Multiple Sclerosis Discovery -- Episode 31 with Dr. Lloyd Kasper

[intro music]   Hello, and welcome to Episode Thirty-One of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.   This week’s podcast features an interview with Dr. Lloyd Kasper about the gut microbiome and its role in MS. But to begin, here is a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.   Last week our parent organization, the Accelerated Cure Project, launched its latest endeavor called “iConquerMS.” iConquerMS aims to enroll 20,000 people living with MS to play an active role in research, empowering them to securely submit their health data, influence the studies that are carried out by the initiative, and stay informed about the research. Visit iConquerMS.org for more information.   Vision and sensorimotor problems go together in some MS patients. A recent publication in the journal Neurology examined the relationship between MRI measures of the spinal cord and retina in patients with MS. The investigators found some correlation between the two types of metrics, but they also found that damage in each structure had independent relationships with disability. Read the full story in our “news and future directions” section.   And lastly, our previous podcast contained an error. We mentioned a story about a proof-of-concept study of a novel way to monitor lesion repair. However, the story was withheld from publication due to a delay in the release of the research article. The story is now live on our website.   [transition music]   Now to the interview. Dr. Lloyd Kasper is a faculty member of the Geisel School of Medicine at Dartmouth College. He met with MSDF Executive Editor, Bob Finn, to talk about his research on the gut microbiome and MS.   Interviewer – Robert Finn Dr. Kasper, welcome.   Interviewee – Lloyd Kasper Thank you.   MSDF So to start, why on earth would someone interested in a neurological disease such as MS concern himself with bacteria in the intestines; what’s the connection?   Dr. Kasper That’s actually a very valid question. And the answer to that question is pretty straightforward, is that there’s a very clear brain-gut access so that the brain talks to the gut primary modulating the physiology of the gut through secretion of a variety of molecules, vasoactive proteins, etc. That in turn affects the motility of the gut. By affecting the motility of the gut, you also affect everything that’s inside the gut, which is – as you mentioned just previously – the 100 trillion bacteria that each and every one of us in this world has. And those bacteria in response to the changes in motility shift their behavior, because these are living organisms, and they secrete a wide range of metabolites.   For the purposes of simplicity, you can look at those metabolites and the effect of those various metabolites on the immune system, taking into account that the gut is the largest immune system in our body – 80% of our immune cells are in the gut. So you’ll have this clear interaction between the brain, its activity physiologically on the gut, and the gut’s activity on the bacteria, and then the bacteria’s activity back on the immune system which leads to issues related to the brain.   MSDF So you partly answered my next question. There are microbiomes in other places besides the gut – the skin, the urinogenital tract, etc. Do those other microbiomes have any affect or any relationship to multiple sclerosis, do you think?   Dr. Kasper First of all, the association between the gut microbiome and MS has not yet been fully established, there’s experimental data that would suggest that there is a relationship between the two but that’s still at the experimental level. There really has been very little exploration of the other microbiomes within the body. Remember, the microbiome is not just the microflora. What the microbiome is is the genome of the flora in its relationship to the genome of its host. So when you look at the genomics of MS, for example, in the host – which there’s a lot of work that’s being done – you’re only looking at a fraction of the genetic material that’s involved in this relationship between the gut and the body that it’s in OR any of the other sites that we have microflora – our mouth, as you pointed out; our ears – inside of our ears; our lungs. Those are all areas that bacteria in our body exists in balance with us to achieve a homeostasis. The reason for looking at the gut microbiome is that because it’s the largest, probably the most complex as well.   MSDF So you focused much of your attention on a single bacterial species. Let me see if I pronounce this correctly – Bacteroides fragilis– am I close?   Dr. Kasper Correct.   MSDF And a single substance that it produces, polysaccharide A, or PSA – which has no relation to prostate specific antigen. Why are you focusing on that species and that product?   Dr. Kasper Well, there is mounting evidence that there are several phyla that colonize the gut. The two major phyla of interest are Firmicutes, which are gram-positive aerobes, and Bacteroides, which are gram-negative anaerobes. I’m talking about at the phyla level over which there is no kingdom, phylum, class, order, family, genus, species. Under each one of those phyla there are many different species. We’ve focused in on primarily Bacteroides because Bacteroides fragilis is a very common commensal that essentially inhabits in the neighborhood of 80-90% of all mankind in the world. Bacteroides as a phyla has been associated with the induction of regulatory T cells. Regulatory T cells live in the colon, in and around the colon, and that’s where Bacteroides live. And it’s been shown that Bacteroides as a phyla have the capacity to drive regulatory T cells.   The reason it’s important in MS is because there is a known deficit in the regulatory T cell population in patients with MS. And we chose Bacteroides fragilis because of all the Bacteroides species, that’s the one that we actually know most about immunologically. There’s at least 20 or 25 years’ worth of very, very important data that shows how this particular molecule, this polysaccharide A – and it’s a polysaccharide, it’s not a peptide, it’s a polysaccharide – how this polysaccharide can drive the immune system to a regulatory phenotype that’s associated with the induction of regulatory T cells, production of IL10, all those factors which are important in MS which we know are deficient in those with MS.   MSDF When you say drive the immune system, drive T regs, what do you mean by that?   Dr. Kasper Basically, these bacteria have the capacity to convert effector cells, which would be CD4 positive CD25 negative cells to a regulatory phenotype, which would be CD4 CD25 positive associated with sort of the standard-bearer of regulatory cells, which is Foxp3, which is a nuclear antigen that’s been characterized with it. So this molecule has a remarkable capacity to do that both in vivo and our studies show you can do that actually in vitro as well. So you can take cells that are negative that would be considered naïve or effector-type cells, culture them with this PSA molecule, and convert them to regulatory cells which we know are important in controlling the disease.   MSDF So remind me whether you want more or fewer of these regulatory T cells.   Dr. Kasper It depends where you are in life. To give you sort of a circumstantial argument, we know that Firmicutes, which is that other major phyla, has been associated with a number of disease states, including obesity – just to name one – atherosclerosis, but we also know that the Firmicutes have the capacity to drive IL-17. The regulatory T cells are cells that control the IL-17 response, so it’s important to have regulatory T cells to control the IL-17. We know experimentally that IL-17 drives the experimental form of multiple sclerosis EAE, and there is mounting data – and pretty conclusive, I think – MS is probably at least in part driven by IL-17 cells. So you need these regulatory T cells to control that IL-17 response which is probably being driven by the Firmicutes population. And I’m oversimplifying this, because you remember, you’ve got a hundred trillion cells downstairs making god knows how many different metabolites with over a million genes. So what I’m presenting to you is a very simplified version of this remarkably complex organ.   MSDF So is this leading toward clinical utility for polysaccharide A?   Dr. Kasper We hope so.   MSDF Can you tell me more about that?   Dr. Kasper Well, again, our experimental data – at least in EAE – demonstrates that animals that have been induced with EAE are protected by this polysaccharide. Animals that have EAE, we can therapeutically treat them with this. So this is the first demonstration that a commensal-derived bacterial product that’s within essentially pretty much all of mankind has the capacity to induce regulatory T cells. We don’t know if MS patients are deficient in this or they have the genetic makeup that they can’t respond to it, or whatever it may be. As I said, there’s a real complexity. But the simple observation as we know is that if we take animals that are susceptible to EAE and we treat the prophylactically or therapeutically, we’re able to protect them very, very nicely against the disease process.   And now we have preliminary data in humans that we can take human cells in vitro out of a person and we can drive those human cells from an effector CD4-positive CD25-negative phenotype to a regulatory phenotype by this molecule; just five days of exposure and you see this very nice conversion that’s associated with increased IL10 protection, etc.   MSDF Do you imagine that the PSA molecule itself, if drug development goes on, is there any chemistry that needs to be done before it might possibly be therapeutic?   Dr. Kasper A lot of the chemistry has been done. We have a pretty good idea of what the molecule looks like, it’s a repeating polysaccharide chain. And we know what the conditions are at least in animals as far as innate response molecules – TLRs, toll-like receptors, etc. So as far as the molecule itself, I think we have a pretty good understanding. As I said, there’s about 20 years’ worth of very solid biology behind this molecule. So how far we are away from the clinic at this point is a matter of time, resources, and money to be able to move it from the experimental stage that we’re in into the clinic.   MSDF So you’re not the only research group working on the connection between the gut microbiome and multiple sclerosis. I wonder if you can talk a little bit about how your research fits in with the various other approaches that are going on.   Dr. Kasper Our research has been focused primarily on immune regulation – how to get the disease under control, at least experimentally and hopefully in MS patients. Most of the other labs are looking primarily at what bacteria or bacteria populations are responsible for affecting the disease; what’s driving the disease. We’ve sort of kept away from that because we were fortunate in being able to find this one molecule derived from a bacteria, as I said, that much of mankind is colonized with, so we’ve been focused mostly on how to regulate the disease rather than what’s driving the disease.   MSDF Now, as you know, there’s been a lot of talk and controversy about the role of diet in multiple sclerosis. Do you think that gut bacteria and the substances they product may provide that missing link connecting diet with MS.   Dr. Kasper I think that diet’s going to turn out to be one of the more critical environmental factors that’s associated with the disease process.   MSDF Can you say a little bit more about that?   Dr. Kasper Well, if you look at all the risk factors that we know for MS, that being genetics, obesity, smoking, gender – just to name a few – there’s about six or seven of them. Every one of those risk factors is associated with the microbiome. The common denominator for all the risk factors we know so far in MS is the microbiome, and that includes genetics. As I said, the microbiome is a two-way street; it induces things in us and we do things in turn to it, so it’s a binary system. So our speculations – and we just had a paper published in FEBs – Federation of Experimental Biology – is we’re speculating that the gut microbiome is the major environmental risk factor for MS because it includes all of the known risk factors.   So how can you adjust that? Well, the most logical way is diet, right, because it’s the change in the human diet over the last hundred years that may be accountable for the rise in the disease process. It may also be the change in the diet in Africa as well as Asia which were relatively unknown for MS, but now the incidents in Asia as well as in Africa is approaching about the same as it is in the United States and Europe. So as diet has changed, so has the incidence of the disease gone up. So I’m speculating that diet will turn out to be a very important factor in controlling the microflora, which in turn allows for the balance, the homeostasis, in individuals.   MSDF Well, very interesting. We’ve come to the end of our time, but is there anything you’d like to add, any important questions that I haven’t asked that I should have asked?   Dr. Kasper No. I think the question about the diet, you know, where do you go from here? Because it’s going to take years and years for scientists and clinicians to sort out what’s actually going on in the microbiome. We’re at the tip of the iceberg in this really, because not only is it the immunology that’s important but it’s the physiology and the physiologic changes that the gut microbiome may be creating in people. So as we get better definition of what activities are going on in the microbiome, the greater the likelihood we’ll have of understanding a whole range of human diseases. And not just MS, but that’s all other autoimmune diseases, cancer, obesity, you know, it’s a long list.   And it may ultimately turn out that it’s a clue to our understanding of cancer, for example, because as the microflora shifts as we grow older – which it does – perhaps what we’re seeing is that early on we have bacteria that induce inflammatory processes – which is why MS is a disease of young people – that tends to peter out as you get older. It’s a well-known thing. It doesn’t go away but it tends to peter out. But that may be parallel to the shift in the microflora that’s going on. So early on in the western diet you’re having mostly Firmicutes. As we get older that shifts to more of Bacteroides, which has more regulation. What does more regulation equal? Well, you’re down-regulating the immune system, and as we get older what do we become susceptible? Cancer. So there’s a real balance that’s going on here. And I think a lot of the clues to human biology as far as disease state are going to ultimately be related to the microbiome.   MSDF Dr. Kasper, thank you very much.   Dr. Kasper Thank you.   [transition music]   Thank you for listening to Episode Thirty-One 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 Robert Finn. Msdiscovery.org is part of the non-profit 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.   We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to [email protected].    [outro music]