U.S. Department of Health and Human Services

Gut Microbes Transmit Susceptibility to Nonalcoholic Fatty Liver Disease Progression

Researchers have shown how changes in the bacteria in the gut play a surprising role in the progression of nonalcoholic fatty liver disease (NAFLD). NAFLD is the liver’s manifestation of metabolic syndrome, a group of risk factors that together increase the risk for cardiovascular disease and type 2 diabetes. In some people, the disease takes a relatively benign form, with excess fat accumulation in the liver, while in others, the disease progresses such that fat accumulation is accompanied by inflammation, liver damage, and scarring, called nonalcoholic steatohepatitis, or NASH. The cause of progression to the more severe form of the disease is still not well understood. However, in light of the direct connection between the intestine and the liver through the portal vein, scientists wondered if gut microbes, and the human host’s microbial response system, might play a role in progression of this disease. Starting with the human immune system, the research team focused on inflammasomes—complexes of immune proteins involved in sensing microbes and triggering responses to those that are harmful. Mice that were genetically modified to lack some inflammasome components developed NASH when fed a special diet, showing that these human immune factors play a key role in putting the brakes on progression of this disease. But, even more interesting was that when these mice with genetic defects in microbe-sensing and severe NASH were housed together with “normal” mice without any genetic alterations or liver disease, the normal mice also developed the severe form of liver disease. The scientists concluded that a unique mix of intestinal bacteria in these mice lacking proper microbe response machinery may have been transmitted to the normal mice, carrying the susceptibility to develop severe liver disease with it. They next sequenced genes characteristic of different types of bacteria from the intestines of the mice to identify the species present. They found a few species in particular that were present in unusually high numbers compared to intestinal bacteria in the normal mouse intestine. They also showed how these intestinal bacteria might bring about NASH by releasing their products into the blood and activating immune factors in the liver that lead to inflammation and damage. In addition, they examined another mouse model, this one genetically modified to be obese; these animals also “caught” the susceptibility to develop severe NASH from the inflammasome-deficient mice. These animals became even more obese and showed signs of increased insulin resistance. These studies have greatly expanded the understanding of how NAFLD’s progression to NASH is related to intestinal microbes. More research is needed to tease out contributions by particular microbial species. However, this work may provide a basis for future antibiotic/probiotic therapies for individuals susceptible to developing NASH.

Henao-Mejia J, Elinav E, Jin C, et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 482: 179-185, 2012.​