High uric acid levels are often seen in people with obesity and other metabolic conditions. New research in mice shows that liver-made uric acid promotes obesity by disrupting a gut-bacteria pathway that typically helps limit fat absorption in the gut.

The findings, published in Cell Host & Microbe, suggest that lowering uric acid could become a new way to treat obesity and related metabolic conditions, though this still needs testing in people.

Previous research has linked uric acid uric acid to metabolic conditions, but it has been unclear whether uric acid helps cause these conditions or simply rises because of them. It is also not known whether uric acid could directly reshape specific gut bacteria to increase dietary fat absorption and drive obesity.

Researchers led by Cheng Tian at the Chinese Academy of Sciences in Shanghai, China, combined human data and mouse experiments to test whether uric acid contributes to obesity.

Metabolic health

People with higher uric acid in their blood tended to have higher body mass index and increased levels of fatty molecules, the researchers found. In overweight or obese people, higher uric acid was linked to lower levels of fat left in stool, suggesting that people with higher uric acid absorb more dietary fat through the gut.

The team then searched human genetic data for genes linked to uric acid levels and identified TIP60 as a strong candidate. In mice, removing TIP60 from liver cells lowered uric acid levels and reduced the activity of genes involved in making uric acid. TIP60 appeared to help activate those genes, the researchers found.

When mice lacking liver TIP60 were fed a high-fat diet, they gained less weight, had less body fat, showed less fatty liver, and had better blood sugar levels than mice with normal levels of TIP60 in their livers. But when the researchers restored uric acid levels, these protective effects disappeared. Transferring gut microbes from mice lacking TIP60 to other mice also reduced fat absorption and improved metabolic health.

Regulating obesity 

Further experiments showed that uric acid works by suppressing Lactobacillus johnsonii, a gut bacterium that makes phenyllactic acid. This molecule typically limits intestinal fat uptake. Giving mice L. johnsonii reduced weight gain and lowered intestinal fat absorption.

Reducing TIP60 in the liver of obese mice also reduced intestinal fat absorption. It also lowered uric acid, increased the levels of L. johnsonii, improved blood sugar levels, and reduced liver fat. 

“Overall, our work redefines [uric acid] from a metabolic waste product to a central regulator in a previously unrecognized host-microbe interaction circuit fundamental to obesity pathogenesis,” the authors say. Althoug the findings have yet to be confirmed in people, they add, the work suggests that targeting liver TIP60 could be a possible strategy for treating both high uric acid and obesity.