Probing the microbiome

Studies of people and their companion microbes shed light on health and disease

By Julia Evangelou Strait

Matt Miller
Jeffrey I. Gordon, MD, the founder of microbiome research, is also known as a dedicated and very influential mentor who has trained a next generation of leaders in this field. Carrie A. Cowardin, PhD, (left) and Vanderlene L. Kung, MD, PhD, are postdoctoral researchers in Gordon’s lab.

Even in our most solitary moments, we humans are never alone. On us and within us, tens of trillions of microbes live and thrive — not as passive hitchhikers, but as interactive, symbiotic shapers of our biology. From the time of our births, these microbes are at work, establishing distinct communities in many regions of our bodies.

In recent decades, scientists at Washington University have led the way in exploring how these microbial communities impact human health. Their work has shaped a new area of study that is revolutionizing our understanding of normal human physiology, metabolism, immunity, growth and neurodevelopment, as well as the roots of many diseases.

A new field emerges

Using the gene sequencing technology of the genome revolution, along with many other experimental and computational methods and tools, researchers worldwide are studying our microbial companions — considering them not in isolation, but rather in the context of the complex communities in which they dwell. Scientists are learning which microbial members exist in a given area of the body, what genes they collectively possess, what their genes do, how community membership varies from person to person, and ultimately, how these communities influence health and disease.

Matt Miller
Medical student researcher I-Ling Chiang pulls bacterial cultures from a freezer in the lab of Thaddeus S. Stappenbeck, MD, PhD.

The work has emerged as a new field called microbiome research, founded by Jeffrey I. Gordon, MD, the Dr. Robert J. Glaser Distinguished University Professor and director of the Edison Family Center for Genome Sciences & Systems Biology at Washington University School of Medicine.

Microbiome is the term given to the collective repertoire of genes possessed by microbes in a given community. Microbiomes are massive; the gut microbiome alone is made up of more than 100 times the number of genes in the human genome. In 30 years of seminal research, Gordon has revealed the fundamentals of how these communities first assemble, how they adapt, how community members cooperate and compete with one another, and how they interact with the human body. What’s more, he and his students were the first to link the gut microbiome to two of the world’s most vexing global health problems — childhood malnutrition and obesity.

“For human societies to flourish, our challenge is to do everything in our power to promote the healthy development of children so that they may realize their full potential,” said Gordon, also professor of pathology and immunology, of developmental biology, of medicine and of molecular microbiology. “There are dramatic disparities in the abilities of children in different parts of the world to live healthy lives. And somewhere in the midst of this challenge to promote healthy development sits the gut microbiome.”

Healthy communities

“No one else was doing this work when Jeff first started, and he was alone in the wilderness for a long time. Now, myriad microbiome projects at Washington University and around the world have built on Jeff’s science, in part because he has trained many of the next generation of leaders in this field,” said Phillip I. Tarr, MD, the Melvin E. Carnahan Professor of Pediatrics and professor of molecular microbiology.

Matt Miller
Barbara B. Warner, MD, left, Lori R. Holtz, MD, MSPH, and Phillip I. Tarr, MD, discuss their research on gut microbial communities in premature and healthy newborns.

Central to the field is learning how to nurture microbial communities in ways that enhance human health — much as one would cultivate the natural flora and fauna common to a forest or wetland to support a healthy, diverse and robust ecosystem. That ability could have massive public health implications, including checking infectious disease, resolving chronic inflammatory conditions, correcting metabolic dysfunction, and tackling the global problems related to the quality of our diets and nutrition — all at a time of rapid population expansion and challenges to environmental sustainability.

“This is a new frontier,” said Tarr, also director of the Division of Pediatric Gastroenterology, Hepatology, and Nutrition. “The rules are now just beginning to be written.”

Therapeutic foods

Central to Gordon’s current work is addressing malnutrition. He and his collaborators at the International Centre for Diarrhoeal Disease Research in Bangladesh have shown that children with malnutrition possess gut microbial communities that fail to develop normally, leaving them with communities that appear younger, or less mature, than those of healthy children. Moreover, current therapeutic foods do not repair this immaturity or correct the long-term effects of malnutrition, including impaired growth, metabolism, immunity and brain development. These findings have led his team to develop new therapeutic foods, composed of affordable, culturally acceptable components that advance development of immature gut communities and improve the health status of malnourished children.

“The Edison family greatly respects Dr. Gordon’s sound thinking and innovative research. His work has global importance and appears to be critical to helping malnourished children throughout the world.”

— Andrew E. Newman, Life Trustee and Edison family member
The Harry Edison Foundation and the Edison family made a major commitment to name the Edison Family Center for Genome Sciences & Systems Biology.

Their work is not only establishing a vital link between formation of healthy microbial communities and healthy growth, but also is revealing how microbial communities transform components of the foods we consume into products that influence numerous features of human postnatal development. At the same time, food science is revealing more about the components of various food staples and how plant genetics and food processing technologies and consumers’ microbiomes influence the nutritional content and value of those foods. Together, these advances should enable discovery, development and deployment of entirely new health-promoting foods and better dietary recommendations for children and their parents, Gordon said.

Preventing disease

Beyond Gordon’s lab, Washington University microbiome researchers are addressing other topics.

Tarr and colleagues Barbara B. Warner, MD, professor of pediatrics, and Gautam Dantas, PhD, professor of pathology and immunology and of molecular microbiology, for example, are studying the gut microbiomes of babies born prematurely. These babies are at risk of developing a potentially deadly condition called necrotizing enterocolitis, a progressive inflammatory process that begins inside the gut and causes tissue death. Sometimes antibiotics are an effective treatment, but some babies need surgery to remove dead tissue. Even with these aggressive therapies, about 30 percent of babies who develop the disease die from this catastrophic event.

Tarr and Warner have shown that babies who develop necrotizing enterocolitis have a different mix of microbes in their intestines than babies who never develop the disease.

“We’re still in the earliest stages of defining which microbes are good and which are bad,” Tarr said. “But broadly, we want to find out what factors make it likely for good microbes to get into the gut and stay and, similarly, what factors help the body get rid of bad microbes. The hope is to ultimately protect premature infants from ever developing this terrible disease.”

The virus hunters

Tarr and his colleagues — including David Wang, PhD, professor of molecular microbiology and of pathology and immunology, and Lori R. Holtz, MD, MSPH, associate professor of pediatrics — also have studied viruses living in the guts of healthy newborns. The viruses’ collective genetic material is called the virome.

“Not only are there many viruses in the digestive systems of infants that we had no idea were present, there are viruses that infect the bacteria in great numbers,” Tarr said. “And this almost certainly plays a role in how the bacterial community develops.”

Matt Miller
David Wang, PhD, right, and PhD student Luis Sandoval are studying viruses in the gut to learn more about their impact on health and disease.

Indeed, the bacteria, viruses and other microbes in the intestine together offer a picture of the gut environment that metaphorically resembles a backcountry wilderness.

And as they explore that wilderness, Wang and his team have viruses in their sights. Wang seeks out previously unstudied viruses to understand how they function and to learn more about how viruses cause disease.

“We want to understand the nature of the whole virome and how it may be associated with health or disease,” Wang said. “We’ve done this in the context of a number of diseases, including acute diarrhea, HIV/AIDS, type 1 diabetes and inflammatory bowel disease. This has been fascinating because we had no idea what to expect.”

“If we are able to help mitigate suffering in any way, that’s a larger contribution to humanity than Debra and I ever envisioned we would have. We feel very fortunate that we can do something that has such potential to help others.”

— George W. Couch III, Trustee
Debra and George W. Couch III provided significant campaign support for research in personalized medicine; in their honor, the university named the Debra and George W. Couch III Biomedical Research Building.

Working with Thaddeus S. Stappenbeck, MD, PhD, the Conan Professor of Laboratory and Genomic Medicine, Wang and colleagues found that the virome in patients with inflammatory bowel disease is different than the virome of healthy people, suggesting viruses may play a role in the development of this condition.

Guardians of the gut

Stappenbeck’s work examines the interaction of gut microbes and human gut tissues, including agents he calls “guardians of the gut.” One such agent is an antibody called immunoglobulin A, or IgA. IgA coats gut microbes and may well calm the response of our immune system to the microbiome. Another is a cell type in the gut lining known as Paneth cells.

“These cells protect the inner lining of the gastrointestinal tract by making a variety of antimicrobial proteins,” said Stappenbeck, also a professor of developmental biology and a former postdoctoral fellow in Gordon’s lab. “In doing so, they help shape the microbiome present in the gut. We know that mice with defective Paneth cells can develop worsened gut inflammation. This suggests that we can use the genetics of the abnormal Paneth cells to diagnose the type of inflammatory bowel disease a patient might have.”

Matt Miller
Thaddeus S. Stappenbeck, MD, PhD, right, reviews slides with postdoctoral fellow Umang Jain, PhD.

A better understanding of these guardians and others may contribute to better ways to diagnose, treat or prevent inflammatory diseases of the gut.

As scientists study the gut microbiome, additional complexity reveals itself. But if researchers can navigate that complexity to understand and promote a healthy gut ecosystem, their work may save preemies from a deadly inflammatory disease, prevent the complications of obesity, or protect children from the ravages of malnutrition. Nurturing a healthy gut may be the next public health revolution.

 

Published in the Winter 2018/2019 issue