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High-salt diet affects the brains of mice

Immune cells that produce a protein called IL-17 (green) accumulate in the small intestines of mice fed a high-salt diet for eight weeks. This image shows the intestinal layer that absorbs digested food and protects against infection. Iadecola lab, Weill Cornell Medicine

Diets that are high in salt (sodium chloride) have long been associated with high blood pressure. High blood pressure raises the risk for heart disease, stroke, kidney failure, and other health problems. Studies have also linked salt intake with brain health, but the mechanisms involved are poorly understood.

Previous studies suggested that high levels of salt in the diet can cause immune changes in the gut. Immune cells called T helper 17 (TH17) cells accumulate in the gut when mice are fed a high-salt diet. Studies suggest that high levels of TH17 could harm blood vessels.

A research team led by Dr. Costantino Iadecola at Weill Cornell Medicine set out to explore the connection between a high-salt diet, TH17 cells, and brain function. They fed mice a diet containing up to 16 times the amount of sodium chloride typically found in mouse chow. The team estimated that this level compares to excessive salt intake in people. The work was funded in part by NIH’s National Institute of Neurological Disorders and Stroke (NINDS). Results appeared online on January 15, 2018, in Nature Neuroscience.

After eight weeks, the mouse brains showed up to a 30% reduction in blood flow compared to mice that ate a normal diet. The mice also had problems in three cognitive tasks: recognizing objects, navigating a maze, and building a nest. When the mice were returned to a normal diet, both brain blood flow and cognition improved, suggesting that the effects of excessive salt consumption could be reversed.

Blood vessels tighten (constrict) to reduce blood flow or relax (dilate) to increase flow. The scientists discovered that blood vessels from the brains of the mice fed a high-salt diet didn’t dilate properly when prompted to. A closer look revealed a reduction in the ability of the enzyme eNOS to produce nitric oxide (NO), a potent signal for blood vessels to dilate. When the amino acid L-arginine, which can increase eNOS activity and NO production, was added, the blood vessels responded normally. When L-arginine was injected into mice fed a high-salt diet, the problems they had with the cognitive tasks went away.

The researchers investigated the potential involvement of TH17 cells in the gut. TH17 cells secrete a molecule called IL-17 into the bloodstream. In a series of experiments, the scientists showed that IL-17 acted directly on blood vessels in the brain. IL-17 suppressed eNOS activity and reduced NO production to restrict blood flow. Notably, this mechanism was independent of blood pressure, which wasn’t affected in the mice.

“These findings together show that a high-salt diet affects the activity of the eNOS enzyme, which in turn leads to problems with blood flow and cognition,” Iadecola says.

“For years researchers have wondered how a high-salt diet harms the brain,” says NINDS program director Dr. Jim Koenig. “This mouse study provides a detailed cellular and molecular diagram for how the problems start in the gut and opens unexpected paths towards new treatments.”

The researchers plan to further investigate how decreased NO production and reduced blood flow lead to changes in cognition. The health implications for people who eat a high-salt diet will also need to be explored.