Dietary Salt Exacerbates Experimental Colitis

Abstract

The Western Diet – characterized by high protein, sugar, fat and low fiber intake – is widely believed to contribute to the incidence and pathogenesis of inflammatory bowel diseases (IBD). However, high sodium chloride salt content, a defining feature of processed foods, has not been considered as a possible environmental factor that might drive IBD. We set out to bridge this gap. We examined murine models of colitis on either a high salt diet (HSD) or a low salt diet (LSD). We demonstrate that a HSD exacerbates inflammatory pathology in the IL-10-deficient murine model of colitis relative to mice fed a LSD. This was correlated with enhanced expression of numerous pro-inflammatory cytokines. Surprisingly, sodium accumulated in the colons of mice on a HSD, suggesting a direct effect of salt within the colon. Similar to the IL-10-deficient model, a HSD also enhanced cytokine expression during infection by Salmonella typhimurium. This occurred in the first three day of infection, suggesting that a HSD potentiates innate immune response. Indeed, in cultured dendritic cells we found that high salt media potentiates cytokine expression downstream of TLR4 activation via p38 MAPK and SGK1. A third common colitis model, administration of dextran sodium sulfate (DSS), was hopelessly confounded by the high sodium content of the DSS. Our results raise the possibility that high dietary salt is an environmental factor that drives increased inflammation in IBD.

The role of salt for immune cell function and disease

“…On the other hand, silencing or overexpression experiments for Nfat5 revealed a critical role for this transcription factor as mediator of the salt response of murine macrophages . Recently, it was shown that bone‐marrow‐derived dendritic cells react to enhanced sodium concentration in an Sgk‐1‐ and p38‐MAPK‐dependent manner, resulting in elevated IL‐23 secretion . In summary, high‐salt conditions could particularly affect the functionality of macrophages, dendritic cells, T H 17 cells and Tregs (Table ).…”

High-Salt Diet Gets Involved in Gastrointestinal Diseases through the Reshaping of Gastroenterological Milieu

“…In order to examine whether and how high salt intake alters mucosal cytokine production, normal intestinal lamina propria mononuclear cells were activated and exposed under HSD. Finally, IL-17A, IL-23R, tumor necrosis factor-α (TNF-α), and retinoic acid-related orphan nuclear receptor-γt (Ror-γT) were found significantly increased in human lamina propria mononuclear cell [12]. Studies have shown that an HSD can induce human circulating monocyte proinflammatory activation and is associated with monocyte-platelet aggregation [13].…”

“…Recently, studies revealed the HSD affects the GI immune system detrimentally [11,12]. First, the sodium was found accumulated in the colons of mice on an HSD, suggesting a direct effect of salt within the colon [12]. HSD provoked a histologically detectable inflammation while exacerbating chemically induced models of colitis in mice by a mechanism dependent on interleukin (IL)-17 production most likely by both type 3 Innate lymphoid cell (ILC3 ) and Th17 cells [11].…”

“…Innate immunity appears rapidly but lacks specificity, and the intestinal mucosa is the first immune defense barrier of gut. Recently, studies revealed the HSD affects the GI immune system detrimentally [11,12]. First, the sodium was found accumulated in the colons of mice on an HSD, suggesting a direct effect of salt within the colon [12].…”

“…Recent studies showed that HSD exacerbated colitis in mice by affecting the gut microbiota and intestinal immune homeostasis [5,11,26]. Actually, an HSD has long been demonstrated to disrupt intestinal immunity and increase the risk of IBD [12], exacerbating experimental colitis in both the ceca and colon while increasing immune infiltration, epithelial hyperplasia, and extensive goblet cell loss [12]. The HSD stimulates the Th17 response in both the small and large intestines, increasing the production of IL-17A but suppressing the function of Treg cells, inhibiting the secretion of IL-10 [5] and altering epithelial signaling cascades to promote inflammation.…”