Alena Moudrá, a recipient of the prestigious MERIT fellowship awarded in the program’s first call, has been pursuing a 30-month research project at the National Institute of Mental Health in Klecany. After years abroad, Alena Moudrá has returned to the Czech Republic. With support of MERIT, she is studying the influence of the microbiome on Alzheimer’s disease. Alena brings not only an attractive research topic but also a fresh approach to science and mentorship.
You have rich international experience. What brought you back to the Czech Republic?
I’ve always wanted to have my own lab. During my postdoc in Cambridge, I didn’t have that opportunity. So, I started looking at various locations across Europe. Then, I got an offer from the National Institute of Mental Health to bring immunology into the treatment of psychiatric disorders. It seemed like a great chance to work independently and gradually build my own group. I wrote a project, secured funding through the MERIT program from the SIC, and began working on it at the start of this year.
MERIT allows researchers worldwide to come to the Czech Republic and develop their research program based on merit. What I found unique about the application process is that you write the entire proposal independently, without help from your mentor. It’s truly your intellectual project, which you then defend before a panel.
Your research links the microbiome, brain immune cells, and the development of Alzheimer’s disease. How did you arrive at this topic?
It’s been a long journey. One of the projects I worked on in Cambridge involved studying microglia – specialized macrophages, or immune cells, that reside exclusively in the brain. Their role is to “clean up” the brain. However, in certain severe physiological conditions, these microglia adopt a pro-inflammatory phenotype, which hampers their function.
Can you provide an example of such a severe physiological condition?
We studied cases of brain trauma caused by head injuries, such as car accidents. Following acute brain injuries, the tissue begins to heal and forms scar tissue, much like scars on the skin. Just as scars on the skin can leave the surrounding area insensitive or less functional, scars in the brain cause loss of function in the affected region.
We aimed to find ways to prevent the loss of brain function after such injuries. Using lab mice, we found that adding a signaling molecule, specifically interleukin-2, to the injured area could reprogram microglia to adopt an anti-inflammatory phenotype. This allowed the microglia to clear the debris from the brain injury, enabling the tissue to heal and fully restore its original function.
How does this connect to Alzheimer’s disease, which you are currently studying?
The same metabolic signaling occurs in Alzheimer’s. Inflammation plays a significant role in its development. Chronic low-grade inflammation contributes to many age-related diseases by stressing cells, leading to DNA damage and more frequent mutations.
If we could intervene in this inflammatory process, prevent its onset or spread, by reprogramming microglia, we could treat these diseases before they manifest and prevent irreversible tissue damage.
What is the hypothesized interaction between microglia and the microbiome?
My hypothesis is that a dysbiotic, or “unhealthy,” microbiome causes microglia to adopt a more pro-inflammatory state, ultimately worsening Alzheimer’s symptoms.
How do the gut microbiome and microglia in the brain communicate?
Communication occurs on several levels, such as through short-chain fatty acids in the bloodstream. The microbiome also contributes, to a small extent, to the presence of D-amino acids in the brain, which are essential for the interplay between these two systems.
However, many labs studying the microbiome are experts in other areas, so interpreting the data requires caution. Methodologies are not yet fully standardized, and recent re-analyses of microbiome studies from the past five years have shown that many published conclusions were incorrect.
You mentioned that germ-free mice (mice without any microbes) are often used to study the microbiome. How practical is this approach?
It’s a challenge because germ-free mice are not entirely healthy. Their development is suboptimal because communication between the microbiome and the brain is crucial during the maturation of neurons and their networking. As a result, germ-free mice have underdeveloped brains.
This affects their aging; they don’t live as long as their healthy counterparts, and their quality of life is significantly reduced due to digestive issues from lacking gut bacteria. Their cognitive functions also suffer, they perform poorly in mazes or memory tests compared to normal mice.
Do you use germ-free mice in your experiments?
We use germ-free mothers. Once they become pregnant, we introduce microbiomes to them because it’s too late for newborn mice to catch up on healthy development. The mothers pass critical metabolites produced by their bacteria to their offspring.
What kind of microbiomes do you introduce to these mice?
We use mice with a mutation that causes Alzheimer’s to develop within a specific timeframe. We also have control mice without the mutation. I collect samples from both groups over time, observing their immune systems, brain structure, and fecal microbiomes.
Eventually, I transplant microbiomes from Alzheimer’s mice into healthy ones to see if the dysbiotic microbiome triggers Alzheimer’s symptoms in previously normal mice.
Do you have evidence that this might work?
Some studies have shown that transplanting microbiomes can induce behavioral changes characteristic of Alzheimer’s in previously healthy mice. However, these experiments were typically short-term. My focus is on longer timeframes.
I’m also planning to administer antibiotics to Alzheimer’s mice, then transplant a “normal” microbiome to see if this delays the disease’s progression. This will help identify the optimal window for intervention in humans.
Can your results be applied to humans?
Mouse and human microbiomes differ due to diet and species specificity. While direct comparisons aren’t always possible, mouse experiments are crucial because they allow for a full-body analysis of organ interactions, something we can’t do in humans.
What challenges do you face in these experiments?
One major challenge is that experiments take an incredibly long time, so funding from a three-year grant often feels like a tight deadline. That’s why, in Cambridge, we maintained a cohort of older mice to use in our experiments.
Another issue is that, until recently, most experiments were conducted on males, whether in animal studies or human research. However, females age differently and at a different pace. This highlights a significant problem in modern medicine and biology: it took an exceptionally long time for the scientific community to acknowledge that women are not just “small men.”
Why is it important to consider sex differences in these studies?
Many diseases manifest differently in women. For instance, heart attacks present with entirely different symptoms, and the immune system functions differently in women. Yet diagnostic tools are often calibrated for men. We also see gender differences in Alzheimer’s disease. It is often diagnosed earlier in men, partly because they frequently have a living spouse who notices the symptoms, takes them to a doctor, and provides care at home.
In contrast, women, who typically live longer and are more likely to develop Alzheimer’s when living alone, often lack such support. As a result, their diagnosis tends to be delayed, since family members are not in daily contact to observe changes.
Gender as a factor is now being incorporated into biological analyses. In fact, many grants will not provide funding unless gender considerations are included.
You mentioned wanting to establish your own lab. Where do you stand in that process?
Currently, I work independently. At the moment, I cannot have students because I don’t have funding for them. To take on a student, I need a project to fund their position. Thanks to support from SIC, I was able to move to the Czech Republic, start working on my own research topic, and have the space to seek additional funding to establish my lab.
This year, I submitted project proposals to the Czech Science Foundation (GA ČR) and the Agency for Healthcare Research (AZV). I am waiting to hear back. Next year, I plan to apply for an ERC Starting Grant.
One of the reasons I’m passionate about having my own lab is the immense joy I get from teaching the next generation, helping young people grow scientifically, and teaching them how to think critically about experiments.
You have experienced both Anglo-American and Czech educational systems. What differences do you notice?
Czech students start university with an intellectual edge over their Anglo-American peers. But during their studies, this advantage diminishes due to differing attitudes toward failure. Czech students fear admitting mistakes, whereas British students are more comfortable seeking help.
To foster openness, I start seminars by asking basic questions, even as someone with a Ph.D. This creates an intellectual space where students feel safe to explore. Creativity flourishes when we question the basics and embrace interdisciplinary approaches.
Ultimately, my goal is to build a diverse, multi-disciplinary team. Collaborating with those who know more than I do is my greatest joy.
