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The prevalence of chronic immune and metabolic disorders is increasing rapidly. In particular, inflammatory bowel diseases, obesity, diabetes, asthma and chronic obstructive pulmonary disease have become major healthcare and economic burdens worldwide. Recent advances in microbiome research have led to significant discoveries of associative links between alterations in the microbiome and health, as well as these chronic supposedly noncommunicable, immune/metabolic disorders. Importantly, the interplay between diet, microbiome and the mucous barrier in these diseases has gained significant attention. Diet modulates the mucous barrier via alterations in gut microbiota, resulting in either disease onset/exacerbation due to a "poor" diet or protection against disease with a "healthy" diet. In addition, many mucosa-associated disorders possess a specific gut microbiome fingerprint associated with the composition of the mucous barrier, which is further influenced by host-microbiome and inter-microbial interactions, dietary choices, microbe immigration and antimicrobials. Our review focuses on the interactions of diet (macronutrients and micronutrients), gut microbiota and mucous barriers (gastrointestinal and respiratory tract) and their importance in the onset and/or progression of major immune/metabolic disorders. We also highlight the key mechanisms that could be targeted therapeutically to prevent and/or treat these disorders.

BACKGROUND: Macrophages control innate and acquired immunity but their role in severe asthma remains ill-defined. We investigated gene signatures of macrophage subtypes in the sputum of 104 asthmatics and 16 healthy volunteers from the U-BIOPRED cohort. METHODS: Forty-nine gene signatures (modules) for differentially stimulated macrophages, one to assess lung tissue-resident cells (TR-Mφ) and two for their polarization (classically- and alternatively-activated macrophages: M1 and M2 respectively) were studied using gene set variation analysis. We calculated enrichment scores (ES) across severity and previously identified asthma transcriptome-associated clusters (TACs). RESULTS: Macrophage numbers were significantly decreased in severe asthma compared to mild-moderate asthma and healthy volunteers. The ES for most modules were also significantly reduced in severe asthma except for 3 associated with inflammatory responses driven by TNF and Toll-like receptors via NF-κB, eicosanoid biosynthesis via the lipoxygenase pathway and IL-2 biosynthesis (all p

Background Asthma is an allergic airway disease (AAD) caused by aberrant immune responses to allergens. Protein phosphatase-2A (PP2A) is an abundant serine/threonine phosphatase with anti-inflammatory activity. The ubiquitin proteasome system (UPS) controls many cellular processes, including the initiation of inflammatory responses by protein degradation. We assessed if enhancing PP2A activity with Fingolimod (FTY720) or 2-amino-4-(4-(heptyloxy) phenyl)-2-methylbutan-1-ol (AAL(S)), or inhibiting proteasome activity with Bortezomib (BORT) could suppress experimental AAD. Methods Acute AAD was induced in C57BL/6 mice by intraperitoneal sensitisation with ovalbumin (OVA) in combination with intranasal (i.n) exposure to OVA. Chronic AAD was induced in mice with prolonged i.n exposure to crude house dust mite (HDM) extract. Mice were treated with vehicle, FTY720, AAL(S), BORT or AAL(S)+BORT and hallmark features of AAD assessed. Results AAL(S) reduced the severity of acute AAD by suppressing tissue eosinophils and inflammation, mucus secreting cell (MSC) numbers, type-2 associated cytokines (Interleukin (IL)-33, thymic stromal lymphopoietin, IL-5 and IL-13), serum immunoglobulin (Ig)E, and airway hyper-responsiveness (AHR). FTY720 only suppressed tissue inflammation and IgE. BORT reduced bronchoalveolar lavage fluid (BALF) and tissue eosinophils and inflammation, IL-5, IL-13, and AHR. Combined treatment with AAL(S)+BORT had complementary effects and suppressed BALF and tissue eosinophils and inflammation, MSC numbers, reduced the production of type-2 cytokines and AHR. AAL(S), BORT and AAL(S)+BORT also reduced airway remodelling in chronic AAD. Conclusion These findings highlight the potential of combination therapies that enhance PP2A and inhibit proteasome activity as novel therapeutic strategies for asthma. This article is protected by copyright. All rights reserved.