Now, a theory is emerging out of left field on why some patients may develop more severe inflammation in the liver. HHMI investigator Richard Flavell at Yale studies bacteria that inhabit people’s guts. He recently discovered problems in the lining of the gut that lead to the body’s inability to control these types of bacteria in mice with susceptibility to inflammatory bowel disease (IBD).

“Once we had found this problem in the gut, it occurred to us that it was unlikely to be limited to just the intestines,” says Flavell. Researchers knew that the blood vessels between the intestines and liver of people with IBD often had leaks, letting unwanted material through.

“The function of these blood vessels is to carry food to the liver,” says Flavell. “But we hypothesized that there could be a way in which the bad components of bacteria—or even whole bacteria—were traveling to the liver.”

So he took mice with mutations that predispose them to IBD and put them on diets that usually lead to NAFLD. “We immediately saw that if the mice don’t have this pathway in the intestines working, they get much worse fatty liver,” he says.

The experiment, which included help from Shulman, was the first to suggest that NAFLD isn’t just a metabolic disease, but could have a link to bacteria. The gut bacteria, while likely not causing fatty liver in the first place, could explain the inflammation that can lead—in a fraction of NAFLD patients—to more severe liver disease. Flavell plans to study how the bacterial populations in the intestines of people with NAFLD vary from those in healthy people. It’s an angle of the disease that may someday lead to ways to identify patients at risk for severe liver disease, or to distinct treatment methods from those targeting obesity and blood sugar.

For now, though, scientists agree on the best way to treat—and reverse—NAFLD: weight loss, exercise, and a balanced diet.

In the same way three cans of soda a day can quickly lead to fatty liver, Loomba says, weight loss and exercise can rapidly reverse it. He’s seen patients, within weeks of beginning an exercise regimen, show improvement in both liver fat levels and insulin resistance in liver cells.

“If we get patients with type 2 diabetes to lose relatively small amounts of weight by diet alone, we can cure most cases of fatty liver, hepatic insulin resistance, and type 2 diabetes,” says Shulman. “But unfortunately getting patients to lose weight and keep it off is one of the most challenging clinical endeavors.”

There are multiple drugs in clinical trials for treating later stages of liver disease—the inflammation and scarring—but no pill to cure early NAFLD. And because of the complex interconnections between diabetes, weight, and liver fat, a single cure-all drug targeting only the liver is unlikely to be discovered. But with each discovery of genes, molecular pathways, and bacteria that contribute to the disease, scientists feel they are getting closer to being able to identify patients most at risk and help lessen the severity of their disease.

“I think we have probably just moved from the infancy to the adolescence of understanding this disease,” says Loomba. “The hope is that our understanding of fatty liver is really going to explode in the next five years. I think we are on the cusp of something big.”

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