Highlight: Is too much salt bad for your guts?

Is eating too much table salt bad for your health? People have debated this for years, with proposed links to several cardiovascular diseases. But a recent expert committee for the Institute of Medicine concluded that the data don’t support such a link [1], keeping the debate alive. Two recent papers in Nature, however, suggest that too much dietary salt might affect our immune system instead — and potentially raise the risk of autoimmune diseases.

Th17 Cells and the Gut

CD4 T lymphocytes can turn into specialized subsets that drive or assist different immune responses. These are called T helper (Th) cells. Each subset is named after the main cytokine it produces — for example, IL-17 for Th17 T cells.

• Th17 cells help protect the body against many bacterial and fungal infections.
• They are common in intestinal tissue, where they help maintain the gut’s barrier function and keep intestinal bacteria where they belong [2].
• But too much of a good thing applies here too: Th17 cells also play a harmful role in several autoimmune diseases.

This means the body needs a delicate balance to control Th17 cell numbers and function.

Researchers already knew that the gut lumen and the Th17 cell response talk to each other. For example, a few years back, researchers showed that the frequency of a common gut bacterium could change how many Th17 cells appear in intestinal tissue [3]. Two new studies now show that table salt (sodium chloride, NaCl) is a surprising new factor that changes the frequency and function of Th17 cells [4-6].

How Dietary Salt Drives Th17 Cell Differentiation

Adding 40 mM NaCl — a level found in the intestinal tissue of animals fed a high-salt diet — to in vitro cultures increased Th17 cell differentiation [4, 5]. Similarly, feeding mice a high-salt diet increased the frequency of Th17 cells in intestinal tissue, though not in the lymph nodes or spleen. In both settings (in vitro and in vivo), the resulting Th17 cells produced large amounts of pro-inflammatory cytokines.

Analyzing mRNA expression, both research groups identified three key players in sensing NaCl and carrying out its effects:

• The MAP-kinase p38
• NFAT5 (nuclear factor of activated T cells 5)
• SGK1 (serum glucocorticoid-regulated kinase-1)

Removing any of these factors from the T cells — either by genetic ablation or by suppressing their expression with RNA interference (shRNA) — blocked the boost in Th17 cell differentiation that NaCl otherwise caused.

All three proteins work within the same pathway, but SGK1 appeared central to regulating the NaCl-induced effect. This finding, while surprising, lines up with SGK1’s known role in sodium transport and balance [7]. Increased NaCl concentrations turned on SGK1 expression, and so did the cytokine IL-23, which plays a key role in stabilizing and reinforcing the Th17 phenotype [2]. Because NaCl also increased expression of the IL-23 receptor, this created a positive feedback loop that strengthened Th17 cell differentiation. Importantly, both research groups also showed that raising dietary salt levels could worsen the severity of EAE (experimental autoimmune encephalomyelitis), a mouse model for the autoimmune disease multiple sclerosis [4-6].

What This Means for Autoimmune Disease Risk

In short, these reports show that high dietary salt levels can make mice more prone to a form of autoimmune disease driven by harmful Th17 T cells. The data suggest that high NaCl concentrations might be an environmental risk factor for autoimmune diseases. That said, high NaCl concentration alone did not trigger autoimmune responses — the EAE animal model still needed immunization with a known self-antigen. Autoimmunity comes from a complex mix of many genetic and environmental factors. These new reports [4, 5] suggest that high dietary salt might tip the balance slightly toward autoimmunity in people who are already genetically predisposed.

Still, reality will likely be more complicated, as it usually is. For example, researchers still need to confirm that the link between dietary NaCl and Th17 cells holds in humans too. Other factors may also matter: SGK1 expression is also triggered by several hormones, including natural steroids like stress hormones [7]. This suggests that stress might also help drive Th17 cell induction. These intriguing new reports [4, 5] will likely spur further research to answer these questions. Until then, going easy on salty junk food seems like a reasonable idea in general.

References

[1] Strom, Brian (2013). Sodium Intake in Populations: Assessment of Evidence. Washington, DC: The National Academies Press: The Institute of Medicine.

[2] Weaver, C. T., Elson, C. O., Fouser, L. A. & Kolls, J. K. The Th17 pathway and inflammatory diseases of the intestines, lungs, and skin. Annu Rev Pathol 8, 477–512 (2013).

[3] Ivanov, I. I. et al. Induction of Intestinal Th17 Cells by Segmented Filamentous Bacteria. Cell 139, 485–498 (2009).

[4] Kleinewietfeld, M. et al. Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells. Nature (2013). doi:10.1038/nature11868.

[5] Wu, C. et al. Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1. Nature (2013). doi:10.1038/nature11984.

[6] O’Shea, J. J. & Jones, R. G. Autoimmunity: Rubbing salt in the wound. Nature 496, 437–439 (2013).

[7] Lang, F. & Shumilina, E. Regulation of ion channels by the serum- and glucocorticoid-inducible kinase SGK1. The FASEB Journal 27, 3–12 (2013).