Uncovering the Mycobiome: Fungi, Gut Health, and Disease

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Daniel Simon, MD: Hello everyone, this is your Science@UH host Dr. Dan Simon. Today, I am happy to be joined by Professor Mahmoud Ghannoum. Dr. Ghannoum is the Marti D. and Jeffrey S. Davis Family Master Clinician in Cancer Innovation, the Director of the Integrated Microbiome, a cancer center resource, and the Director of the Center for Medical Mycology. He is also a professor at Case Western Reserve University School of Medicine. Welcome Dr. Ghannoum.

Mahmoud Ghannoum, PhD: Thank you. Thank you for having me.

Daniel Simon, MD: Well, it's really a pleasure to have you here today. I put you in what I call the healthcare royalty of University Hospitals. So, it's a real treat.

Before we really jump into your impressive science and research contributions worldwide, I thought it would be great if you could just tell us a little bit about your truly inspiring personal journey to come to the US and to UH and just tell us a little bit about yourself. It's very interesting.

Mahmoud Ghannoum, PhD: Thank you for asking this question because it's amazing what happened in my life when I was still younger than I am now. I was professor at Kuwait University for 11 years and I was on holiday in 1991 in England when Saddam Hussein came and took the country. And overnight I lost my job in Kuwait and the household and everything. So that was a traumatic experience.

The lucky thing is, I'm always fortunate that things work in what way, I was invited to give a talk at the Willard Hotel in DC on the 1st World Congress on the biology of garlic. And when I was in Kuwait, this professor, a Kuwaiti guy, all, every day, he comes to me, he says, “listen, you have to study the effect of garlic candida”. I say, “leave me alone. I don't want to do this”. And because he didn't leave me, I published 2 papers and lo and behold, I got the invite to DC.

So, I had the visa, I had everything, so I called the organizer I said please send me my ticket to England and they sent it to England, and they came there and to cut long story short, I went to the National Institute of Health where I met Dr. Jack Bennett who became the. President of the Infectious Disease Society of America. I told him. Listen, Dr. Bennett, I need a job. He said, “Who are you?”  I said, “listen, I just lost my job” and he was such a kind person, you know? He again to make it shorter, he invited me to his house, where there was all the PIs in the medical mycology in the US in his house for a meeting on fungal infection model in mice. So at that evening I got 2 jobs, one at UCLA and one at Wayne State, and I took the UCLA, stayed five years there and then the opportunity came to come to UH and Case, to direct the Center for medical mycology and that's what happened in 1996.

Daniel Simon, MD: Wow, that is an amazing story, and I guess, what follows that word that many of our grandparents told us, which is when life gives you lemons, make lemonade, and you certainly turned a personal tragedy of war into the ability for you to really excel professionally. So, congratulations and we're so lucky to have you.

Well, I want to jump in here and you know you can't open anything in the newspaper, on the internet without hearing about the microbiome. And when we think of the microbiome, we're all trained to think of bacteria. Of course, I met you many years ago, and you told me, Dan, the microbiome includes viruses and also fungal pathogens, or commensal fungal organisms, and so it's really fungi, viruses and bacteria. Tell me a little bit about why, when we think of the microbiome, we have to think about more than just bacteria. Why are viruses in the gut, and fungi in the gut so important?

Mahmoud Ghannoum, PhD: You know, because these communities, they collaborate together towards our good or detriment. So what happens when I used to go nearly 15 years ago to meetings and they talking about the microbiome, they all talked about bacteria, I said, “Listen, guys please. I want to take you back when I was in England doing my doctorate and it was on the effect of steroids and the antibiotics on candida. So guess what? When you kill the bacteria the fungus overgrow and then it start to cause issues” and that's where I wrote an opinion piece, 2010, saying we really need to look at both because these organisms are present together and they affect each other. But you know, the usual story nobody listens, so, 2016 I wrote another article saying it's called the microbiome and science emphasizing the same thing and the good news is that in 2021, people started to come from the NIH and IDCR, for example, started to say, look, we need to look at the complex microbiome to include bacteria, fungi and viruses. So, that pleased me tremendously because it's something which I was hoping will happen and it did happen.

Daniel Simon, MD: So that's great. So, I think our listeners all need to understand that when you hear the word mycobiome for fungus that is one of Professor Ghannoum's great contributions. Now let me ask you another question, because I don't think people know that candidal infections, a yeast, a fungus, can be a problem, especially in people who are immunosuppressed. You've done a fair bit of work on fungal virulence factors such as adherence and biofilms. I know that you worked globally in candida infections and HIV; tell us a little bit about your work understanding what is a biofilm? How does our body fight fungal infections? How do bacteria help do that? So, tell us a little bit about that.

Mahmoud Ghannoum, PhD: We in the lab think when we grow organisms, we grow it in liquid, its suspension which called planktonic growth, but in fact in our body organisms tend to adhere or stick to our tissues or for example, the gut lining and oral cavity and they start to form what we call biofilms. To make it simple, is the plaque in our teeth is a biofilm. And really, I was fortunate again thinking about, you know what, we should start looking at the fungal biofilm because everybody was looking at the fungi and lo and behold, we started that line. We were funded by NIH to study the role of the biofilm, especially we looked at both, bacteria and fungi because they come together and they form biofilms, which is really complex, polymicrobial biofilm, what we call them. And when they form, they provide really protection for these organisms because it's like they are in a Jello and inside the Jello you have M&Ms or raisins, these are the bacteria and fungi, and when, with Jello, it does not allow the antibiotics or antifungal as well as by the way host cells the immune cells to come and kill these organisms. So, it is really big problem and that's where we started looking into it, especially at the beginning. We looked at catheter infections because that's where biofilms live and cause really big issues for immunocompromised patients.

Daniel Simon, MD: Well, that's really interesting You know your recent publications have focused on a number of diseases, including Crohn's disease, inflammatory bowel disease, autism and cancer. I think your autism work is especially interesting to people because we know that there is a gut permeability problem in autism and the microbiome is altered.  Could you tell us a little bit about your work and how you actually can therapeutically alter that microbiome to improve the gut permeability and gut side effects that can be very compromising in patients with autism?

Mahmoud Ghannoum, PhD: I'm glad you asked about autism even though I love Crohn's and the cancer diseases, but autism because It's close to heart.. because we help young people with this disease. And what happened... to start looking into the microbiome, we did a clinical trial. My son Afif called me, he said, “Dad. You have to do clinical trial and autistic kids we have to help them.” So we did this trial about eighty-one patients, and we compared the microbiome of kids with autism and their siblings with no autism, and what we found is there is imbalance or what is called dysbiosis, the imbalance of the microbiome. And particularly we showed that there is an increase in candida, but also there was a bacteria called delftia which is very interesting. It is associated with people with epilepsy, for example, and to our luck anyway, it also forms biofilms. So, in a way, we were lucky because microbiome make the biofilm. And what happens, this organism, once it forms a biofilm in the gut lining, the first thing happens is start causing damage to the gut lining and that's where we see leaky gut and that sort of thing. So, the next step was what can we do to try to address this? And we screened a number of probiotic strains that are generally regarded as safe or what we call grass, and we identified three different organisms, probiotic, that are able to break down the biofilm of delftia. Also, they can affect the candida biofilm as well.

So now what we are doing is putting it all together and try to see can we develop a formulation to reverse or otherwise rebalance the microbiome and maintain it in these kids with the special focus on the gastrointestinal issues because they have bloating, they have abdominal discomfort. So, we really need to help them in that case and we are very excited and thanks to your support in getting the grant on trying to do a small clinical trial, proof of concept, to see can we really rebalance the microbiome and as a result of that, can we really get rid of these gastrointestinal symptoms?

Daniel Simon, MD: Well, you know, it's so remarkable, Mahmoud, that you've been able to identify not only is there, as we say, dysbiosis or an altered microbiome, but you've determined the organism that's responsible and a probiotic that addresses that biofilm abnormality. And we're so hopeful that our pilot project that’s supporting you and your team can make progress in a small, randomized trial so that we can bring this and have an impact on a larger and very significant patient population in the US.

Well, before I ask you the final question about the future, tell us a little bit about your work in cancer, because after all, my good buddy Jeff Davis and his wife Marty have named you master clinician so Jeff's going to want me to make sure I talk about cancer since he runs the Seidman Leadership Council. So, tell me a little bit about your work in cancer and how important the microbiome is in cancer.

Mahmoud Ghannoum, PhD: You know, it's so funny you should say sometimes, you know, I'm getting old, but these days I am so excited about not only autism, but cancer as well. And that's why people say, are you going to retire? No, no, no, my friend. I need to look at this.

So, in cancer what we did, we looked at a couple of studies which was published in collaboration with people from University Hospitals, like Amr Mohamed and Greg Cooper, where we looked, number one on the gastrointestinal cancer; how does it affect? What's the relation to the microbiome on that?  And we were able to identify the imbalance, OK, in those. We also published paper in lung cancer. We worked with a colleague of mine, Charis Ang, God bless her she passed away recently and we were able to identify this imbalance and again what we are finding like we found in Crohn's disease patients that we have imbalance in both bacteria and fungus. And that's really what's so exciting about it. And now we are going to continue to look into, for example, melanoma. We did a study in melanoma at the department of dermatology with our colleague Brian, and again my aim is how can we address this imbalance in cancer? And I'm really excited about that because especially with Dr. Amr, he is identifying some IP or some approaches to rebalance this and hopefully, we can help him to make this happen to help our patients.

Daniel Simon, MD: Well, it's very exciting to think that probiotic approaches would become part of the armamentarium in cancer prevention and cancer treatment. It calls to mind the observations that many people have made right now. Its very, very concerning we're seeing an explosion of colon cancer in younger and younger people, people in their 30s and 40s, the screening age for colonoscopies going down, but we're hearing about colon cancer in younger populations. And obviously, when people say, well, why is it happening? There’s been a lot of hypotheses, environmental, micro plastics, but one of the big ones is a change in the microbiome for how we're eating and what we're eating. So, any thoughts about that? Are we seeing changes in the microbiome, in people in their 30s and 40s that potentially are different than the microbiomes that we've seen in the past?

Mahmoud Ghannoum, PhD: Certainly, I think you touch upon a very important point, which is nowadays we really should look at a holistic approach. It's the microbiome. It's the diet you are having. Do you exercise? The stress level? All of these things come together to make the incidence of diseases and conditions increase, so therefore to me it's one piece of the puzzle is for us to have a pill to treat something we really need to try to adjust ourselves, our lifestyle, exercise, you know this. I'm not going to go into detail about it.  In fact, I wrote a book called Total Gut Balance where it provides what type of diet you need to eat, what type of lifestyle you have, and what sort of probiotics and prebiotics can help us. So, this is a really very hot area. And I'm very excited because I started to work now with a number of integrative medicine at University Hospitals, David Miller, for example, and Dr. Rao as well, who is the integrative oncology to try to start to address these issues. So it's very exciting area and I hope with our different expertise coming together we'll be able, hopefully, to prevent some certain conditions.

Daniel Simon, MD: Well, I think it's so great that you mentioned exercise. So, as a cardiologist, of course we know, from very large studies and hundreds of thousands of patients, that the incidence of cardiovascular disease and cardiovascular mortality is reduced by up to 40% with about 6000 to 6500 steps a day. But very interestingly in those studies, they show that cancer incidence and cancer mortality is also reduced with 6000-6500 steps a day. So, you are on to something that lifestyle, nutrition, diet, environmental exposures, what we're eating is really very important.

Well, with that Dr. Ghannoum, I want to thank you so much for joining me today. Every time I talk to you, I get excited because you're basically telling me that I have to be much more careful with my diet, that my coke, my frito lays and my potato chips and chocolate are not good enough for lunch anymore.

To learn more about research at University Hospitals, please visit. Uhhospitals.org/UHResearch.

Thank you, Doctor Ghanoum.

Mahmoud Ghannoum, PhD: Dan, it's always a great pleasure to talk to you and see you. Thank you, my friend.