Q&A: Can a Plant Compound Impact Interaction Between Food Allergy, Microbiome?

Researchers tested berberine containing natural medicine (BCNM) in mice with peanut allergy and found the treatment regimen induced long-term tolerance to peanut and a profound, sustained reduction of immunoglobulin E (IgE). In an interview with The American Journal of Managed Care^®, Kamal Srivastava, PhD, director of Basic Science Research at General Nutraceutical Technology, explained the growing importance of gut and skin microbiota when it comes to treatment of food allergy.

AJMC^®: Your study found that berberine-containing natural medicine treatment regimen induced long-term tolerance to peanut in mice accompanied by a profound and sustained reduction of Immunoglobin E. Can you explain what berberine is and how you came to discover it as effective?

Srivastava: Berberine is a naturally occurring plant compound. It's a quinolizidine alkaloid that's found in many plants. Our discovery of it came from herbs that were part of a food allergy herbal formula that our lab, headed by Dr. Xiu-Min Li at Mount Sinai. We had done a lot of research with taking herbal formulas that were inspired from traditional Chinese medicine and adapting them as potential therapies for food allergy. From this research, where we were looking at the individual herbs in this form, we found that one specific herb, phellodendron, really was very effective at lowering IgE, which as you know, is the antibody related to food allergy. Breaking down the components of this one herb further led us to isolate this plant compound, berberine, as an active compound that lowers IgE. When we did this and tests using IgE producing cell lines, we did this in human blood cells from the allergy patients, and we saw that this compound could down regulate IgE production. We then went back to forming a herbal medicine, focusing on this active compound and we found that one of the things that limits this active compound use by itself is the fact that it's very poorly bio-absorbed. The bioavailability of berberine is very low. We noticed that when we administered berberine to mice by itself, we couldn't really see it in the blood. Then when we looked back at our data with the formula, we found that when it's within the herbal formula, berberine is present in the blood in higher amounts. So we thought, well, maybe there's something about the herbal formula that helps berberine get into the blood more. We did some more research and identified some other herbs. For example, angelica sinensis, we found to be a big main helper to get berberine into the blood. We then refined our approach and we developed this berberine containing natural medicine approach, which we called BCNF. This is basically using berberine as the main component, together with the angelica sinensis herbs. Then we found that we could then lower IgE in the blood of mice that are allergic to peanut. It's important to stress that we don't think this herbal medicine is antigen specific. So while we tested it in a model of peanut allergy, our future experiments are going to be also testing it for allergy in models where mice are allergic to other foods as well. That's sort of the background from where we came from, which is basically finding active components of traditional botanical medicines, and then taking them forward to address specifically food allergies.

AJMC^®: What are the next steps in testing the safety and efficacy of this treatment?

Srivastava: There's some very standard practices that need to be followed to assess the safety first, because we would never would want to bring anything from the lab into a clinical trial. Safety is first and foremost. So what our next step will be is to do acute and chronic safety testing in mice. For acute safety testing, we will basically feed mice 10 to maybe 14 or 15 times the daily dose that we use for regular treatment. Then following that, after 2 weeks of observation where we follow the mice in terms of their behavior, bodyweight, general health condition, we will then euthanize or sacrifice these mice and then we will look at blood parameters, immune system parameters, tissue health and pathology. Once we've gotten a pre-clinical safety assessment, we can then plan human safety trials once we get there. That's usually the standard path that is followed. Now as far as efficacy trials go, once we are satisfied with the preclinical and clinical safety data, we can then perform a small efficacy trial in human patients. In mice, we have already seen very good efficacy. I think the next step would be to see human efficacy but before we can do any human efficacy trials will have to go through rigorous safety testing.

AJMC^®: In your abstract, you said that BCNM's benefits are associated with a distinct microbiota signature. Can you elaborate on that?

Srivastava: One of the things that people are recognizing is that the gut microbiota affect our general health, both on an everyday basis and within the context of disease. Because food allergies are so intimately linked with gut health, it's been recognized in many, many studies now, that susceptibility to food allergy, disease pathology, and recovery from food allergy, all at various stages are linked with changes in the gut microbiome. We were interested to see if at the end of our studies, could we find any patterns that seem to suggest that the mice that are given DCNM treatment had any differences in their gut microbiome? One of the things that we saw was a realignment of the firmicutes-to-bacteroidetes ratio. Firmicuties and bacteroidetes are the 2 main phylum of bacteria that inhabit our gut. In many disease systems or general states, it's been seen that a higher bacteroidetes ratio seems to track with an anti-inflammatory profile. So it seems that healthier guts, in terms of an inflammatory profile have more bacteroidetes. That was one of the things that we noticed.

The other thing that we noticed was that there was a specific bacteria family called the Verrucomicrobia. Now the verrucomicrboia are an interesting bacteria because it seems like healthier adults who have more normal body weights, or who have a healthier metabolic status, tend to have higher numbers of Verrucomicrobia. That was one thing that we were a little surprised at. We saw that mice that were treated and now had lower or very reduced levels of IgE and were protected from peanut challenges seemed to have a higher level of Verrucomicrobia, which means that there was some, at least in our model, some link with a protective effect from allergy being linked with also a better metabolic status, at least as far as this bacteria are concerned. I think we're now interested in further looking to the reasons why these things were linked in our study. We referenced a recent paper from another lab showing that if you transfer the gut microbiome of obese mice to the gut microbiome of healthy mice, the healthy mice then begin to show a susceptibility to allergy, suggesting that while we don't understand the precise mechanisms yet, there might be some links as to how our immune systems are somehow related or track with the metabolic cues of our body. So that was an interesting finding. We're really interested and excited about trying to track how that happens. What are the mechanisms that would explain this linking?

AJMC^®: Does this study open up the possibility of testing similar microbiota treatments on other food or substance allergies?

Srivastava: Already there is a lot of interest in trying to isolate microbiota components or specific bacterial families that may be having some benefit for treating allergies. In mice there have been data coming out of Cincinnati and even Boston where people have taken gut microbiome of mice and swap them into other mice and shown that there is a beneficial effect. Some studies show that tregs, which are beneficial or immuno protective T cell populations, can be expanded if you change the microbiota around. Others have shown that there might be other benefits to the gut integrity, meaning the gut lining seems to get more healthy, but there's not a lot of antigen leaking or allergen leaking. There's various aspects to this.

People are already doing some experiments which are possible to do in mice. Now, how we can translate this into humans is obviously a challenge. I think a lot of labs now are focusing on what these beneficial bacteria can do. Is it that they produce something or they secrete metabolites or other molecules that can be then isolated, refined, or maybe just produced outside bacteria, and can be given to humans as treatments? Or is it that certain bacteria being present change the prevalence of harmful bacteria? Is there something about reordering the microbiome itself, which has been essential? I think the answers lie in many ways, probably a combination of everything that might be beneficial about changing bacteria, not just reordering the populations. Maybe there are biomolecules produced by bacteria that are helpful and may be used as a treatment, or it's the different ways in which bacteria modify whatever we eat, to then benefit the body in better ways. This is really just at the frontier now, where the more we understand the more we can apply this in useful ways.

AJMC^®: Do you have any other findings you want to highlight or any concluding thoughts on your research that you would like to share?

Srivastava: We are at New York Medical College, but our lab also is associated with a startup company. Our research focus both for commercialization and academic research is trying to find out ways in which botanical medicines are changing our immune balance in beneficial ways. We're interested not just in the gut microbiome, but we're also interested in the skin microbiome. I think I think in the future, we're going to hear much more about how, because allergy is so much about allergen exposure, which can happen both by way of eating or by way of being exposed via skin or because of environmental exposures, our research focuses on trying to sort of bring back a healthy balance of microbiota, whether it's the skin or the gut, to then create a more lasting, beneficial anti allergic profile for an individual. This will then work with other standard therapies such as, allergen immuno therapy as we know now that allergen avoidance as well as desensitization using oral immunotherapy. A lot of these things sometimes have adverse events, because the individual's overall immune balance is sort of not ready yet to respond very well to these therapies. That's why we think somehow using natural products or botanical medicines to rebalance, the individual immune system will help in not just creating a therapy but also as an adjunct or a complimentary approach to standard therapies that are being tried.