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Yao syndrome (YAOS) is a systemic autoinflammatory disease (SAID), formerly termed nucleotide-binding oligomerization domain-2 (NOD2)-associated autoinflammatory disease. Due to the recent identification of YAOS, the molecular mechanisms underlying its disease pathogenesis are unclear. With specific NOD2 variants as characteristic genotypic features of YAOS, our study examined NOD2 expression, transcript splicing, signaling pathway activation, and cytokine profiles in peripheral blood mononuclear cells (PBMCs) from 10 YAOS patients and six healthy individuals. All participants were genotyped for NOD2 variants; all YAOS patients were heterozygous for the NOD2 IVS8+158 variant (IVS8+158) and four patients also carried a concurrent NOD2 R702W variant (IVS8+158/R702W haplotype). Resembling other SAIDs, plasma levels of TNFα, IL-1β, IL-6, IFNγ, and S100A12 were unaltered in YAOS patients. Intron-8 splicing of NOD2 transcripts was unaffected by carriage of NOD2 IVS8+158. However, NOD2 transcript level and basal p38 mitogen-activated protein kinase (MAPK) activity were significantly elevated in PBMCs from IVS8+158 YAOS patients. Moreover, these patients’ cells had elevated basal IL-6 secretion that was enhanced by muramyl dipeptide (MDP) stimulation. Tocilizumab treatment of a YAOS IVS8+158 patient resulted in marked clinical improvement. In contrast, MDP-stimulated NF-κB activity was uniquely suppressed in haplotype IVS8+158/R702W patients, as was TNFα secretion. Our study demonstrates for the first time that NOD2 expression and pathway activation are aberrant in YAOS, and specific NOD2 genotypes result in distinct NOD2 expression and cytokine profiles. These findings may also help select therapeutic strategies in the future. [ABSTRACT FROM AUTHOR]

In the latter half of the 20th century, societal and technological changes led to a shift in the composition of the American diet to include a greater proportion of processed, pre-packaged foods high in fat and carbohydrates, and low in dietary fiber (a “Western diet”). Over the same time period, there have been parallel increases in Salmonella gastroenteritis cases and a broad range of chronic inflammatory diseases associated with intestinal dysbiosis. Several polysaccharide food additives are linked to bacterially-driven intestinal inflammation and may contribute to the pathogenic effects of a Western diet. Therefore, we examined the effect of a ubiquitous polysaccharide food additive, maltodextrin (MDX), on clearance of the enteric pathogen Salmonella using both in vitro and in vivo infection models. When examined in vitro, murine bone marrow-derived macrophages exposed to MDX had altered vesicular trafficking, suppressed NAPDH oxidase expression, and reduced recruitment of NADPH oxidase to Salmonella-containing vesicles, which resulted in persistence of Salmonella in enlarged Rab7+ late endosomal vesicles. In vivo, mice consuming MDX-supplemented water had a breakdown of the anti-microbial mucous layer separating gut bacteria from the intestinal epithelium surface. Additionally, oral infection of these mice with Salmonella resulted in increased cecal bacterial loads and enrichment of lamina propria cells harboring large Rab7+ vesicles. These findings indicate that consumption of processed foods containing the polysaccharide MDX contributes to suppression of intestinal anti-microbial defense mechanisms and may be an environmental priming factor for the development of chronic inflammatory disease. [ABSTRACT FROM AUTHOR]