Inflammation Information: An Eye on the Individual Microbe—Jakob Begun, MD, PhD—The University of Queensland School of Medicine

Richard Jacobs: Hello, this is Richard Jacobs with the Finding Genius podcast. I have, my guest is Jakob Begun. He is a professor at the University of Queensland School of Medicine in Australia. He doesn’t sound like he is from there, so he must have moved there at some point. We’ll get into that and he is studying IBD, Irritable Balance Disorder, and various topics surrounding immunity, inflammation, etc. So, Jakob, thanks for coming.

Jakob Begun: Thank you very much, it’s nice to be here.

Richard Jacobs: Where did you start at? How did you end up in Australia, by the way?

Jakob Begun: Oh that will be our first story. So, as you can tell from my accent, I am American, although I was born in Norway, we moved back to America with my parents when I was a young kid at 4 years old. When I was 13, my parents decided it was time to see the world a bit and we took off from Newport, Rhode Island, and actually by sailboat started sailing around in what was supposed to be a trip around the world. We ended up making it about halfway; to Australia when they decided to settle down but they had two children back into high school at the time and they’ve been here ever since. So, after I finished High School in Australia, I came back to America for university and medical school and the Ph.D. and my post-doctoral training and medical training, and then I came back to Australia 6 years ago, to Brisbane.

Richard Jacobs: So, do you study predominantly IBD or do you study just information? What’s your research and background?

Jakob Begun: So, I am an MD PhD and my medical training was in gastroenterology and so I’m a practicing gastroenterologist. I spend about half of my time treating patients at the hospital here, the Model Hospital, and there, I run the inflammatory bowel disease clinic. Although I am generally interested in inflammation in the gut and a variety of inflammatory disorders, in the other half of my time, I run a small research laboratory in the University of Queensland and our lab is really focused on understanding the gut microbiome and our immune system and how the bacteria in our gut can influence inflammation in our body. Inflammatory bowel disease is a very common, I shouldn’t say common; it is a very high incidence disease in Australia.

Australia has actually one of the highest rates in the world of inflammatory bowel disease, things like Crohn’s Disease and also Colitis, which people may have heard of. It’s been a real mystery why the diseases are increasing in incidence around the world and it was originally a disease just of the developed world or western countries and really it wasn’t seen in the developing world. Nowadays when there has been industrialization of the developing world, we find more and more increasing rates of inflammatory bowel disease, which is quite interesting.

Richard Jacobs: When you eat food, who eats first? Is that a trick question because there is interplay? I mean, the enzymes in the mouth and all that, I know they start to degrade the food but bacteria there ready in the stomach and the intestines. It’s weird, I mean have you looked at the interplay of, are substances passed back and forth? What happens?

Jakob Begun: I think that’s a great question. So, as you alluded to in your question, there is a gradient of bacteria within our digestive tract, we think of, as sort of mouth to anus. There is a rich ecosystem of microbes in the mouth and certainly, there are primary energy sources, the food that we put into our mouths, and then, as you go down into the stomach, the concentration of bacteria decreases markedly. The stomach is a very hostile place for bacteria with very low pH, so high acid levels and then as you get into the small bowel, you start seeing that the bacterial concentration increases, the more, the further down you go in the small intestine and then when you get to the colon, that’s really when the major load of bacteria is encountered. The average person has several kilos or almost 10 pounds worth of bacteria in their GI tract and your point about the nutrients, so yes bacteria do rely mainly on the nutrients that you are putting in your mouth although they also can live off the mucus that all of the cells lining our gastrointestinal tracts produce.

So, in terms of what eats first, certainly, in the mouth, the bacteria are eating first but when it comes down to the lower digestive system, a lot of nutrients have been absorbed in the upper small bowel and then what’s leftover, that goes down to the lower bowel, the undigestible, if you will, food. That’s what the bacteria really thrive on.

Richard Jacobs: Okay, so you are studying the immunity and how the gut bacteria contribute to that. In general, do you believe that our immunity is combined, is it enforced by both our gut bacteria and our somatic cells or is it really our somatic cells that create the immunity and the bacteria just have to be monitored for their role in how they modulate it? I mean, how do you think our immunity arises?

Jakob Begun: Our immunity arises very early in life and there is a lot of everything that goes on in the very early years. This is why there has been a lot of research in the mode of delivery, the role of breastfeeding, the role of formula, what you are exposed to early in your life in terms of potential allergens. So, a lot of immunity is formed early in life and what happens early on if things go smoothly is there is something called tolerance that develops in the gut, which is to say that the immune system is aware of the bacterial presence. There is constantly signaling in the immune system yet it tolerates this presence so there is not a huge immune response in your gut, you don’t have a lot of gut inflammation in general, just a tiny bit which is exactly the amount that you need. However of course, when we get an infection which, for example, if you had a pathogenic bacteria like salmonella that you encountered because you ate some bad meat or something like that then the immune system has a vigorous response to clear this pathogen out of the gut which involves the influx of immune cells, the production of pro-inflammatory signaling molecules and a lot of damage to the gut which gives people symptoms of course, like diarrhea, bleeding in the gut, etc. to clear this pathogen out.

But these pathogenic exposures are relatively rare and for the most part, the gut just helps and the immune system tolerates those bacteria that are in the gut. So, how does that happen? It’s really interesting and also, why does it break down in some people? So, we’ve come to appreciate that there is a lot of crosstalk between the immune system and the gut microbiome which all focus on bacteria but of course, there are also fungi and viruses there as well. What we’ve appreciated is that the microbiome is producing a lot of metabolites and signaling molecules. These are secreted by the cells in the microbiome, they diffuse through the gut and they interact with the immune system, the somatic cells of our body if you will and the immune cells have evolved to respond to these signals either ramping up inflammation in the case of pathogens when they recognize certain pathogenic signals or in general, come down and tolerate these microbes living in our gut.

Richard Jacobs: So, when irritable bowel arises, I mean you don’t know and you certainly don’t want to wish it upon someone, you don’t want to cause it but is there a set of conditions that scientists have figured out where someone is very likely to get IBD within a certain number of years and if so, can you sample those people’s microbiomes longitudinally before and through it to see what happens?

Jakob Begun: It’s a great question. So, I’ll just distinguish between two different conditions because it’s important probably to distinguish and also recognize what goes on in both of them. So there is a condition and the names are very similar which makes it confusing. There is a condition called IBS which is Irritable Bowel Syndrome and this is a very common condition. In industrialized countries, it might affect 30% of the population characterized by irregular bowel habits, pain, and this is also thought to be linked to the microbiome but also linked to the diet and there might be some small degree of inflammation contributing to that particular syndrome. It certainly and some patients respond to antibiotic therapy, for example, whereas inflammatory bowel disease or IBD which is mainly Crohn’s disease and also colitis is at a different end of the spectrum where there is a significant amount of inflammation that has developed, that’s pathologic regions, these patients are often quite sick and sometimes require surgery or very potent medication to control these inflammatory responses.

So, with respect to the role of the microbiome I development of the disease, we know from some epidemiological studies that there are certain risk factors that are associated with the incidence of inflammatory bowel disease. These things include childhood exposure to antibiotics and kind of point a little bit towards the microbiome. There is some evidence of C-section versus vaginal delivery. Vaginal delivery might be protective. In addition, breastfeeding might also be protective in large cohort studies although epidemiology is always susceptible to bias, etc. But there are a few clues there that microbiome might be important. There are, as you meant because the incidence of this disease is only 30 per 100,000, it’s a little unfeasible to go out and check 100,000 people and look at them every year to see for those 30 who developed the disease but there have been a few notable studies that happened recently. One study is a study from Canada where they looked at high-risk individuals, so these are people who have a first degree relative with inflammatory bowel disease or multiple second-degree relative and in this patient population, the rate of IBD is much higher and they looked at these patients longitudinally to see if there are changes in the microbiome that precede their diagnosis of inflammatory bowel disease.

Then there is another data set, which is from the US military actually, where they’ve collected serum samples from army personnel going over 20 or almost 30 years and they’ve looked at changes in the blood tests over these years and they can find evidence that there are immune responses in these blood tests well before these patients develop the disease and what the trend seems to point to is that something happens in the gut where the normal diversity of that is there where we have generally graded in 350 species of bacteria, the main species of bacteria in the gut, this diversity contracts and we see a loss of diversity and this seems to be the strongest signal that we see associated with inflammatory bowel disease. The actual individual bacterial species that are going up and down in prevalence, that is a little bit harder to harmonize across all of the various studies that have been done.

There does seem to be some general trends in terms of a large family of organisms that tend to go up and tend to go down but overall the message that comes out is there seems to be less diversity and associated with that lower diversity is a dysregulation of the immune system where it becomes more active and more inflammation in the gut.

Richard Jacobs: So, if I think of the bacteria in the gut, the gut is a job center for the bacteria, a lot of people talk about diversity. There is more diversity in healthy people and less; it doesn’t really tell me much that there is less diversity but if I think about it as maybe of a job center, maybe that means that certain jobs are unfulfilled therefore certain compounds that we need to be healthy are not being made by the bacteria and perhaps that’s the reason for the pathology. What’s your take?

Jakob Begun: That is a fantastic segue into what we are doing in the labs. So thanks very much for that, so I agree completely. So, the technological advantages that we have seen recently, that have allowed us to get to that detailed level of understanding that we have of the gut bacterial mechanism has really been based on this next-generation sequencing of DNA which has revolutionized many aspects of biology in the last couple of decades. So this allows us to sequence the DNA in the stool and from those sequences, we can then put together a map of this particular species of E-coli represents a 0.1%, and this particular species of streptococcus is represented 2% and that’s how we get these maps of the microbiome. So that type of mapping tells you which bacterial species are there and that’s fabulous. We know so much detail about that, which is great but it doesn’t tell you what those bacteria are doing at a functional level, it doesn’t tell you about these chemicals that they are producing, even if the genes that are producing these molecules are there, they may be turned on or not.

We don’t really have that level of detailed understanding of that. We are beginning to get that with techniques like Metatranscriptomics which is looking at the RNA expression levels of bacteria and also Metabolomics which is looking at the chemicals that these bacteria are producing and that the body is producing as well. So, in my lab, what we are trying to do is to understand the function of individual bacteria in the gut. I think that field, as a whole, has been focused on the communities which is great but to really understand how the individual members of the community might be interacting or might be influencing the host, we feel that we really have to look individually. So what we do I my lab is taking samples, usually stool samples and under our anaerobic culturing facilities, we are able to grow out various bacteria of individual cultures that exist in that sample and then once we have that single bacterial species, we can look to see what they produce under various situations in terms of what nutrients we give them, what growth conditions there are and we can test the chemicals that they are producing in assays in our lab. Assays are biological tests.

So, we can see if the bacteria are producing chemicals that tend to suppress inflammation in our test tubes in the lab or tend to promote inflammation. We can also check the whole stool sample as well to see if that overall community, on the whole integrated tends to promote inflammation or not. But this greater understanding of the individual bacteria and what they are producing is now going to inform all these data sets we have that show, oh look, these genes are there and now, in the lab, we are able to say, if those genes are there and they are turned on, then we have this sort of function and functional annotation of these genes is what’s really been lagging behind the genomic revolution and so, we are hoping to contribute in that way and therefore inform everyone else’s study as well of hat function these genes might have that they are finding.

Richard Jacobs: Well, I’ve heard friends, I don’t know, I’ve got to take a fibroid hormone and supposedly T3 to T4 is converted in the gut. So it’s in the gut, I’ve heard serotonin, the preponderance of it’s made in the gut, the vitamins are made in the gut. So, if we understand what’s going on and what the bacteria have produced, from a metabolic standpoint, maybe then we can use blood markers as a good proxy to see the condition of the gut and what’s going on there; what jobs are either being or not being fulfilled. Let’s say, the gut bacteria make certain B-vitamins and IBD always seems to be associated with a lack of certain B-vitamins, maybe the two correlate together and you can gain some understanding that way.

Jakob Begun: Yeah and then certainly, it’s a lot more attractive to look at blood tests and stool tests to look at these sorts of metabolites and people are looking at blood, they are also looking at urine which has the advantage of the sort of, doing a bit of filtering out the normal blood proteins, etc. and allowing the metabolites to be concentrated in the urine. So, that’s another attractive place to look and certainly, there are many examples of nutrients that are bio-converted by gut bacteria. I think, one of the probably most classic examples is Vitamin-K which is activated in the gut. But as you mentioned, there are a lot of vitamin deficiencies we see associated with the disease. Vitamin-D is another one that we commonly see in inflammatory conditions, IBD ad also other immune-mediated disorders and I think that that’s a really nice idea about the thinking about the deficiencies that we find and not just looking at, that must mean that the intake of that is too low but also thinking about the bio-conversion that is happening in the gut as a precursor to mature nutrients that our body needs and potentially supplementing that.

I will say that the research field for probiotic supplementation has been a fairly disappointing one in term s of being able to see supplementation of particular bacteria have beneficial effects on people and some of them might just be the numbers game when we are giving someone even billions of organisms as a pro-biotic. That’s still in the sea of 100 trillion organisms. So, in many respects, it’s a drop in the bucket in terms of absolute numbers and then, even if you add those bacteria to the system, whether or not they will be able to set up shop as it were, to find their need to grow into their nation and colonize their gut, that seems to be a difficult task to do when there is already an established gut microbiome there.

Richard Jacobs: Yeah, they have to survive stomach acid, they have to get to their proper resting place and that might be

Jakob Begun: or put down by the bacteria that might be there already

Richard Jacobs: Yeah, that’s true.

Jakob Begun: The one exception to that rule, in inflammatory bowel disease, is, I guess, not a pro-biotic technique but a mega-biotic technique which is a technology called Fecal Micro-biotic Transplantation or FMT and this has gained a lot of success stories, it’s racked up. The major indication for a Fecal Micro-biotic Transplant is recurrent C. difficile colitis which is an infection of the gut that causes quite a bad set of symptoms and FMT seems to be the most effective therapy for that, particularly for people that fail their course of antibiotics. But there has also been now full randomized control trials in inflammatory bowel disease that are showing that FMT can be very effective. As effective as some of our most potent medications, biologic medications like NTTNS, etc. in inducing remission in inflammatory bowel disease. So I think we have at least a poof of principle that certainly, a change in the bacterial composition can affect the disease.

Richard Jacobs: Why do you think FMT works? Is it because that you will get trillions of the right bacteria and therefore it’s enough. One thing that occurred to me is when we take probiotics, is likely, I don’t know, there is probably no phage associated with them but if you do a fecal transplant, there’s going to be trillions and quadrillions of phage associated with those bacteria. So maybe it’s the phage that either caused the success or the lack of success of a bacteria taking hold and not the numbers of the bacteria themselves.

Jakob Begun: That’s a very astute point. So, yes you put a lot of bacteria in when you do an FMT. There is also many more species of bacteria that you put in. So, if you think that maybe there is a deficiency of a few species, you might have better luck with an FMT than you would with pro-biotics. What is common abut phage is a very interesting one. So, yes, you are right, there is many more phages, the phage outnumber the bacteria in the human microbiome and there have actually been some experiments done by Stefan Schreiber’s group in Germany where they filtered the stool from an FMT through a fine filter that would filter out all of the bacteria and they put that filtrate in instead of putting in the whole FMT and they had similar efficacy with just this filtrate and Stefan postulated what might be in there and certainly phage is one of the things that might be in there. I’ll also say from my own perspective since I study this in my lab that all the metabolites from the bacteria are also in that filtrate so that might also be having an effect as well but you are absolutely right.

We have not studied phage very much at all. It’s a little technically challenging but there is certainly a lot of interest in it and it is something that people have been studying in general for 30 or 40 years now, bacteria, phage, and the role that they can play.

Richard Jacobs: It makes sense what you are saying about the metabolites and possibly about phage because, again, it’s my analogy but if it is a job center, the fact that there is redundancy means that multiple species of bacteria can fulfill at least some of the jobs. So maybe it’s not as important as you have bacteria X as you have the metabolites and you have some bacteria that can do that job versus not.

Jakob Begun: I think that’s right and although with respect to phage, we often focus on the specificity of phage to deplete certain bacteria. So, for example, one phage would only be specific for one class of E-coli and that’s the classic E-coli that they infect and kill off but phage can also transfer genes between different bacteria in the horizontal transmission of genes and they can also be responsible for turning on and off different genes and different metabolites for that matter. It complicated really quickly.

Richard Jacobs: It does. So what are some of the big questions that you are trying to answer? How are you doing it?

Jakob Begun: So, I described briefly one of the techniques that we are using in the lab. So it rests as a whole on being able to culture these individual bacteria and being able to manipulate their environment so that you can study which environmental cues can cause them to secrete these bio-actives. When we have a variety of anal models where we try to study how these bio-actives exert their effects and which immune pathways are these bio-actives targeting. So we can really understand both on the host side and on the bacterial side how the metabolites are produced and what they are interacting with that causes their effect. Some of these, we go on to characterize structurally, so we have identified the structures of these metabolites, some of them, we’ve synthesized chemically so that we can understand the actual bits of chemistry that are important for its biological activity and where I see this going forward.

I work in the clinic, as I mentioned for two and a half days a week and patients are often asking me about I don’t want to take this immune-suppressant because I’d much rather treat the underlying condition which is this imbalance between the immune system and the gut and there is a real demand for these sorts of therapies; therapies that are derived from the bacteria that can have the effects that we want and also just that principle of treating the underlying disorder rather than trying to treat the downstream effects of that disorder. So, from my perspective, the big unanswered questions are what is really the driver of gut information and it applies to IBD which is my field of interest but actually it applies to many other immune-mediated diseases of which we are seeing a huge increase around the world, be it rheumatoid arthritis, ankylosing spondylitis, autoimmune thyroid disease, for example, other autoimmune conditions. A lot of these have been linked to alterations in the gut microbiome and dysregulated immune system. So I think it applies to many immune-mediated diseases and really, in trying to mine that knowledge, the community, that natural process to understand where things are going wrong and why we are seeing this increase in disease in our world and perhaps how we can correct that in a way that treats that underlying disequilibrium.

Richard Jacobs: Have you seen papers where people that have Crohn’s or IBD when they were given antibiotics in broad-spectrum and did that worsen their condition or improve that or change it?

Jakob Begun: With both Crohn’s disease and also colitis, there are data out there in the world of antibiotics and you can improve inflammation by treating with antibiotics. One of the problems with this approach is that the antibiotics themselves also have side effects that are not desirable in the long term and in general, when you stop the antibiotics, disease symptoms recur. So, it’s not a long-term strategy, unfortunately. More interest recently, I think and more excitement has come about altering the microbiota through pre-biotics and pre-biotics is a fancy word for the food that we are feeding them which goes back to one of your first questions. So there have been some nice successes recently on dietary therapy and the role of diet in controlling inflammation and when we think about this increase in disease around the world and particularly in developing countries as they become more westernized, if you will, one of the major issues is the industrialization of the food supplies in these countries, their use of emulsifiers which have been shown to alter gut microbiota including the important mucus lining of the gut but also highly processed foods. These have all been associated with an increasing incidence of immune-mediated diseases. So I think there is a real interest in shaping the microbiota and shaping the immune interactions through diet where we can.

Richard Jacobs: Is there room for another class? We have pro-biotics, which is the bacteria itself, we have pre-biotics, food. What about metabolites? What if you were to eat certain metabolites in significant amounts?

Jakob Begun: I think that’s really interesting. Yeah, I think that’s a really interesting idea and there has been some work in this area. In my lab, we are certainly interested in looking at these metabolites and seeing if they would work as supplements. There has been some work in other supplements, for example, tryptophan supplementation has been something that’s been quite actively studied. Quite effective in mice, less effective in humans. Similarly, Vitamin D has been studied in the past as well and supplementation of Vitamin D again, in mice can be quite effective at controlling inflammation. However, in large trials, in humans, it’s been less successful, unfortunately. So, even though we’ve cured inflammatory bowel disease in mice many times over, it still remains a bit elusive in patients but we keep on looking for that right metabolite or maybe the right combination of metabolites that we could treat using supplement approach.

Richard Jacobs: Yeah, I guess you could also have precursors to other compounds. I mean, there are lots of ways to; is anyone considering, let’s say you have IBD, I guess all the technology is there in separate pieces but why not have a little bit of preferential phage that preys upon a certain bacteria that seems to be and do have a high prevalence in the gut and at the same time, a narrow-spectrum antibiotic and at the same time a pre-biotic to feed what you want to have there instead and at the same time, a probiotic as well to bolster that. Why not a little bit of 4 or 5 different interventions to try to restore a gut instead of one sledgehammer?

Jakob Begun: Yes, in fact, and I think that approach is very attractive. Sometimes it’s called a personalized medicine approach or a precision medicine approach and that’s because each individual is slightly different. We don’t think there is one size fits all, as your question implies and that would involve, sort of profiling a patient beforehand before you design the treatment, if you will, and looking to see where those deficiencies are and then designing a custom treatment for that particular patient’s combination of microbiome deficiencies or overabundances, their metabolic profile and potentially also, their dietary deficiencies and coming together with a precision-based approach. Now, that is not; when you move away from one size fits all, it becomes a lot more complicated obviously and also difficult using existing models of care which isn’t to say it shouldn’t be done, it just means that if we have to rethink the way that we are approaching this problem somewhat in order to design a solution that works best for individual patients.

Richard Jacobs: Yeah, because it’s such a community and there is such interdependency and everything depends on everything else, it seems. It just doesn’t seem like anyone thing supplementing with Vitamin D or having this one drug or one thing that is really going to, I mean the system is really going to trick it away and maintains its current stasis or I don’t know, it just doesn’t seem like, it seems it’s hypothetical the way our gut works or the microbiome works. I know it calls for a much more difficult approach but I don’t know. 

Jakob Begun: No, I think that it’s a very aspirational goal and it is something that one should be aspiring to and in general, I think that medicine as a whole is appreciating individual variability in our patient populations that not everyone is the same and as you say, just using one drug or one approach is probably not going to lead to the best results but rather a multi-model approach where you target the various aspects that we understand through all of our associative studies and mechanistic studies targeting those individuals or targeting the whole group of disturbances that we see in the patients rather than just the individual parts either the T cells seems to be active or the microbiome or the gut lining or whatever it is, we target all of it together and we think that would probably be much more successful and maybe someday we will be able to cure this disease rather than manage it which is what we do currently.

Richard Jacobs: Yeah. I’m not going to be solving it by thinking but I’m just thinking about this. Has anyone ever tried to develop a gut organoid where you can approximate a little gut and feed it things and see what it does?

Jakob Begun: Yeah, so, In our lab, we do this and in many other labs around the world is we do use these organoids or mini-guts and what these are derived from is when you do a colonoscopy and take a biopsy, you are going to take that biopsy back to the lab and then, with the right factors in a 3D gel, you can have these little organoids or steroids that grow and they have many aspects of the gut epithelial. The gut itself is made up, not just of the epithelial cell lining, that is the outermost cell lining which itself has at least 5 different cell types in it but also the supporting stroma and then the immune system that comes in. So, when you try to mimic that whole system, the immune system, the supporting tissue, and the epithelium, it gets complicated. There have been some attempts at doing it. They have things that are called gut on a chip where they have at east the immune system and the epithelial cell compartments and sometimes stromal compartments.

But of course, when you are doing it on a chip, it’s very regulated and it doesn’t quite capture the complexity but it’s getting closer and in these gut on a chip approaches or organoid approaches, we can test individual prohibitions and combinations and in our own lab when we looked at the differences in responses of organoids derived from different patients, we see inter-individual differences in their response to treatments that we use in the lab and so one day I would love to have the situation where we could have a patient, we grow their organoids in the lab, we then test that organoid on a variety of metabolites and a variety of bacteria that we have in our collection. We find out what that patient’s organoids respond best to in the lab and then we concoct a combination of factors that seem to be best suited for their genetic background, for their immune phenotype that would work best for them. I would love to see that reach maturity and become a standard affair. That would be fabulous.

Richard Jacobs: Just a couple more questions. In terms of immunity, do you see that the proper functioning gut, could you consider it the first line of defense and our immune system a second line or does that not make sense? Is there not one before the other or either both or the absence of both?

Jakob Begun: Absolutely, so when we think of the first line of defense in our bodies and in terms of the immune system, we often think of the innate immune system and the innate immune system encompasses the barrier function, for example of our skin, of our lung lining or of our gut. These are all the first-line therapies so even in those epithelial cells, the outermost lining of cells of the gut or the lung or the skin is making antimicrobial peptides. So these are proteins that the gut is making that specifically seem to target pathogenic bacteria. The gut also makes a very protective mucus lining that’s very important for homeostasis, to have this nice mucus lining and so that is the first line of defense. It’s only once the bacteria gets through this outer lining of defense that they get exposed to the adaptive immune system, the B cells and T cells that make up our adaptive immune system as well as a variety of other cells.

So yes, it’s very reasonable to think about it as a two-stage process but those two aspects of the immune system are in constant communication with each other, so the innate immune system, the epithelial cells, etc. can signal back to the adaptive immune system to mount a vigorous response and vice versa, the adaptive immune system can also influence the tone of the innate immune system.

Richard Jacobs: What do you think is going to be possible from your research in the near term? In the next year or two? Any breakthroughs that you are nearing?

Jakob Begun: We have a few metabolites in the lab that we pulled through the process all the way down to structural characterization and synthesis and we think with some of these we might be able to develop into therapeutics, that’s probably over the next few years, I hope. In the shorter term, we are hoping to understand and better characterize a handful of species that we have been focusing on, a few dozen, in fact, and start looking at the abundance of these and the abundance of metabolites they are making inpatient cohorts and healthy controls to see if there are differences at least to point us in the right direction for the approach that we are talking about before about metabolite augmentation be that either through pre-biotics or through the metabolite directly and just by identifying these, hopefully, we will find some that are generally regarded as safe grass molecules. It could be taken in the form of supplements or even perhaps a combination of strains that would be a super pro-biotic if you will.

Richard Jacobs: Okay, very good. Jakob, what’s the best way for people to find out more about your work and what you do? 

Jakob Begun: Thank you. You can certainly find me on the Model Research Institute’s webpage. You can see information about the lab and about what we do and I encourage you to come in and look.

Richard Jacobs: Okay, very good. Jakob, thanks for coming, I appreciate it.

Jakob Begun: Thanks very much. It has been a great conversation.