BackgroundDietary changes are suggested to play a role in the increasing prevalence of allergic diseases and asthma. Short‐chain fatty acids (SCFAs) are metabolites present in certain foods and are produced by microbes in the gut following fermentation of fibers. SCFAs have been shown to have anti‐inflammatory properties in animal models. Our objective was to investigate the potential role of SCFAs in the prevention of allergy and asthma.MethodsWe analyzed SCFA levels by high‐performance liquid chromatography (HPLC) in fecal samples from 301 one‐year‐old children from a birth cohort and examined their association with early life exposures, especially diet, and allergy and asthma later in life. Data on exposures and allergic diseases were collected by questionnaires. In addition, we treated mice with SCFAs to examine their effect on allergic airway inflammation.ResultsSignificant associations between the levels of SCFAs and the infant's diet were identified. Children with the highest levels of butyrate and propionate (≥95th percentile) in feces at the age of one year had significantly less atopic sensitization and were less likely to have asthma between 3 and 6 years. Children with the highest levels of butyrate were also less likely to have a reported diagnosis of food allergy or allergic rhinitis. Oral administration of SCFAs to mice significantly reduced the severity of allergic airway inflammation.ConclusionOur results suggest that strategies to increase SCFA levels could be a new dietary preventive option for allergic diseases in children.

In order to improve targeted therapeutic approaches for asthma patients, insights into the molecular mechanisms that differentially contribute to disease phenotypes, such as obese asthmatics or severe asthmatics, are required. Here we report immunological and microbiome alterations in obese asthmatics (n = 50, mean age = 45), non-obese asthmatics (n = 53, mean age = 40), obese non-asthmatics (n = 51, mean age = 44) and their healthy counterparts (n = 48, mean age = 39). Obesity is associated with elevated proinflammatory signatures, which are enhanced in the presence of asthma. Similarly, obesity or asthma induced changes in the composition of the microbiota, while an additive effect is observed in obese asthma patients. Asthma disease severity is negatively correlated with fecal Akkermansia muciniphila levels. Administration of A. muciniphila to murine models significantly reduces airway hyper-reactivity and airway inflammation. Changes in immunological processes and microbiota composition are accentuated in obese asthma patients due to the additive effects of both disease states, while A. muciniphila may play a non-redundant role in patients with a severe asthma phenotype.

The immune-modulating properties of certain bifidobacterial strains, such as Bifidobacterium longum subsp. longum 35624 (B. longum 35624), have been well described, although the strain-specific molecular characteristics associated with such immuneregulatory activity are not well defined. It has previously been demonstrated that B. longum 35624 produces a cell surface exopolysaccharide (sEPS), and in this study, we investigated the role played by this exopolysaccharide in influencing the host immune response. B. longum 35624 induced relatively low levels of cytokine secretion from human dendritic cells, whereas an isogenic exopolysaccharide-negative mutant derivative (termed sEPS neg ) induced vastly more cytokines, including interleukin-17 (IL-17), and this response was reversed when exopolysaccharide production was restored in sEPS neg by genetic complementation. Administration of B. longum 35624 to mice of the T cell transfer colitis model prevented disease symptoms, whereas sEPS neg did not protect against the development of colitis, with associated enhanced recruitment of IL-17 ؉ lymphocytes to the gut. Moreover, intranasal administration of sEPS neg also resulted in enhanced recruitment of IL-17 ؉ lymphocytes to the murine lung. These data demonstrate that the particular exopolysaccharide produced by B. longum 35624 plays an essential role in dampening proinflammatory host responses to the strain and that loss of exopolysaccharide production results in the induction of local T H 17 responses. IMPORTANCEParticular gut commensals, such as B. longum 35624, are known to contribute positively to the development of mucosal immune cells, resulting in protection from inflammatory diseases. However, the molecular basis and mechanisms for these commensalhost interactions are poorly described. In this report, an exopolysaccharide was shown to be decisive in influencing the immune response to the bacterium. We generated an isogenic mutant unable to produce exopolysaccharide and observed that this mutation caused a dramatic change in the response of human immune cells in vitro. In addition, the use of mouse models confirmed that lack of exopolysaccharide production induces inflammatory responses to the bacterium. These results implicate the surfaceassociated exopolysaccharide of the B. longum 35624 cell envelope in the prevention of aberrant inflammatory responses. T he gut microbiota contributes significantly to host health via multiple mechanisms, including the digestion of foods, competitive exclusion of pathogens, enhancement of epithelial cell differentiation, and promotion of mucosa-associated lymphoid tissue proliferation (1, 2). Furthermore, accumulating evidence suggests that the composition and metabolic activity of the gut microbiota has profound effects on proinflammatory activity and the induction of immune tolerance within mucosal tissue (3-5). Certain microbes induce regulatory responses, while others induce effector responses, resulting in the case of healthy individuals in a balanced homeostatic...

In addition to microbial exposure, increased exposure to non-microbial-derived Neu5Gc might contribute to the protective effects associated with the farm environment.

The deliberate activation of H R, or its downstream signaling molecules, may represent a novel therapeutic target for chronic lung inflammatory diseases, especially when CD1d-mediated presentation of lipid antigens to iNKT cells is contributing to the pathology.

Background Fatty acids and lipid mediator signaling play an important role in the pathogenesis of asthma, yet this area remains largely underexplored. The aims of this study were (i) to examine fatty acid levels and their metabolism in obese and nonobese asthma patients and (ii) to determine the functional effects of altered fatty acid metabolism in experimental models. Methods Medium‐ and long‐chain fatty acid levels were quantified in serum from 161 human volunteers by LC/MS. Changes in stearoyl‐coenzyme A desaturase (SCD) expression and activity were evaluated in the ovalbumin (OVA) and house dust mite (HDM) murine models. Primary human bronchial epithelial cells from asthma patients and controls were evaluated for SCD expression and activity. Results The serum desaturation index (an indirect measure of SCD) was significantly reduced in nonobese asthma patients and in the OVA murine model. SCD1 gene expression was significantly reduced within the lungs following OVA or HDM challenge. Inhibition of SCD in mice promoted airway hyper‐responsiveness. SCD1 expression was suppressed in bronchial epithelial cells from asthma patients. IL‐4 and IL‐13 reduced epithelial cell SCD1 expression. Inhibition of SCD reduced surfactant protein C expression and suppressed rhinovirus‐induced IP‐10 secretion, which was associated with increased viral titers. Conclusions This is the first study to demonstrate decreased fatty acid desaturase activity in humans with asthma. Experimental models in mice and human epithelial cells suggest that inhibition of desaturase activity leads to airway hyper‐responsiveness and reduced antiviral defense. SCD may represent a new target for therapeutic intervention in asthma patients.

Interactions between the host and the microbiota are thought to significantly influence immunological tolerance mechanisms at mucosal sites. We recently described that the loss of an exopolysaccharide (EPS) from Bifidobacterium longum 35624™ eliminated its protective effects in colitis and respiratory allergy murine models. Our goal was to investigate the immune response to purified EPS from B. longum 35624, determine if it has protective effects within the lung and identify the protective mechanisms. Isolated EPS from B. longum 35624 cultures was used for in vitro, ex vivo and in vivo studies. Human monocyte-derived dendritic cells (MDDCs) were used to investigate in vitro immunological responses to EPS. Cytokine secretion, expression of surface markers and signalling pathways were examined. The ovalbumin (OVA) respiratory allergy murine model was used to evaluate the in vivo immunomodulatory potential of EPS. In addition, interleukin (IL)-10 knockout (KO) mice and anti-Toll-like receptor (TLR)-2 blocking antibody were used to examine the underlying protective mechanisms of intranasal EPS administration. Stimulation of human MDDCs with EPS resulted in IL-10 secretion, but not proinflammatory cytokines. IL-10 secretion was TLR-2-dependent. Eosinophil recruitment to the lungs was significantly decreased by EPS intranasal exposure, which was associated with decreased expression of the Th2-associated markers C-C motif chemokine 11 (CCL11), C-C chemokine receptor type 3 (CCR3), IL-4 and IL-13. TLR-2-mediated IL-10 secretion was shown to be required for the reduction in eosinophils and Th2 cytokines. EPS-treatment reduced eosinophil recruitment within the lung in a respiratory inflammation mouse model, which is both TLR-2 and IL-10 mediated. EPS can be considered as a novel molecule potentially reducing the severity of chronic eosinophil-related airway disorders.

Abstract. Uveitis is a clinical feature of the Blau syndrome, a disease linked to CARD15 (also referred to as NOD2) mutations. Three main mutations in this gene (R334W, R334Q and L469F) have been reported as Blau syndrome risk factors, a disease that manifests uveitis as one of its clinical features. However, little is known on the involvement of this gene in idiopathic uveitis. We thus sought to determine the frequency of these Blau-related CARD15 mutations in a cohort of Spanish patients with idiopathic uveitis. To this aim, 110 patients with idiopathic uveitis, followed at the Department of Ophtalmology of a tertiary hospital (Hospital Universitario Alcalá de Henares, Madrid. Spain) were enrolled. As a control population, 104 healthy subjects were used. DNA was extracted from blood samples and the Blau-related CARD15 mutations were analysed either by PCR-RFLP or direct DNA sequencing. None of the mutations studied was found in any of the individuals tested, whether diseased or healthy. It seems thus that Blau syndrome-related CARD15 mutations are not involved in idiopathic uveitis, a finding which allows us to suggest that the genetic aetiology of the idiopathic uveitis or the Blau-associated uveitis is different.