Eating too much salt can trigger an adaptive immune response in the gut that leads to reduced resting blood flow in the brain and the development of dementia, at least in mice, according to researchers at Weill Cornell Medicine. Constantino ladecola, Ph.D., and colleagues suggest that their studies are the first to demonstrate how a high-salt diet (HSD) can impact resting cerebral perfusion, neurovascular regulation, and cognitive function by mechanisms that are independent of any effects on blood pressure. “We discovered that mice fed a HSD developed dementia even when blood pressure did not rise,” explains Dr. ladecola, who is director of the Feil Family Brain and Mind Research Institute (BMRI) and the Anne Parrish Titzell Professor of Neurology at Weill Cornell Medicine. “This was surprising since, in humans, the deleterious effects of salt on cognition were attributed to hypertension.”

The team’s results also highlight a potential target for reducing the harmful effects of excess salt consumption on the brain. Describing their studies in Nature Neuroscience, the team says the findings “unveil a previously undescribed gut–brain axis whereby dietary habits compromise the brain microvasculature, leading to altered brain function and cognitive impairment.” Their published paper is entitled “Dietary Salt Promotes Neurovascular and Cognitive Dysfunction through a Gut-Initiated TH17 Response.”

An estimated 90% of people in the U.S. eat more salt (sodium chloride) in their diets than the recommended 2300 mg per day. Too much salt causes high blood pressure, which is linked with cardiovascular diseases, but studies also indicate that the harmful effects of eating too much salt extend beyond those on blood pressure. A HSD has also been associated with cerebrovascular diseases and stroke, as well as cognitive impairment, the authors explain. “These changes in the gut have been shown to promote autoimmunity and exacerbate experimental allergic encephalomyelitis, an animal model of multiple sclerosis.”

More recent reports have also suggested that a HSD leads to immune changes in the gut, “resulting in increased susceptibility of the brain to autoimmunity,” the authors write. “A diet rich in salt induces the accumulation in the gut of T-helper lymphocytes producing the proinflammatory cytokine interleukin-17 (TH17).” The pathways involved suppress the anti-inflammatory function of regulatory T cells.”

To investigate the effects of dietary salt more closely, the researchers fed mice a diet containing either 4% or 8% salt, representing an eight-fold and 16-fold increase, respectively, compared with a normal mouse diet. The salt content of the mouse diets was equivalent to the upper end of human dietary salt consumption spectrum. After eight weeks, magnetic resonance imaging studies of the mouse brains identified a 28% decrease in resting cerebral blood flow in the cortex and a 25% decrease in blood flow the hippocampus, two areas of the brain that are involved in learning. The HSD also hindered brain endothelial cells from producing nitric oxide, which normally acts to relax the blood vessels and increase blood flow. There was no evidence of any vascular inflammatory effect that may have caused the endothelial dysfunction.

“Similarly, there was no upregulation of inflammatory genes in cerebral endothelial cells sorted from mice fed a HSD, suggesting that the neurovascular dysfunction was not due to a massive inflammatory response in cerebrovascular cells,” the authors comment. Encouragingly, the effects of a HSD on cerebral blood flow and endothelial cell function could be reversed, by switching the animals back to a normal diet for four weeks.

Normal cognitive function requires well-regulated blood flow. The researchers found that mice kept on a HSD developed dementia and performed worse on a number of tests, including an object recognition test and a maze test. Switching the animals back onto a normal diet resulted in improved performance on the novel object recognition test. A HSD also affected normal nesting behavior, with HSD-fed mice using less nesting material and demonstrating impaired nest-building ability. 

Further investigations showed that animals eating a HSD developed an adaptive immune response in their guts and higher numbers of TH17 cells, which led to increased IL-17 production and circulating IL-17 levels. IL-17 plays a role in regulating immune and inflammatory responses and signaling a reduction in nitric oxide production by endothelial cells.

Interestingly, treating mice with IL-17–targeting antibodies blocked the endothelial dysfunction and cognitive deficits induced by a HSD. Similarly mice engineered to lack IL-17 also didn't develop cognitive problems in response to being fed a HSD.

In a final set of experiments, the team treated HSD-fed mice using an ROCK kinase inhibitor Y27632, which acts to prevent suppression of nitric oxide activity.  The treated animals also showed lower circulating levels of IL-17 and improved cognitive and behavioral functions.

“The IL-17-ROCK pathway is an exciting target for future research in the causes of cognitive impairment,” suggests Giuseppe Faraco, Ph.D., assistant professor of research in neuroscience in the BMRI and first author of the team’s published study. “It appears to counteract the cerebrovascular and cognitive effects of a HSD, and it also may benefit people with diseases and conditions associated with elevated IL-17 levels, such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, and other autoimmune diseases.”

“We have demonstrated that HSD induces a TH17 response in the gut that leads to increases in circulating IL-17, which, in turn, acts on cerebral endothelial cells to suppress endothelial NO [nitric oxide] production, leading to reductions in cerebral perfusion and cognitive dysfunction,” the authors conclude. “These data have implications that go beyond the pathology associated with HSD,” they state. “Our findings suggest that the IL-17–ROCK pathway is a putative therapeutic target to counteract the deleterious cerebrovascular and cognitive effects of HSD and of other conditions associated with TH17 polarization. Activation of the TH17 cell–IL-17 pathway is observed in a number of diseases associated with cerebrovascular dysfunction, including, for example, multiple sclerosis, rheumatoid arthritis, psoriasis and inflammatory bowel disease. Counteracting the deleterious effects of IL-17–ROCK on the cerebral endothelium would be beneficial to reduce cardiovascular risk in these conditions.”

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