The gastrointestinal (GI) barrier serves a critical role in survival and overall health of animals and humans. Several layers of barrier defense mechanisms are provided by the epithelial, immune and enteric nervous systems. Together they act in concert to control normal gut functions (e.g., digestion, absorption, secretion, immunity, etc.) whereas at the same time provide a barrier from the hostile conditions in the luminal environment. Breakdown of these critical GI functions is a central pathophysiological mechanism in the most serious GI disorders in pigs. This review will focus on the development and functional properties of the GI barrier in pigs and how common early life production stressors, such as weaning, can alter immediate and long-term barrier function and disease susceptibility. Specific stress-related pathophysiological mechanisms responsible for driving GI barrier dysfunction induced by weaning and the implications to animal health and performance will be discussed.

In this manuscript, a plant polymer based TLR-4 agonist was discovered as a novel vaccine adjuvant.

Mast cell corticotropin-releasing factor subtype 2 suppresses mast cell degranulation and limits the severity of anaphylaxis and stress-induced intestinal permeability. Permalink https://escholarship.org/uc/item/8t3660m4 Journal Abstract 33 34 Background: Psychological stress and heightened MC activation are linked with important 35 immunological disorders including allergy, anaphylaxis, asthma, and functional bowel 36diseases, but the mechanisms remain poorly defined. We have previously demonstrated that 37 activation of the corticotropin releasing factor (CRF) system potentiates MC degranulation 38 responses during IgE-mediated anaphylaxis and psychological stress, via CRF receptor 39 subtype 1 (CRF 1 ) expressed on MCs. 40 41 Objective: In this study, we investigated the role of CRF receptor subtype 2 (CRF 2 ) as a 42 modulator of stress-induced MC degranulation and associated disease pathophysiology. 43 44 Methods: In vitro MC degranulation assays were performed with bone marrow derived MCs 45 (BMMCs) derived from WT and CRF 2 -deficient (CRF 2 -/-) mice and RBL-2H3 MCs transfected 46 with CRF 2 -overexpressing plasmid or CRF 2 -siRNA. In vivo MC responses and associated 47 pathophysiology in IgE-mediated passive systemic anaphylaxis (PSA) and acute 48 psychological restraint stress were measured in WT, CRF 2 -/-, and MC-deficient Kit W-sh/W-sh 49 knock-in mice. 50 51 Results: Compared with WT mice, CRF 2 -/exhibited heightened serum histamine levels and 52 exacerbated PSA-induced anaphylactic responses and colonic permeability. In addition, 53 CRF 2 -/mice exhibited increased serum histamine and colonic permeability following acute 54 restraint stress. Experiments with BMMCs and RBL-2H3 MCs demonstrated that CRF 2 55 expressed on MCs suppresses store-operated Ca 2+ entry (SOCE) signaling and MC 56 M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 3 degranulation induced by diverse MC stimuli. Experiments with MC-deficient Kit W-sh/W-sh mice 57 systemically engrafted with WT and CRF 2 -/-BMMCs demonstrated the functional importance 58 of MC-CRF 2 in modulating stress-induced pathophysiology. 59 60 Conclusions: MC CRF 2 is a negative, global modulator of stimuli-induced MC degranulation 61 and limits the severity of IgE-mediated anaphylaxis and stress-related disease pathogenesis. 62 63 Key messages 64 • Loss of CRF 2 function induces exacerbated MC degranulation, IgE-mediated 65 anaphylaxis and psychological stress-induced intestinal barrier dysfunction. 66 • MC-specific CRF 2 suppresses degranulation induced by diverse MC stimuli via 67 negative regulation of SOCE. 68 • Further characterization of the mechanisms by which CRF 2 negatively modulates MC 69 activation could lead to novel therapeutic approaches for stress-related immunological 70 disorders associated with MC hyperactivity. 71 72

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