The Gut Microbiota: Our Microbial Allies

Approaching and addressing health from the microbiota perspective

Anyone who has had a digestion problem, or anyone living in the age of well-being in general, has probably been advised to "eat more yogurt," or to "eat more fiber." One of the reasons why probiotics like yogurt or dietary materials like fiber are so important is that they feed the microorganisms lining our gastrointestinal tract (i.e. the GI tract) that supplement our health. From birth to old age, this gut microbiota plays a key role in human health as it partners with our body to carry out essential functions. The trillions of microbes, representing thousands of species of bacteria in our GI tract, help us digest and process the foods we eat, producing some of the vitamins and byproducts that are most vital to our body. Because of its importance, many even believe that we should consider the microbiota to be another organ in the body. Dr. Claire Fraser, Professor of the University of Maryland School of Medicine and Director of the Institute for Genome Sciences, studies the structure and function of the gut microbiota in health and disease, with the ultimate goal of designing interventions through diet, probiotics, etc., to promote homeostasis in the gut to maintain health and/or mitigate disease.

While the overall composition of the gut microbiota is similar in most people, there is a great deal of inter-individual variability that likely reflects host genotype, diet, environment, and other factors; as humans, we all carry a different makeup of these communities of microbes -- like how we each have different fingerprints. The significance of these differences across individuals from a functional perspective is one of the most important areas of Dr. Fraser's current research. Another area that Dr. Fraser investigates is how changes in microbiota affect our health. The composition of the microbiota is relatively stable over time for the most part, but it can change in some situations, creating a condition known as dysbiosis, which has been described in a number of diseases. Dr. Fraser and her lab are studying dysbiosis in Crohns' disease, obesity, diabetes and the metabolic syndrome, as well as in people with HIV infection. A major goal of this type of research is to determine whether or not we can restore homeostasis in the gut microbiota following perturbation, and what interventions may be most effective. Many studies have demonstrated the beneficial effects of prebiotics and probiotics, and Dr. Fraser's laboratory is carrying out detailed studies to elucidate the mechanisms of actions of these interventions.

Current areas of focus include:

  • Longitudinal changes in the gut microbiota in patients with Crohn's disease - Crohn's disease is a type of chronic, inflammatory bowel disease that cannot be cured. The nature of this disease is such that patients move between flare-ups and remission, and  a myriad of powerful treatments are used to keep the disease under control. Dr. Fraser and her team are looking at how the gut microbiota changes over time in patients with Crohn's disease, studying how these changes in the microbiota may contribute to remission and flare-ups. Their hope is to track and understand why Crohn's disease patients are missing some of the beneficial bacteria that reside in the human gut, and how this change may contribute to the symptoms of the disease. They also hope to use that information to develop a test to predict when patients are going to have a flare-up, which will allow them to target the disease accordingly. In order to intervene in a positive way, they must understand what is changing; the first step is to figure out how fluctuations in the gut microbiota are correlating with different stages of the disease, and once they have that information, they hope to design new strategies that will target the microbiota part of Crohn's disease.

  • Impact of the gut microbiota on the response to live oral-attenuated vaccines against Salmonella and challenge with virulent Salmonella: Salmonella is an intestinal pathogen and a source of food poisoning, particularly in developing countries. Transmitted by contaminated food and water, Salmonella causes very bad diarrhea and some children can die from Salmonella infections. Just below the layer of cells lining the GI tract is a very complex network of immune cells, the largest immune organ in the body. When Salmonella gets ingested, it interacts is with the immune system in the GI tract. Dr. Fraser and her team are collaborating on efforts to develop oral vaccines for Salmonella, that will target the immune system in the place it is most relevant. In their previous work in humans as well as non-human primates, the team discovered that the response to an experimental Salmonella vaccine is different for each individual; people who had a very high diversity gut microbiota responded better to vaccines and were reasonably well protected when challenged with Salmonella. Such results validate the premise that when we understand how differences in the gut microbiota across individuals can impact our physiology, then we can intervene in a way that affects a beneficial outcome. Dr. Fraser thus aims to understand the interplay of the gut microbiota, the immune system, and intestinal pathogens.

  • Influence of the gut microbiota on the growth and development of infants born to mothers who are infected with HIV but on antiretroviral therapy: Targeted to countries like Nigeria where the prevalence of HIV is very high, this study aims to understand ways we can improve the development of babies born to mothers with HIV-infection. Although now people can live with rather than die from AIDS thanks to antiretroviral therapies, infants born to HIV-infected mothers on antiretroviral therapies still struggle through their growth and development. Babies obtain their microbiota from their mothers during birth, and the microbiota in women with HIV is different from the microbiota in women without HIV, a difference that may have long-term consequences for these newborns. By comparing the microbiota in HIV-infected and uninfected mothers and in their babies during the first two years of life, Dr. Fraser hopes to understand how differences in the microbiota in young infants may impact normal growth and development, with the ultimate goal of finding a way to restore the normal microbiota in infants born to HIV-infected women.

  • Impact of probiotics on the commensal gut microbiota in healthy adults: Another important focus of Dr. Fraser's research is on the effect of probiotics on the structure and function of the gut microbiota. Although probiotics have been used for hundreds of years and are claimed to be of benefit in maintaining health, the tools to specifically study their effect on the microbes that live in the gastrointestinal tract have only recently become available. Dr. Fraser's laboratory is one of the first to specifically investigate how probiotics impact the gut microbiota in ways that might benefit us as the host. One of the recent results from her lab shows that a particular probiotic, Lactobacillus rhamnosus GG, changes gene expression in gut bacteria that produce butyrate, a compound which has been shown to have anti-inflammatory properties. Another important question that Dr. Fraser's work is addressing is whether a single probiotic organism has a different effect in different individuals -- a hypothesis based on the fact that we are all carriers of different microorganisms. Ultimately, this work may lead to a more rational approach to the use of probiotics -- targeting the right probiotic to the right person based on knowledge of the properties of his or her gut microbiota.

Bio

Interested in science from an early age, as a kid Dr. Claire Fraser had a rock and mineral collection (basically a lot of rocks) and studied those rocks for hours at a time using a magnifying glass. Then, in her freshman year of high school, she took her first biology course and could not stop talking about how exciting it was to dissect a frog and see inside a complex organism. From that point on, Dr. Fraser admits, she "couldn't get enough exposure to biology."

Dr. Fraser went to Rensselaer Polytechnic Institute as an undergraduate so she could concentrate on science courses, and while she was interested in chemistry and physics, the courses in the life sciences continued to capture her imagination. She believed she would go onto medical school; she didn't know any other way to make a career out of her interest in science. But during her senior year at RPI, she took an advanced laboratory research course and worked with Dr. Lenore Clesceri on isolating and characterizing bacteria from Lake George that could use herbicides as a sole carbon source. She spent every spare moment in the lab, and realized as the year drew to a close that she wanted a career in research more than anything else. She thus hastily changed her plans and started to apply to graduate schools and started as a Ph.D. student in Pharmacology at SUNY Buffalo in August 1977.

Dr. Fraser's thesis work was on the molecular characterization of beta-adrenergic receptors, and one of the most important lessons she learned in graduate school was to never be afraid to try something new -- even if people thought it couldn't be done. For her, that was the goal of generating monoclonal antibodies against the receptors she was interested in.

Dr. Fraser spent nearly 20 years working on this important receptor family and assumed that it would be the focus of her entire career. However, in the late 1980s, automated DNA sequencing first emerged as a new technology and it was a game-changer in the field of molecular biology. Dr. Fraser quickly applied these new approaches to the study of receptors with great success.

Through an unexpected opportunity, she had the chance in 1994 to use the same approaches to try to decipher the first complete genome sequence of the bacterium, Haemophilus influenzae. While the sequencing of the H. influenzae genome was a landmark event, the speed at which the new field of microbial genomics advanced was unprecedented. This was due to the almost single-handed efforts of Dr. Fraser, whose name is synonymous with microbial genomics. The impact of Dr. Fraser's work is extraordinary. Between 1997 and 2008, she was the most highly cited investigator in the field of microbiology - her published work has been cited more than 56,000 times. In 2005, she and her colleagues began to apply the same approaches that had been used to study single bacterial species to the study of complex microbial communities. She is fascinated by the microbes that live in and on the human body.

Outside of her research lab, Dr. Fraser enjoys fly fishing, ballroom dancing, and making jewelry, working mostly with gemstones and pearls as well as Japanese braiding. She also enjoys making wine, which allows her to use her microbiology background; just as yeast ferments the sugar in grapes to make the alcohol, bacteria in the GI tract ferment sugars or fibers to generate beneficial byproducts. In addition, Dr. Fraser enjoys is participating in agility/obedience competitions with her two Standard Poodles.

Awards

Maryland's Top 100 Women, 1997

Ernest Orlando Lawrence Award, Department of Energy, 2002

AAAS Fellow, American Association for the Advancement of Science, 2004

Elected into the Institute of Medicine of the National Academies, 2011

Thomson Reuter's The World's Most Influential Scientific Minds, 2014