The microbiome is a broad topic. What specific areas are you most interested in?
Dr. Cresci: I originally got interested in the microbiome back in the nineties, when I was working in a critical-care setting. As a nutrition support dietitian I was caring for patients receiving enteral feeding. Immune modulated enteral formulas were just being introduced. That was about the same time when antibiotics started to go to the wayside, with bacteria becoming more resistant to antimicrobial therapies. We were trying to enhance the host’s own immune system in order to be able to fight off infections and not have to rely on antibiotics, by feeding immune-modulating nutrients. I started getting interested in the microbiome because of that concept. Research was beginning to look into the microbiome and appreciate the role it has in modulating immunity.
Since then, I got my PhD in biomedical sciences, with a major in biochemistry and molecular biology. I was interested in learning more about the molecular and cellular effects of probiotics and their fermentation byproducts. I studied different receptors and transporters expressed in the intestine that we learned interacted with short-chain fatty acids, fermentation byproducts of the gut microbiota. I’ve been particularly interested in the short-chain fatty acid, butyrate.
Butyrate is an important molecule to intestinal wellness; it helps keep the colon healthy. While I am interested in the microbiome, I am particularly focused on on how it becomes dysregulated. My research involves both animal and human research in which there is a disease association with gut dysbiosis. My laboratory investigates different nutritional-based therapies with the goal of restoring homeostasis in order to correct the pathology.
Are you a pediatric specialist as well?
Dr. Cresci: In the last year, my primary appointment moved to pediatric gastroenterology, but I still work in different areas with adults. It is interesting to think about studying the microbiome in a pediatric population exciting, actually. With this population the opportunity arises to prevent progression of dysbiosis-associated diseases by identifying and mitigating it early. We have started recognizing that in different diseases states there are early microbiome alterations in a pediatric population, therefore being able to remedy progress to adult disease is an interesting concept.
Are you able to see changes in a child’s microbiome that can impact or improve health more rapidly than in an adult? Is it easier to change the child’s than an adult’s?
Dr. Cresci: Studies have shown that the microbiome shifts within days of a dietary change. The more lasting changes take a bit longer. Changes have been observed pretty quickly in both populations, but I would speculate that in pediatrics the negative shifts would revert more readily back to a healthy state than in adults because they haven’t, hopefully, been exposed to so many negative altering factors. It just depends upon what is going on with the individual.
When you first address cleaning up the microbiome for either adults or children, what is your first step?
Dr. Cresci: I would first address their diet. The first thing would be to eliminate processed foods, as much as possible. There are so many additives and preservatives that are foreign to the microbiome, which doesn’t have the metabolic machinery to handle it—just like we don’t, as the host. Most of the dietary approaches to treating gastrointestinal functional gut disorders, share the elimination of processed foods as a main component. Accompanying elimination is to enhance the diet with the preferred food sources for the microbiome. That would be increasing fermentable soluble fibers. That can be accomplished through consumption of fresh fruits and vegetables and whole grains. Some fermented foods can also be added, and at the same time meats and saturated fats and simple sugars that are disruptive can be eliminated
You said that you originally got into this research because of ineffectiveness of antibiotics. Do you think that antibiotics can be replaced with diet?
Dr. Cresci: There is definitely a need for antibiotics for certain infections. But a lot of disorders in the gut are treated with antibiotics, and in most circumstances it is antibiotics that caused the problems in the first place.
For instance, for small intestinal bacterial overgrowth (SIBO), one of the main treatments is to give more antibiotics. We have actually done studies here, at Cleveland Clinic, where we gave the patient a probiotic that secretes its own antibiotic —a bacteriocin. This antimicrobial protein is secreted right at the site where the pathogen is causing havoc. The effect becomes localized, as opposed to giving an antibiotic systemically that causes lots of other destruction. That is just one area.
Another area of my research investigates negative effects of antibiotic use and what can happen when the immune response is inadequate. An ever-increasing problem in hospitals and the community is Clostridium difficile infection. I have been studying Clostridium difficile infection and trying to develop a targeted synbiotic approach for that situation. With this we combine a targeted commensal bacteria with a prebiotic that upon fermentation will yield increased amounts of a metabolic byproduct; in this case we are targeting butyrate yield. We’re trying to protect the gut, not only the gut’s integrity, but also the gut’s immune function when attacked by antibiotics and then exposed to pathogens.
What about prebiotics?
Dr. Cresci: A prebiotic is typically a naturally occurring polysaccharide that the host cannot digest but the gut microbiota can ferment. Upon ingestion, prebiotics help to maintain a “healthy” gut microbiota diversity and functionality. My laboratory takes a synbiotic approach, one which combines a prebiotic with a probiotic. Because each strain of bacteria has different properties and therefore behaves differently, we give a targeted a strain of bacteria, such as a butyrate-producing bacteria, and combine it with a targeted prebiotic, such as one known to yield butyrate upon fermentation, with the goal of maximizing intraluminal butyrate when butyrate is known to be depleted.
For the young-adult population right now, who as kids took antibiotics for every little thing, do you think that childhood exposure is related to gut issues that they are having now?
Dr. Cresci: It would be my speculation that it is. After one course of antibiotics, most people rebound and their microbiome shifts back to what it was before they took the antibiotic. But when there are repeated courses of antibiotics—and each antibiotic has different effects on the bacteria—it not only affects the bacteria, it also affects gut integrity and immune function. Several papers have done very nice work in reviewing how different antibiotics affect both. When you, in the long run, alter both of those factors, that can lead to a lot of other problems down the road.
Is it a struggle to convince the doctors to look at a treatment course other than an antibiotic?
Dr. Cresci: It’s interesting. This morning I gave grand rounds to physicians—all pediatricians. I asked them, “How many of you have heard of the microbiome?” And they had. So I asked, “How many of you recommend probiotics?” And half of them raised a hand. So then I asked, “Well, do you know what you’re recommending?” They had to admit that they did not.
They just say, “Take a probiotic.” But they have no idea. I think more and more physicians are on board with the fact that probiotics are out there, and maybe that you should take one when taking antibiotics, but they do not know anything more than that. I actually had the question today—I get it all the time—”Should you take the probiotic with the antibiotic? And how should you do it?”
Awareness is becoming more and more prevalent amongst clinicians, and even the patients. The lay population are reading about it; you can pick up magazines or hear commercials for it. As people become more aware, they are asking the doctor about it. So, it is coming full circle, and it is prime time to educate. Has a bacterial strain been studied and shown to have the properties of a probiotic and then shown to have any beneficial effect.
The counts of colony-forming units, or CFUs, are emphasized but not necessarily what is the focus when trying to interact with a certain situation. While 1 billion CFU is typically emphasized, in my animal research, a million also shows a beneficial effect. The real message is that probiotics are strain-specific. So, make sure that the strain of bacteria you are providing has been studied for whatever it is that you’re trying to treat, and then use the right strain.
For example, there are commercially available probiotic products targeted for bowel regularity. They contain a probiotic strain that has been studied to help regulate the neuroendocrine and motility function of the intestine. But that same strain will not likely protect immune function for someone taking antibiotics. There are other strains that have been identified to assist with that scenario. However, people become confused and take the motility promoting probiotic for antibiotic prescription and then do not realize a benefit and conclude probiotics don’t work.
Probiotic is such a generic term. It is like saying, “Have a drink.” Okay, a drink of what? What does that mean? Each strain is unique in its mechanism of action, and may react differently in different environments, too.
Most of the original work with probiotics was done in children, in an outpatient setting, in children with ear infections. Probiotics were given because the children were taking an antibiotic; the probiotic strains studied were beneficial in preventing antibiotic-associated diarrhea. So, while a particular strain is effective in a pediatric population, or an ambulatory population, it may not have the same effect in a geriatric population, or those hospitalized that are taking antibiotics. When providing the same probiotic strain they still have diarrhea. What might be going on?
There are several things potentially going on there. A pediatric population and a geriatric population that are both healthy have different microbiome composition in their gut. We know that as you age the microbiome changes. For instance, if a Lactobacillus species was provided and the benefit found in a pediatric population was not found in the elderly population, it could be that the elderly population has a higher abundance of lactobacillus bacteria. Therefore, providing more lactobacillus when it’s not depleted will not result in any benefit. It’s similar to taking a vitamin-C supplement if you are not vitamin-C deficient; it is not likely going to help you.
Therefore, it’s important to understand what is lacking and then work towards restoration. This is is where the research is still in development. The other component is these bacteria are viable. They are living organisms, so they are going to behave differently when they are in a different metabolic environment. And so strain specificity is important. Even within the same lactobacillus species, each strain is going to behave differently.
I like to use the analogy of canines; like a dog, a pet, and a wild wolf. They are both canines, but we know that a golden retriever will have a different disposition than a wolf. The same thing goes for bacteria. When exposed to various environmental conditions, (e.g., altered pH, temperature, ion concentration, energy supply), they are going to behave differently. Just because they are all Lactobacillus doesn’t mean that they all behave the same all the time.
So, how does this relate to the presentation that you’re going to be giving?
Dr. Cresci: I am going to talk more about the metabolic byproducts of the gut microbiome and how that influences health. I mentioned how there is gut dysbiosis, which is important, but I am more interested in how that alters the host. The microbiome does many good things for us. It helps synthesize different vitamins and enzymes—all these fermentation byproducts. And we know that when there is dysbiosis, there are alterations in the output of those, which is associated with pathology. So how can we correct that? By correcting the microbiome, can correct some of these negative effects? Or, can you just give back those byproducts and get a beneficial effect? I am going to talk more about that.
What do you hope that the people who listen to your presentation are going to come away with?
Dr. Cresci: I hope they come away with an idea of how to protect the gut microbiome and address gut dysbiosis. Hopefully, they will think first to clean up the diet. Then, based on any improvement—or if there is no improvement— what else can be attempted? There are ways to specifically target certain aspects of the gut microbiome. The bacteria may be depleted and need to be repleted. Or overall diversity numbers may be down. Can you address that through a prebiotic supplement? So, hopefully, they will begin to think through the situation in a more focused way to actually tackle the problem.
Gail A.M. Cresci, PhD, RDN, is a staff member in the departments of Pediatric Gastroenterology and Inflammation & Immunity in the Pediatric and Lerner Research Institutes; and Director of Nutrition Research within the Center for Human Nutrition in the Digestive Disease & Surgery Institute at Cleveland Clinic and assistant professor of medicine at Cleveland Clinic Lerner College of Medicine and of Case Western Reserve University. She has published more than 85 peer-reviewed manuscripts in the areas of nutrition, critical care, surgery, and the gut microbiota and its fermentation byproducts. She is currently involved in research to develop strategies for correcting the negative effects of gut dysbiosis including protecting gut integrity, intestinal inflammation and immune function, and associated liver injury. In particular she has been investigating the role of the fermentation byproduct, butyrate, in protecting immune function and gut-liver injury induced by ethanol consumption, intestinal injury caused by antibiotics, as well as reducing Clostridium Difficile colonization.
