The National Heart, Lung, and Blood Institute (NHLBI) convened a working group of multidisciplinary researchers on May 29, 2014, in Bethesda, MD, to share current knowledge regarding the effects of dietary salt on the human body and to explore and identify scientific gaps and challenges.
This working group is responsive to NHLBI Strategic Plan Goals 1, 2, and 3 (2007).
Humans have had a long and complicated relationship with salt. While highly valued in many societies, dietary salt has long been associated with high blood pressure, or hypertension, and, more recently, other diseases. One study found that about half of the subjects with high blood pressure had salt-sensitive hypertension, a condition more prevalent among African Americans, older persons, and individuals with renal insufficiency or diabetes. In general, for those with salt-sensitive hypertension, excess sodium intake is associated with high blood pressure, while a low-salt diet decreases blood pressure. In spite of this well-known association, the basic biological mechanisms underlying the effects of salt on blood pressure regulation are still not well understood. In addition, although individuals with high blood pressure are at increased risk for coronary artery disease, heart failure, stroke, and renal disease, it is unclear whether a high dietary salt intake directly leads to cardiovascular diseases—i.e., in the absence of hypertension.
Our understanding of the effect of salt on health grew even more complex with a recent finding. Researchers reported a new connection between salt and autoimmunity: a high-salt diet was shown to accelerate autoimmune activity in a mouse model of multiple sclerosis. Interestingly, recent research has also revealed a connection between hypertension and the immune system: basic science experiments demonstrated that the immune system contributes to hypertension, and clinical observations indicate an increased incidence of hypertension in patients with certain autoimmune conditions, such as psoriasis. As is the case with hypertension, salt, and cardiovascular disease, scientists have not yet worked out the causal relationships between salt, immunity, and hypertension (e.g., how salt may mediate interactions between the immune system, vasculature, brain, and kidney to control blood pressure).
Working Group Discussion:
The working group brought together 14 experts from diverse backgrounds in hypertension, epidemiology, preeclampsia (a pregnancy complication involving high blood pressure), and cardiovascular, renal, and autoimmune diseases. NIH staff from the NHLBI, the National Institute for Allergies and Infectious Diseases (NIAID), and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) organized and participated in the meeting. The working group reviewed existing and emerging scientific evidence that connects salt to human diseases, with a focus on hypertension and immune diseases. The main areas of discussion addressed the bases of relationships between (i) dietary salt and hypertension, (ii) salt, autoimmunity, and cardiovascular diseases, and (iii) hypertension and immunity in various organs and systems (brain, kidney, skin, and vasculature). The group also considered the potential effect of endogenous factors (genetics, sex, and race) and environment on these relationships. A final session discussed associations between salt, immune cells, and genetics. Since the working group members came from diverse backgrounds and most had not collaborated before, the meeting provided an excellent opportunity for cross-disciplinary thinking and discussions and highlighted the potential for future collaborations.
Working Group Recommendations:
The working group concluded that the initial research that has implicated salt as a factor in important diseases points to the need to further illuminate the biological mechanisms and pathological processes to which salt may contribute. To guide this research into how salt may connect several human diseases, the working group members identified scientific gaps and challenges and highlighted some opportunities for scientific inquiry and technical development.
The working group recommended various research topics that scientists should investigate:
- Hypertension and immune disease (including autoimmune diseases), using existing experimental models, sex-specific animal models, and new experimental models
- Salt-sensitive hypertension; in particular:
- the relative importance and interactions of several cytokines (specifically, IL-17, IFN-γ, TNFα and IL-6)
- the relationships between genes and environment (i.e., epigenetics)
- the role of the gut microbiome and the lymphatic system
- The underlying mechanisms of salt storage in the skin; for example, the regulatory mechanisms influencing the interaction between sodium and glycosaminoglycan, which binds excess sodium in skin to store it
- How pro-hypertensive neural inflammatory processes and peripheral immune cell activation by sodium interact to affect health
- Cardiovascular disease development in women who have had preeclampsia
Finally, the group identified tools and technologies that are needed to move this research agenda forward:
- standardized protocols to determine salt sensitivity at an individual level;
- reliable diagnostic tests for preeclampsia; and
- new technologies to measure sodium concentrations in human tissues and animal models.
The kinds of technologies that would be helpful include methods to measure electrolyte distribution in skin microvasculature and easily accessible Sodium Magnetic Resonance Imaging (MRI). Unlike traditional MRI, which forms images based on detecting hydrogen atoms in water, lipids, and other macromolecules in the body, Sodium MRI can reveal extracellular and intracellular sodium levels, which will help with understanding the role of salt in health and disease. As these technologies, protocols, and diagnostic tests become available, it will be critical that they are adopted.
During the general discussion, the working group members also noted that it may be necessary to adopt a new term—homeostatic immune response—to describe the evolving concept of the physiological role of immunity and inflammation.
The working group plans to prepare a manuscript for publication in a peer-reviewed journal.
Working Group Members:
David Harrison, M.D., Vanderbilt University
- Lawrence J. Appel, M.D., MPH, Johns Hopkins University
- David A. Hafler, M.D., Yale University
- Jiang He, M.D., Tulane University
- Bina Joe, Ph.D., University of Toledo
- Ananth Karumanchi, M.D., Harvard Medical School
- David Mattson, Ph.D., Medical College of Wisconsin
- Nehal Mehta, M.D., National Heart, Lung and Blood Institute
- Gwendolyn Randolph, Ph.D., Washington University
- Michael Ryan, Ph.D., University of Mississippi Medical Center
- Kathryn Sandberg, Ph.D., Georgetown University
- Jens Tizte, M.D., Vanderbilt University
- Glenn M. Toney, Ph.D., University of Texas Health Science Center
- Ralf Dechend, M.D., University of Berlin
- Lawrence Fine, M.D., Clinical Applications and Prevention Branch, DCVS, NHLBI
- Zorina Galis, Ph.D., Vascular Biology & Hypertension Branch, DCVS, NHLBI
- Christine Maric-Bilkan, Ph.D., Vascular Biology & Hypertension Branch, DCVS, NHLBI
- Young Oh, Ph.D., Vascular Biology & Hypertension Branch, DCVS, NHLBI
- Eser Tolunay, Ph.D., Vascular Biology & Hypertension Branch, DCVS, NHLBI
- Katarzyna Bourcier, Ph.D., Division of Allergy, Immunology, and Transplantation, NIAID
- Chris Ketchum, Ph.D., Division of Kidney, Urology and Hematology, NIDDK