High salt diets disrupt the gut microbiome and impair memory in mice

A new study demonstrates that both abnormally high and abnormally low dietary salt intake can induce cognitive impairment in mice, though through distinctly different biological pathways. The research reveals that while excessive salt triggers systemic inflammation, severe salt restriction starves the gut microbiome of metabolic byproducts needed for optimal brain function. The findings were published in the journal Food Research International.

The human digestive tract is home to trillions of microorganisms, collectively known as the gut microbiome. These microbes engage in constant communication with the central nervous system through a biochemical pathway called the gut-brain axis.

Health professionals routinely recommend reducing dietary sodium to protect cardiovascular health. Diets heavily loaded with 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 formation.

The neurological effects of eating extremely small amounts of salt remain much less understood. 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 systematically mapped out.

Researchers from Zhejiang University in China, 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 utilized a technique called microbiome humanization.

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The researchers designed a small study using 32 male mice. They first treated the majority of the animals with antibiotics to deplete their natural gut bacteria. They then fed the mice a solution containing human fecal matter, allowing human-derived bacteria to colonize the animals’ digestive tracts.

Following this colonization period, the humanized mice were divided into three groups and fed distinct diets for 14 weeks. One group received a normal-salt diet, another received a heavily restricted low-salt diet, and the third group consumed a high-salt diet. A fourth control group of standard mice maintained their natural gut bacteria and ate a normal-salt diet.

After the 14-week feeding period, the researchers tested the animals’ memory and anxiety levels using a series of behavioral tests. They used a Y-shaped maze to evaluate short-term spatial working memory by tracking how well the mice remembered which arms of the maze they had already explored. They also used a novel object recognition test, which measures long-term memory by seeing if the mice spend more time investigating a new item compared to a familiar one.

Both the low-salt and high-salt groups exhibited substantial impairments in short-term spatial working memory and long-term recognition memory compared to the normal-salt group. The high-salt diet produced the most severe cognitive deficits. These mice also displayed elevated anxiety-like behavior in an open arena test and drank substantially more water. The low-salt group experienced memory deficits without the added symptoms of anxiety or excessive thirst.

To understand why these behavioral changes occurred, the researchers examined the animals’ brain tissue. They specifically focused on the hippocampus, a brain region highly sensitive to metabolic disruptions. The scientists measured the levels of specific proteins that help build synapses, which are the physical communication junctions between neurons.

Both extreme diets reduced the abundance of key synaptic proteins and essential growth factors. One suppressed protein was brain-derived neurotrophic factor, a molecule that 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 sending and receiving ends of a synapse. The low-salt diet primarily affected the proteins involved in structural stability and synaptic adaptability, leaving the physical abundance of neuronal vesicles relatively intact.

The team then sequenced the genetic material of the bacteria living in the animals’ colons to see how the diets altered the microbiome. The high-salt diet prompted an expansion of bacteria associated with inflammation. The low-salt diet caused a different shift, slightly increasing certain specialized bacteria but reducing the overall population of beneficial microbes like those in the Lactobacillus genus.

Next, the researchers measured the metabolic byproducts produced by these gut bacteria. When microbes digest food, they produce compounds called short-chain fatty acids that help regulate immune responses and nourish the brain.

Both extreme diets reduced the levels of two helpful short-chain fatty acids called propionate and butyrate. The low-salt diet, however, also caused a sharp drop in two additional compounds, acetate and isobutyrate. Acetate is a primary metabolic signal that can travel from the gut to the brain, and its depletion suggests a broad suppression of microbial metabolism under severe salt restriction.

The researchers also analyzed lipids in the animals’ intestinal tracts. The high-salt group showed signs of severe oxidative stress, a condition where reactive oxygen molecules damage cells, and an increase in pro-inflammatory fats. The low-salt group experienced a drop in certain lipids that support neuronal membranes, but they did not exhibit the oxidative stress seen in the high-salt group.

Finally, blood tests were conducted to measure circulating cytokines, which are signaling proteins that trigger immune responses. The high-salt diet elevated multiple inflammatory cytokines, indicating a state of systemic inflammation. The low-salt diet did not produce any observable increase in these inflammatory markers.

The study suggests that severe salt restriction is not biologically neutral and might represent a distinct risk factor for cognitive decline. Extreme low-salt intake appears to impair memory by starving the gut microbiome of its ability to produce essential metabolic signals, rather than by triggering the aggressive inflammation seen with high-salt consumption.

Several caveats should be kept in mind when interpreting these results. This was a small study conducted entirely on male mice. While the humanized microbiome technique makes the findings more relevant to humans, the biological responses of a mouse may not perfectly mirror human physiology.

The study highlights statistical correlations between specific bacteria, metabolic byproducts, and memory scores, but it does not definitively prove that the missing short-chain fatty acids directly caused the memory loss. The experimental diets represented extreme ends of the sodium spectrum, which were necessary to isolate biological mechanisms but do not necessarily reflect typical human eating habits.

Future research will need to establish the exact lower limits for healthy human salt consumption. Scientists also need to determine whether supplementing specific missing metabolites could prevent the cognitive decline associated with imbalanced sodium intake.

This research provides a foundational step in understanding how dietary minerals influence neurological health. 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.