Allergies and inflammation: what is your gut telling you?

Severine Navarro:
So an allergy is actually an inappropriate immune response to a harmless allergen. So an allergen can be just about anything. It can be a food, it can be pollens, it can be cat dandruff, and it could be house dust mites, which is one of the most common allergens causing lots of trouble to millions of people throughout the world. So an allergen basically is something that we shouldn’t be responding against, but unfortunately the immune system has evolved in a way that is just considering this as a dangerous signal and triggers all sorts of inflammatory responses and destruction of the tissues and the airways and the well-known discomfort that causes rhinitis or conjunctivitis, and in worst cases, asthma and food allergy and anaphylaxis in the very, very bad conditions.

Clare Blake:
What causes it to happen?

Severine Navarro:
So it’s essentially a major defect in the immune system in its ability to regulate. Some people that have sensitisation to these allergens, the immune system essentially recognises this as a danger and they will just amplify and amplify and go to the site of [the] allergy. So for example, if it’s an inhaled allergen, it will go to the airways. And you see immune response in that site and causes all sorts of trouble. At the end of the immune response, normally the response contracts and retracts and goes back to normal, but in allergic patients, they lack that ability. And basically, the immune response goes on and on and on, contributing to all the negative impact on the tissues. This absence of retraction is because of a failure of regulatory cells to come into the sites of action and just tell these effector cells, effector responses to go back to a steady state. So this is essentially the root of the allergic immune response.

Clare Blake:
And I guess your research is based on why that happens or doesn’t happen?

Severine Navarro:
That’s exactly it. So the defect in immune regulation is really at the core of multiple diseases. So allergy is one, food allergy as well, but it’s also at the centre of a range of other conditions, such as autoimmune diseases as well. So what we really focus on is different ways to promote these immune regulatory processes and make sure that we can restore them in people suffering from allergy in particular.

Clare Blake:
We’ve been hearing a lot about the gut microbiome. Can you explain what that is?

Severine Navarro:
So the gut is essential for health in general. We find out that it’s directing a lot of the things and particularly, the immune system has a very close relationship to that gut. And we found out that it can affect the airways, it can affect other regions of the body and it can even affect the brain. And we find this is all coming back down to the microbiome. So the microbiome is essentially, millions and millions of small organisms that live within us. That accounts for bacteria, but also viruses and also fungi. So it’s kind of like an amazing ecosystem that lives within us, where actually they’re more numerous than we are in terms of human cells. This is quite amazing. But we sort of developed this symbiotic relationship over thousand years of evolution. And that microbiome really interacts very closely with the immune system and influences health and disease.

Clare Blake:
So what do we know at this stage about the role our gut health plays in allergies and autoimmune conditions?

Severine Navarro:
So we know that when the microbiome is imbalanced, so we call it dysbiotic. So that means that… A normal ecosystem in the microbiome should be very diverse, lots of different species of bacteria. And now we’re starting to delve a little bit more into the importance of the commensal viruses, as well as fungi. So all these three organisms interact together. So this should be rich and diverse and should also be producing small molecules that affect the immune processes. These should be all harmonious and promoting health in a sorts. When it’s dysbiotic, so imbalanced, that means that it’s not as rich and diverse as it should be. And basically, it’s orienting the immune response in one direction that’s not necessarily helpful to maintain health.

Clare Blake:
When you say this is fairly recent, how long have researchers been able to make this link between gut health and allergies?

Severine Navarro:
I guess it’s been all happening in the last decades or so. So the microbiome is not new obviously. There’s lots of environmental research that’s been conducted on the microbiome. We find it in biofilm and surfaces and in nature everywhere. Up until quite recently, I would say the last five to 10 years, we really thought that the microbiome in the gut was the only site that was occupied by organisms. But we’ve found that now the microbiome is essentially covering almost the entire surface of our body – between the skin, the scalp, the mouth obviously, even in breast milk, in the lungs, in the airways. The microbiome is everywhere and that’s where we really need to consider it as a site of immunosurveillance that really helps the immune system respond appropriately to assault, if you want – so like, a pathogen.

Clare Blake:
So stop thinking about it just being in your stomach?

Severine Navarro:
That’s exactly right. But what’s important to know is that if we modify the microbiome in the gut, we can positively as well influence other sites as well. So it can influence the microbiome, for example, in the airways and immune response that happen there, or immune response on the skin, and also modify immune responses that happen at these sites.

Clare Blake: 
Good place to start. Can you have an unhealthy gut microbiome and not know?

Severine Navarro:
Well, so you know when you’re having all these weird pains that can sometimes affect… you know, pain in the shoulder and then it lasts for a few weeks and then it moves away. And then you can have maybe a skin inflammation that lasts for a few weeks and goes away. You can also have problems digesting and then it’s temporary and then moves on. Headaches. You know, those random bouts of inflammation that seem to be changing location on a regular basis…

Clare Blake:
Yeah.

Severine Navarro:
…You can’t really go to your GP and say, ‘I’ve got a shoulder problem. Please fix me.’ It’s just random things that seem to happen and appear and go away. So this could be one possibility that shows you that maybe your gut flora is not as healthy as you would think.

Clare Blake:
What can we do to have a healthy gut?

Severine Navarro:
Well, one very simple thing is to change your diet and your lifestyle. So nowadays, we tend to be driving everywhere and not walking to get our newspaper or to the grocery store because they’re at further distance than they used to be. So sedentary lifestyle is one of them. But also the food that we eat is not necessarily the healthiest options as well. We are very busy. Sometimes we have to get takeaway or do pre-prepared meals. All these kinds of things are not necessarily very healthy and impact our gut flora in a negative way, if you want. So changing our diet to more fresher options and less pre-packaged foods, all these other kinds of very easy steps that we can take to just make sure our immune system, our flora, and then the immune system is a bit healthier.

Clare Blake:
That we already know – keep away from the processed foods, [eat] fresh and healthy [foods]. And I should say this information is general in nature and not personalised medical advice. So you should always seek medical advice about your own personal circumstances. So is there any evidence, Severine, on whether improving your gut health can help lessen or manage allergies?

Severine Navarro:
Well, yes. In terms of research output – so publications from peers, peer immunologists, or microbiome experts – in the field, yes, there’s definitely evidence. Now, this evidence, whether it has really come through to the markets and in terms of either medication or over-the-counter therapeutics potentially for the public, you will see a range of probiotics on the market available and supposedly can treat allergy, but the evidence linking probiotics to improvement of the condition is not necessarily there. But there are a range of changes that we can make to maybe dampen the severity of allergy. That being said though, an allergic response that amounts to asthma or an asthma attack, or even anaphylaxis, you can’t imagine treating this with, for example, a change of diet or going off medication and just go on and say, ‘Yep. I’m going to eat healthy. I’m not going to have an attack anymore.’ This is not the case. Your GP needs to be consulted at every step of the way. But if you’re thinking of changing your diet, for example, to minimise the recurrence of flare ups, then by all means, this is a good thing to do in addition to your ongoing treatment.

Clare Blake:
Right. And we have to talk about how hygiene standards in developed countries have had an impact. What is the evidence there?

Severine Navarro:
So this is actually very, very interesting because the evolution of humanity in particularly first-world countries where we’ve improved sanitation, and now we’ve become actually experts at killing all germs that are surrounding us – whether it is in the kitchen, or even just the overuse of antibiotics – this has really had a strong impact on our microbiome and, therefore, our immune system. This has actually revealed a very important factor in medicine now, is we’ve discovered what we call a ‘window of opportunity’. So we know that young infants and newborns, we know that they’re most likely to develop allergy at this point, which is usually perceived in the terms of atopic dermatitis or eczema; so your skin inflammation. Lots of babies suffer from it, and this is a sign of allergy. Usually eczema, especially in families with a history of allergy, eczema will develop in food sensitivities or food intolerance, as well as rhinitis and asthma later in life. So we can narrow down actually, the development of allergy to that neonatal window, which has been labeled the ‘window of opportunity’. This has been strongly linked to an imbalanced microbiome, gut microflora if you want, of these babies that has been directly linked to [the] development of allergy. So babies that are not dysbiotic – so that don’t have this immune imbalance – are less likely to develop allergy.

Clare Blake:
So this is brilliant. We see that this is happening in babies and that’s an indication, but then what?

Severine Navarro:
So it’s actually an amazing finding in the sense that now we know when we can possibly intervene to stop this from developing even further. For example, we can imagine a family, a mother or parents with family history of allergy. They’re quite likely to have a child who will be developing allergies. We know that first off, maybe they could change their lifestyle – make sure they eat plenty of fruits and vegetable or reduce the amount of takeaway or processed food. That’s something that they all can already do on a daily basis. Then we can possibly introduce novel interventions, for example, something that could prevent the development of these allergies very early on, so these families don’t have to go through all the heartache of having to discover what the food sensitivity is with their child, or the development of asthma and having all these worries and scares…

Clare Blake:
It’s terrifying. You and I both know parents that are terrified to leave the gate at daycare because of what their child might be exposed to. It can be fatal.

Severine Navarro: 
Absolutely. So anaphylaxis is actually crippling; crippling for the family, crippling for the child. There’s a strong incidence on mental health because… it will trigger anxiety in the poor small child. And also, it’s terrifying for a parent to have to drop off their child at daycare with no guarantee whatsoever that the staff will be able to have their eyes on that child a hundred percent of the time during the day, making sure that nothing happens.

Clare Blake:
It’s terrifying. So what is the hope in your research for these people?

Severine Navarro: 
So we’ve taken a very surprising look, if you want, at the development of [allergies] in the first world where we’ve seen that there is something that we’ve eradicated from the first world that used to be present, but is still very, very present in developing countries where they actually cause major public health problems. So it’s not about reintroducing these types of things, but it’s just really to take a new look, a fresh look at these. So parasites are a heavy disease burden in developing countries, but we’ve completely eradicated them from our lives since sanitation and hygiene was implemented several decades ago. So we’ve taken a fresh look. We found that there are some parasites that are better than others. And we found that hookworms in particular have more of a symbiotic relationship with their human hosts rather than a parasitic one. So they do live off of that human obviously, but they live for decades, for at least a decade within the human host without being detected and just evacuated from the host. And this is because in return for that meal that they get from the human, they return a lot of things in terms of trying to make sure that the host is happy. If a host is happy, then it will be unlikely to want to evacuate that worm from its gut.

Clare Blake: 
So what do they do to make us happy, hookworms?

Severine Navarro:
Hookworms, they will make sure that… So they live in the gut, in the duodenum and they will make sure that first off, that gut is very healthy. Then they make sure that the immune system is working properly, as in making sure that it doesn’t have an inappropriate immune response. So this is what’s very important and this is where we’ve been working a bit further. So they make sure that the immune system works properly and that immune regulation is working properly. What we’ve done in our group is rather than just imagining re-introducing hookworms in kids and just having to deal with all the side effects…

Clare Blake:
What, you don’t think that’d be well received?

Severine Navarro: 
Exactly.

Clare Blake: 
Everybody, we’re bringing back hookworms!

Severine Navarro: 
That’s right. Give me your babies, let’s infect them. I don’t think it will go over very well. Plus, there could be some side effects, particularly for the patients suffering from allergies. So that’s not really something that we want to do. But rather, looking at what is in these worms that promotes immune regulation.

Clare Blake:
What did you find?

Severine Navarro: 
We’ve actually found a couple of proteins that we’ve called anti-inflammatory proteins because that’s exactly what they do. They suppress inflammation in a very smart way where it is not an immunosuppressant. So that means it doesn’t suppress all immune responses. It just suppresses inappropriate immune responses; so all the ones that shouldn’t be developing. It’s doing that by reeducating the immune system in allowing immune regulation to be happening functionally, normally, the way it should have been from the beginning. So this is very interesting because that means that we can potentially develop these hookworm proteins as potential therapeutics for allergy and allergic diseases in general.

Clare Blake: 
I know it’s been associated, hookworm and coeliacs and gluten intolerance, but this looks like it’s a wider perspective as well.

Severine Navarro: 
That’s right. So immune regulation is a defect that’s in the core of multiple diseases; not just allergy, but also all autoimmune diseases like inflammatory bowel disease, coeliac disease, even multiple sclerosis. So I don’t want to go into too many because we don’t necessarily have the evidence that at this point, that worm proteins could be effective. But because of these common mechanisms for these other diseases, there is hope that we could potentially bring these as potential therapeutics.

Clare Blake:
So instead of having a hookworm, you could have a synthetic version of the protein to help you digest gluten.

Severine Navarro: 
Yeah. Like a, just a normal medication that we could take orally like Panadol: I’m going to take my hookworm protein and not have allergy anymore. Or even we can imagine a nasal spray.

Clare Blake:
How far away are we from knowing whether this could lead to new medications?

Severine Navarro: 
Well, we know we do have something with a high potential. We know that it works in mice – so this is the kind of work that we have to do in terms of bringing something to the market. We have to go through a wide range of pre-clinical experiments, pre-clinical data to move this forward. So in-vivo systems are very important, but we also know because we worked with human tissues and human samples, like blood and other different types of cells, that we also know that it translates very well to human cells. So that means that this particular therapeutic has a very high potential to go into the [clinic] in the future.

Clare Blake: 
Is there a potential there to treat those newborns and maybe prevent that from happening?

Severine Navarro: 
Well, that’s the thing that’s quite amazing about this is we actually found that we could use that window of opportunity to intervene with our hookworm protein and reeducate the immune system at the very beginning to make sure that actually, allergy and potentially autoimmune diseases don’t develop. So if we educate the immune system very early on, then they will no longer be sensitive to pollen or house dustmites or…

Clare Blake: 
Would that be potential treatment for all children or the ones displaying symptoms, early symptoms?

Severine Navarro: 
Because hookworms in general are very safe and quite well tolerated, we have reason to believe that this could be a safe approach for anyone, not necessarily kids that come from a family with a history of allergy. But I’m going to go as far as saying, for example, we don’t necessarily have allergy in my family, but my youngest was born with terrible eczema and food allergies. So I wouldn’t necessarily have imagined that this would have happened, but this is the life that we have now where the environment, the food we eat, the lifestyle, lots of different factors contribute to the fact that people develop allergies at any moment of their life. And we’re more prone to developing these diseases than we were maybe 10, 20 years ago. So we could potentially imagine that this should be happening to maybe all kids.

Clare Blake: 
Severine, you have been looking at developing a molecule version of the hookworm, for want of a better word. What is the link between gut health and that window of opportunity for babies?

Severine Navarro:
We’ve linked a gut health imbalance; so a microbiome imbalance in newborns as a signature for the development of allergies later on in life. So eczema first and then leading onto food allergies and then asthma. The molecule we’ve identified within the hookworm that can be beneficial for suppressing allergic immune responses, we actually found that it also modified the gut microbiome and in a way that was sort of reestablishing microbiome balance. The link with the window of opportunity is that we could then rebalance that gut microbiota in these babies and therefore, restoring proper gut health from beginning, to start with. And as well, the normal processes that are essential to induce immune regulation, and therefore, preventing the development of allergies in these babies.

Clare Blake: 
Really exciting research. We really look forward to sharing more of your results in the future. Thanks so much Severine.

Severine Navarro:
Thanks Clare. It was a pleasure.

Clare Blake:
And for more on Severine Navarro’s studies and all our latest research, go to qimrberghofer.edu.au.

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