The frontier that lines the gut
Dr. Lora Hooper more or less stumbled into the research for which she is now internationally known – studying the trillions of bacteria and other microbes that live inside the gut – and she was lucky enough to enter the microbiome field just as it took off.
It all began when she became a postdoctoral researcher at Washington University in St. Louis in the laboratory of Dr. Jeffrey I. Gordon, then known for studies on intestinal cell growth and development rather than the microbiome.
“The new discoveries about obesity suggest we might be able to intervene in obesity or malnutrition by altering the microbiome.”
For her Ph.D. at the same university, Dr. Hooper had focused on the biochemistry of enzymes. After spending years scouring slaughterhouses for castoff cow parts from which she could tease out enzymes, “I wanted to work on something that was very different from animals but was physiologically relevant,” says Dr. Hooper, Chair of Immunology at UT Southwestern and an Investigator in the prestigious Howard Hughes Medical Institute.
“I was looking for an interesting problem – I didn’t necessarily have a specific ambition,” she adds.
Dr. Gordon had been mulling over questions that had quietly bubbled up in the scientific community since the days of Dr. Louis Pasteur in the 1800s. The French scientist came up with the theory that germs cause most illnesses, but he also noticed that some microorganisms seem to coexist with humans. “He wondered whether – just as microorganisms can cause disease – these resistant microorganisms might be essential for health,” says Dr. Hooper, also a Professor of Immunology and Microbiology and a member of the Center for the Genetics of Host Defense.
“Dr. Gordon inspired me to begin work on the microbiome – which I had never thought about in my life,” she says.
The rest is microbiome history.
Bit of a backwater
When she began her research, the microbiome field was considered “a little bit of a backwater,” she says. “The idea was that you had these microorganisms, particularly in the gut, and they were probably just inert – not really doing anything.”
This was fine with Dr. Hooper. “It was a very sparsely populated field at the time – which I really liked because anything we did was new. You could go in any direction,” she recalls.
Since then, scientists have learned just how many microorganisms are in and on the human body and some of the things they are capable of – both harmful and helpful, such as aiding the digestion of the food we eat.
Dr. Hooper’s many findings have helped make gut microbiota research a quickly emerging field. A study published in the Proceedings of the National Academy of Sciences in 2008 found that Paneth cells stand guard between bacteria in the intestinal channel (the lumen) and the gut lining by emitting antimicrobial proteins that keep microbes at bay. Specifically, she found that Paneth cells sense bacteria via MyD88-dependent toll-like receptor (TLR) activation – a pathway known to be key in the immune system’s host-defense mechanism.
Her laboratory also found that the gut has a backup strategy in case an invader knocks out that first line of defense. Paneth cells usually use the Golgi apparatus to push out the protective proteins, which act like little land mines safeguarding the lining of the gut. When that strategy fails, Paneth cells use cellular machinery from a process called autophagy, which cells more commonly use to rid themselves of malfunctioning or destroyed parts, to deliver protein weapons to the front lines.
The same study, published last year in Science, also suggests a link to Crohn’s disease, an inflammatory bowel disease. The researchers found that mice engineered to have the same genetic mutation seen in many human Crohn’s patients had trouble using that backup defense system.
“That study was the first report of an alternative secretion pathway for immune defense proteins in an animal,” she adds.
In other recent research, Dr. Hooper also reported last year in Science that the intestinal microbiota interacts with the circadian clock, via the transcription factor NFIL3, to regulate fat uptake and storage.
This year, her lab found that intestinal inflammation activates dormant viral pathogens called Proteobacteria that hide within gut bacteria (Nature Microbiology, July). This activation alters the microbiome of the intestines.
Dr. Hooper, a member of the National Academy of Sciences and holder of the Jonathan W. Uhr, M.D. Distinguished Chair in Immunology as well as a Nancy Cain and Jeffrey A. Marcus Scholar in Medical Research, in Honor of Dr. Bill S. Vowell, says she feels lucky to have fallen into microbiome research when there were so many unanswered questions.
“There are about 100 trillion bacteria in the human intestine,” says Dr. Hooper. “Why are they there? Are they benefiting us? How are they benefiting us?”
Also, the time was ripe for discovery. Dr. Pasteur was unable to create germ-free mouse models to study what happens if you remove all the microbes. However, in 1885 he hypothesized that such a colony would be an excellent way to study the effects of the so-called good (commensal) bacteria. Dr. Pasteur also lacked modern tools like high-throughput transcriptomics, which allow researchers to look at changes in gene expression in order to investigate what happens to an organism in response to changes in the composition of its microbiome. Dr. Hooper has run a germ-free colony for years.
Dr. Hooper’s fascination with science began with reading the astronomy and physics books her father left lying around the house when she was a child growing up in Nashville, Tennessee. He encouraged her interest. When she was 14, she saved up a year’s allowance and babysitting money to buy the components needed to build a telescope. Together, she and her dad put the telescope together.
Now, she says, her proudest achievement is mentoring the junior scientists in her lab. Among them are Dr. Shai Bel, lead author of the autophagy study and now on the faculty at Bar-Ilan University in Israel. In April, Dr. Bel was awarded the Brown-Goldstein Award for Excellence in Postdoctoral Research at UT Southwestern. The award is the University’s highest honor for a postdoctoral scholar.
Looking back on her early days, Dr. Hooper says, “I really felt insecure when I first started my own lab. I didn’t know what discoveries lay ahead. The ‘aha’ moment for me was realizing that there was this chemical barrier at the surface of the intestine.
“We were the first to identify antimicrobial proteins that were regulated by the microbiome. We contributed to the fundamental understanding of how the intestinal epithelium defends its borders to keep bacteria from penetrating through and causing disease,” she adds.
That’s been the focus of her research – how to keep the bacteria in the lumen of the gut where they can do their work yet not invade.
Now, Dr. Hooper is intrigued by recent findings in the field linking the composition of the microbiome to obesity, diabetes, and heart disease. For instance, one study identified differences in the composition of microbiomes in obese people and lean people.
“The new discoveries about obesity suggest we might be able to intervene in obesity or malnutrition by altering the microbiome,” Dr. Hooper says. “I’d like to do that.”