Cedars-Sinai Researchers Are Exploring Humans' Internal Ecosystems

We are outnumbered in our own bodies: With more than 100 trillion microbes residing in the gut alone, for every one of our own cells, we host 10 others such as bacteria, fungus and a plethora of other microscopic agents.

These tiny entities form what's called the microbiome, a relatively new frontier for researchers who have only begun to examine how this internal ecosystem might affect the function of our bodies. Scientists at Cedars-Sinai are learning more about the microbiome in hopes of uncovering better understanding of diseases and how to fight them. They join a growing number of researchers who believe that changes in the makeup of this system could be contributing to conditions such as diabetes, obesity, Crohn's disease and irritable bowel syndrome.

Are Tiny Organisms Contributing to a Global Health Crisis?

Ruchi Mathur, MD, medical director of the Anna and Max Webb and Family Diabetes Outpatient Treatment and Education Center in the Division of Endocrinology, Diabetes and Metabolism, is investigating the role of the gut-dwelling microbe Methanobrevibacter smithii, which she suspects plays a role in obesity and Type 2 diabetes.

"This particular microbe is believed to work with other microorganisms in the gut to harvest more energy," Mathur said. "This means that some people could be harvesting more calories from their food, contributing to obesity."

Overgrowth of M. smithii can be detected with a breath test that looks for methane and hydrogen. Mathur has shown in a recent study that patients with detectable levels of methane and hydrogen in their breath had significantly higher body mass indexes than those whose breath tested negative for the gases. Now, with a grant from the American Diabetes Association, she has embarked on a new study to confirm the link between the microorganism, obesity and prediabetic conditions by determining how efficiently subjects digest food with and without M. smithii.

Participants who have traces of methane on their breath are given a standard diet over three days, and swallow a "smart pill" to track how fast the food moves through their bodies, allowing researchers to determine how many calories are being harvested during digestion. Then participants will repeat the process after taking a targeted antibiotic to wipe out the bacteria.

"This should let us know just how many more calories people are squeezing out of their meals because of this bacteria," Mathur said. "We're only beginning to understand these incredibly complex communities that live inside of us. If we can pin down how they affect our bodies, we may get to the point we could manipulate that microbiome with medications – and drastically improve health."

Promising Research Linked with Microbiome Genetic Makeup

At the Cedars-Sinai F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, scientists are combining their formidable knowledge of the genetics of inflammatory bowel disease with their growing understanding of the microbiome. In research funded by the Crohn's and Colitis Foundation of America, researchers are looking not only at the bacterial species, but also viruses and fungi residing in an individual. This research also is looking at proteins and other molecules found in the gut, their relationship to both the microbiome and the person's genetic configuration, and how this combination leads to the development of Crohn's disease.

"It's important that we look at all the different factors together if we are truly going to understand the causes of Crohn's disease and ulcerative colitis," said Dermot McGovern, MD, PhD, director of translational medicine at the institute and the Joshua L.and Lisa Z. Greer Chair in Inflammatory Bowel Disease Genetics. "The preliminary results from our research are indicating pathways and processes 'driven' by the microbiome that could be targets for new ways for treating the disease. One exciting possibility from this research is that we could identify individuals with Crohn's disease, in whom a change in diet could lead to a change in microbiome and therefore subsequent control of their disease without the need for immunosuppressant therapy. We have some way to go before we realize this dream, but these data are very exciting."

After recent Cedars-Sinai research identified fungi living in the gut, it became the focus of new research. While scientists long suspected there were fungi as well as bacteria inhabiting the digestive system, a Cedars-Sinai study was the first to catalogue it. In addition to finding 200 fungal species, half of which had never been described before, the research indicated this flora might play a role in inflammatory bowel disease.

The researchers, led by David Underhill, PhD, were intrigued by previous studies that linked a signaling molecule known as CARD9 – which plays a key role in triggering the immune system's detection of fungal cells – to higher rates of inflammatory bowel disease. This molecule interacts with another protein produced by white blood cells and used by the immune system to detect and kill fungi. In the course of their research, they found subjects lacking this protein were prone to developing more severe ulcerative colitis.

In collaboration with the IBD genetic and translational researchers at Cedars-Sinai, Underhill and his colleagues examined data from hundreds of ulcerative colitis patients seen at Cedars-Sinai identifying that those with the most severe disease and who ultimately required surgery to address their condition tended to have mutations affecting this crucial protein.

These studies are examples of the possibilities now that we have begun to delve into the organisms living the human gut.