Thursday, September 19, 2019

Autism And The Gut Microbiome: An Interview With Dr. Ruth Ann Luna

Dr. Ruth Ann Luna and Shannon Rosa. Photo © TPGA
[image: A Latina woman with long dark brown hair, and a white woman
with chin-length fluffy red hair and glasses, smiling and posing together.]

Our editors Carol Greenburg and Shannon Rosa spoke with Dr. Ruth Ann Luna about her research on autistic kids and their incredibly diverse gut microbiomes during INSAR 2019, How her research is not about "special diets for autism," how GI issues are co-occurring conditions and not a core trait of autism, how there’s no one universal single bacteria that is associated with autism, how GI profiles are ofter family- rather than neurotype-specific, and how this research may translate into real world supports for autistic people.

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Shannon Rosa: Thank you so much for being here. Can you tell us a little bit about your background and what brought you into this area of autism and gut microbiome research?

Dr. Luna: so I have a super-weird background. I have degrees in genetics and bioinformatics and clinical laboratory sciences,  so, a long time ago, 20 years ago, I was with Human Genome Sequencing Project…

Rosa: Back when it was a 3 million dollar enterprise?

Dr. Luna: It was. And it’s so funny to me, because what once took years of generating, we could now do in a week in my lab in a little test with a laptop. Progression is pretty crazy in terms of sequencing. But I’ve been workin in clinical life and diagnostics for 10 years.

And everything we do in our lab is set up to be clinically viable, so it’s sort of a step beyond what you basically see in a research laboratory.

Rosa: Got it. So what got you interested in gut autism and gut microbiome research specifically?

Dr. Luna: So I was in the microbiome center directing all of our sequencing efforts when my son was diagnosed with autism. We were already doing things in the gut microbiome with other pediatric issues. So we were looking at IBS, and ulcerative colitis, and some respiratory microbiome pieces. We had all of the resources there to do it

And then my son was diagnosed, so it seemed like a perfect marriage. But I had a very hard time convincing some of our, our, well, our digestive diseases in there within the medical center where I worked that GI issues were relevant in autism. It was a bit of an uphill battle.

I joke that I couldn’t get them to pay 30k for a pilot study, but yet we had an over a million dollar grant to do the big study. And yet every parent I ran into would say, “Oh, yeah, we, we need help with this.”So it took a long time for them to believe us that this was an issue worth looking into.

Rosa: Where are you currently working?

Dr. Luna: We’re at Texas Children’s Hospital in Houston. The work that we’ve done is (obviously) in the pediatric population. All of the laboratory work is being done there, in my lab.

We recruited participants from, across the country, including Nationwide Children’s Hospital Ohio and UT Southwestern Dallas. But we also had so many families from across the country that wanted to participate that, if we could arrange to ship materials and specimens back and forth, then we did. Because we wanted to give them that opportunity.

Rosa: Can you explain fo the non-researcher community members what multi-omic means?

Dr. Luna: [laughter] Well, different people have different definitions of multi-omics. It’s sort of how much can we jam into that 'multi.' So, so you talk about genomics. You talk about microbiomics or metabolomics, etc. It’s how you merge all of the laboratory data that we’ve generated in a meaningful way.

And it sounds highly complex, but we spend most of our days playing with intricate Excel spreadsheets [laughs]. So they turn into these block files of, of different rates and different amounts of bacteria or metabolites, and it’s the merging of all that data that creates what we call a multi-omic profile. And then we layer on phenotypic data. And then we see what the clinical picture looks like for each individual. What challenges do they face, what are their GI symptoms. Do we know anything about their genetics.

Rosa: It sounds almost like CSI, but medical.

Dr. Luna: It is! There’s a lot of data [laughs].

Rosa: Can you please tell us about your research sample. What were your selection criteria and why?

Dr. Luna: We tried to be as inclusive as possible. Everyone had to have a confirmed diagnosis of ASD, generally via an ADOS [Autism Diagnostic Observation Schedule], because we still can’t agree upon a single gold standard, and we had to pick something. Families that did not have an ADOS were eligible to get an ADOS through this study.

We did not exclude for GI symptoms because those were a lot of the kids we were really interested in looking at or profiling. They could not take any antibiotics or really intake antimicrobials. So no antifungals or antivirals for 3 months before participating. Other than that, unless they had some major genetic abnormality that was not associated with their ASD diagnosis or some other major medical condition that are beyond what we happen to know to be ASD comorbidities, then we took all comers. It didn’t matter if they were on a specialized diet, if they were taking supplements. That was all fine. If they were taking psychiatric medication, that was okay. We just tabulated what those differences were so we could compare it later.

Carol Greenburg: So, a truly diverse sample.

Dr. Luna: We, that’s what we tried to do. We tried to get big numbers so we could ask more specific questions with some of those variables, at least at a pilot level, but we felt that some of the other studies had been so exclusive, they didn’t get a really good picture of the entire spectrum.

Rosa: So what, if you could describe this within the parameters of this interview, what were the findings the primary findings of your studying?

Dr. Luna: Probably the big takeaways are that one, there’s no one universal single bacteria that is associated with autism. And there’s no, like, one particular bacteria that’s associated with autism. it’s really a dynamic community. There were certain bacteria associated with different characteristics: with repetitive behaviors, with self-injurious behaviors, with communication abilities, with diet, and especially with GI symptoms, so that within our larger cohort, we have these subgroups that fit with these complex phenotypes who likely look very different and would need very different treatments if treatment at all. And so, that’s really our big takeaway, that there is no one thing that we need to target. It’s very dynamic, and it’s, in the end, maybe very individualized in terms of treatment strategies.

Rosa: Could you could test for specific bacteria to see if autistic people have them, and then say that they could possibly have a specific co-occuring condition?

Dr. Luna: Um, you know, and I’m very cautious about we talk about those types of data, because for us and what we’ve discovered, at least as a microbiome science community, we can talk about composition: which particular bacteria are there, but we see time and time again that beyond what that composition looks like, their function is more important. So beyond who is there, we need to know what they are doing. And that’s why we’ve also done metabolomics in this study, so we can look at what active products that bacteria community is producing, and that is most likely going to have a bigger impact on what GI symptoms are present, and how a person's overall body is functioning.

Rosa: Were there any findings that surprised you? 

Dr. Luna: Well, I won’t say it surprised me, but it wasn’t something we were chasing, and that was the idea that we’d originally intended to include the siblings that didn’t have any GI symptoms. But then, of course, once we knew to ask the parents, you know, describe your kids, let’s go through your clinical picture, and they’d give us the laundry list on their autistic child, and then turn to the sibling and say, “We’ll, they’re completely fine, they don’t have any issues.”

But when the siblings completed their own diary that asked them to write the number of days they had abdominal pain and those types of things, and then the parents had to ask directed GI questions of the siblings, we found that over 50% of the siblings also met criteria to be placed in our GI group.

Rosa: Wow.

Dr. Luna: Yeah. It was surprising that we found so many siblings, but when you hear about all the things that we knew happened in the family, it’s really not that surprising. So it was just good to get that on record, that this is real, these shared symptoms that we see a lot of the times. And when we talk to parents, many times they may have GI issues too. A lot of the siblings may rate their GI symptoms compared to what their sibling may be experiencing, and may think, “Oh, mine isn’t that bad,” but for them, it really is.

Rosa: Did you factor in whether or not the siblings were genetically related, and if so did that have any effect?

Dr. Luna: We did, that’s an excellent point. We only included full siblings, because we didn’t want any additional confounders with genetics. We wanted to be able to control for environment and genetics, so they had to be full siblings, and living in the same home.

Rosa: How would you like the findings of your study to affect the approaches of autism and medical professionals to supporting autistic individuals in the real world?

Dr. Luna: I think we’ve seen a lot of people that are quick to jump on the latest probiotic or dietary intervention. And what we’ve said, time and time again, is that this is the baseline study that we needed before we made any of those leaps. We need to approach these matters with caution, but know that we want to be able to triage specific treatments to these complex phenotypes that we’re creating here.

We want everyone to take a pause for a second. But at the same time, if it’s something that’s relatively benign, like a change in diet, and if families and autistic individuals are keeping their own data on whether they’re feeling better or worse, by all means. Because it could be very real. But it’s simply, there is not a one size fits all treatment strategy for [autistic] GI issues right now.

Rosa: Can you talk about how research in the area of GI and other, and similar co-occurring conditions has evolved over time, and specifically how your research differs from the special diets for autism approaches?

[Everyone laughs]

Dr. Luna: It’s actually been an unfortunate history. If you look at the evolution of looking at GI issues in autism, for instance the original vancomycin trial that was in 2000 where they saw considerable benefits in children on antibiotics, what it meant is that gut microbiome matters and changes could effect positive changes in GI symptoms.

And then of course we had a stalling point, because no one wanted to touch GI issues in autism for very obvious political and ethical reasons for a long time. It has taken this new crop of parents that are seeing in their autistic kids changes when they’re on antibiotics or significant GI issues to say, “Why aren’t we further along in research?” I’m certainly partnered with some parents who are trying to fund this research, who observed some of these same things and know that for their child, it’s probably one of the biggest impacts on quality of life. And so we’re trying to push it forward the best we can. But it’s been very slow-going and very frustrating.

Rosa: Do you think there’s an increased recognition now that GI issues are a co-occurring condition and not a core trait of autism? Because there are a lot of parents who seem to think that a change in diet is a change autism, when what we hear from other researchers, and from autistic people themselves, is that if you’re a human being and you feel better, you act like you feel better.

Dr. Luna: That’s exactly what we’ve talked about. When you can relieve these chronic GI symptoms, you’re going to see improvements across the board. You’ll see improvements in behavior and improvement in cognitive ability and above all, when you’re improving GI pain, you’ll see improvement in sleep.

And we’ve seen with other presenters at INSAR that sleep is paramount in your overall functioning for anyone, much less individuals who are oversensitive to a lot of changes, to whole body differences like when you’re sleep-deprived. So yes, we think that alleviating these symptoms leads to a much better quality of life, and much better full-body functioning, but, that’s sort of the starting point, and not necessarily something that we’re trying in other areas. Much as we talk about all these interventions, the primary question should be, “are you doing things because you want to alleviate GI symptoms?”

Greenburg: Yes! Did you find a lot of school avoidance or stigmas of kids with GI issues and autism? Did you find a lot of anxiety about being out of the house in general, even not at school, or for pleasurable activities?

Dr. Luna: That’s an excellent question. I don’t know that any of our surveys asked about school avoidance specifically, but there are anxiety-specific questions that I’ve not looked at yet. The behavioral analysis we’ve done so far has looked at the sub-components and sub-skills associated with self-injury and repetitive behaviors, but we’ve only captured the information in such a way that we can drill down the specific questions. I know there are questions about not wanting to leave the house and social avoidance in that subsection.

Greenburg: I was autistic who had a lot of GI problems. One of the problems with that co-occurring problem was that I was afraid to leave the house. I was afraid to go to school. I was afraid that I would feel sick. I was unable to deal with it, would have to go to the nurse’s, and it would have to be terrible. So I had anxiety over what might happen.

Rosa: Your anxieties had anxieties.

Dr. Luna: [laughs]

Greenburg: My anxieties have anxieties, yes.

Dr. Luna:  Which only makes the GI symptoms worse. [laughs]

Greenburg: Which is a cycle.

Dr. Luna: It is. It absolutely is.

Greenburg: Yeah. So in addition to the physical pain, there was the mental anguish making me sick again. That wasn’t recognized as such. As a female, I was not taken seriously.

Dr. Luna: And we talk about that, about the gut-brain analysis sphere. You know, it’s less about the chicken and the egg, and more about disrupting that cycle. Can you cause interference enough to cause positive change throughout the body. That’s really what we focused on.

Rosa: What are your next steps?

Dr. Luna: [laughs] A lot of data analysis. A lot of the microbiome work is based on sequencing something called the 16S or RNA gene, but we now we can do a full metagenomic analysis, so we can confirm what we’ve seen in this initial microbiome study. We can also look at the fungal profile, and even some viral pieces.

Again, this is to give us more clues as to what we’re seeing in specific genes that might be causing some of these GI symptoms, and so we have a lot of data we’re going to dig through. We also know that there's a whole lot more we can do to look at the dietary factors. So I’ve been having some pretty fruitful discussions with some dietitians who’ve thought about ways to look at picky eating.

And because we have a full two-week diet diary, we can look at the number of unique foods the child eats over that period of time, and create a different kind of scale: not of how diverse the microbiome is, but how diverse their diet is and how that might impact things.

Rosa: Wow. Well, we’ve definitely been getting a lot of feedback lately from people who are saying, well, “It’s not that I’m picky, it’s that I’m selective because certain foods cause GI distress.” Or there are sensory reasons why they don’t want to eat those. So it’s not just being picky. There are legitimate reasons.

Dr. Luna: Right, this self-restrictive diet can be for a variety of reasons. And most studies only do a 24-hour to 72-hour diet diary. We wanted the full two weeks because we know that there’s ebb and flow in eating habits, and in how someone is feeling in the GI symptoms. We wanted to capture all of that as much as we could reliably. Which is hard.

Rosa: Wow. I can’t imagine how much data you’re crunching.

Dr. Luna: [laughs]

Rosa: Is there anything else that you’d like to add?

Dr. Luna: No. Just that, you know, I’ve been really glad to see how well-received this study has been. We look at it as a family, and there’s not a lot of guidance out there as to how to approach this. And, as many of us know, it’s even hard to get the medical community to acknowledge these issues, many times. So I really appreciative being able to share this and obviously, we’re always open to feedback. We’re active members of the community, so anything anyone would like, we’re an open book for questions.

Rosa: Right. Well, thank you so much. I really appreciate you taking the time to talk with us.

Greenburg: And thank you for all your work.

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Interview transcription by Sara Liss