Guest speaker helps NIEHS gauge the potential of microbiome research
By Melissa Kerr
Developmental biologist John Rawls, Ph.D., spoke March 1 at NIEHS on the relationship of intestinal tract flora balance and risk of obesity, an important public health challenge that affects one-third of adults and nearly a fifth of children and adolescents in the U.S. Rates of overweight and obesity have increased steadily in recent years, suggesting a link to other environmental factors, in addition to the usual suspects of sedentary lifestyle and increased food intake.
At the beginning, Rawls introduced the theme that would run throughout his talk. “One of my main goals in life is to try and come up with novel approaches to treat obesity and prevent it as well,” he said. “Collectively, our nation needs to lose about 4.6 billion pounds.”
Hosted by Health Scientist Administrator Lisa Chadwick, Ph.D., Rawls’ talk on “Microbial and developmental regulation of vertebrate energy balance” also gave his audience an opportunity to consider how similar lines of research on the trillions of microbes that colonize humans might advance the NIEHS mission of discovering the ways environment affects people, in order to promote healthier lives (see text box).
Rawls is an assistant professor in the department of cell and molecular physiology and the department of microbiology and immunology at the University of North Carolina (UNC) at Chapel Hill School of Medicine, where he conducts research in the areas of microbiology and gastroenterology. In 2004, Rawls published the first in a series of papers on the development of germ-free zebrafish as a model organism for microbiome research. His current research is supported by three grants funded by the National Institute of Diabetes and Digestive and Kidney Diseases.
Making science transparent
Rawls explained that he uses zebrafish in his work because of the transparency of its tissues during development, its size and rapid development, and the extent to which its biology is evolutionarily conserved in mammals. This optical transparency, Rawls said, permits real-time in vivo imaging of host tissues and their microbial inhabitants. The small size of the zebrafish enables high-throughput screening.
Through these experiments, he hopes to come to an understanding of how gene transcription is affected by different microbial populations, using comparative studies of zebrafish that are germ-free, conventionally raised, and conventionalized — colonized with defined microbiota after being conceived germ-free.
Some of Rawls' work identified certain intestinal microbes that could influence a host's ability to promote fat storage. The unique ability of scientists to observe zebrafish tissue has revealed that certain gene transcriptions are modified by microbial interactions, specifically expression of a circulating inhibitor of lipoprotein lipase called angiopoietin-like 4 (Angptl4).
Microbes seem to play a role in the regulation of Angptl4 in the intestine, promoting fat storage in the host. Thus, there is potential for using Angptl4 as a target for obesity intervention.
Along with research into gut microbial ecology and regulation of host nutrient metabolism, Rawls is also exploring the morphogenesis of white adipose tissue (WAT), which is used by the body as sites of energy storage, as well as regulators of energy balance and inflammation. “It matters how we store fat and it matters how adipocyte tissue is built,” said Rawls.
As he explained, the origin of these tissues, or adipogenesis, is not well understood. Also, the role of environmental factors and diet in the development of adipocytes is not yet clear. Rawls’ group is the first to use zebrafish as a model organism for studying WAT development.
Rawls argued that understanding WAT development could lead to novel approaches for obesity intervention and prevention. Although he readily admits there are more ideas than information about WAT development, Rawls' group is gaining insights from their model into the dynamics of vascularization and patterns of what he described as temporal oscillation between increases in their size of cells and their number. Vascular architecture, he said, determines growth of WAT, and the pattern of antagonism between increases in size and number of cells seems to influence inflammation and insulin sensitivity.
(Melissa Kerr studies chemistry at North Carolina Central University. She is currently an intern in the NIEHS Office of Communications and Public Liaison.)
Advancing understanding of the microbiome
The microbiome consists of the collection of microorganisms that live on and in a human being. Within a person, there are around 160 bacterial species and anywhere from 10-100 trillion microorganisms — 10 times the number of human cells.
As part of her work in the NIEHS Division of Extramural Research and Training, Chadwick is the Institute’s representative for the Human Microbiome Project, a large program funded by the NIH Common Fund. One of the goals of this program is to develop a reference microbiome that would consist of information from many different body sites within a healthy individual. This information, and other studies funded by this program, is helping us better comprehend the relationship between microbial balance and disease development.
In addition, Chadwick administers the NIEHS extramural research program investigating how the microbiome interacts with the environment. NIEHS is interested in how the function of the microbiome may be permanently altered by exposure to environmental chemicals, particularly during early life exposures when the microbiome is being colonized. It has also been discovered that some environmental chemicals can be metabolized by an individual's microbiome. “Everyone has a slightly different microbiome, so you can imagine that this could be a factor in why people respond differently to the same exposure,” said Chadwick. NIEHS would like to know more about this process, and the range of chemicals that are metabolized in this way.
Rawls' research is clearly related to Chadwick’s planning for future initiatives. Previous experiments have shown that the microorganisms within a person's intestines have an impact on the host's metabolism of dietary nutrients, and, because of the import role of the gut in immunity, the microbiome can influence health throughout the body.
“This is kind of a new area for [NIEHS] and I wanted to bring someone to talk about it. Dr. Rawls' work is particularly interesting, because he uses zebrafish as a model, one which is also frequently used in toxicology studies,” said Chadwick.