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Research Discoveries Boost Personalized Treatment for IBD

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Dr. Daniel Simon: Hello everyone. My name is Dr. Daniel Simon. I am your host of the Science@UH podcast sponsored by the University Hospitals Research and Education Institute. This podcast series features University Hospitals’ cutting edge research and innovation.

Thank you for listening to another episode. Today, I am happy to be joined by Dr. Fabio Cominelli, Chief of the Division of Gastroenterology and Liver Disease and the Chief Scientific Officer of the Digestive Health Institute at University Hospitals. What a treat it is today to be joined by my dear friend and colleague who is widely considered one of the worldwide experts in inflammatory bowel disease research.

In fact, his research group was the first to report that specific blockade of a single pro-inflammatory cytokine, in this case, interleukin-1 (IL-1), was effective in reducing tissue disease severity in an animal model of experimentally induced colitis. Dr. Cominelli is one of the highest funded researchers at Case Western Reserve University with RO1 grants, a T32 as the PI, and most importantly, the Principal Investigator and Director of the Cleveland  NIH P30 Digestive Disease Research Care Center.

Fabio, it's really a pleasure to honor you and welcome you today. Before we begin about the science and really sort of dig into your amazing career, tell me a little bit about yourself. Where'd you grow up? Where'd you go to medical school? Tell me about your training in Italy and what brought you to the U.S. and eventually to UH?

Dr. Fabio Cominelli: Thank you very much Dan for the kind introduction. So I grew up in Florence, Italy and my father was a General in the Air Force and my mother was a high school teacher. So I didn't have a tradition of medicine in my family, but since I was a child I always had this passionate desire to help other people, to cure disease. So after my high school studies, I went to medical school at the University of Florence, which is one of the oldest universities in Italy. And after finishing my medical school and my training in internal medicine, in gastroenterology, my mentor professor in Italy, Professor Paulo Gientilini…who was a visionary in terms of sending his students to abroad to learn more, to obtain rigorous trainings in research and clinical… I went to Los Angeles at UCLA, Harbor-UCLA.

When I started to work with my American mentor (Robert) Bob Zipser, I was doing hepatology at that time. Bob was changing his interest in inflammatory bowel disease and its there that I developed a passion for this condition, that very devastating disease for which there was no a cure -there is not still a cure today. And then I developed the passion to be a physician-scientist, to someone who does basic research, but also apply that information to develop new therapies and relieve the sufferance from patients affected by these conditions.

Dr. Daniel Simon: So, you know, Fabio, inflammatory bowel disease, which refers to Crohn's disease and ulcerative colitis affects more than 3 million adults in the United States, according to the CDC. And to date there really is no cure for this disease. However, as an expert in this field, you've really been a leader in taking us down the path of disease modifying therapy, similar to what we see now in RA (rheumatoid arthritis) and in psoriasis.

Tell us a little bit about what you learned in your lab related to what controls inflammation in the gut and how is it that we've been able to develop now so many effective therapies that have really changed the course of the disease, everything from cytokines to TNF-alpha to other therapies. Tell us a little bit how did that happen and how did your lab participate in that?

Dr. Fabio Cominelli: See, I was very fortunate to work in the late eighties with the expert in the new field in research, it was the cytokine field, and I was very fortunate actually, to be able to participate in the cloning, in the molecular biologies of these cytokines. And then in my lifetime career, I've been able to see drugs developed from this basic science discovery for patients approved by the FDA. This doesn't happen very often. As you know, drug takes sometimes 30-40 years to be developed.

So my contribution in the field of cytokines working with other outstanding mentors…such as Charles Dinarello in Boston, who is the father of the cytokine field… I was able to demonstrate that blocking a single cytokine such as IL-1, was very effective in producing a robust anti-inflammatory effect in animal models of colitis at that time. And that was an important concept because at that time there were many cytokines, you know, there was many interleukins… today we have 42 interleukins… many tumor necrosis factor, other type of cytokines. Everybody was thinking that “oh, you block one and another one takes over and another one takes over” so that was a very important concept.

Then that led to the first anti-TNF drug and many other drugs that are in the field. Basically, we know that these cytokines now are key mediators of the inflammatory process in these patients, not only in inflammatory bowel disease, but like you said, rheumatoid arthritis, asthma, and other conditions. And by blocking these cytokines, we don't cure the disease, but we are able to really make a very significant effect on disease progression, quality of life of this patient - what I call inducing permanent remission.

So, a patient can have a normal quality of life, and from there have a normal lifespan and normal quality of life. And I had patients at the beginning of this revolutional therapy that were not able to function, they were not able to sit down on a chair, have a normal meal and then because of this therapy, they were able to have a normal life again.

Dr. Daniel Simon: So Fabio, with increased knowledge, obviously, you just mentioned that we're now up to 42 cytokines, so you just taught this cardiologist something new, I didn't know they were that many. There are ones that are more specific to the gut. IL-17, IL-23, you know, the list goes on. Are the therapies more specific now to the gut? Are there less immunosuppressive side effects fighting infection elsewhere? Tell us about what's the state of the art therapy today?

Dr. Fabio Cominelli: Yes, so, you know, when you block these cytokines, they have really multiple pleotropic effects, although there's also a price that we pay in terms of immunosuppression, possibility of side effects, sometimes possibility or worries about, you know, lymphoma and malignancy. So, the field now is moving towards blocking cytokines there or pathways that are more specific to the gut, avoiding systemic side effects. Now, we don't have… I would say, cytokines that are specifically to the gut, but for example, there are other treatment blocking influx of lymphocytes into the gut mucosal, the intestine - they are really gut specific really. But obviously, it is a very interest of mine and another investigator, really, to find treatments that are more specific to the gut, to the intestine, and with less side effects systemically in the brain, in other organs, and so on.

Dr. Daniel Simon: So Fabio, IBD is thought to develop as a result of interactions between the environment, genetics and importantly now, the microbiome, the gut microbiome. Many studies have shown that that gut bacteri, and the microbiome is different in patients with IBD compared to that in healthy controls. Tell us a little bit, how has your group studied the gut microbiome to determine what may be useful to treat IBD? Are there specific bacteria that are bad? And can our diet play a role in the management of IBD?

Dr. Fabio Cominelli: Yeah, this is an excellent question and we know now that patients with IBD similar to other diseases experience what we define as dysbiosis. So it changed the composition of the millions of bacteria that are in our intestine. With decreased diversity, there is decreased diversity of bacteria and also the predominance of bacteria that are more pro-inflammatory reversal…other there are more beneficial. And although I personally don't think that the gut microbiome per se is the cause of the disease, when we are able to modulate the composition and function of the microbiome, we are able to obtain very important results in our patient.

A little bit similar, what we have seen for immunotherapy or cancer, for example, where the microbiome composition of function seems to be really important to determine how a patient responds to chemotherapy and other immunotherapy. So in the case of the microbiome, there are different ways in which we can modulate the microbiome.

One is diet. We know that changing the composition of the diet we can change the microbiome. Therefore, there are some studies now showing, for example, the Mediterranean diet or other diet that are rich, for example, in protein. In certain type of protein are beneficial. In our own group at University Hospital Cleveland Medical Center, we are performing now a clinical trials using a diet that is rich in soy protein, soy protein of vegetarian origin. And we are having some very important results in this area. And the other way is to administer probiotic…so, beneficial bacteria that can correct dysbiosis. Again, in our group, we have studied both in animal models and patient that we are starting very soon.

And the other very important area is what we call now postbiotics. So we know that this bacteria produce certain metabolized enzymes, there are the beneficial effect to the host, to patients. And now we are trying to develop, you know, combination of these metabolites that can be synthesized as drugs and given to patient to have beneficial effects for their gut inflammation.

Dr. Daniel Simon:Wow, it's really cool. So, we'll have to have you back next year, the year after, to see the results of some of those studies. So, Fabio, your group recently published a very interesting paper in Gut showing that gay men are more than twice as likely to develop inflammatory bowel disease as heterosexual men. And you obviously, this is very important work and received a very significant grant from NIH to expand this study area. Can you tell us about this research findings and potentially how it can help to prevent or treat IBD in the gay population?

Dr. Fabio Cominelli: Yes, so this is a study, a retrospective study, that we conducted using a large database of patients from large number of hospital, almost 120 million patients, including in this database where we study, as you said, the prevalence of inflammatory bowel disease in this very important patient population that, we know have decreased access, traditionally to healthcare. So the important thing is that because inflammatory bowel disease is a syndrome with probably different cause in different population, when we are able to identify a specific population that is more, I would say homogeneous, have more controllable exposure to the environment.

That's where we can really make advances in understanding the cause of the disease. And I give you an example, the genetics of IBD that was originally discovered in the Ashkenazi Jewish population…that's an example of a more homogeneous population where we were able to identify genes and then apply to the general population… gave us incredible information about the genetics of this condition. Actually, IBD is probably the most successful example of accomplice disease where the understanding of the genetics allow major important advance.

So this type of research is not only for the purpose of understanding the cause of the disease and, and, benefit the entire population, but also to benefit this specific population. We know that this specific population have less access to healthcare. We have developed a special clinic now at Cleveland Medical Center that is staffed by myself and my collaborators, like Dr. Vu Nguyen, where we specifically provide, you know, more attention to this patient population, more access, more psychological support, more ethical support.

And I think we are very excited about this study. And the NIH has shared the enthusiasm for this type of study because I think we can really make a very significant impact in, in this disease affected this population. We are doing a similar thing now where we are in the process of receiving another grant with the HIV patient population where people affected by HIV, where we are starting the GI manifestation of disease in this patient in relationship to the gut microbiome to find out if the gut microbiome plays a role.

And we are very excited to work with our outstanding collaborator, Grace McComsey, who is the very famous and international investigator in the field of HIV and also vice President for Research here at Cleveland Medical Center to successfully also complete this study.

Dr. Daniel Simon: So, Fabio, you've told us about a lot of players that are involved in this complex disease, cytokines, the microbiome environment even genetic factors and other social determinants. Looking into the future what do you think we'll be doing to IBD three to five years from now? Will there be a cure or will it still be, as you say, management for prolonged remission?

Dr. Fabio Cominelli: I think, you know, probably the latter is the most likely outcome in terms of management or permanent remission. I think a cure of diseases, in my opinion, happen by chance sometimes. I mean, if you look for example of the Helicobacter Pylori story for ulcer disease, again, I was fortunate in my career Barry Marshall… who won the Nobel Prize for Helicobacter… was a member of my division when I was at the University of Virginia. And really that's an example how that discovery happened totally by chance, but incredible discovery that allow us by treating with antibiotic for two weeks to eradicate an infection that is causing a disease and in the past was causing morbidity, recurrence, bleeding, or surgery.

So I think the cure for IBD, in my opinion, would occur by chance, by someone very intelligent, we make an important discovery or by the systematic approach that we are using, you know, step by step, making progress. But I think in the immediate futures, this is a disease where if we can personalize treatment for each patient, and as I always mentioned, put the patient in permanent remission, this patient are able to have a normal life, normal quality of life and not being affected by the devastating effect of this disease when the symptoms are uncontrolled or the disease is not under remission by therapy.

Dr. Daniel Simon: Well, Fabio, thank you so much for taking the time to speak with us today. You are truly one of the giants of University Hospitals, and you really embody our mission of healing, teaching and discovering in everything that you do every day.

For our listeners, interested in learning more about research at University Hospitals, please visit uhhospitals.org. Thank you for participating today.

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