Salt is new culprit in autoimmunity

The health risks of eating high amounts of salt make up quite a laundry list: high blood pressure, heart attacks, stroke, and kidney stones, to name a few. Now, School of Medicine scientists have discovered another potential detriment of a high-salt diet. Salt, they’ve found, may drive the progression and severity of autoimmune diseases, through its interactions with certain immune molecules in the gut.

The research, which appeared in the March 6, 2013 issue of Nature, is based on experiments with mice, but likely applies to human autoimmune diseases, including multiple sclerosis, says David A. Hafler, M.D., Gilbert H. Glaser Professor and chair of Neurology, professor of immunobiology, and senior author on the new paper.

“This goes to show that the immune system may well be linked to what you eat, in unexpected ways,” Hafler says. He is confident enough in the findings, he adds, that he is already recommending that his patients who are prone to autoimmune disease reduce their salt intake.

Scientists have long known that a type of immune cell, called T helper 17 (TH17) cells, is involved in several autoimmune diseases, including multiple sclerosis, psoriasis, type 1 diabetes, and rheumatoid arthritis. Patients with these conditions, scientists have shown, have higher levels of TH17 cells, which helps to explain why their immune systems are more likely to attack their bodies’ own cells.

But over the past 50 years, the incidence of these autoimmune diseases has increased, and first author Markus Kleinewietfeld, Ph.D., associate research scientist, Hafler, and colleagues wondered whether there was something in the environment that affected TH17 cells. When they followed the diets of patients, something jumped out at them. “People who are at a fast-food restaurant more than once a week had higher levels of TH17 cells,” Hafler says.

To test whether it was the high levels of salt in most fast food that accounted for this difference—rather than levels of fat or other compounds—the researchers first tested TH17 cells growing in the lab. When they added salt to the culture surrounding these cells, more than 10 times as many cells matured.

Hafler’s group then tested the implications of this finding in a strain of mice prone to developing a version of multiple sclerosis. When they added moderate amounts of extra salt to the diets of these mice, the severity of their disease increased. Normally, salt levels are much lower in the blood than in surrounding tissues. While a high-salt diet doesn’t drastically increase the level of salt in the blood, it does increase the salt that’s free in the gut, and Hafler believes that a high-salt diet could activate TH17 cells there. Such a diet also could change the balance of bacteria living in the gut, which could likewise affect the immune system.

There are more than 150 genes linked to autoimmune disease risk in humans, and when Hafler took a fresh look at the genes on the list, he discovered that almost 30 percent of these genes were activated by salt, further supporting the connection.

“This really opens up a whole new area of investigation,” Hafler says, adding that there are likely to be environmental factors other than salt that are responsible for the increased prevalence of autoimmune disease, so there are numerous avenues of research yet to be followed.

David Fox, M.D., a rheumatologist at the University of Michigan, calls Hafler’s results “exciting” but agrees that more research is needed. “The story may be more complicated than it seems,” Fox says. “I don’t think this one paper completely proves that there is a link between diet and multiple sclerosis.”

Moreover, he points out, the effect of salt on TH17 cells is unlikely to have the same impact on all autoimmune diseases. The incidence of rheumatoid arthritis, for example, has not risen over the time period that multiple sclerosis has, so it may not be as affected by diet.

John O’Shea, M.D., chief of the National Institutes of Health’s Molecular Immunology and Inflammation Branch, agrees. Changing official dietary recommendations without clinical trials would be premature, he says, but also points out that low-salt diets are already recommended for some patients with risk factors for other disorders.

“The findings are interesting and provocative, but we don’t know if this is pertinent to humans with autoimmunity,” says O’Shea. “Lots more work needs to be done to establish this point. Nonetheless, the study raises an exciting possibility for intervention.”

Motivated by that possibility, Hafler and colleagues are beginning a new dietary study in humans to more firmly establish the link between salt intake and autoimmunity.

But in his role as a physician, Hafler says, he’s not waiting to suggest dietary changes to his patients.

“If you have a high susceptibility to autoimmune disease in your family, especially if you have an infant, I would recommend trying to keep salt levels low,” says Hafler. “We have to be careful in extrapolating this to human disease at this point,” but, like O’Shea, he believes the potential benefits of a low-salt diet outweigh any risks.