Episode 64 with Dr. Helen Tremlett on pediatric MS and the gut microbiome
Editor's picks:
Paper: "Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination," Nature 2011, Berer et al. Related news story: "Gut bacteria linked to MS," Science News.
Full transcript:
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Host – Dan Keller
Hello, and welcome to Episode Sixty-Four of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller.
Today we continue our talk with Dr. Helen Tremlett. Last week, we talked about vitamin D and MS. Today, Dr. Tremlett will discuss her work on pediatric MS and the gut microbiome.
During the past week, MSDF found more than 60 newly published papers that could lead to better understanding and treatment of MS and related disorders. You can browse through them at msdiscovery.org. Click on the “papers” tab. You’ll see two papers caught our attention as editor’s picks.
There's been a lot of excitement about anti-B-cell therapy in MS. One such B-cell-depleting drug, rituximab, is recommended off-label to treat neuromyelitis optica, or NMO. It doesn’t work for everyone and may make some people worse. A new paper adds two examples of patients with severe NMO whose symptoms worsened after treatment. The China-based authors said their cautionary cases highlight that in a small proportion of patients with refractory NMO rituximab may either fail or may induce rapid relapse of NMO. So they urged new treatment strategies for refractory NMO. Their report is published the Journal of Clinical Neuroscience.
A paper in American Health and Drug Benefits reviews unmet needs in MS in addition to finding a cure, which is, of course, the top priority. The varied list includes: further delaying progression and developing better treatments for progressive MS; providing neuroprotection; delaying or avoiding disability; and reducing active symptoms more effectively. In addition, it suggests identifying new tools and biomarkers; predicting who would benefit from specific treatments, that is, creating the means for individualizing treatment; and obtaining better measures of functional outcome.
Now, let’s take a look at the latest Drug Development Pipeline. This past week’s updates include findings suggesting that dimethyl fumarate has protective effects at the blood-brain barrier. All told, for the month of December, the drugs with important additions and changes are dalfampridine, dimethyl fumarate, fingolimod, estriol, glatiramer acetate, GNbAC1, interferon beta-1a, interferon beta-1b, MEDI-551, natalizumab, rituximab, and secukinumab.
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And now to our interview. I spoke with Professor Helen Tremlett at the ECTRIMS meeting in Barcelona in October. She said a Nature paper on germ-free mice in 2011 led her to look at the gut microbiome in early pediatric MS.
Interviewer – Dan Keller
In terms of your study on gut microbiome in early pediatric MS, what's the hypothesis?
Interviewee – Helen Tremlett
I guess we would hope we would find that there is a difference in individuals with MS and people without MS, and that would somehow tell us something about multiple sclerosis. But I suppose it really stems from there was a paper by a group out of Munich, in Nature 2011, where they had mice in the germ-free environment, and they could not trigger EAE. They could not trigger the animal model of MS in those mice that were in that germ-free environment until they transplanted the normal gut microbiome, normal feces, into those mice, and then they could trigger EAE. So perhaps gut microbiome is somehow needed or on that pathway to triggering MS.
MSDF
You're doing a fairly small study at this point. Who are you looking at?
Dr. Tremlett
So this is a study out of UCSF, University California San Francisco, with Emmanuelle Waubant and her US Pediatric Network team. So we had 18 pediatric MS cases and 17 controls. It's a cross-sectional study, so you have gut microbiome, samples from these children one point in time. And we were essentially comparing the gut microbiome of the children with MS or within two years of MS onset – so very early in their disease course – and controls to see if we could see any differences between them first up. And also, because we know very little about gut microbiome in MS, we wanted to know if there were any other characteristics that might influence gut microbiome that we needed to know about, and therefore be careful in terms of designing future studies. And so, for both pieces, we found some interesting findings that have helped us design now future studies.
MSDF
Interesting findings in what sense?
Dr. Tremlett
So, first up, with these 18 cases – 18 children with MS – and the 17 controls, we did not find any big differences in terms of the gross gut microbiome community composition. So that's looking at big picture measures of diversities such as evenness and richness. The richness in terms of sort of numbers of different species, and evenness in terms of how even they were. Because if a gut microbiome community is not very even, if there's an over bloom of one particular microbe, that's kind of potentially seen as not good. But ultimately, we did not see big differences between them. But on the individual (6:15) level, or you can almost think of it as on the individual bug level/microbe level we did see differences that appeared to be significant and were pretty interesting. We also saw overlap in terms of those gut microbes that seemed to be enriched or depleted in our MS cases relative to controls. We saw overlap with our findings with what's already out there published in the inflammatory bowel disease; some literature, you know, Crohn's and celiacs, which is really interesting. And I suppose the other piece we found that the children on an immunomodulatory drug for MS those children their gut microbiome did look very different to the children not on any drug. So, again it's a cross-sectional study, so I can't say one caused the other. But it does seem that immunomodulatory drug exposure may be associated with big shifts in the gut microbiome, which is interesting. We obviously don't know what this means. We need to tease that out in future studies. And we also need to show that drug treatment does actually shift the gut microbiome in longitudinal studies, but that was pretty interesting.
MSDF
Since you're assessing your gut microbiome by looking at 16S rRNA, are you missing fungi and the yeast?
Dr. Tremlett
Absolutely, and that's a very good question. Through the 16S rRNA sequencing, you're predominantly picking up the bacterial in (7:45) communities. For future work that we've just got funded through the Canadian Pediatric Network of the MS Society of Canada, we will be looking at the gut virome. But looking at all those other pieces – viruses and fungi and so on – is really challenging. And the technology in those kind of fields is still very much emerging. So I think they're really interesting, but it's tough going. The bacteria do seem to be the most predominant in the gut, but it's not to say that the gut virome and fungi and other things won't necessarily play an important role, as well.
MSDF
Are you looking at any specific genes and specifically those encoding glutathione?
Dr. Tremlett
What we did is we ran our 16S rRNA sequencing through this software called PICRUSt (8:30). But essentially, what it allows you to do is assess the functionality of the gut microbiome based on the genes that are present in their from 16S rRNA sequencing. So, it allows you to infer functionality. It's a hypothesis-generating information. And we certainly saw that the genes encoding glutathione metabolism in the gut microbe seem to be upregulated or enriched in our MS cases relative to controls. But again, those findings are very much hypothesis-generating, very interesting, but it needs further work to tease out what exactly is going on there.
MSDF
At this point, what can you conclude?
Dr. Tremlett
Much more work is needed. And it is worth investigating. The gut brain access a lot now has been more has been written on it, but these preliminary findings give us the understanding that there does appear to be a difference – albeit a subtle difference – between these children very early in their disease onset. And controls that are similar for age and sex there do seem to be these subtle differences in the gut microbiome, and they need to be explored further.
MSDF
Is there any thought about fecal transfers or probiotics?
Dr. Tremlett
I mean a lot of people are thinking and talking about it. It's too early, obviously, to do anything in multiple sclerosis outside of a controlled trial. So, they're all interesting ideas, but there's nothing evidence-based to say that you should go for fecal transplant, or there's no evidence to suggest one probiotic will be useful over another. But there's certainly interesting areas.
MSDF
Anything to add that we've missed?
Dr. Tremlett
Well, watch this space because hopefully in a couple of years’ time I'll come back and give you some results from our exciting study that's funded by the MS Society of Canada. We'll be looking with Brenda (10:25) and her team and accessing the Canadian Pediatric Cohort Study and collecting gut microbiome samples from those children and assessing the gut virome. That will be exciting.
MSDF
That's up to somewhere above 500 patients now?
Dr. Tremlett
For the gut microbiome study, we're focusing on specific groups of children. I think we'll hopefully enroll around 100 to 200 children.
MSDF
It will be nice to have some frozen samples before anybody develops disease to see the course of their gut microbiome as they approach a diagnosis or approach even being symptomatic.
Dr. Tremlett
That would be fabulous. If you happen to know of anyone who's got a freezer stuck to those, I'll be very interested. A lot of people will be very interested. But (skip 11:05) kind of wonder now if – as with other studies or even other programs or even clinical trials or whatever – where people have routinely frozen and banked, you know, blood and serum maybe stool will become routine, and then these opportunities will arise where you will have stool samples of young people before they develop MS. But, to do a prospective study on that, that would be challenging, but it would be interesting.
MSDF
Good. Thank you.
Dr. Tremlett
Thank you very much for your questions.
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MSDF
Thank you for listening to Episode Sixty-Four of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Carol Cruzan Morton. Heather McDonald curated the MSDF drug database updates. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations.
Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.
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For Multiple Sclerosis Discovery, I'm Dan Keller.
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