condition including metabolic dysfunction, vascular breakdown, and neuroinflammation.

At the very centre of this inflammatory response are microglia: the brain’s resident immune cells, acting as its primary line of defense. Previously dismissed as cellular scaffolding or the brain’s clean-up crew, microglia are now increasingly being recognized as active drivers of Alzheimer’s progression. Initially, these cells were hypothesized to be activated by the amyloid plaques, however, there is now consistent evidence that microglial response occurs prior to amyloid plaques.

In recent human postmortem studies, it has been revealed that microglia exist in unique states in Alzheimer’s disease patients’ brains, compared to the brains of healthy older individuals. This suggests that there may be aspects of microglial functioning that alter specifically during neurodegeneration in the brain.

Microglia in the brain act as a double-edged sword: in the early stages of the disease acting as protection by swarming around amyloid plaques and encapsulating and clearing them. However, as the pathology progresses, microglia become overwhelmed and chronically activated, becoming destructive instead of defensive. Instead of protecting the brain, microglia begin to engulf healthy synapses, driving the accumulation of tau tangles, and actively fueling the neurodegeneration they were meant to prevent.

There are various ways that microglia have been hypothesized to cause neuroinflammation and disease progression in Alzheimer’s. The manner that the microglia behave and respond in is largely dependent on their fuel, i.e. their immunometabolism. Precisely speaking, when microglia detect a threat, they switch from slow, efficient energy production to fast glycolysis. The cells are not solely reliant on glucose; they are also able to use ketones, fats, and amino acids like glutamine, which allows continued microglia functioning, even in the absence of glucose. This is vital as although microglia can normally switch fuel, in Alzheimer’s, chronic glucose shortage may permanently lock microglia into a glycolytic state which fuels, instead of limits neurodegeneration. Overall, this means that microglia are reprogrammed, requiring fine tuning to restore normal functioning.

What could cause alterations in microglia functioning leading to neurodegeneration? How is the gut involved?

One of the major upcoming research areas that is associated with neuroinflammation, and Alzheimer’s is the gut-brain axis. The gut-brain axis is the communication between the brain and the gut. Recent research suggests that the neuroinflammation evident in Alzheimer’s may be driven by gut microbiota alterations. Dysbiosis is the dysregulation of beneficial gut bacteria and harmful microbes. It has recently been linked to neuroinflammation, which is further known to cause neurodegeneration and lead to the progression of Alzheimer’s. Studies have shown that changes in the gut ecosystem can disrupt intestinal barrier function, causing products of gut bacteria such as lipopolysaccharides to end up in the bloodstream. When lipopolysaccharides end up in the bloodstream, they can lead to immune cell activation and trigger an overall inflammatory response, contributing to neuroinflammation.

Tackling the neuroinflammation becomes vital due to its ability to worsen neuronal loss whilst contributing to amyloid plaque and tau tangle accumulation. Once neuroinflammation begins, it can also contribute to bloodbrain barrier dysfunction, allowing the immune cells, otherwise known as microglia, to enter the brain and further contribute to neuroinflammation, neurodegeneration, and cognitive impairment in Alzheimer’s.

Another aspect of Alzheimer’s that is impacted by an altered gut microbiome is the production of neurotransmitters like serotonin and dopamine. Dysfunction in the production of these neurotransmitters further leads to cognitive decline and behavioral changes in Alzheimer’s patients. The gut microbiome is an important area to investigate, especially with neurodegenerative conditions, due to alterations in the gut microbiota being observed in Alzheimer’s patients. Although this remains a correlation at the present, further research may be able to utilize this as a target for therapeutics if the correlation is found to be causation.

What are the microglia really doing in Alzheimer’s?

Microglia have two roles in neurodegeneration: their activation reduces amyloid buildup but also activates inflammatory cascades which lead to synapse loss.

Several studies have shown a bidirectional relationship between gut dysbiosis and neuroinflammation and cognitive decline in Alzheimer’s. Overall, bidirectional communication between the gut and the brain plays a vital role in homeostasis. Homeostasis is the healthy resilient equilibrium of different pathways and processes in the body. As microglia play a pivotal role in Alzheimer’s, restoring homeostasis in the gut may in turn fine tune the microglia and halt disease progression.

How can we target the gut to halt neuroinflammation and AD progression?

The connection between neuroinflammation and gut microbiome alterations creates potential for therapeutic intervention to mitigate microglia related neuroinflammation, thus reducing the risk of Alzheimer’s. Various recent studies suggest that resetting the microglia from a destructive, pro-inflammatory state back into a protective state may halt disease progression. Currently, there are various ways that the gut is being targeted. These include targeted probiotics, also called psychobiotics, restoration of the blood-brain barrier, and dampening microglia hyper-reactivity. Microbiota transplantation is also being investigated; there are several clinical models that have shown a dramatic decrease in microglial activation as well as a reduction in cognitive decline. Additionally, there are also microbial amyloid inhibitors being researched to prevent the “priming” of microglia, thus preventing these immune cells from over-reacting to brain plaques.

Overall, recent studies recognizing the gut’s role in Alzheimer’s related neuroinflammation are highly valuable as the gastrointestinal tract offers a far more accessible and modifiable therapeutic target than the brain. Although more research is a must to confirm how beneficial a target the gut may be, current findings provide hope!