April 11, 2017 – Dr. Richard Fedorak, Dean of Medicine, U of A.

Dr.  Richard Fedorak is interim dean of the faculty of medicine & dentistry at the University of Alberta, and professor of medicine in the Division of Gastroenterology. In addition, he serves as director for the Centre of Excellence for Gastrointestinal Inflammation and Immunity Research, and director of the Northern Alberta Clinical Trials and Research Centre.

Outside of the university, Dr. Fedorak is president of the Canadian Digestive Health Foundation and chairman of the World Gastroenterology Organization’s research committee.

He is an active medical staff member at both the University of Alberta Hospital and the Cross Cancer Institute, and is a consulting physician at the Stollery Children’s Hospital and the Royal Alexandra Hospital.

A recipient of numerous awards, research fellowships and grants, Dr. Fedorak is a recognized expert in inflammatory bowel disease.

Dr. Fedorak has served as director for the Centre of Excellence for Gastrointestinal Inflammation and Immunity Research and director of the Northern Alberta Clinical Trials and Research Centre, as well as president of the Canadian Association of Gastroenterology, president of the University of Alberta Hospital Medical Staff, president of the Alberta Society of Gastroenterology, president of the World Congress of Gastroenterology Bid Federation,  general secretary of the Pan American Congress of Gastroenterology and president of the World Congress of Gastroenterology.

In 2008, Dr. Fedorak was appointed fellow, Royal College of Physicians, London; in 2009, fellow, Canadian Academy of Health Sciences; and in 2011, fellow of the Royal Society of Canada.

He received his medical degree with first class honours from the University of Alberta in 1978.

At home, Dr. Fedorak enjoys life to its fullest with his wife Karen and their two children, Kristin and Bryan.

 

Notes on Dr Fedorak’s Presentation

I’m going to take you through a story because indeed I think we are on the threshold of something that’s very new. As Hugh said we’ve lived with bacteria through the eons but we’ve always seen them as injurious and bad things. The plague, pneumonia, those diseases caused by bacteria and as antibiotics came along we conquered some of that but only recently have we become to recognize that the gut microbial is really critical.

As a point there’s a hundred times more bacteria in you than you have actual body cells. So the bacteria on you, in you, dominates over all the cells you have.

So let’s just walk through a bit of a story. I’m going to take you through four things. The how, why and why now. Why is it important to us?

I’ll tell you about the origin of the gut microbial, how you were born and how it changed, what it is now for you. I’m going to tell you that many of the diseases that we have are modulated or due to your gut microbial. Who knew? And then at the end I’m going to talk about entrepreneurship and commercialization because I know we’re going to be able to use the gut microbial for new drugs and new treatments.

Why now?

So when most of us went to school or in college or universities in the ‘70s we still had a gut like this. What did your intestines do? In biology classes in high school or university the gut was there for absorption. It was meant to absorb your food, assimilate it, get in the blood stream and keep it healthy.

We had no conception of gut bacteria.
In the 1980s there was something that we identified and it had this name clostridium difficile and we learned that when we gave an antibiotic and in the ‘80s we were developing potent antibiotics… when we gave that antibiotic to people, and we subsequently learned that it can happen with other antibiotics, this spore forming organism clostridium difficile got under control and started growing wildly inside your intestines and would lead to a very severe colitis infection in your intestines, so severe that many patients got very sick from it meaning admission to the hospital leading to intensive care and some people even died from it. Often the only way to solve it was to take out the large intestine completely. That’s how severe it got.

And it all came about because we’ve given you an antibiotic maybe to treat a skin infection or a bit of pneumonia or a urinary tract infection and all of a sudden this thing grew up and went wild like weeds in a garden.
So in the 1980s we began to visualize that something was happening in our gut that there were good bacteria and bad bacteria and possibly the antibiotics we were giving people were actually getting rid of the good guys allowing the bad guys to grow.

And then in 1986 something changed.

Barry Marshall and Robin Warren won the Nobel Prize for it. So those of you that are physicians in the audience would know that for many years ulcer disease was maybe stress. We don’t know. We would treat you with antacids, hospitalization. In 1986 we identified that peptic ulcer disease was because of a bacteria called helicobacter pylori and that’s what won these two gentleman their Nobel Prize.

I was in Chicago at the time and when this happened we looked back at the stomach biopsies that we had saved in Chicago from the 1920s and those bacteria were there. So it was pretty clear that bacteria growing inside a person is capable of causing disease beyond the simple food poisoning and gastroenteritis that you might get.

We also did another thing in the 1980s.

We could actually take a mouse and it would be born in a sterile environment and it would never have bacteria in its gut. It was a mouse in a bubble and it lived without any access to bacteria. When we studied what happened to that mouse it had changes in its digestive function, it had a different type of stress response. It actually didn’t have very good immunity against other diseases.

So we learned that helicobacter pylori could cause ulcer disease, who knew, and we learned that if we took the bacteria away from the mouse something changed in that mouse. So we’d come from the ‘70s when the gut was only good for absorption and food all the way into the late ‘80s and early ‘90s and we’re learning that the gut microbial is playing an important role in disease.

Why is the gut so important to health? Let’s explore that a little bit.

Let’s start with the bowels. There are probably good bacteria and there’s bad bacteria and you live with that balance and those gut bacteria are an important part of your healthy living. They help you metabolize your food, they allow you to have good immune function and they allow your gut to work normally to have a normal bowel motion to have normal mobility.

But when things get out of whack on the upper part you can see some things begin to happen. Bacteria and obesity, bacteria and mental health, bacteria and other diseases.

We need this balance. Keep that in mind: balance.

Why does it all happen? For the IT guys in the room it’s due to computing power and I told you there is a hundred times more bacteria on you, in you, than you have body cells. In order to identify those to DNA sequence them, to find those bacteria we needed storage capacity and only recently have we had enough computer power to be able to take a sample of your stool or your gut and find all those bacteria.

So in the ‘70s and ‘80s when we were thinking about it we didn’t have enough technology to actually find them and even now if you take a sample of stool and DNA sequence that and look for all of the bacteria in that stool the computer is running for days.

We needed this big data capacity. We needed to be able to cloud computing, analytics and networking. So that is how and why it has happened.
The other thing we needed to happen, and I talked about DNA sequencing, this is sort of a graph of about 10 to the seventh, 10 to the tenth different types of bacteria in your gut. You all remember these petri dishes from high school or university.

Culturing could only identify 20 or 30 different types of bacteria in your gut and there’s 10 to the 7th or more. So we were just beginning to see these bacteria and as technology developed with different sorts of DNA sequencing we are now not doing culture but we are taking those stool samples, identifying the DNA in them and identifying bacteria using that technology. So that is the why.

And we take that DNA and we run it through those computers that are running day and night, identifying and matching the DNA and bacteria in your stool to the DNA in the various libraries around the world trying to find out what type of bacteria you have.

So the technology has helped us.

There is a core amount of bacteria we all have that’s the same but then there’s this blue part you each have the blue part that is unique to you. From all this DNA sequencing taken from thousands and hundreds of millions of people and looking at the bacteria they have in their gut we’ve learned that there’s a big amount that’s conserved amongst all of us and then we have a blue amount that’s unique to us.

There was a movie called Andromeda Strain you might remember it and it was where a bacteria got out of control and killed a town. Even in the movies we began to understand there’s this balance and if you get this balance out of whack then something’s going to happen.

So I talked a little bit about why now and why now is about the technology and science inching forward every day, every month and every year. Big data and computers have all helped us identify the bacteria that each one of has.

So let’s assume, “check,” we know that. So what about the origin of the microbial and how it changes?

On the day you are born you are in the uterus and you are sterile. You have virtually no bacteria in your gut, virtually no bacteria on your skin and then you are born. In the first couple of years of life… many of you have grandchildren. You kiss them and slobber on them and they roll on the floor and lick the rug, eat the sand and dirt. They are populating their gut with bacteria.

It’s so interesting that families populate their children with the same types of bacteria. So if you look at your grandchildren they are going to have the same type of bacteria in their gut as their parents and grandparents for the most part because those are the people that hug them the most and if you swab the rug or the floor that’s the rest of it.

It’s constant through life. So once you populate your gut with those bacteria, particularly that blue part that’s unique to you, it’s hard to change. It stays constant like your fingerprint.

So I could take a sample of your gut bacteria today and five years from now it’s going to be pretty much the same and if I could go back and get that sample from you 30 years ago it’d be pretty much the same. It doesn’t change a hell of a lot.

So what does that mean? It’s constant through life like your fingerprint but now we want to talk a little bit about what makes it change.

Here’s our life baby to old age and here’s my depiction of your gut microbial. You’re born, I told you you’re sterile and then over the next few years you populate your gut with something and then it remains relatively stable after there.

As you’re populating it as an infant it changes. It’s a little unstable so you can take an infant and move them around to different places and they are going to have different types of bacteria here and there and then through your life it stays relatively stable.

Your gut microbial can change temporarily as a result of illness, a virus or antibiotics.

Interestingly as we get older it becomes unstable again just like an infant, unstable. And we know there are diseases that occur in children and we know that as we get older there are diseases that occur because of this instability in your gut microbial.

So what do we know about disease?

Like your fingerprint your gut microbial is relatively stable, you ramp it up in childhood and stay stable throughout your life, you can have changes when something major happens in your life and then when you get older it becomes unstable again.

I want to use an example. There’s something called inflammatory bowel disease and we’ve worked on this. It’s sort of the poster child for looking at the gut microbial and it’s taught a lot.

Inflammatory bowel disease is two disease: Crohn’s disease and ulcerative colitis. You may have heard those words and it effects the lining of your intestine and your intestine becomes inflamed. We don’t know what really causes it.

We’ve done a lot of work on it and here’s what we’ve learned. Microbial, so the gut bacteria, the diversity of differences is decreased in inflammatory bowel disease.

I drew this forest here to show you diversity. A healthy forest, my analogy, has all sorts of trees and if one species dies the other one’s around, it populates and grows up. It’s a healthy forest. That’s normal.

Normal forest and normal bacteria in the gut. A lot of diversity. 10 to the 7th different types.

With inflammatory bowel disease you lose that diversity. You only have in my picture here one type of tree and that’s not a healthy forest. If that tree gets sick that forest is toast.

With inflammatory bowel disease we have the same thing, the diversity of bacteria is way down and you just have a few types rather than lots and lots of types.

And the stability of the bacteria is also different in patients with inflammatory bowel disease. It can change at a moment’s notice. If you get some stress, move to a different place, eat different food, take an antibiotic, something that wouldn’t affect you normally, in cases of inflammatory bowel disease that instability causes big changes.  And not only that, the composition is different. People with inflammatory bowel disease have different bacteria than the entire rest of the world.

So inflammatory bowel disease taught us a lot. It taught us that these individuals have loss the diversity and stability have a completely different gut microbial driving their disease.

So now we have gut microbial actually causing something systemic in your gut. The obvious question was, “why can’t you fix that gut microbial?” Because diversity, composition and stability would keep you well and let’s just fix it. And we did that.

This is inflammatory bowel disease, it’s a picture of inside the gut. It looks red and raw and doesn’t look so healthy and here’s one where we did a fecal transplant. A fecal transplant is exactly what you think of it.

So we get someone who is healthy, they come in in the morning, they poop in a pot and we put it in a blender and then you take it over to somebody with inflammatory bowel disease and we put it up their bum. We call that a fecal transplant.

But this was done in our university. So this was the patient before, they don’t look very healthy. Four weeks after we shot somebody’s stool up their bum it looks like this. We fixed them. We fixed the diversity, stability and composition.

You could say we cured them.

And look what happened, five months later it’s back. And the reason it’s back is because of the story I told you that like your fingerprint your body wants to go back to the original type of bacteria it normally had and so in this patient the bacteria shifted all the way back to what that person normally had and they got their inflammatory bowel disease back.

It’s so funny how your body wants to keep itself to whatever it was and doesn’t like change. But there’s a message here, there’s a great story.

We have changes in gut microbial causing this disease and then we can actually in our crude way fix the problem. My analogy it’s like the dawn of the computer age back in the ‘60s. This is the dawn of being able to change the gut microbial. Come back in 20 or 30 years and see what we can do.

Lots of studies done across Canada, here at UBC, I know that St. Paul’s is doing some of this work. We are all trying to identify how we can better do this without actually doing a fecal transplant. What is it in that feces that is a therapeutic agent?

We’ve discussed the origin of microbial and how you get it at birth, it becomes stable, it can get… I’ve used inflammatory bowel disease as an example of how changes can occur and how we are crudely trying to fix those changes and how we can see success and then it gradually comes back.

But that’s a gut disease. Let me tell you about some real exciting research on how the gut microbial effects all different parts of your body.

Biomarkers:

I want to talk about these bacteria being your enemies. These are two little cute mice, one is different than the other.

We got a skinny mouse, we got an obese mouse. So you know what we did we these mice? We took the feces from the obese mouse and we put it into the skinny mouse and the skinny mouse became fat. And we did the reverse. We took the stool from the skinny mouse and put it in the fat mouse and the fat mouse became skinny.

Now these aren’t humans and they don’t talk back and they are really compliant. But we are able to show that just with moving gut microbial from one to another we could actually change.

So as science goes we start in the animal world and move into the humans. We’re actually doing fecal transplants now in humans for the treatment of obesity as part of clinical studies. It’s not ready for prime time yet and you shouldn’t be doing this at home!
I think you’d have to find a very good friend.

But it’s proof of concept that microbial is incredibly important in determining lots of things in your body.

Let’s look at another thing.

Do you know how a lot of you have dieted and gained the weight back? This was another study where even though the animals in this study were on a diet and lost all this weight, as soon as that diet stopped and they went back to their regular food they gained the weight back just like that. Just like us. What we learned was that the gut bacteria induced by obesity didn’t change. So although they were on this low diet the gut bacteria didn’t change. They had the obese type bacteria in those animals and no matter how long they were on the diet that bacteria didn’t change and as soon as they stopped the diet they got obese again.

So if we are going to treat obesity we have to consider the gut microbial and not just what you put in your mouth.

If you want to treat obesity long term we probably want to change that gut microbial yet the body wants to come back to homeostasis so we have a lot of work to do.

Here’s another thing: kids.

Remember I told you that in childhood you start picking up these bacteria until you reach about three years of age and then it’s relatively stable after that time? We also know that antibiotics in early childhood can change that bacteria. If you take antibiotics for a while then your bacteria changes and once you stop antibiotics it goes back to your normal state.

You also have probably heard that diseases like eczema and asthma are on the rise. Maybe some of your own grandchildren have those problems.

So this was an interesting study. All you need to know is that when we looked at these kids and looked at the antibiotics they received if kids were receiving antibiotics to change their gut microflora between the ages of about 3 and 6 they had asthma developing at a higher rate than if they didn’t receive the antibiotics. And, same thing with eczema. The kids that received antibiotics to change their gut microbial early in their life get more instances of eczema.

The funny thing is that doesn’t happen with adults.

Diabetes. Some of us in this room will have diabetes.

This was an interesting study.

A fecal transplant in patients with diabetes changes their gut microflora so someone with diabetes received a fecal transplant from someone who didn’t have diabetes and for a while it treated their insulin resistance and they didn’t have diabetes. Amazing. Just changing your gut microflora changed the diabetes.

Can bacteria reduce heart attacks? What about asthma, eczema, diabetes? Amazing.

Let me take you through this a little bit.
If you eat eggs, cheese and a lot of red meat, depending on what microflora you have, you produce TMAO. It doesn’t matter what the word is. This thing gives you atherosclerosis in the coronary arteries.

Look at this. These people here have high TMAO and antibiotics change their gut microflora. Just changing the gut microflora in these patients and they didn’t have any of this TMAO and they didn’t develop atherosclerosis and then they stopped and went back to their normal microflora and they started getting atherosclerosis.

So all of us are sitting here thinking that we love that red meat, cheese or those eggs and we’re getting those little plaques built up. It’s due to this enzyme that causes atherosclerosis and if you can change your gut microflora somehow you wouldn’t get those atherosclerosis plaques which means we are going to reduce the incidence of heart attacks.

DEPRESSION

Rats get depressed. Under certain situations when you put them in certain cages they have these behavioural changes that looks like depression to us. In this study from just last year we could take the feces from those depressed rats and put them in rats that were happy and those happy rats became depressed.  They exhibited the same features so something in those bacteria, in the gut of those rats was reaching the brain to make those rats turn depressed.
And it’s the same thing with autism. Humans with autism have a certain type of bacteria fingerprint that’s different from the rest of the world and in 2013 there was this bacteria called Bacteroides fragilis.

 When this bacteria grows really crazily in children with autism it produces this enzyme. It is 40 times higher in the children with autism than those who don’t have autism.

So why am I telling you this? This study was really interesting because it’s building on that story. It’s not necessarily the bacteria but it’s what those bacteria might produce. Those of you who are chemical engineers will know that chemical engineering uses all sorts of bacteria to produce different chemicals.

And lo and behold it may be that, yes, this gut microbial goes crazy and yes you have this growing up but it’s not really this bacteria that cruises up to your brain and causes autism but the chemicals it’s producing.

Alzheimer’s.

It’s the same thing with Alzheimer’s. We look at those people that have a special type of early onset Alzheimer’s. They have a completely different gut microbial than those patients that don’t at the same age.

We also know that irritable bowel syndrome. This has been studied even more.

The severity of your symptoms are dependent upon this very distinct signature. Pain, cramps and diarrhea in these patients and the severity was dependent on this signature.

I’ve given you these examples, many of them were in animals. I want to take you a little further in this story now to humans.

In medicine we do clinical trials. We try to take a control group or an experimental group and show that any drug or treatment that we want to do is going to be effective.  We’re starting to do that now.  I showed you a little bit around fecal transplants. We’re trying to get away from fecal transplants and do different things.

Here’s a study where we took the first human clinical trials showing probiotics. You’ve probably all bought probiotics at a health food store. You eat yogurt, that’s a probiotic. What we think are good bacteria.

In these Alzheimer’s patients their cognitive score, the scores measuring their ability to think and improve. This group was treated and changed their gut microbial.

Early evidence.

Here’s what I like the most. This is a study we did in Dublin at the University of Cork.

We took patients in a long-term care facility and measured their gut microbial and found out what it was and measured their cognitive activity, so how well they were thinking, we measured what they did every day and we took that entire group about 70 people living in a long-term care facility and changed their gut microbial temporarily by giving them different types of probiotics, different types of food, changing what they were eating and within four weeks there was nearly 100 percent improvement in the amount of time they were up and walking around and a significant improvement in their cognitive ability, the ability to think and do things just by changing their gut microbial.

We didn’t change one other thing. We didn’t change their environment or their nutrition, we changed their gut microbial.

I’m going to take you to the last little bit. The link between the gut microbial and commercial diagnostics and where this is going because I told you that the gut microbial is important, you are born with it, it stabilizes over a lifetime, if you change that gut microbial it can actually cause disease and if you get it back to some other state you can actually treat diseases.

You may have seen some of these in the newspaper. Dogs sniffing in the airport. This dog can sniff out if you have cancer. What do you think he’s sniffing? Do you think he’s smelling the cancer cells? No. He’s smelling the gut microbial and the metabolites, the products that that gut microbial makes.

There’s a new science called metabolomics. The bacteria in your gut are made up of genes and enzymes and then at the end this yellow pyramid here. Those bacteria in your gut, 10 to the tenth of them, have waste products and a lot of those waste products get peed out in the urine and if we can measure those products in the urine it could give us a picture of what your gut microbial looks like way easier than measuring your stool.

So in this example this dog is actually sniffing one of the metabolites made by the bacteria.

We try and exploit that. We can measure these metabolites in the urine, about 8,000 of them. We can identify them, we can put them on a computer and identify the concentration of each and whether they are changing.

Here is an early study where we had people pee in a pot and try and identify whether you are healthy or whether you have Crohn’s disease. By analyzing that urine we could tell if you had disease and what we were analyzing was the different metabolites that were popping out in your urine. The waste products from your gut microbial.

Here’s another one, colon cancer.

Colon cancer comes from the growth of colonic polyps, little mushrooms that start growing in your colon.  When they reach 2 cm in size they become cancerous. If you can get them before they become cancerous and pluck them you prevent colon cancer.

That is the reason why we have colon cancer screening programs in our province. That’s why over the age of 50 you’re supposed to be tested and if you have those polyps you’ll end up with a colonoscopy to take them out.

But how do we find those polyps? Now you have to poop in a pot and look for blood in the stool. We said let’s use what we know about gut microbial and metabolomics because if you’re developing colon cancer because your gut microbial is not right then we should be able to measure that change in the waste products from those bacteria that are not right in your urine which is what this shows. All of the red dots are those patients that have polyps and the white dots are the patients that don’t.

So by measuring these metabolites in your urine we can tell if you have a polyp or not.

So now we are using gut microbial as a diagnostic test by measuring those end products and those waste products from the bacteria. We are exploiting the gut microbial.

The changes in the gut microbial may cause disease in order to develop a diagnostic test. So this is the test we actually compared it against all the different types of stool tests that exist here in British Columbia. Peeing in a pot we’re more likely to pick up your polyps than if we did a stool test.

So it’s a way for us to use that gut microbial to our advantage. The changes that occur.

This is the future so as we go forward we’re going to learn more and more about the gut microbial and how it causes obesity, diabetes, depression, autism, Alzheimer’s, heart disease etc. We’re going to learn that gut microbial is way more important than you ever thought.

So when you sit on the toilet tonight and are thinking about having a bowel motion do think about this lecture every time.

That microbial you have is really determining your wellness and determining your health and we’re at the infancy of understanding this. By 2020, 2030 and 2040 we’ll know more.  We’re going to be able to manipulate that gut microbial as I’ve shown you we did identifying and diagnostic testing polyps but we’re going to be able to do much more.

The multi-billion dollar diagnostic is going to be determining in my view what in that gut microbial made those mice skinny.

If you could identify the molecules or a couple of molecules or the one or two bacteria that made that fat mouse skinny that is the billion dollar drug and I can tell you that the Beijing Genomics Institute in China has 3,000 people and hundreds of cloud computers working on identifying what in the feces made that fat mouse skinny.

And Pfizer is doing it, and Roche is doing it and all of these major companies are trying to understand that. That’s where the money is going to be.

So I’m going to end here. We talked a lot about the gut microbial, why it’s happening now, why the IT stuff is important, why diagnostics are important all the way down to how the science of metabolomics and gut microbial is going to change the way we look at disease and the various drugs and treatments we have.

 

 

 

 


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