Dr. James Versalovic, M.D., Ph.D, is the director of the Texas Children’s Hospital Microbiome Center and head of the Pediatric Infectious Diseases Section. He is also a professor at Baylor College of Medicine. As the Gut Microbiota for Health expert on research tools, Dr. Versalovic spoke with us about his pathology and immunology research related to the gut microbiome.
How did you become interested in studying the gut microbiome?
In graduate school as an M.D./Ph.D. student at Baylor College of Medicine here in the U.S., [I] was very interested in how microbes cause infections. That was a main clinical area of interest. And when I moved to Boston to continue my training, we were studying mouse models of human disease, and that’s when I began to get fascinated by the commensal, or beneficial, microbes that live within us, and studying the different responses of mice that were related to differences in their microbiomes. Of course, we didn’t call it the microbiome at the time in the late 1990s, but the real impetus was, at that time, understanding that mice that had different bacterial communities in the intestine had different susceptibilities to disease.
I began [by starting] my own laboratory when I finished my training in Boston at MIT and the Massachusetts General Hospital, to try and understand how gut microbes that were not causing infections — the commensal or beneficial gut microbes — how they were communicating with the immune system and affecting GI physiology.
What led you to study children?
In terms of medical specialties, I was torn between pediatrics and pathology. I was very interested in medical microbiology, so I decided to do pathology, and medical microbiology within that, but I was always very much interested in human development and pediatrics. So when I had the opportunity to move to Houston to direct the medical microbiology laboratory at Texas Children’s Hospital, I jumped at the opportunity. Since then, [I] have tried to fuse my interest in the gut microbiome with pediatrics. I’ve been most interested in how our microbiomes contribute to early development, and also how they impact diseases in children.
What is unique about studying these concepts in children?
Children tend to be less affected by these secondary things… there are many confounding factors that influence disease, and children are relatively ‘clean’ to study. They’re a little bit easier in that they haven’t lived as long.
Every area has its complicating features, and [temporal dynamics is] certainly one in pediatrics. The changes over time are definitely more substantial than what we see in adulthood.
How does your work with children contribute to knowledge about adult disease?
We have been very interested in mucosal immunity and intestinal inflammation since I started the laboratory because… we were studying colitis in the mouse as a model of inflammatory bowel disease (IBD). We were immediately interested in how gut microbes could suppress inflammation [in general]… But we also realized that children have intestinal inflammation and babies get necrotizing enterocolitis, and children and adolescents, but even pre-adolescents, get ulcerative colitis or Crohn’s disease or IBD, so it is relevant to pediatrics.
Because of this whole framework that was developed in the last 10 or 15 years around the developmental origins of human disease… we’re appreciating much more the impact of those disorders early in life and what it means in terms of lifetime risk of diseases that appear in adulthood. We know that IBD increases the lifetime risk of colorectal cancer, for example, and so by studying children with inflammatory bowel disease, we are hoping to make an impact on their risk of getting colorectal cancer later in life.
So things that may seem to be much more adult actually have their origins in childhood, like cancer… We’re also studying recurrent abdominal pain, irritable bowel syndrome (IBS), which is very common in children and common in adults. In fact, many children who have IBS… will continue to have IBS as adults. So again, the connection between pediatrics and adult medicine is very important to us.
Can you give us some highlights of your recent research projects?
In the area of intestinal inflammation and the gut microbiome… I’ll highlight the story of histamine and amino acid metabolism. We’ve discovered that gut microbes can convert amino acids that come from protein in the diet to… different compounds. And one chemical compound that’s made is histamine. Now, we know antihistamines and the common cold, and the fact that antihistamines may provide symptomatic relief [as] over the counter medications. But we’re talking about histamine now in a different way. It’s working through a different receptor, and in the gut, histamine, it seems, can suppress inflammation. We are now realizing that this may be one of the chemical signals that bacteria make in the intestine that can modulate immunity and suppress inflammation. So we’re doing more work about that.
This has led us to put a lot of effort into microbiome-mediated biochemical conversions in the intestine: so, how do microbes change or alter the metabolites that may be there in the gut?
In the area of recurrent abdominal pain we know that the children with abdominal pain have different bacteria in the intestine, there are differences in the bacterial community… We are now focusing on the metabolites… that are different in children with IBS and healthy children. So we’re now trying to understand that. We haven’t published that yet, but that’s very recent.
We’re trying to bridge in the Microbiome Center microbial metabolomics with the metagenomics, so connecting the genes in the microbiome to the pathways and the compounds that are made, that may provide new biomarkers to help us diagnose patients, and to help us manage patients with different diets. An example is that we’ve worked with our pediatric gastroenterologists and identified some differences in patients who respond to a specific diet for IBS. They have a lower pain frequency.
I would add, beyond the intestine, we’re doing some work in the airways, in pulmonary medicine. We’re studying changes in the microbiome of the human airway that may help us predict who is at risk for complications following lung transplantation, and the features of the… pulmonary microbiome, that may also give us information regarding cystic fibrosis (CF) and the progression of CF in pediatric patients.
In the area of Clostridium difficile infection in children, we are using fecal transplantation to change the microbiomes of children. So our center is working also actively in medicine to collect donor feces and advance the science of fecal transplantation for both C. difficile infection and refractory ulcerative colitis. So that’s a new area of clinical research and we’re studying how these patients respond, how their microbiome changes in both disorders.
What are some of the biggest challenges in your research?
Certainly the biggest challenge we have is in trying to bridge: bringing together the multi-omics and the comprehensive data sets that we’re generating, to really integrate those and to bring the DNA/RNA sequencing data with the protein and metabolomics data, and to mesh that with the clinical phenotype, and even the evaluation of healthy individuals in different age groups with different diets and different ethnicities. Bringing all of that together and creating an intelligent framework to understand how differences in the microbiome contribute to health and disease and how we may be able to explain susceptibility to disease based on the function of the microbiome and then how we may be able to change the microbiome to treat, manage, or cure disease, this is a big challenge… Multi-omics is the big challenge and being able to handle huge amounts of data will require continuing evolution of the field of bioinformatics and large-scale big data analysis.
The second challenge beyond the analysis is, then, what do we do it with [the data]? How do we really utilize this? It’s just going to take years to continue step by step to find ways in which we can harness our knowledge of the microbiome to help us promote dietary changes that can prevent disease, and to use different methods of changing the composition and function of the microbiome to manage or cure disease. So those are big challenges for medicine, and as I call it, ‘metagenomic medicine’, [to] try and get beyond fecal transplantation to more refined, sophisticated approaches in which we can take particular elements of the microbiome and use them to our benefit.
You mention the role of dietary changes. In your medical practice, how do you use diet to help manage disease?
In IBD we know about elemental diets, which are largely amino acid based, used more commonly in Europe, that seem to have played a very effective role in managing or mitigating the disease in some IBD patients.
In IBS, the latest is FODMAPS, or low fermentable substrate diets (LFSD), which are basically diets that are deficient in certain carbohydrates. You can think of them as a low-carb diet. And what that does is it takes out some of the sugars that are actively fermented that may lead to the production of gas and other compounds in patients, that would exacerbate their abdominal pain. There have been multiple studies that have been published in the past several years in the adult and pediatric GI literature that lend support to the use of this special FODMAP or LFSD in some IBS patients, so there are subsets of patients that will respond to changes in diet, and other patients that will not respond… those that respond have… specific bacteria in their gut microbiome, and specific metabolites produced from their gut microbes. So those compounds and microbes may be biomarkers that simply help us predict who may or may not respond; they may also help explain why some patients respond, and that’s still a work in progress.
In the video appearing below, you say, “Our efforts will ultimately be about making the microbiome a better partner with those patients with different GI and other metabolic diseases.” How do you see this happening in the future?
It does get back to lifestyle and diet. Of course there are other factors in addition to diet that may help us fine-tune the microbiome in terms of its composition and function, so it’s not just about who’s there but what they’re doing and how they’re behaving.
I think clearly diet will have a lot to say about that. And it’s not just diet in a very general sense as we’ve become accustomed, over the years, to dietary recommendations for the general population, but hopefully allowing us to tailor things. We’ve talked about personalized medicine for years and, what does that really mean? Here’s the opportunity for partnership. If we can analyze somebody’s microbiome, which we’ll be able to easily do — we can already do it now in terms of bacterial composition fairly easily… and then determine the best match of diet and microbiome to try and enhance its good or beneficial elements and try to suppress anything that could hamper human health. That customization, if you will, and the ability to maximize the function of the microbiome will depend on diet as well as possibly exercise and other factors. I think it will help us to tailor things more effectively, so that we’re not just talking about human genetics and somebody’s genetic predisposition to disease, but their microbiome as being another big element.
Beyond that, when it comes down to patients getting beyond optimizing human health and preventing disease, certainly when we have patients that we can study like we do now… we can see not only that the microbiome is ‘sick’, it’s abnormal. But how is it abnormal, and then how might we be able to fix it? So that hopefully… by being able to provide the missing elements or simply add things that enhance the function we then can help the microbiome be a partner in allowing somebody to recover from disease, or at a minimum to have fewer symptoms.
This interview has been edited for clarity and length.
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