For decades, it’s been thought that people with heart failure should drastically reduce their dietary salt intake, but some studies have suggested that salt restriction could be harmful for these patients. A recent review in the European Journal of Clinical Investigation that assessed all relevant studies published between 2000 and 2023 has concluded that there is no proven clinical benefit to this strategy for patients with heart failure.
Most relevant randomised trials were small, and a single large, randomised clinical trial was stopped early due to futility. Although moderate to strict salt restriction was linked with better quality of life and functional status, it did not affect mortality and hospitalisation rates among patients with heart failure.
“Doctors often resist making changes to age-old tenets that have no true scientific basis; however, when new good evidence surfaces, we should make an effort to embrace it,” said author Paolo Raggi MD, PhD, of the University of Alberta.
Those at risk for Type 2 diabetes may already know to avoid sugar, but new research suggests they may want to skip the salt as well.
A new study from Tulane University published in Mayo Clinic Proceedingsfound that frequently adding salt to foods was associated with an increased risk of developing Type 2 diabetes.
The study surveyed more than 400 000 adults registered in the UK Biobank about their salt intake. Over a median of 11.8 years of follow-up, more than 13 000 cases of Type 2 diabetes developed among participants. Compared to those who “never” or “rarely” used salt, participants who “sometimes,” “usually,” or “always” added salt had a respective 13%, 20%, and 39% higher risk of developing Type 2 diabetes.
“We already know that limiting salt can reduce the risk of cardiovascular diseases and hypertension, but this study shows for the first time that taking the saltshaker off the table can help prevent Type 2 diabetes as well,” said lead author Dr. Lu Qi, HCA Regents Distinguished Chair and professor at the Tulane University School of Public Health and Tropical Medicine.
Further research is needed to determine why high salt intake could be linked to a higher risk of Type 2 diabetes. However, Qi believes salt encourages people to eat larger portions, increasing the chances of developing risk factors such as obesity and inflammation. The study found an association between frequent consumption of salt and higher BMI and waist-to-hip ratio.
Qi said the next step is to conduct a clinical trial controlling the amount of salt participants consume and observing the effects.
Still, Qi said it’s never too early to start searching for low-sodium ways to season your favorite foods.
“It’s not a difficult change to make, but it could have a tremendous impact on your health,” Qi said.
Results from a clinical trial published in the Journal of Internal Medicine reveal several health benefits of moderate salt restriction in patients on standard medical treatment for primary aldosteronism/ These included lowered blood pressure and reduced depressive symptoms.
Primary aldosteronism – when adrenal glands produce excess aldosterone – is a common cause of secondary hypertension. The combination of aldosterone excess and high dietary salt intake leaves affected patients with a higher risk of cardiovascular disease than patients with hypertension from other causes. Mineralocorticoid antagonists are the main treatment of primary aldosteronism, but these medications do not completely normalise patients’ elevated cardiovascular risk.
Because elevated aldosterone and high dietary salt intake have detrimental effects on patients’ health, investigators wanted to find out whether salt restriction might benefit patients. In the non-randomised single-arm Salt CONNtrol trial that included 41 patients, moderate salt restriction reduced blood pressure and depressive symptoms without detectable adverse effects.
“The study shows that a moderate dietary salt restriction is feasible, when combined with a dedicated smartphone app for continuous motivation, and has a strong antihypertensive effect in patients with primary aldosteronism,” said corresponding author Christian Adolf, MD, of Ludwig Maximilian University of Munich, in Germany. “Our findings will help to improve care for patients with primary aldosteronism and, likely, also for subgroups of patients with essential hypertension.”
Regulatory T cells ensure that immune responses happen in a controlled way. But eating too much salt weakens these cells’ energy supply, thus rendering them temporarily dysfunctional. This salt-induced ‘load shedding’ may have implications for autoimmunity, researchers report in Cell Metabolism.
Excessive salt consumption not only causes cardiovascular problems, it could also adversely impact the immune system. The study found that salt can disrupt regulatory T cells by impairing their energy metabolism. The findings may provide new avenues for exploring the development of autoimmune and cardiovascular diseases.
A few years ago, research by teams led by Professor Dominik Müller and Professor Markus Kleinewietfeld revealed that excess salt in the diet can negatively affect the metabolism and energy balance in certain types of innate immune cells called monocytes and macrophages and stop them from working properly. They further showed that salt triggers malfunctions in the mitochondria. Inspired by these findings, the research groups wondered whether excessive salt intake might also create a similar problem in adaptive immune cells like regulatory T cells.
Important immune regulators
Regulatory T cells, also known as Tregs, are an essential part of the adaptive immune system. They are responsible for maintaining the balance between normal function and unwanted excessive inflammation.
Scientists believe that the deregulation of Tregs is linked to the development of autoimmune diseases like multiple sclerosis. Recent research has identified problems in mitochondrial function of Tregs from patients with autoimmunity, yet the contributing factors remain elusive.
“Considering our previous findings of salt affecting mitochondrial function of monocytes and macrophages as well as the new observations on mitochondria in Tregs from autoimmune patients, we were wondering if sodium might elicit similar issues in Tregs of healthy volunteers,” says Müller, who co-heads the Hypertension-Mediated End-Organ Damage Lab at the Max Delbrück Center and the ECRC.
Previous research has also shown that excess salt could impact Treg function by inducing an autoimmune-like phenotype. In other words, too much salt makes the Treg cells look like those involved in autoimmune conditions. However, exactly how sodium impairs Treg function had not yet been uncovered.
Salt interferes with mitochondrial function of Tregs
The new international study led by Kleinewietfeld and Müller has now discovered that sodium disrupts Treg function by altering cellular metabolism through interference with mitochondrial energy generation. This mitochondrial problem seems to be the initial step in how salt modifies Treg function, leading to changes in gene expression that showed similarities to those of dysfunctional Tregs in autoimmune conditions.
Even a short-term disruption of mitochondrial function had long-lasting consequences for the fitness and immune-regulating capacity of Tregs in various experimental models. The new findings suggest that sodium may be a factor that could contribute to Treg dysfunction, potentially playing a role in different diseases, although this needs to be confirmed in further studies.
“The better understanding of factors and underlying molecular mechanisms contributing to Treg dysfunction in autoimmunity is an important question in the field. Since Tregs also play a role in diseases such as cancer or cardiovascular disease, the further exploration of such sodium-elicited effects may offer novel strategies for altering Treg function in different types of diseases,” says Kleinewietfeld, who heads the VIB Laboratory for Translational Immunomodulation. “However, future studies are needed to understand the molecular mechanisms in more detail and to clarify their potential relationship to disease.”
Researchers have found that, besides raising blood pressure, too much salt can disrupt the immune system by affecting their energy balance in immune calls and weakening them.
Back in 2015, the researchers had found that raised sodium concentrations in the blood affect both the activation and the function of patrolling monocytes — the precursors to macrophages.
“But we didn’t know exactly what was happening in the cells,” said Dr Sabrina Geisberger of the Berlin Institute for Medical Systems Biology (BIMSB) at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC). She is lead author of the study of an international research team led by MDC scientists together with colleagues from University of Regensburg and from Flanders Institute for Biotechnology (VIB) /Hasselt University in Belgium.
The researchers began in the lab by measuring the metabolism immune cells exposed to high salt concentrations.
Changes appeared after just three hours. “It disrupts the respiratory chain, causing the cells to produce less ATP and consume less oxygen,” explained Prof Geisberger. ATP (adenosine triphosphate) powers all cells, providing energy for the ‘chemical work’—synthesising proteins and other molecules—needed for muscle power and metabolic regulation. ATP is produced in the mitochondria, the cell’s ‘power plant,’ using a complex series of biochemical reactions known as the respiratory chain. “Salt very specifically inhibits complex II in the respiratory chain.”
Consequences include the monocytes maturing differently due to a lack of energy. “The phagocytes, whose task is to identify and eliminate pathogens in the body, were able to fight off infections more effectively. But this could also promote inflammation, which might increase cardiovascular risk,” explained Professor Dominik Müller of the Experimental and Clinical Research Center (ECRC). Salt was shown to affect the functioning of human phagocytes in the same way.
Researchers at the ECRC then conducted a study in which healthy male participants six grammes of salt in tablet form to their usual diet every day for 14 days. In another clinical study, the researchers investigated a familiar scenario: eating a pizza from an Italian restaurant. After analysing the monocytes in the participants’ blood, they saw that the mitochondrial dampening effect doesn’t just happen after an extended time with high salt intake—it also happens after a single pizza. The pizza experiment showed that the effect was fairly short. After eight hours, the effect was barely measurable.
“That’s a good thing. If it had been a prolonged disturbance, we’d be worried about the cells not getting enough energy for a long time,” commented Prof Müller. Mitochondrial activity is therefore not permanently stalled. However, the risk remains if a person eats very salty foods throughout the day. The pizza, incidentally, contained ten grammes of salt. Nutrition experts recommend that adults limit their daily intake to five or six grammes at most. The calculation includes the salt that is hidden in processed foods.
“The fundamental finding of our study is that a molecule as small as the sodium ion can be extremely efficient at inhibiting an enzyme that plays a crucial role in the respiratory chain,” said biochemist and metabolomics expert Dr Stefan Kempa of BIMSB. “When these ions flood into the mitochondria—and they do this under a variety of physiological conditions—they regulate the central part of the electron transport chain.” It therefore seems to be a fundamental regulatory mechanism in cells.
The next step is determining whether salt influences this mechanism in other cell types. Prof Kleinewietfeld believes that this is extremely likely because mitochondria aren’t just present in immune cells; they exist in every cell of the body, save for red blood cells.
Though the way in which different cell types regulate sodium influx into the mitochondria is still not properly understood, the study confirms that overconsumption of salt is unhealthy. “Of course the first thing you think of is the cardiovascular risk. But multiple studies have shown that salt can affect immune cells in a variety of ways. If such an important cellular mechanism is disrupted for a long period, it could have a negative impact—and could potentially drive inflammatory diseases of the blood vessels or joints, or autoimmune diseases,” said Professor Markus Kleinewietfeld of Hasselt University and VIB.
More information: Sabrina Geisberger et al, Salt Transiently Inhibits Mitochondrial Energetics in Mononuclear Phagocytes, Circulation (2021). DOI: 10.1161/CIRCULATIONAHA.120.052788
