The Microbiome & How it Affects Disease – with R. Balfour Sartor, MD

This is Episode Nine of “Autoimmune Disease: Pieces of the Picture.” Dr. Balfour Sartor explains how the state of our microbiome affects disease. Dr. Sartor is the Midget Distinguished Professor of Medicine, Microbiology & Immunology in the UNC Division of Gastroenterology and co-directs the UNC Multidisciplinary IBD Center.

Ron Falk, MD: Hello, and welcome to the Chair’s Corner from the Department of Medicine at the University of North Carolina.

This is our series where we explore topics related to autoimmune disease. These podcasts are aimed at helping patients and their loved ones understand and manage their condition. Today, we’re going to be talking about something called the microbiome and how it affects disease—autoimmunity in general and inflammatory bowel diseases in particular.

We welcome Dr. Balfour Sartor who is the Midget Distinguished Professor of Medicine, Microbiology, and Immunology in our Division of Gastroenterology. He co-directs the UNC Multidisciplinary Inflammatory Bowel Diseases Center and is a world expert on inflammatory bowel diseases and the microbiome. Welcome, Dr. Sartor.

Balfour Sartor, MD: It’s a great pleasure to be here. Thank you.

The microbiome & what influences it

Falk: Balfour, what on earth is that term microbiome? What does that mean?

Sartor: It’s a confusing term, Ron. The microbiome is the huge number of bacteria, viruses, and fungi that inhabit our bodies, primarily in the gut, but also in the mouth, the skin, any mucosal surface. These are metabolically active products that eat what we eat, and spew out chemicals that influence our body’s function, in particular the immune function.

Falk: It’s a funny concept, but one that, when one thinks about it, is evident.

Sartor: Well, you’ve got to remember how we evolved. Bacteria were here before we were. So we evolved to coexist with these bacteria and viruses.

Falk: Most of the time they are very much important in our day to day activity.

Sartor: Yes, in fact, we are colonized at birth, particularly with vaginal delivery, and the microbes influence how the gut works in particular, they help digest our foods, and they produce very important products such as butyrate and short chain fatty acids that are important both nutritionally as well as feeding our gut’s cells, for example.

Falk: If one gets rid of all of those bacteria and viruses and other living tiny organisms with an antibiotic, for example, what happens?

Sartor: Well, many things can happen. Number one, diarrhea is very common. Yeast infections can develop after broad spectrum antibiotics because these normal bacteria prevent overgrowth of pathogenic organisms—the bad bacteria. The best example of bad bacteria is something called Clostridium difficile—“C. diff”—it’s a toxin-producing bacteria whose spores are present in our gut all the time, but they don’t hatch because the huge number of normal bacteria prevent them from taking hold. If those normal bacteria are removed, then there’s an ecologic niche that can be filled by these pathogenic bacteria.

Falk: So every time a physician prescribes an antibiotic, what you’re saying is that’s going to alter the microbiome?

Sartor: It definitely will, and so physicians and patients need to think carefully—“Is an antibiotic really indicated?” Antibiotics can be prescribed by reflex when you have a virus, a cold. They’re not going to help that. So I think it’s quite appropriate to question your physician, “Is an antibiotic necessary?” And try to use the most specific antibiotic so it’s selected for the detrimental, bad bacteria rather than the good bacteria.

Falk: If one wants to try to improve one’s microbiome—and we have to talk about if that’s even possible—how can a patient alter their microbiome?

Sartor: It’s a great question, and it’s one that doesn’t have an easy answer. Basically, your microbiome is pretty well set by the time weaning occurs, so between age 9 months and age 2 in humans. The microbiome evolves from a relatively simple set of bacteria and fungi to a very complex group. That’s pretty much set by age 2. Now you can tweak the system as far as the composition by dietary products, eating different foods, but you can change in a major way metabolic function of these bacteria. So for example, high fiber diets will increase the number of beneficial bacteria and particularly cause them to produce butyrate and other short change fatty acids that are very helpful for both the lining of the gut, for metabolic fuel, as well as programming protective immune responses. On the other hand, bad diets can have the opposite effect.

Falk: There are, in many foods, advertised on TV and in health food stores, bacteria that have been purposely introduced into yogurt or milk or in tablet or liquid form. Does any of that actually work to alter the microbiome?

Sartor: Another really important question, because advertisements for food products don’t require FDA approval, so there are many claims that really aren’t substantiated. Probiotics are a very popular area. If you go to any drug store, you’ll see shelves of probiotics. The problem with the traditional probiotics is they aren’t the bacteria that normally live in the gut. So yes, they will colonize the gut if you eat yogurt that is non-pasteurized —you’ve got to remember that some yogurt is pasteurized and heat kills the bacteria, but the probiotics that are typically found, many Lactobacillus species only transiently colonize the gut. As long as you’re taking the probiotic, they’re there, and they’re functioning, but as soon as you stop, they’re gone—no staying power.

How the microbiome affects disease

Falk: What’s the effect of the microbiome in health and disease on influencing the immune system?

Sartor: Well, the immune system is educated in a major way by the bacteria in particular but to a lesser extent the fungi. The way it works, is that certain bacteria stimulate protective immune responses, and they do it in several ways. I’ll try to make this palatable for the audience, but one way is they have cell wall components that stimulate so-called hard wired responses that stimulate the same response in almost any cell. They also produce metabolic products, I mentioned butyrate earlier that stimulates the evolution of protective immune cells, Treg’s—regulatory T cells that prevent inflammation. And then they also have antigens that are very specialized proteins that are recognized by the T cells. Some T cells have beneficial activities—Treg’s for example, others induce inflammation and those are the detrimental T cells, the ones that produce interferon gamma and IL-17. Those are the ones that we try to target to treat IBD and other immune-mediated diseases.

Falk: Your own research has shown a substantial interaction between the microbiome and inflammatory bowel diseases. Can you help our audience understand the importance of that work, which is really ground breaking?

Sartor: Well, you’re very kind. I’ve been working in this area and I’ve been doing research here at UNC since 1979. In a nutshell, we’ve shown over the years that there’s a balance of beneficial and aggressive bacteria in our normal gut—these aren’t the infections that we think about—but in the normal gut, there’s a balance of good and bad bacteria. We’ve demonstrated in genetically susceptible mice and rats that without bacteria, there is no chronic inflammation. So if you add bacteria to a genetically susceptible mouse or rat, they develop colitis. In the absence of bacteria, they don’t. We, very importantly, I think, demonstrated that some bacteria are good and some bacteria are bad.

Falk: Some bacteria can actually help the disease and some bacteria can actually cause the disease.

Sartor: Yes, in our experimental colitis models. We think that that concept is rolling over now into IBD. The importance of this is that you can consider then how to manipulate one’s microbiota.

Falk: So if you’re a patient with a newly diagnosed inflammatory bowel disease or another autoimmune disease having just listened to what you’ve just said, you’d be saying to yourself, “Okay, how can I as a patient improve my chances of perhaps feeling better, doing better by stacking the deck on my side, and figuring out how to get as many good bacteria in me as possible?” You talked a little about the possibility of altering the microbiota with food. Any other recommendations for that person?

Sartor: First of all, current therapy, in IBD in particular, and in most immune-mediated diseases, is targeting the aggressive immune response. So corticosteroids, prednisone, biologic therapies, remicade, Humira, for example, are designed to block the immune response. It is still speculative that altering the microbiota will have a beneficial effect in humans. We clearly have shown that in mice. My research at the present time is trying to translate that to humans.

In theory, and I want to stress this isn’t ready for prime time—you don’t want to stop your regular medications—one could alter the microbiome. One, by diet, in particular in the gut, avoiding refined sugars, high fructose corn syrup, which seem particularly to stimulate growth of bad bacteria, and increase the amount of fiber. Beyond that, antibiotics can alter the microbiome short-term, not long-term. Probiotics we’ve talked about. I think we need to get better probiotics, the ones currently in use in the drug store don’t have staying power. We need to harness those protective beneficial bacteria already in our guts. Fecal transplant is all the rage now. That again is still speculative, except in the setting of C. diff—recurrent C. diff infection.

Fecal transplant

Falk: Okay, so fecal transplant. What on earth are you talking about?

Sartor: Well, it sounds outlandish, but in fact it’s become quite trendy among certain circles. Basically a fecal transplant is taking feces from a normal healthy patient and putting them either by enema form or by a tube going down the nose into the stomach, normal fecal material, which has a normal set of bacteria, viruses and fungi with the idea of restoring one’s balance more toward normal. It’s used clinically with great efficacy, it’s probably the best way of getting people who have recurrent C. diff. infections back to normal.

Falk: It’s been remarkable.

Sartor: Yes, 93% in a New England Journal of Medicine study, people responded to up to two fecal transplant, most with one transplant, 85% with one transplant. But with autoimmune diseases and IBD, it’s still speculative, it’s still experimental. There are YouTube videos, however, of people showing how to do a fecal transplant at home with your own blender, enema bag, etc. There are two groups of people—those who think it’s great, and those who think it’s pretty yucky.

Falk: There is a risk associated with it because you are now transferring from another individual potentially viruses that you don’t want.

Sartor: Absolutely. Not only viruses, but bacteria and fungi as well.

Falk: You could transfer a number of viruses that are threatening.

Sartor: Absolutely, that’s why it’s not ready for prime time. I think this isn’t the long term best approach, because done under medical supervision, there’s a very deep screening process to exclude all the pathogens that we know about. The trouble is that there are many viruses we don’t know about.

Falk: You’re excluding hepatitis B, hepatitis C, HIV, there are lots of viruses and pathogens who we can’t name that are going to be in fecal transplants also.

Sartor: Not only that, but there’s been some evidence at least in mice that fecal transplant from an obese donor can transfer obesity, for example, to the recipient. So I believe the wave of the future is going to be in defined cocktails of bacteria that are grown in the test tube. Therefore you know that there’s no contamination and that they’re safe, and also you can match the transplant with the defects, the abnormalities in the recipient.

Butyrate & fiber

Falk: You have used the word “butyrate” on several occasions here. What is butyrate, how can I get it, and what should I know about it?

Sartor: Butyrate is a bacterial product that is the consequence of metabolism of non-absorbed carbohydrates, particularly fiber in the diet. That’s why eating fiber is beneficial. Butyrate has many functions in our intestines. Number one, it feeds the colon epithelial lining, the lining cells of the colon, it helps restore their activity, helps heal an inflamed area. Secondly, it has very important immune function. It decreases the activity of the aggressive T cells and decreases the proinflammatory mediators.

Falk: So we all want some butyrate running around.

Sartor: Well, we all do, and it also increases those regulatory T cells that I mentioned. The problem is, taking butyrate is very difficult because it is rapidly metabolized outside the body. So the best way to get it is to produce it in your body—so have beneficial bacteria, feed them a high fiber diet, and voila, you get butyrate in the right location.

Falk: What’s a high fiber diet that you would recommend?

Sartor: Well, the bacteria tend to preferentially use bran products, whole wheat bread, bran cereals, rather than vegetables and cellulose, which is lettuce, for example. I think if you wanted to feed your bacteria and stimulate good responses, probably a high fiber diet with bran cereals, muffins, oatmeal would be predominant rather than salad-based.

Possible future treatments

Falk: If you project out into the future and think about how one would want to treat inflammatory bowel disease in particular, autoimmune disease perhaps in general, let’s move forward 10, 15, 20 years and you’re going to do it from a microbiome-changing approach, your thought is then to harvest very particular bacteria. How would you pick those bacteria? How would you pick those bugs?

Sartor: In the animal models, we’re picking them by measuring beneficial immune responses. We have mice that are genetically engineered to have their cells light up with a green fluorescent protein when they are producing beneficial substances like IL-10. So we can put in different cocktails of bacteria and look at protective immune functions. The reason this is important, as I mentioned earlier, I think we can define bacteria that normally grow in the gut, and harness their protective activities and try to create cocktails of beneficial bacteria, and that’s where I would love to see the field go over the next 5, 10, 20 years. We currently emphasize bashing the immune response and knocking the immune response down. It’s very effective at blocking inflammation, the trouble is the side effect is opening the door for infections. What I would love to do is augment that approach by using bacteria and natural products to stimulate protective immune responses, stimulate the lining of the gut, and even alter the profile of the protective bacteria. I think if you do that in a very nontoxic, and hopefully cheap approach, with the combination of carefully thought out probiotics, carefully thought out diets that are palatable and try to minimize the use of immunosuppressive drugs over the long haul.

Falk: It might be helpful to think about prevention of disease in the first place. One could imagine in a susceptible individual, to modulate the microbiome before the disease occurred.

Sartor: I’m really glad you brought that up, because the ultimate frontier is prevention. We know that many of these immune-mediated diseases—which is my preferred term over autoimmune—happen in families. We know that there are 200 genes associated with Crohn’s disease. It would be wonderful, if at age 2, when one has the microbiota that you’ll have for life, you go in and measure the levels: is it normal or abnormal? If it’s abnormal, correct it early in life where it’s probably more amenable to correction and hopefully prevent onset of disease rather than wait for symptoms to happen and then try to catch up and treat.

The Hygiene Hypothesis

Falk: You have brought up the important concept that the microbiome of an individual is established by age 2, and then tweaking occurs thereafter. Then nicely pointed out that after the age of 2 perhaps one could think about preventative. One of the thoughts about what might cause autoimmune processes is that kids are in sterile environments and are not exposed to bacteria and other bugs in the soil—it’s called “The Hygiene Hypothesis.” We’ve become so fastidious about wiping out every germ in our environment that we’ve created an environment that’s potentially detrimental to the long-term health of our children. Any credibility from a microbiome experts to that hypothesis?

Sartor: I think there’s quite a bit of evidence that epidemiologically, that many of these immune-mediated diseases preferentially occur in Western Europe and America that are industrialized and tend to have a very clean environment. In fact, many studies have shown cities, urban areas, have a higher incidence of these diseases than rural areas. If you have pets in the house, it’s protective. If you’re the second child in the family, it’s protective. I think there’s a lot of epidemiologic evidence. I like the idea—it’s still a hypothesis, it’s not proven—but I like the idea, because as mentioned, the normal gut bacteria are critically important in shaping one’s immune system. If there is delayed exposure to these normal complex gut bacteria that live in dirt, that live in less pristine environments, then the immune education is delayed. There’s some evidence in mice that I think is quite well done that there’s a window of opportunity, that if you don’t educate the immune system during a critically important time, maybe pre-weaning, or certainly during the weaning process, you’ve lost the opportunity to develop protective immune responses. So I think there are huge opportunities to explore this in man and capitalize on that, again, in the prevention concept.

Falk: So we should all have our children and grandchildren go roll out in the dirt.

Sartor: I’m a strong believer in eating dirt.

Falk: Thank you, Dr. Sartor. And thanks to our listeners for tuning in. If you enjoy this series, you can subscribe to the Chair’s Corner on iTunes or like the UNC Department of Medicine on FaceBook. Stay tuned for our next episode.

*

//