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An ounce of prevention

UND neuroscientist: How food allergies and gut microbiota may affect anxiety, depression — even Alzheimer’s

Kumi Nagamoto-Combs, assistant professor of biomedical sciences at UND’s School of Medicine & Health Sciences, is a neuroscientist whose research focuses on how changes to intestinal microbiota affect not only Alzheimer’s but also behavioral health. Photo courtesy of UND School of Medicine & Health Sciences.

Editor’s note: A researcher with her doctorate in neuroscience from the University of Rochester in New York, Kumi Nagamoto-Combs has been with the UND School of Medicine & Health Sciences in a variety of capacities — neuroanatomy instructor, research associate, biomedical technology transfer officer, assistant professor — since 2005. Fresh off news of receiving a two-year, $380,000 R21 grant from the National Institutes of Health’s (NIH) National Institute for Allergy and Infectious Diseases (NIAID) in 2020 and a five-year, $1.8 million R01 grant from NIH/NIAID this year, the assistant professor in the Department of Biomedical Sciences sat down with North Dakota Medicine in March to talk allergies, inflammation, the gut, and the brain — all of which are connected, she says.

Thank you for your time, Dr. Nagamoto-Combs. Tell me first about your NIAID grants.

We’re studying the long-term effects of chronic allergen exposure in mice with non-anaphylactic food allergy. For this, we sensitize mice to a milk allergen to establish mild milk allergy, and we put them on a diet that contains the offending allergen. Because they are asymptomatic, they can eat the food without any observable symptoms. But because they’re sensitized, they still develop inflammation.

For the R21-funded project, we are using a mouse strain that is genetically predisposed to develop Alzheimer’s disease-like pathologies and investigating whether the development or progression of their pathologies can be exacerbated or accelerated by the allergen-induced inflammation. For the R01-funded study, we are elucidating whether allergen-activated peripheral immune cells are involved in the development of neuropathologies. We will also test whether the food allergy-associated inflammation can be prevented by pharmacologically protecting intestinal integrity.

Incredible. So, you’re a neuroscientist by training who focuses on how changes to intestinal microbiota affect not only Alzheimer’s but behavioral health, right? Hives or asthma aside, do we have evidence that things like anxiety or depression may in part be the result of inflammation or allergies to foods in the gut?

Yes. In our mouse model of non-anaphylactic milk allergies, we have seen anxiety- and depression-like behavior. We showed previously that these mice have intestinal inflammation and altered gut microbiota. We’ve also seen neuropathological features in the brain, such as reactive glia and blood-brain barrier impairment that indicate neuroinflammation.

But perhaps the most interesting finding we have in the brain of allergic mice is cortical demyelination. The axons of many neurons are coated with insulating material called myelin that protects electrical signals during neurotransmission. But if that coating gets damaged, neurons can’t send signals efficiently. An example of such a condition is multiple sclerosis.

We don’t know what’s causing the cortical demyelination in our mice, but at least we may have a possible explanation for their behavioral abnormalities.

We were discussing our kids earlier. Has your experience as a mother of children with allergies influenced your interest in this sort of research?

I do have a lot of allergies in my family with different severity, so I started wondering what the long-term consequences of allergies might be. People with severe allergies with immediate reactions, like throat swelling, hives, and vomiting, know to avoid the offending food. But some people are asymptomatically sensitized, meaning they have elevated levels of antibodies toward allergens, but they don’t react severely. They might not even know that they are sensitive to something they eat because their symptoms are mild, if any, or symptoms happen a few days later so they don’t make the connection and continue to eat allergens.

But what happens if they keep eating the offending allergens? What is the long-term effect, especially on brain function? We don’t know much about this population because most studies are focused on more severely sensitized people with life threatening symptoms.

To that point, gluten free diets, dairy free, low carb, and so on are everywhere. Do we know enough as researchers to be able to say that even if people don’t seem to be exhibiting obvious symptoms, things like dairy or gluten or soy might be causing inflammation in ways that have consequences for some of us down the road?

So, in something like celiac disease, people are sensitive to gluten in wheat products. They have chronic inflammation in the intestines, which can lead to changes in microbiota, gut physiology and the immune system. These changes are thought to influence brain function by altering the levels of bacterial metabolites, nutrient absorption and inflammatory factors.

Although the trigger is different, our sensitized mice have intestinal inflammation, neuroinflammation and behavioral abnormalities, so it is likely that intestinal “insults” by dietary allergens can affect the health of the brain and body, especially when the inflammation persists. We looked at microbiota in our allergic mice and found altered intestinal bacterial populations, or dysbiosis. One of the most drastic changes was a decrease in Akkermansia muciniphilia, a bacterial species that helps protect the mucus layer by stimulating mucus production. This bacterium is known to be important for diabetes and obesity, but also its decreased levels have been associated with autism spectrum disorder and Parkinson’s disease.

So, there are connections to the loss of Akkermansia and brain disorders. If that’s the case, we’re wondering if we can restore or supplement Akkermansia to prevent or attenuate the intestinal pathology and improve behavioral outcomes.

Has this research influenced the way you eat or how you feed your family, or changed the way you shop?

[Laughs] Yes. We’ve been doing that ever since we had children. Not for “health food” per se, but in our family, we have a severe allergy case and because of that we read every single label when we shop. That has been a part of our life. When we feel tired or when we feel so-called “brain fog” we wonder “What did I eat last night…or two days ago?” We think that immediately.

Exactly. And to that point — feeling sick generally and food exacerbating inflammation — can you make a connection between food allergies, microbiota, anxiety behavior, and what’s going on with the population in terms of SARS-CoV-2 broadly these days?

Sure. Being a neuroscientist, I’m always interested in what can affect brain function and ultimately behavior. When I was going to graduate school, the brain was believed to be an “immune privileged” site, but that concept has completely broken down. We know that immune cells can communicate with the brain, although the communication is tightly regulated. We see immune cells in and around the brain. If these immune cells are activated by food allergy and become the culprits of a brain disorder, then it’s a lot easier to prevent them from going to the brain than trying to target the brain itself through the protection of the skull and the blood-brain barrier.

Recent observations of cognitive problems in some COVID sufferers have indicated that viral infections can affect the brain. My colleague Dr. Catherine Brissette is studying how bacterial infections from tick bites affect the brain. The notion that peripheral inflammation influences the brain is now well-accepted. And since food allergy can be a chronic inflammatory condition, why can’t we include food allergy-induced gut inflammation in this category?

If I’m hearing you right, you’re implying that while we obviously need to treat people who are suffering from Alzheimer’s or diabetes, one of the takeaways from your work is that prevention is key, and we can potentially prevent a lot of this stuff through diet.

Yes. Prevention is way better than palliative care, in my opinion. Once something is broken, it’s hard to fix it. Around seven years ago, I was hit by a pick-up truck …

Oh no!

… (and) I really hit the concrete hard and had a concussion and whiplash. I went to a lot of rehab, but I’ve never been the same. Even right now, I’m suffering from neck pain. I’d be much better off without the accident. Again, pain is another chronic inflammatory condition. So, I sometimes wonder what it’s doing to my brain.

But, yes, prevention is definitely a lot more effective than trying to patch up something that has been broken. And it’s a lot more cost-effective!