Salt at Fault?

Two groups of researchers independently showed that high salt exposure stimulates cells implicated in multiple sclerosis and other autoimmune diseases.

By | March 6, 2013

MICHEL32NL AT NL.WIKIPEDIASalt may play an important role in autoimmune diseases, according to two new papers published today (March 6) in Nature. Exposure to high levels of salt was found to make both cultured mouse and human T cells more pathogenic, and high-salt diets worsened autoimmune disease in mice.

“I thought the papers were very exciting and provocative,” said John O’Shea, a doctor at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), who wrote a Nature commentary accompanying the new findings and was not involved in the study.

Lawrence Steinman, a neurologist and immunologist at Stanford School of Medicine, who was also not involved in the work, said, “I think it’s beautiful research looking at the pathways that feed to one of the major types of autoimmune cells.”

The first research team, based at Harvard University, the Massachusetts Institute of Technology (MIT), and the Broad Institute, came to investigate salt in a roundabout way. Some forms of T helper cells, called T helper 17 (TH17) cells, have been implicated in a variety of autoimmune diseases, and the researchers wanted to understand what makes naive, immature T cells differentiate into pathogenic ones.

Under ordinary circumstances, T helper cells protect the body from pathogens, and each differentiated T helper cell type specializes in a different type of invader. The TH17 cells target bacteria and fungi. But a certain flavor of TH17 cells, which the researchers call “highly pathogenic,” appears to be involved in attacking the body’s own cells.

To understand how TH17 cells come to be, Aviv Regev, a computational biologist at the Broad Institute and MIT, worked with colleagues to take snapshots of regulatory circuits as T helper cells developed into TH17 cells. Collaborating with the lab of Vijay Kuchroo of Brigham and Women’s Hospital, the researchers organized the proteins into a hierarchy of importance as nodes in regulatory pathways that influenced the development of TH17 cells, which they published in a third paper in Nature today. The enzyme SGK1 was at the top of their list.

Knowing that SGK1 is involved in mediating salt uptake in the gut and salt reabsorption in the kidneys, the researchers decided to see what happened if they added extra salt to the cells.  Not only were the salt-cultured mouse T helper cells more likely to develop into TH17 cells, but the cells that developed were more pathogenic. When the researchers fed mice a high-salt diet and induced EAE, a mouse model for multiple sclerosis, the mice showed worse symptoms than usual. When they knocked out SGK1, salt’s ill effects went away. “Salt has got this unique ability to convert the non-pathogenic cells to the pathogenic ones,” Kuchroo said.

Meanwhile, David Hafler’s lab at Yale University was coming to similar conclusions from the opposite direction. The group had completed a study where they measured TH17 cells in the blood of healthy human subjects, sequenced the people’s microbiomes, and had them fill out questionnaires about their diets. While the study was supposed to be focused on the influence of the microbiome, the researchers noticed that participants who frequently ate in fast food restaurants had elevated levels of pathogenic TH17 cells. They hypothesized that the saltiness of the food could be part of the explanation.

“That led to a whole series of experiments trying to figure out the role of salt,” Hafler said. Unlike Regev and Kuchroo’s labs, which looked at TH17 differentiation in mouse cells, Hafler’s lab added salt to human cell cultures. They also found that it was associated with more pathogenic TH17 cells. “Salt just seems to trigger all the genes associated with bad autoimmune T cells,” Hafler said.

He and colleagues looked at the genes expressed in the cells during development using a microarray chip. A variety of genes involved in salt-related inflammation, including SGK1, were upregulated, and a series of tests showed that several of these genes were necessary for salt to have its deleterious effect. Experiments in mice with EAE also supported the findings, and Hafler is now seeking grants to study the effects of a low-salt diet on autoimmune disease in humans.

“It suggests a very interesting hypothesis about an environmental factor that we all consume in our diet and a set of immune disease we see greatly increasing in Westernized cultures, “ said Regev.

But O’Shea cautioned that salt has not been explicitly shown to have an effect on human autoimmune diseases. “This is an artificial model of autoimmunity,” he said. The scientists induced autoimmunity in the mice, and the salt only exacerbated their condition. It remains to be seen, he said, whether salt can induce or worsen disease in humans.

C. Wu et al., “Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1,” Nature, doi:10.1038/nature11984, 2013.

M. Kleinewietfeld et al., “Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells,” Nature, doi:10.1038/nature11868, 2013.

N. Yosef et al., “Dynamic regulatory network controlling TH17 cell differentiation,” Nature, doi:10.1038/nature11981, 2013.

Add a Comment

Avatar of: You



Sign In with your LabX Media Group Passport to leave a comment

Not a member? Register Now!

LabX Media Group Passport Logo


March 7, 2013

There is just one little snag. There is no way the Na concentration can exceed 141 mmol/L as the glomeruli excretes 0,7 to 1,4 grams of sodium chloride per minute or 1 000 to 2 000 grams of sodium chloride per 24 h. Then 99 % is reabsorbed in tubuli to maintain 141 mmol/L in the blood.

The problem is not to get rid of excess salt, the problem is to keep the 141 mmol/L Na in the blood. 

We excrete the excess of ingested salt. But we can not reabsorb more salt than we ingest so with intake of less than 7.5 grams of salt may lead to death due to salt deficiency (less than 121 mmol/L or four grams lower salt amount in the blood). 

So do eat enough (more than 7.5 grams of) salt to stay healthy.

The problem with the reseach above is that is in vitro with an unphysiologically elevated salt concentration that never will be reached in vivo as long as the kidneys work properly.

And MS is caused by vitamin D3 deficiency according to latest scientific (not epidemiological) studies. 

Avatar of: HFC


Posts: 1

March 9, 2013

Responding to the comment by Björn Hammarskjöld.  Normal Na concentrations in human blood are136-145 mmol/L for adults and the elderly. Values above 180 mmol/L are associated with a high mortality rate, particularly in adults.  Such high value are rare but possible.

His recommendation that eating less than 7.5 g salt/day (this is equivalent to about 3 g Na/day) may lead to death due to salt deficiency does not agree with all the research on the subject that I have seen. 

For several million years the evolutionary ancestors of humans, and modern humans until recently, ate a diet that contained about 800 mg Na/day.  (For more information, see the article on Paleolithic nutrition in a 1997 issue of the European Journal of Clinical Nutrition.)  This implies that present-day humans are genetically programmed to a salt intake of this amount.

To make it clear that a low-salt diet is not harmful, the INTERSALT study, in a paper published in a 1989 issue of Hypertension, reports on four remote populations.  I will mention two of these populations – one with the lowest salt intake, and one with the highest.

The Yanomamo, who live in the Amazon rain forest, had an average blood pressure of about 95/61.  It does not increase as they get older, and they have no high blood pressure or obesity.  Their diet was very low in sodium (only 21 mg/day, the lowest ever measured) and high in potassium (2475 mg/day), giving a potassium to sodium ratio of 118. 

The Kenyan rural villagers had the highest sodium intake of about 1300 mg/day (3250 mg salt) and an average blood pressure of 111/66, even though their potassium intake was about half their sodium intake.  The other populations had an average sodium intake between the Yanomamo and the Kenyans, and also had an average blood pressure between the two.  Adults in all four remote populations were physically active and generally appeared healthy, with no physical signs of malnutrition or protein deficiency. 

Clearly, humans adapted to a low sodium intake during evolution. 

According to a March 1996 article in Hypertension, 20 to 40 % of the US population are “salt sensitive.”  These are people whose regulatory mechanisms fail at the average salt intake of the US diet, leading to increased blood pressure, especially as we get older.  (The current US average intake is 10,000 mg salt/day or 4000 mg Na/day.) The average blood pressure in the US is 127/77, within the 2003 National Heart, Lung, and Blood Institute clinical guidelines for blood pressure.  A normal reading is considered to be less than 120/80.  But about 30% of Americans have high blood pressure, defined as being greater than 140/90, as is shown in a May 2003 article in the Journal of the American Medical Association.  People who have between normal and high blood pressure are said to have “pre-high blood pressure.”

Extensive data from prospective population studies indicate that lowering blood pressure levels could substantially reduce rates of major cardiovascular diseases and mortality from all causes.  This can be accomplished for many people by lowering salt intake, increasing postassium, calcium and magnesium intake, reducing obesity and alcohol intake, and increasing exercise.



Avatar of: victor ocasio

victor ocasio

Posts: 1

March 12, 2013

I just want to thank you both(Bjorn & HFC) for your interesting comments and insights on this topic.

Certainly, food for thought!

Popular Now

  1. Scientists Continue to Use Outdated Methods
  2. Secret Eugenics Conference Uncovered at University College London
  3. Like Humans, Walruses and Bats Cuddle Infants on Their Left Sides
  4. How Do Infant Immune Systems Learn to Tolerate Gut Bacteria?