Interview with EAT Funded Researcher: Cathryn Nagler, Ph.D.
by Jill Robertson-Li
Cathryn Nagler, Ph.D., Bunning Food Allergy Professor at the University of Chicago, researches how the microbial composition of the digestive tract affects the development of food allergy. EAT has funded Dr. Nagler’s research study, “Prebiotic Dietary Fibers to Prevent or Treat Food Allergy.”
Scientific research suggests one potential cause of allergic disease is an altered gut microbiota. In a breakthrough discovery, Dr. Cathryn Nagler identified a specific class of bacteria, called Clostridia, that blocks allergic sensitization by secreting butyrate, a substance that protects the lining of the digestive tract. She is currently working to develop therapeutics targeting the microbiome to treat, prevent, and hopefully cure food allergies.
Part 1: Why do so many people have allergies these days?
Dr. Nagler hypothesizes that the dramatic increase in food allergy and other immunological disease has been driven by lifestyle changes that have altered the composition of the microbiome. In this interview with EAT, Dr. Nagler shares valuable insight into her research:
EAT: What changes have occurred to the human microbiome in western industrialized countries?
Dr. Nagler: Microbial diversity has been reduced compared to earlier generations. At this point we can’t specifically say what has been deleted, and we don’t fully understand the composition of a healthy microbiome, but we believe that a healthier microbiome is one that has more diverse bacteria. It is clear that diversity has been reduced by antibiotics.
EAT: You mentioned antibiotics have reduced microbial diversity. Are there other aspects of our modern lifestyle that have contributed to this change?
Dr. Nagler: It’s not just prescribed antibiotics. For example, antibiotics are used in raising cattle to help them grow larger. So, we have subclinical exposure to antibiotic residue in our food and water supply, and this low level exposure does cause changes to the microbiome.
Diet also affects the microbiome. Bacteria eat what we eat. We co-evolved with our microbiota, and historically humans had a high fiber, low fat diet. Our diet is very different now, and that has led to changes both individually and across the population. Interestingly, diet can also cause transient changes to the gut microbiota on a daily timescale.
Reduced exposure to infectious disease is another factor affecting the microbiome and immune response. It is well-established that immunological disease increases in countries as infectious disease decreases. We don’t want to see more infectious disease. But the absence of exposure to infectious disease may be contributing to priming the immune system to respond to things that are harmless.
Caesarian birth and formula feeding versus vaginal delivery and breastmilk are other factors that affect the development of an individual’s microbiome.
Then there is also processed food with additives and emulsifiers that affect microbiota. So many things have changed at the same time, and piecing together whether it is any one of these changes, or all of them, is the challenge.
EAT: It sounds like these changes would affect all of us. Why has an altered microbiome resulted in allergy in some, but not all, people?
Dr. Nagler: As with most diseases, there is clearly a genetic predisposition along with the contribution of the environment. In the case of allergy, there is likely something that disrupts epithelial barrier function so that antigens are presented to the immune system, and then that response snowballs. Even knowing all the factors, some people sharing the same risks will develop disease while others do not. Twins have the same genes and environment, but they don’t all have the same allergies.
EAT: Do probiotic supplements help restore a healthy microbiome?
Dr. Nagler: Conventional probiotic bacteria are almost always lactobacillus and bifidobacteria that we have been able to culture for 40 years. They are prominent in healthy infants, but not adults. Lactobacillus come from vaginal delivery, and bifidobacteria thrive on proteins present in breastmilk. Research has shown there is some beneficial effect of LGG [Lactobacillus rhamnosus GG] given to infants with cow milk allergy. Outside of infancy, there is little evidence that these probiotics change the immune response. They may make your stomach feel better, but they cannot cure food allergy.
EAT: How is the bacteria that you are studying different from conventional probiotics?
The types of gut bacteria that seem to have the biggest effect on modulating the immune system are anaerobic, meaning they don’t grow in oxygen. Oxygen is everywhere, so they don’t survive in a normal environment. They have not previously been studied as probiotic drugs because they can’t grow in test tubes. They were discovered through genetic sequencing.
Part 2: Taking care of our gut microbiome
EAT: The bacteria you are studying do not grow in oxygen. How do people typically become colonized with bacteria that don’t survive in a normal environment with oxygen?
Dr. Nagler: Mostly from the environment. Bacteria that are susceptible to oxygen are often spore-forming, so we are colonized by spores. Everything we pick up, everything we inhale or put in our mouth, is covered by bacteria. Some of these beneficial bacteria just happened to get into our mouths at the right point in time. Most colonization happens in early childhood.
There is a theory, and I think there is some truth to it, that part of the problem is that we have less exposure to the natural environment. School kids play with the ipad versus playing in the dirt, and we live in sealed houses as opposed to houses with open windows. Microbial diversity has been reduced by the fact that we spend most of our time indoors in sealed environments.
EAT: If colonization doesn’t occur at birth or during early childhood, can people still benefit from these bacteria acquired later in life?
Dr. Nagler: We don’t know exactly what happens with later colonization. We’ve created a start-up company called ClostraBio that is developing microbiome-modulating therapeutics to prevent or treat food allergy. I’m hoping that by using bacterial products, as opposed to the bacteria themselves, we will be able to replace the function of the missing bacteria. For younger kids, we may be able to use the bacterial product as a preventative therapy.
I’ve always thought that the first indication for our product would be as an adjunctive to oral immunotherapy (OIT). I hypothesize that would work well for older children and teenagers. Oral immunotherapy alone may be limited in its ability to induce tolerance because it only treats one part of the aberrant immune response. It doesn’t treat the epithelial barrier. If we do both, it should potentiate oral immunotherapy by restoring barrier function.
EAT: Do you think this would reduce the gastrointestinal side effects that accompany oral immunotherapy?
Dr. Nagler: Yes we do postulate that it would reduce GI side effects.
EAT: Why did you choose to focus on the bacterial byproduct instead of a probiotic formulation of the bacteria itself?
Dr. Nagler: I chose to focus on this route several years ago, probably because I work with a fantastic synthetic chemist who has been able to make a nano-formulation of this bacterial product. It is currently our lead candidate.
Past research showed that restoring the Clostridia class of bacteria reversed food allergy in a mouse model, and we have subsequently been able to narrow down the effective Clostridia bacteria to a single human strain. We now are studying that single bug and whether it can replace the function of a healthy infant microbiome. If it does, we may decide to develop that bacteria and go down the pathway of bugs as drugs as well as bacterial metabolites.
EAT: While we wait for the research to progress in this area, what are some of the most important things we can do now to promote the type of healthy microbiota that resists allergy?
Dr. Nagler: A couple of caveats: I’m not trained to give medical advice, and I don’t want to trivialize a complex problem. However, there are a few things I am willing to say:
First, be judicious in your use of antibiotics. People should ask questions before they accept a prescription of antibiotics. Antibiotics should only be used when there are signs of a bacterial infection. I am not saying patients should disregard medical advice. However, it is okay to ask questions and have a discussion about whether the antibiotic is medically indicated.
Also, we should stop using antimicrobial products, like triclosan, that appear in toothpaste and hand soap. Skin microbiota does not need to be killed, and there is emerging evidence that this is deleterious.
Finally, increasing dietary fiber is beneficial. The drug we are developing is directly linked to dietary fiber. The bacteria we are studying are the ones that ferment dietary fibers and secrete byproducts that are the basis of our drug.
EAT: Is there a type of fiber that is especially beneficial?
Dr. Nagler: It’s not that simple. We had hoped to find a particular fiber to expand the protective bacteria, but that wasn’t the case.
EAT: Is this due to the variability of the individual microbiome?
Dr. Nagler: Yes. In the future, we may screen fecal samples from people with food allergies to see what fibers they do or don’t ferment. We may be able to provide individualized dietary recommendations to optimize the function of their gut microbiome. At this point, I recommend a diet that includes a variety of fibers from the consumption of plants.
EAT: The study of the microbiome and its effect on human health sounds very promising. How would you describe the current state of microbiome research?
Dr. Nagler: At this point, there is more that we don’t know than there is we do know. We need a lot more information to know what exactly constitutes a healthy, functioning microbiome and how to restore it to where it was generations ago.
Key terms:
Butyrate: metabolic byproduct arising from bacterial fermentation of dietary fiber; reduces inflammatory response
Microbiome: the collection of microorganisms living inside or on the human body, including the skin, mouth, eyes, nose, lungs, digestive tract, and reproductive organs
Epithelial barrier: protective tissue that lines mucosal surfaces, including the digestive tract
Immunological disease: disease caused by dysfunction of the immune system, including allergy and asthma, and autoimmune disorders such as inflammatory bowel disease, juvenile diabetes, arthritis, and multiple sclerosis
Infectious disease: disease caused by microorganisms, such as bacteria, fungi, viruses, or parasites
Antigen: a substance that may provoke the immune system to respond by producing antibodies
Epithelial barrier: protective tissue that lines mucosal surfaces, including the digestive tract
Spore: protective covering of dormant bacteria
Nano-formulation: enhanced formulation of a drug that provides targeted delivery of medicine through microscopic particles