A diet rich in salt is linked to an increased risk
of cerebrovascular diseases and dementia, but it
remains unclear how dietary salt harms the brain.
In a new mouse study, scientists link changes in the
gut caused by a high-salt diet to impaired blood
flow in the brain.
This reduced blood flow can eventually lead to
impaired cognition that could be reversed by
changing back to a normal diet.
“For years researchers have wondered how a high-salt
diet harms the brain,” said Jim Koenig, Ph.D.,
program director at the National Institute of
Neurological Disorders and Stroke (NINDS), part of
the National Institutes of Health, which supported
the study. “This mouse study provides a detailed
cellular and molecular diagram for how the problems
start in the gut and opens unexpected paths towards
In this study, mice were fed a high-salt diet (HSD)
containing 16 times the amount of sodium chloride
typically found in their food.
After eight weeks, their brains showed a 20 to 30
percent reduction in blood flow compared to mice
that ate normal food.
This drop in blood flow was accompanied by the
appearance of dementia-like symptoms, including
defects in the ability of HSD mice to recognize
objects, navigate a maze, and properly build a nest.
When the mice were returned to a normal diet, both
blood flow and cognition improved, suggesting that
the negative effects of excessive salt consumption
could be reversible.
“The brain is extremely dependent on getting the
right amount of blood at the right time.
If blood flow isn’t matched to what the brain needs,
things go wrong,” said Costantino Iadecola, M.D.,
director and chair of the Feil Family Brain and Mind
Research Institute at Weill Cornell Medicine in New
York City and senior author of this study.
To study further how salt affects blood flow in the
brain, blood vessels were taken from the brains of
mice fed a high-salt diet and grown in a dish.
Normally, these vessels tighten (constrict) to
reduce blood flow or relax (dilate) to increase
flow. However, those taken from HSD mice did not
dilate properly when stimulated to do so.
A closer look revealed a reduction in the function
of the enzyme eNOS that is responsible for producing
nitric oxide (NO), a potent signal for blood vessels
When the amino acid L-arginine, which can increase
eNOS activity and NO production, was added to the
dishes containing blood vessels from HSD mice, the
cells responded normally.
When L-arginine was injected into HSD mice directly,
the defects in cognition were also rescued.
“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,” said Dr. Iadecola, who is on the
strategic advisory board and receives a consulting
fee from Broadview Ventures Inc.
One clue came from evidence showing that eating high
levels of salt changes the immune system of the gut,
a finding that was first reported by scientists
studying salt’s effects in a model of multiple
Specifically, a high-salt diet increased the
appearance of TH17 immune cells.
These TH17 cells secrete a molecule, IL-17, that can
have toxic effects on blood vessels.
Because the researchers did not observe any TH17
cells in the brains of HSD mice, they concluded that
it must be IL-17, moving throughout the circulatory
system, that was acting directly on the brain’s
The combined results of three additional experiments
helped to confirm this hypothesis.
First, HSD produced no effects in the brains of mice
that lacked the gene for IL-17.
Second, the effects of HSD could be reversed by
treating mice with an antibody that binds up IL-17
and prevents it from affecting blood vessels.
Third, effects similar to those produced by HSD were
seen in normal mice that were injected directly with
Together, these findings suggest that it is IL-17,
released from cells in the gut in response to a
high-salt diet, that acts on the blood vessels in
the brain to affect blood flow.
In humans, high levels of salt in the diet has long
been associated with high blood pressure, and
increasing evidence has linked blood pressure and
brain health. However, the blood pressure of HSD
mice was not affected, suggesting a very specific
and independent mechanism for the changes seen here.
In future experiments, Dr. Iadecola and his
colleagues plan to further investigate further how
decreased NO production and reduced blood flow leads
to changes in cognition.
For more information
Dietary salt promotes neurovascular and cognitive
dysfunction through a gut-initiated TH17 response
The National Institute of Neurological Disorders and