黑料网

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 黑料网 Division of Gastroenterology and co-directs the 黑料网 Multidisciplinary IBD Center.

Ron Falk, MD: Hello, and welcome to the Chair鈥檚 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鈥檙e going to be talking about something called the microbiome and how it affects disease鈥攁utoimmunity 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 黑料网 Multidisciplinary Inflammatory Bowel Diseases Center and is a world expert on inflammatory bowel diseases and the microbiome. Welcome, Dr. Sartor.

Balfour Sartor, MD: It鈥檚 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鈥檚 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鈥檚 function, in particular the immune function.

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

Sartor: Well, you鈥檝e 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鈥檚 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鈥攖he bad bacteria. The best example of bad bacteria is something called Clostridium difficile鈥斺�淐. diff鈥濃�攊t鈥檚 a toxin-producing bacteria whose spores are present in our gut all the time, but they don鈥檛 hatch because the huge number of normal bacteria prevent them from taking hold. If those normal bacteria are removed, then there鈥檚 an ecologic niche that can be filled by these pathogenic bacteria.

Falk: So every time a physician prescribes an antibiotic, what you鈥檙e saying is that鈥檚 going to alter the microbiome?

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

Falk: If one wants to try to improve one鈥檚 microbiome鈥攁nd we have to talk about if that鈥檚 even possible鈥攈ow can a patient alter their microbiome?

Sartor: It鈥檚 a great question, and it鈥檚 one that doesn鈥檛 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鈥檚 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鈥檛 require FDA approval, so there are many claims that really aren鈥檛 substantiated. Probiotics are a very popular area. If you go to any drug store, you鈥檒l see shelves of probiotics. The problem with the traditional probiotics is they aren鈥檛 the bacteria that normally live in the gut. So yes, they will colonize the gut if you eat yogurt that is non-pasteurized 鈥攜ou鈥檝e 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鈥檙e taking the probiotic, they鈥檙e there, and they鈥檙e functioning, but as soon as you stop, they鈥檙e gone鈥攏o staying power.

How the microbiome affects disease

Falk: What鈥檚 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鈥檒l 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鈥檚鈥攔egulatory 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鈥擳reg鈥檚 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鈥檙e very kind. I鈥檝e been working in this area and I鈥檝e been doing research here at 黑料网 since 1979. In a nutshell, we鈥檝e shown over the years that there鈥檚 a balance of beneficial and aggressive bacteria in our normal gut鈥攖hese aren鈥檛 the infections that we think about鈥攂ut in the normal gut, there鈥檚 a balance of good and bad bacteria. We鈥檝e 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鈥檛. 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鈥檚 microbiota.

Falk: So if you鈥檙e a patient with a newly diagnosed inflammatory bowel disease or another autoimmune disease having just listened to what you鈥檝e just said, you鈥檇 be saying to yourself, 鈥�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?鈥� 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鈥檛 ready for prime time鈥攜ou don鈥檛 want to stop your regular medications鈥攐ne 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鈥檝e talked about. I think we need to get better probiotics, the ones currently in use in the drug store don鈥檛 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鈥攔ecurrent 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鈥檚 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鈥檚 balance more toward normal. It鈥檚 used clinically with great efficacy, it鈥檚 probably the best way of getting people who have recurrent C. diff. infections back to normal.

Falk: It鈥檚 been remarkable.

Sartor: Yes, 93% in a study, people responded to up to two fecal transplant, most with one transplant, 85% with one transplant. But with autoimmune diseases and IBD, it鈥檚 still speculative, it鈥檚 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鈥攖hose who think it鈥檚 great, and those who think it鈥檚 pretty yucky.

Falk: There is a risk associated with it because you are now transferring from another individual potentially viruses that you don鈥檛 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鈥檚 why it鈥檚 not ready for prime time. I think this isn鈥檛 the long term best approach, because done under medical supervision, there鈥檚 a very deep screening process to exclude all the pathogens that we know about. The trouble is that there are many viruses we don鈥檛 know about.

Falk: You鈥檙e excluding hepatitis B, hepatitis C, HIV, there are lots of viruses and pathogens who we can鈥檛 name that are going to be in fecal transplants also.

Sartor: Not only that, but there鈥檚 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鈥檚 no contamination and that they鈥檙e safe, and also you can match the transplant with the defects, the abnormalities in the recipient.

Butyrate & fiber

Falk: You have used the word 鈥渂utyrate鈥� 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鈥檚 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鈥攕o have beneficial bacteria, feed them a high fiber diet, and voila, you get butyrate in the right location.

Falk: What鈥檚 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鈥檚 move forward 10, 15, 20 years and you鈥檙e 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鈥檙e 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鈥檚 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鈥檚 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鈥檓 really glad you brought that up, because the ultimate frontier is prevention. We know that many of these immune-mediated diseases鈥攚hich is my preferred term over autoimmune鈥攈appen in families. We know that there are 200 genes associated with Crohn鈥檚 disease. It would be wonderful, if at age 2, when one has the microbiota that you鈥檒l have for life, you go in and measure the levels: is it normal or abnormal? If it鈥檚 abnormal, correct it early in life where it鈥檚 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鈥攊t鈥檚 called 鈥淭he Hygiene Hypothesis.鈥� We鈥檝e become so fastidious about wiping out every germ in our environment that we鈥檝e created an environment that鈥檚 potentially detrimental to the long-term health of our children. Any credibility from a microbiome experts to that hypothesis?

Sartor: I think there鈥檚 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鈥檚 protective. If you鈥檙e the second child in the family, it鈥檚 protective. I think there鈥檚 a lot of epidemiologic evidence. I like the idea鈥攊t鈥檚 still a hypothesis, it鈥檚 not proven鈥攂ut I like the idea, because as mentioned, the normal gut bacteria are critically important in shaping one鈥檚 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鈥檚 some evidence in mice that I think is quite well done that there鈥檚 a window of opportunity, that if you don鈥檛 educate the immune system during a critically important time, maybe pre-weaning, or certainly during the weaning process, you鈥檝e 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鈥檓 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 or . Stay tuned for our next episode.

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