A high-salt diet compromises antibacterial neutrophil responses through hormonal perturbation

Abstract

The Western diet is rich in salt, which poses various health risks. A high-salt diet (HSD) can stimulate immunity through the nuclear factor of activated T cells 5 (Nfat5)–signaling pathway, especially in the skin, where sodium is stored. The kidney medulla also accumulates sodium to build an osmotic gradient for water conservation. Here, we studied the effect of an HSD on the immune defense against uropathogenic E. coli–induced pyelonephritis, the most common kidney infection. Unexpectedly, pyelonephritis was aggravated in mice on an HSD by two mechanisms. First, on an HSD, sodium must be excreted; therefore, the kidney used urea instead to build the osmotic gradient. However, in contrast to sodium, urea suppressed the antibacterial functionality of neutrophils, the principal immune effectors against pyelonephritis. Second, the body excretes sodium by lowering mineralocorticoid production via suppressing aldosterone synthase. This caused an accumulation of aldosterone precursors with glucocorticoid functionality, which abolished the diurnal adrenocorticotropic hormone–driven glucocorticoid rhythm and compromised neutrophil development and antibacterial functionality systemically. Consistently, under an HSD, systemic Listeria monocytogenes infection was also aggravated in a glucocorticoid-dependent manner. Glucocorticoids directly induced Nfat5 expression, but pharmacological normalization of renal Nfat5 expression failed to restore the antibacterial defense. Last, healthy humans consuming an HSD for 1 week showed hyperglucocorticoidism and impaired antibacterial neutrophil function. In summary, an HSD suppresses intrarenal neutrophils Nfat5-independently by altering the local microenvironment and systemically by glucocorticoid-mediated immunosuppression. These findings argue against high-salt consumption during bacterial infections.

Gut Microbiome, Intestinal Permeability, and Tissue Bacteria in Metabolic Disease: Perpetrators or Bystanders?

“…In conjunction with evidence that environmental factors such as diet or other industrial food additives (i.e., salt [63,64]), as well a proinflammatory gut environment can lead to an increased intestinal permeability [65] and susceptibility to invasive pathobionts [66], and that inflammation per se can shift gut microbial composition [67], it is currently unclear whether inflammation is at the dispensing/receiving or both ends of gut microbiome shifts culminating in increased bacterial translocation.…”

High-salt diet suppresses autoimmune demyelination by regulating the blood–brain barrier permeability

“…To identify the mechanisms behind these changes, we focused our investigations on circulating components with the potential to alter BBB. Highsalt intake is known to induce changes in mineralocorticoid and glucocorticoid levels in both mice and humans (15)(16)(17)(18). We detected elevated levels of corticosterone in the serum of HSD-fed OSE mice (Fig.…”

Metabolic acidosis exacerbates pyelonephritis in mice prone to vesicoureteral reflux

“…In ischemic tissues, neutrophils catabolize Gln as a carbon source for free radical and cytokine production via anaplerotic shunting of Gln to the Krebs cycle (Cruzat, Macedo Rogero, Noel Keane, Curi, & Newsholme, 2018; Metallo et al., 2011; Newsholme et al., 1999; Wang et al., 2019). In a recent study investigating the impact of a high‐salt diet on susceptibility pyelonephritis, Jobin et al reported that glucocorticoid‐mediated suppression of neutrophil function exacerbates pyelonephritis in mice (Jobin et al., 2020). Elevated corticosterone levels in acidotic rodents has been reported (May, Kelly, & Mitch, 1986) and therefore stimulation of glucocorticoid production by metabolic acidosis may represent an alternative mechanism for increased susceptibility to pyelonephritis.…”