A new study from Zhejiang University in China has found that both extremely high and extremely low dietary salt intakes can impair cognitive function in mice, albeit through distinct biological routes. The research, published in Food Research International, shows that excessive salt triggers systemic inflammation and hippocampal disruption, while severe salt restriction starves the gut microbiome of metabolic byproducts essential for brain health.
The human digestive tract is home to trillions of microorganisms, collectively known as the gut microbiome. These microbes communicate with the central nervous system through a biochemical pathway known as the gut-brain axis.
Health professionals routinely advise reducing dietary sodium to protect cardiovascular health. Diets rich in salt are already known to disrupt the gut microbiome and impair memory. A high-salt environment can promote inflammation and harm the hippocampus, a brain region central to learning and memory.
Salt extremes disrupt gut-brain axis, study finds
Little is known about the neurological effects of eating extremely small amounts of salt. Clinical observations occasionally link severe sodium deficiency with cognitive difficulties, but the direct biological mechanisms connecting extreme salt restriction to brain function have not been mapped out in detail.
Researchers from Zhejiang University, led by Anji Chen, designed a study to compare the neurological and metabolic effects of high-salt and low-salt diets. To make their animal model more relevant to human biology, they employed a microbiome humanisation approach.
The team conducted a small study using 32 male mice. They first treated most of the animals with antibiotics to deplete their native gut bacteria. They then fed the mice a solution containing human faecal matter, allowing human-derived bacteria to colonise the animals’ digestive tracts.
After this colonisation period, the humanised mice were divided into three groups and fed distinct diets for 14 weeks. One group received a normal-salt diet, another a severely restricted low-salt diet, and a third a high-salt diet. A fourth control group consisted of standard mice maintaining their natural gut bacteria and eating a normal-salt diet.
Following the 14-week feeding period, the researchers tested the animals’ memory and anxiety levels using a series of behavioural tests. They employed a Y-shaped maze to assess short-term spatial working memory and a novel object recognition test to gauge long-term memory.
Both the low-salt and high-salt groups showed substantial impairments in short-term spatial working memory and long-term recognition memory compared with the normal-salt group, with the high-salt group experiencing the most pronounced deficits. These mice also displayed heightened anxiety-like behaviour in an open-field arena and drank considerably more water. The low-salt group showed memory deficits without the accompanying anxiety or thirst observed in the high-salt group.
To understand why these behavioural changes occurred, the researchers examined brain tissue, focusing on the hippocampus, a region highly sensitive to metabolic disruptions. They measured levels of specific proteins that support synapse formation—the connections through which neurons communicate.
Both extreme diets reduced the abundance of key synaptic proteins and essential growth factors. One suppressed protein was brain-derived neurotrophic factor, or BDNF, which supports neuronal survival and helps the brain adapt to new information.
The high-salt diet caused a widespread reduction in proteins that structure both the presynaptic and postsynaptic elements of a synapse. The low-salt diet primarily affected proteins involved in structural stability and synaptic adaptability, with the overall quantity of neuronal vesicles remaining relatively intact.
The researchers then sequenced the gut bacteria of the animals to see how the diets altered the microbiome. The high-salt diet led to an expansion of bacteria associated with inflammation, while the low-salt diet promoted shifts towards certain specialised bacteria but reduced the overall population of beneficial microbes such as those in the Lactobacillus genus.
Next, the team measured metabolites produced by gut bacteria. Short-chain fatty acids, which help regulate the immune system and nourish the brain, were diminished in both extreme diet groups. The low-salt diet, however, caused a sharper drop in two additional compounds, acetate and isobutyrate. Acetate serves as a principal metabolic signal that can travel from the gut to the brain, so its depletion suggests a broad suppression of microbial metabolism under severe salt restriction.
The researchers also analysed lipids in the animals’ intestinal tracts. The high-salt group showed signs of severe oxidative stress and an increase in pro-inflammatory fats, while the low-salt group experienced a reduction in lipids that support neuronal membranes, though without the oxidative stress seen in the high-salt group.
Blood tests measured circulating cytokines, signalling proteins that trigger immune responses. The high-salt diet elevated multiple inflammatory cytokines, indicating systemic inflammation. The low-salt diet did not produce a detectable rise in these inflammatory markers.
The study concludes that severe salt restriction is not biologically neutral and may represent a distinct risk factor for cognitive decline. Extreme low-salt intake appears to impair memory by depriving the gut microbiome of its ability to produce essential metabolic signals, rather than by causing the inflammatory damage seen with high-salt consumption.
Several caveats should be kept in mind. This was a small study conducted entirely in male mice. While the humanised microbiome approach aims to improve relevance to humans, animal physiology may not fully mirror human responses.
The researchers acknowledge statistical correlations between particular bacteria, metabolic byproducts and memory scores, but stop short of proving that the missing short-chain fatty acids directly caused the memory loss. The diets represented extreme ends of the sodium spectrum, necessary to isolate mechanisms but not necessarily reflective of typical human eating habits.
Future work will need to establish the lower limits of healthy human salt consumption and determine whether supplementing specific missing metabolites could prevent cognitive decline associated with imbalanced sodium intake.
The study, “Long-term low-salt and high-salt diets differentially disrupt the gut – metabolite – brain axis and induce cognitive impairment,” was authored by Anji Chen, Shilong Hu, Fansen Zeng, Chengfeng Yu, Danying Chen, Xingqian Ye, Zengliang Jiang, and Shiguo Chen.
