The Gut Microbiome Could Speed Up the Progression of Alzheimer’s Disease

The microbes in the gastrointestinal tract influence the immune system and the brain, possibly playing a role in the development of Alzheimer’s

For approximately all the human cells in our body, a tiny microorganism lives inside us. On our skin, in our lungs, in our mouth, in our intestines and more. This set of bacteria, viruses and fungi are called microbiomes. Sometimes these organisms only coexist, but sometimes they can harm their human hosts.

Microbiome and Alzheimer's disease
The community of bacteria that live in the gastrointestinal tract - the intestinal microbiome - is generally harmless, but because they affect the activity of the immune system, they can influence a wide range of diseases, even in organs as far away as the brain.

Recently, these microorganisms have become closely associated with diseases such as cancer, diabetes and Parkinson's disease. In a study published in the Journal of Experimental Medicine earlier this year, microbiologist Hemraj Dodiya of the University of Chicago and his colleagues investigated whether a bacteria in the gut could influence the progression of Alzheimer's disease.

This dementia affects 50 million people worldwide. Alzheimer's disease is one of the most common forms of dementia, characterized by memory loss, confusion and other cognitive symptoms that gradually progress to near-total dependence and immobility. About one-third of people living to age 90 will develop some form of dementia. Medications can alleviate some symptoms but cannot stop the progression of this disease.

Although we do not fully understand how Alzheimer's disease causes these symptoms, it is characterized in part by an accumulation of protein aggregates in the brain, called beta-amyloid plaques, that appear with cognitive decline. Although the accumulation of beta-amyloid characterizes the disease, there is still much to learn about how these plaques cause so much damage to the brain.

Normally, the immune system plays an important role in the elimination of beta-amyloid, but scientists believe it may also perpetuate and accelerate Alzheimer's disease. Microglia, immune cells that live in the brain, look for harmful substances and danger signals.

Microglia release inflammatory chemicals
When they encounter beta-amyloid plaques, the microglia turns to a pro-inflammatory state. When this happens, microglia release inflammatory chemicals that, at high concentrations, can aggravate Alzheimer's symptoms and contribute to brain cell death.

Regardless of their role, this inflammatory state reflects an altered ability to maintain healthy tissues, not only in Alzheimer's disease, but also in other neurodegenerative disorders such as Huntington's and Parkinson's diseases.

How does microglia become a useful machine against beta-amyloids as a dangerous supplier of excessive inflammation that can kill neurons? While many factors certainly play important roles, changes in intestinal bacteria could play a key role in triggering or maintaining the microglia that induce inflammation. In their study, Dodiya and colleagues found evidence that bacteria can influence Alzheimer symptoms in male mice.

They tested the effects of these microbes in the intestine on beta-amyloid and microglia in the brain using a line of transgenic mice developed specifically to have amyloid precursor proteins.

First, the researchers administered antibiotics to the mice, which altered their intestinal microbial communities. When they examined the brain tissue of these mice, they found that their microglia had remained in check and that these mice had fewer beta-amyloid plaques.

To confirm that this change in microbial communities could contribute to these effects, they then reintroduced microbes by transplanting feces from healthy mice into another group of mice treated with antibiotics.

The reintroduction of the microbes partially restored the amyloid beta plates and increased the markers of the microglia causing the inflammation. And although the researchers tested both male and female mice, they only found these changes in male mice.

Females are more likely to be affected by Alzheimer's disease
For unknown reasons, females are more likely to be affected by Alzheimer's disease than males. The researchers examined this fact and therefore tested both male and female mice. The effects of the microbiome on plaques and microglia apply only to male mice: beta and microglial amyloid levels have not changed in response to antibiotics in female mice.

Researchers often use male mice, based on historical precedents and prejudices, but this does not reflect the reality of how our bodies work. Diseases are often more frequent in one sex; Alzheimer's disease occurs more frequently in women, but disorders such as Parkinson's disease occur more frequently in males.

In addition to this, the effects of the microbiome can also be gender-specific, regulating sex hormone levels and the fate of autoimmune diseases. This is not the first study to compare the different roles of the microbiome by gender, but it highlights the importance of taking gender into account when considering therapeutic strategies for Alzheimer's disease and other diseases.

Although it is unlikely that we will start administering antibiotics in the long term to treat Alzheimer's disease, it is now possible to take advantage of the fact that antibiotics have reduced the symptoms of Alzheimer's disease in male mice in order to better understand the timing and influence of intestinal bacteria in this disease.

More studies are needed
Is there a time window in which bacterial function is critical? Will we be able to seed ourselves with specific bacteria in the future to reduce Alzheimer's symptoms? More studies are needed to understand these processes and use the lessons learned in mouse models in human diseases.