How Is The Microbiome Keeping Peace? Ask The Immune System

IRA FLATOW: This is Science Friday. I’m Ira Flatow. It’s taken about, well, 10 years, but finally the term microbiome is not such a foreign sounding word to us anymore. We all know about the trillions of bacteria that live in our gut and digestive tract. Different species living and growing together in the same playground.

Now, researchers are trying to learn more about what keeps microbes living together in such harmony. Scientists suspect the secret microbe whisperer is actually a member of the immune system, a molecule called immunoglobulin A. You probably know IgA. It’s something that is not foreign, but it’s a molecule that both keeps the GI system free of pathogens and researchers hope might one day be used to combat diseases of the digestive tract.

Here to tell us what we’re learning about how IgA affects the microbiome are my guests, Thaddeus Stappenbeck, professor of pathology and immunology at Washington University School of Medicine in St. Louis. Dr. Stappenbeck, welcome to Science Friday. Are you there?

THADDEUS STAPPENBECK: Thank you very much for having me on. Yes, thanks for having me on.

IRA FLATOW: You’re welcome. Margaret Conner is associate professor of molecular virology and microbiology at Baylor College of Medicine in Houston. Dr. Conner, welcome to Science Friday.

MARGARET CONNER: Thank you.

IRA FLATOW: I want to give out our phone number, 844-724-8255 if you want to talk about the microbiome and IgA. And also, you can tweet us at SciFri, S-C-I-F-R-I. All right. Let’s walk through this, Dr. Stappenbeck. First, so we’ve known for a while about the trillions of microbes living together in the gut. The question that researchers are exploring now is, how are they doing that? Is that right?

THADDEUS STAPPENBECK: Yeah, that’s right. The intestines a really interesting environment. You have a lot of challenges there. You have this really thin barrier of epithelial cells that’s required because you have nutrient exchange that’s going on. But at the same time, you have this other organ living in the lumen of the gut called the microbiome that’s really required to really maximize the nutrient uptake from specific food products.

And so it’s quite a challenge. The paradox is, how do you keep the peace then in this particular organ? And scientists have been studying various things that we make to try and keep microbes at bay. Mucus is something that is very popular to study and very interesting. We make a number of proteins that will kill bacteria, almost like antiseptic type molecules.

But then there’s this really curious observation where our immune system makes a specific type of immunoglobulin– immunoglobulin A– and secretes nearly four grams of this a day into our GI tract. And it’s this immunoglobulin A that seems to be a really key peacekeeper in the intestine. So because of our understanding of the diversity of the microbiome, we’ve become very interested in what microbes in the gut are bound to IgA, and then what are the consequences of this.

So there’s a lot of very interesting studies going on looking in health and disease at what microbes actually get tagged by IgA. And then what molecules on the bacteria actually get bound by IgA.

IRA FLATOW: Dr. Conner, immunoglobulin is part of the immune system. So how does it end up in the microbiome?

MARGARET CONNER: Well, it is produced by B cells that sit below the epithelial layer. And these cells produce the IgA that then is bound to a specific receptor that sits on the membrane of the epithelial cells, what we call the basal membrane. And the IgA is specifically bound to this receptor that’s called the poly immunoglobulin receptor.

And once that’s bound– the IgA bound to that receptor is trancytosed or transported across the epithelial cell, and released from the apical side of the cell that then is released into the lumen. There’s a cleavage so that a piece of that immunoglobulin receptor is still attached to the IgA molecule. And at that point, we call it secretory IgA. And it then, as I say, is released into the lumen, or the interior of the gut. And it typically can– it binds and resides in this mucous layer that sits over top of the epithelial cell.

IRA FLATOW: Dr. Stappenbeck, what keeps the IgA from just attacking all the bacteria in the microbiome as if they were pathogens if it’s part of the immune system?

THADDEUS STAPPENBECK: Yeah, so I think this is the really awesome thing about IgA. So normally when in an immunoglobulin, say immunoglobulin G in your bloodstream, tags a pathogen, this thing gets recognized by specific cells in your immune system, and then there’s a way to kill it. You set off a pro-inflammatory response. The opposite actually happens in the intestine with IgA.

So the interesting thing is that the bugs that are bound with IgA, if they happen to be seen by the immune system, say there’s local damage or there’s another type of infection, this will mute the immune response and keep the intestine essentially from destroying itself.

IRA FLATOW: And Dr. Conner, you published a paper that showed how the microbiome coats itself with this IgA to protect against pathogens.

MARGARET CONNER: Yes, this was work that was actually primarily done in my collaborator’s lab. But they used a specific bacteria called Bacteroides fragillis. The work was primarily done by Greg Donaldson and his advisor, Sarkis Mazmanian. And they showed with this particular bacteria that’s normally a commensal in the gut, and is, I guess, what we would call a friendly commensal.

It’s there and it resides in the mucous layer over top of these epithelial cells. And it adheres very closely to the epithelial layer. But yet, it doesn’t induce a inflammatory response. And what they showed is that these bacteria– they have basically a fuzzy layer on the bacteria that’s produced by the bacteria.

And it actually is what they call commensal colonization factor, that it appears to be made up primarily of immunoglobulin-like variable chain molecule that actually then attaches to IgA that’s specifically made to the Bacteroides fragillis bug. And by attaching to that, then this bug can actually sit next to the epithelial cells and provide a colonization niche, without inducing an inflammatory response.

IRA FLATOW: Our number– let’s give out the number, 844-724-8255. Let’s go to Durham, North Carolina. Hi, Jennifer. Welcome to Science Friday.

JENNIFER: Hi.

IRA FLATOW: Hi there.

JENNIFER: Sorry, my phone just cut out. I was just calling because I have a pretty serious case of celiac disease and my IgA numbers are usually very high, and have been negative since as a term. And I’m just wondering, as far as fighting off infection and more serious diseases, what impact that might have.

IRA FLATOW: OK. Good question. What does IgA have to do with these various diseases that people get in their stomachs and their intestines? Dr. Stappenbeck, go ahead.

THADDEUS STAPPENBECK: Yeah, sure. So I think the role of IgA in celiac disease is a little bit of a puzzlement. Because as the caller mentioned, there is higher levels of secretory IgA in this particular disease. It can be associated with food products that are in gluten containing diets.

What I think is still not really clear is, in this particular case, instead of the IgA being immunomodulatory or down-modulating immune responses, it seems to have the opposite response and stimulated immune response. This could have something to do with our own genes. But there’s also some really interesting work suggesting that there could be prior viral infections that could actually set us up to have this opposite response to secretory IgA in this particular disease.

IRA FLATOW: So if you have celiac or a disease like it, your body is reacting just the opposite the way it should be.

THADDEUS STAPPENBECK: Exactly.

IRA FLATOW: And we don’t know why that is.

THADDEUS STAPPENBECK: No, not yet.

IRA FLATOW: But you’re saying in a healthy gut, the IgA is there to help regulate and calm things down in the microbiome. And that’s what you’re talking about here.

THADDEUS STAPPENBECK: Yeah, that’s exactly right. So we and others that do experiments in mice and inflammatory models, we know that there is variation that we can see in these models with the amount of inflammation in the intestine. And what my lab has tied this to is the levels of IgA that are present in the intestine.

So mice that have very low levels of intestinal IgA have an enhanced damage response, or enhanced inflammatory response. And mice that have normal levels of IgA have the opposite. So usually that’s the case.

IRA FLATOW: So is there any talk about giving people more IgA? It seems weird if people with celiac have too much IgA, why would we want to give them more? But you’re saying that if we don’t have the right balance, could you give more IgA, and that maybe help out with what’s going on in your microbiome?

THADDEUS STAPPENBECK: Yeah. So the strange thing about IgA deficiency is the real defects can be an autoimmune enhancement of auto immunity and an inflammatory response. So giving the IgA would really be to help calm down the level of inflammation in those types of diseases. So I don’t think celiac would be a great candidate for this, but something like inflammatory bowel disease might be.

IRA FLATOW: And Dr. Conner, where would you like to come out? Is there any treatment here, maybe a vaccine of some sort using IgA?

MARGARET CONNER: Well, there are a number of vaccines that are in the process of being developed or maybe undergoing licensure. There’s one vaccine, rotavirus vaccine, which is targeted to the gut because rotavirus causes diarrhea, primarily in young children. And that particular vaccine is an oral vaccine, it’s live. It induces IgA responses and these are likely contributing to protection.

We had showed a number of years ago using a mouse model that IgA was actually critical to protection from reinfection. And in the absence of mice that lack IgA were not able to be protected when they were reinfected. So IgA is probably critical for some of the pathogens. So we want to have IgA there specifically to a pathogen that’s coming across the gut epithelia and causing diarrheal diseases.

But it’s been very hard to make those vaccines that induce high levels of IgA. But in some cases, people are proposing also to use– when you are talking about do we want to administer IgA– it’s not currently being used. But there are certainly many studies and animal models that passive administration, like feeding of IgA, can block infection by many different pathogens.

IRA FLATOW: That’s interesting. I’m Ira Flatow and this is Science Friday from WNYC Studios. I’ve heard over the years of people getting immunoglobulin shots at the doctor to tweak up their immune system. Is this the same– is this IgA? Or is this something totally different, Dr. Stappenbeck?

THADDEUS STAPPENBECK: I think it’s something that’s potentially the same type of idea. So IgG is given to patients that have an immunodeficiency. And this is usually– this is really important because this is a lifesaving type of therapy. IgA– I think this is something that if we can identify that we have patients that are deficient for IgA in their intestines, particularly in the lumen of the intestine, this is something I would say we would want to consider actually trying.

IRA FLATOW: Let’s see if we can get a couple of phone calls in before we go. Let’s go to Jenny in Mount Laurel, New Jersey. Hi. Welcome to Science Friday.

JENNY: Hi. I was wondering about the effect of not producing any IgA at all, which is my case. Most doctors don’t seem to have any information about this. I was wondering if there could be any connection to overproduction of histamine.

IRA FLATOW: OK. Let me get a question answered. Dr. Stappenbeck?

THADDEUS STAPPENBECK: Sure. So this is a pretty common condition called IgA deficiency. About one in 700 people have this particular deficiency. And there’s actually a lot of controversy around over whether or not this is actually a problem or not. Many physicians will say that this is something that you can live with and this is OK. And then some people worry about autoinflammatory diseases occurring.

I think what is going on here with many people with IgA deficiency is there’s compensation by other immunoglobulins. Namely, immunoglobulin M can compensate for the loss of IgA, particularly in response to infections. But I think the interesting piece here is this predisposition to autoimmunity.

And to me, I think that that’s something that needs to be further explored. So I think your doctor’s confusion is probably still justified because we don’t have a good enough handle on this. But I’m hoping that my lab and many other people in the field will solve this.

IRA FLATOW: Here’s a tweet from Michael. It says, I’ve been taking probiotics supplements whenever I feel sick, especially for gastro sickness. My recovery timeline is greatly reduced. Is this related to IgA? Thaddeus?

THADDEUS STAPPENBECK: Sure. So what’s very interesting is when you introduce a new microbe into the intestine, it takes a few weeks to develop an immune response to it– to develop IgA. It takes about two weeks. The interesting thing is that these IgA responses then are thought to be durable over several months. So I think if you’re talking about effects then that are shorter time than two weeks, that’s probably something else that’s going on with the probiotic.

But there are potentially effects related to IgA being produced in response to a probiotic that you’re taking.

IRA FLATOW: We know so little about the microbiome, don’t we? And what’s going on down there. It’s amazing.

THADDEUS STAPPENBECK: I think it’s true.

MARGARET CONNER: I would agree.

IRA FLATOW: We’ve talked so much about this and it’s the same. It’s just like a new frontier for us, isn’t it? OK. Well, we’ll have you all back. Thaddeus Stappenbeck is professor of pathology and immunology at Washington University School of Medicine in St. Louis. Margaret Conner, associate professor of molecular virology and microbiology at Baylor College of Medicine in Houston.

Thank you both for taking time to be with us today.

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