Richard Flavell, Sterling Professor of Immunology and Howard Hughes Medical Institute Investigator, uses a technique of his own invention, known as reverse genetics, so study immunology. His current project is on nonalcoholic fatty liver disease, and he published an article Feb. 1 in the journal Nature.
Q. What is nonalcoholic fatty liver disease, and how does it develop, based on your findings?
A. Nonalcoholic liver disease is the accumulation of fat in the liver of people who drink little or no alcohol. It may lead to liver failure. In a normal mouse the genetically expressed inflammasomes (an immune system cell that activates inflammation) in the lining of the gut direct the synthesis of molecules that keep different species of microbes. We found that when the inflammasomes aren’t working, because the genes are not expressing them, the system gets out of control and the microbe composition changes radically. The bacteria then invade the epithelium of the gut, where it is not normally found. The immune system responds causing inflammation and killing the bacteria. But then the pieces of dead bacteria, we also found, travel through the bloodstream to the liver, which are then attacked by immune system cells, causing inflammation. This inflammation is liver disease.
Q. Because the infection involves bacteria, it could be easily transmitted, right?
A. Yes. That was a surprising finding. When placed in the same cage and fed the same Western diet, the mouse that was immunocompromised infected the healthy mice. The infected mice became obese and developed fatty liver disease.
Q. What are these bacteria? Have you identified them?
A. Almost. We’re still working on proving that they’re the ones. We have a candidate that we know increase when the mice goes into a Western diet, one associated with inflammatory diseases. But we haven’t yet proved that it is this one, as the bacteria are very hard to grow. It is exciting to know that they occur in people though. Because they are of the same family of those involved in gum disease and heart disease, and inflammatory diseases, they’re very good candidates of what’s happening here.
Q. How does diet fit into the process of developing fatty liver disease?
A. In the lining of the gut, we have many and varied types of bacteria. Their composition is determined by our diet. At the same time, diet influences obesity, when the mice get fatter and develop much worse fatty liver disease.
Q. How does the focus of your research compare to other works in metabolic syndrome?
A. We’re interested in the interaction between our genes, our food and our environment as it influences metabolic syndrome. All three play a role. It’s well-established that if you eat healthy you’ll do better, being less prone to diabetes, obesity and liver disease, but less is known about the contributions of bacteria and much less on the contribution of immune genes.
Q. What is the role of genes, food and environment?
A. Without the diet, you don’t get obesity, which is influenced by the microbes. The genes increase the damaging influence of the microbes.
Q. How large is the impact of nonalcoholic fatty liver disease in the U.S.?
A. It’s really serious. A third of the population is considered to be obese, and at least 75 percent of them have nonalcoholic fatty liver disease. But this disease goes far beyond our country. It is the most common cause of liver disease worldwide.
Q. When did you start this project?
A. We started this towards the end of 2009, that’s when we looked at the immune system genes. It took us about a year and a half to make the gene-microbe connection. It has taken at least a year and a half or two years.
Q. What are the next steps in your research?
A. I would like to show first that the bacteria and the means of transmission that we found apply to people. Then I would like to work on developing a drug that works in mice, as a model for people. Ultimately, the goal is to find a drug that will work on people.
Q. What do you think a potential cure might look like?
A. It might be an antibiotic, although I’m not quite sure. But we do know that if the outcome of our work applies to humans, it might lead to treatments that will help to reduce obesity medically. Yet again, there’s still a lot to do.