IL-1 regulates the IL-23 response to wheat gliadin, the etiologic agent of Celiac Disease

Celiac disease (CD) is an autoimmune disease prevalent in ~1% of the general population. CD is unique because both the major genetic (Human Leukocyte Antigen-DQ2/DQ8 alleles) and etiologic factors (dietary glutens) for susceptibility are known. While these alleles are responsible for the inappropriate T cell response that characterizes CD, they are not sufficient since most HLA-DQ2+/DQ8+ individuals exposed to glutens never develop disease. The reasons for this have not been explained; however our novel findings strongly advocate a role for interleukin-23 (IL-23) in the immunopathogenesis of CD. We demonstrate that wheat gliadin stimulates monocytes to produce significantly higher amounts of inflammatory cytokines IL-1b, IL-23, and tumor necrosis factor-a (TNFa) in CD patients compared to HLA-DQ2+ healthy individuals. Furthermore, we determine that IL-1 signalling is obligatory for production of IL-23, since IL-1b triggers IL-23 secretion in a dose-dependent manner and IL-1 receptor antagonist (IL-1ra) blocks IL-23 responses to gliadin. Our results suggest that gliadin activation of monocytes and the subsequent robust secretion of IL-1b and IL-23 initiate the immune response cascade that is manifest as CD, and reveal for the first time that the IL-1 system regulates production of IL-23. The discovery of IL-23 has highlighted the critical role of the innate immune response in autoimmunity and other inflammatory conditions. We anticipate that our novel findings will lead to the discovery of therapeutic targets for this disease and other inflammatory diseases mediated by IL-23

Gluten Related Disorders: People Shall not Live on Bread Alone

Once upon a time, gluten was not part of the human diet, and therefore, there were no gluten-related disorders. With the advent of agriculture 10,000 years ago, the introduction of gluten-containing grains in the human diet created conditions for human diseases related to gluten exposure. These diseases, including celiac disease, non-celiac gluten sensitivity, and wheat allergy, have distinct pathophysiological mechanisms, serological markers, and long-term treatments, but similar, often overlapping clinical presentations. Though current research strives to clarify the boundaries between these entities, their differences can be difficult to distinguish. For a very long time, awareness of these disorders has been limited and, therefore, the epidemiology of gluten-related disorders has been a “work in progress”. New epidemiological studies have revealed that gluten-related disorders are not limited to European regions; rather, they are present worldwide. After centuries of neglected attention to celiac disease and other forms of gluten reaction, now we are observing another interesting phenomenon that is generating great confusion among health care professionals. Nearly 25% of Americans (many more than the projected 3 million celiac disease (CD) patients in the U.S.) are reducing or cutting gluten from their diets. This remarkable trend in the general population reflects the misconception that gluten can be harmful for everybody and, therefore, should be avoided to stay healthy, to lose weight, or even to prevent severe diseases. This Special Issue Book of Nutrients contains contributions from leading experts in the field of gluten-related disorders that will help dissipate this confusion by sharing their evidence-based science, which will help the reader to distinguish facts from fantasies

Atomistic modeling of water infiltration in defective zeolite for thermal storage applications

In this article, the impact that zeolite materials may have in the near future in loss-free, more compact and efficient thermal storage systems is numerically investigated. Water infiltration within MFI zeolite presenting different concentrations of hydrophilic defects is studied by Molecular Dynamics (MD) simulations. Results show that the characteristic infiltration pressure of water in the considered zeolite framework is reduced with increased hydrophilicity. Dubinin-Astakhov model is then applied to link zeolite-water interaction energy with the resulting infiltration isotherms of the nanoporous material. The effort, therefore, is to gather some model-driven guidelines towards innovative materials for thermal systems that may be manufactured and employed in the near future for addressing a great challenge of our society: storage and use of thermal energy

Water/Ethanol and 13X Zeolite Pairs for Long-Term Thermal Energy Storage at Ambient Pressure

Thermal energy storage is a key technology to increase the global energy share of renewables - by matching energy availability and demand - and to improve the fuel economy of energy systems - by recovery and reutilization of waste heat. In particular, the negligible heat losses of sorption technologies during the storing period make them ideal for applications where long-term storage is required. Current technologies are typically based on the sorption of vapour sorbates on solid sorbents, requiring cumbersome reactors and components operating at below ambient pressure. In this work, we report the experimental characterization of working pairs made of various liquid sorbates (distilled water, ethanol and their mixture) and a 13X zeolite sorbent at ambient pressure. The sorbent hydration by liquid sorbates shows lower heat storage performance than vapour hydration; yet, it provides similar heat storage density to that obtainable by latent heat storage (40-50 kWh/m^3) at comparable costs, robustness and simplicity of the system, while gaining the long-term storage capabilities of sorption-based technologies. As a representative application example of long-term storage, we verify the feasibility of a sorption heat storage system with liquid sorbate, which could be used to improve the cold-start of stand-by generators driven by internal combustion engines. This example shows that liquid hydration may be adopted as a simple and low-cost alternative to more efficient - yet more expensive - techniques for long-term energy storage

Interplay between hydrophilicity and surface barriers on water transport in zeolite membranes

A comprehensive understanding of molecular transport within nanoporous materials remains elusive in a broad variety of engineering and biomedical applications. Here, experiments and atomistic simulations are synergically used to elucidate the non-trivial interplay between nanopore hydrophilicity and surface barriers on the overall water transport through zeolite crystals. At these nanometre-length scales, these results highlight the dominating effect of surface imperfections with reduced permeability on the overall water transport. A simple diffusion resistance model is shown to be sufficient to capture the effects of both intracrystalline and surface diffusion resistances, thus properly linking simulation to experimental evidence. This work suggests that future experimental work should focus on eliminating/overcoming these surface imperfections, which promise an order of magnitude improvement in permeability.MITOR ProjectNANO-BRIDGE (PRIN 2012, grant number 2012LHPSJC)NANOSTEP (Fondazione CRT, Torino) projectsScuola Interpolitecnica di Dottorato—SCUDOISCRA initiative (CINECA award)Center for Clean Water and Clean Energy at MIT and KFUP

Dysbiosis and zonulin upregulation alter gut epithelial and vascular barriers in patients with ankylosing spondylitis

Background: Dysbiosis has been recently demonstrated in patients with ankylosing spondylitis (AS) but its implications in the modulation of intestinal immune responses have never been studied. The aim of this study was to investigate the role of ileal bacteria in modulating local and systemic immune responses in AS. Methods: Ileal biopsies were obtained from 50 HLA-B27+ patients with AS and 20 normal subjects. Silver stain was used to visualise bacteria. Ileal expression of tight and adherens junction proteins was investigated by TaqMan real-time (RT)-PCR and immunohistochemistry. Serum levels of lipopolysaccharide (LPS), LPS-binding protein (LPS-BP), intestinal fatty acid-BP (iFABP) and zonulin were assayed by ELISA. Monocyte immunological functions were studied in in vitro experiments. In addition the effects of antibiotics on tight junctions in human leukocyte antigen (HLA)-B27 transgenic (TG) rats were assessed. Results: Adherent and invasive bacteria were observed in the gut of patients with AS with the bacterial scores significantly correlated with gut inflammation. Impairment of the gut vascular barrier (GVB) was also present in AS, accompanied by significant upregulation of zonulin, and associated with high serum levels of LPS, LPS-BP, iFABP and zonulin. In in vitro studies zonulin altered endothelial tight junctions while its epithelial release was modulated by isolated AS ileal bacteria. AS circulating monocytes displayed an anergic phenotype partially restored by ex vivo stimulation with LPS+sCD14 and their stimulation with recombinant zonulin induced a clear M2 phenotype. Antibiotics restored tight junction function in HLA-B27 TG rats. Conclusions: Bacterial ileitis, increased zonulin expression and damaged intestinal mucosal barrier and GVB, characterises the gut of patients with AS and are associated with increased blood levels of zonulin, and bacterial products. Bacterial products and zonulin influence monocyte behaviour

Microbial Biomarkers of Intestinal Barrier Maturation in Preterm Infants

Intestinal barrier immaturity, or “leaky gut,” is the proximate cause of susceptibility to necrotizing enterocolitis in preterm neonates. However, the impact of intestinal microbiota development on intestinal mucosal barrier maturation has not been evaluated in this population. In this study, we investigated a longitudinally sampled cohort of 38 preterm infants < 33 weeks gestation monitored for intestinal permeability (IP) and fecal microbiota during the first 2 weeks of life. Rapid decrease in IP indicating intestinal barrier function maturation correlated with significant increase in community diversity. In particular, members of the Clostridiales and Bifidobacterium were highly transcriptionally active, and progressively increasing abundance in Clostridiales was significantly associated with decreased intestinal permeability. Further, neonatal factors previously identified to promote intestinal barrier maturation, including early exclusive breastmilk feeding and shorter duration antibiotic exposure, associate with the early colonization of the intestinal microbiota by members of the Clostridiales, which altogether are associated with improved intestinal barrier function in preterm infants