The overall goal of this research is to understand the mechanisms by which early life stress triggers long-lasting defects in intestinal epithelial barrie function. The proposed studies with investigate the interactive signaling between the enteric cholinergic nervous system, intestinal mast cells, and the intestinal epithelial barrier utilizing novel pig and murine model systems. The project, based on previous studies and recent preliminary data, will test the hypothesis, that early life stress-associated GI disease is caused by a multistep mechanism in which long-term sensitization and increased abundance of cholinergic enteric nerves triggers persistent mast cell activation and subsequent intestinal barrier dysfunction. Understanding the early life signaling pathways that trigger long-lasting intestinal barrier dysfunction has relevance understanding the development of important human disorders including the Inflammatory Bowel Diseases (IBDs) and Irritable Bowel Syndrome (IBS). At the same time, these studies will have significant relevance to understanding and treating intestinal disease of agricultural animals such as the pig which undergo early life production stressors that have long-lasting deleterious influence on disease resistance, growth rate, and feed efficiency throughout the animal's production lifespan.
In Specific Aim 1, we will determine the mechanism by which early life stress triggers long-term amplification of enteric cholinergic nervous system activity.
In Specific Aim 2, we will utilize innovative in vitro and in vivo model systems to unravel the mechanisms by which Ach triggers persistent intestinal mast cell activation.
In Specific Aim 3, we seek to understand the impact of early life stress and cholinergic nerve-mast cell signaling on alterations in epithelial tight junction protein function and structure in porcine and human models.
These specific aims are designed to gain a fundamental understanding of how early life experiences contribute to the development of GI disease in adult life and will bring to light opportunities to develop novel approaches for the prevention and treatment of important GI diseases in humans and agricultural animals.

Public Health Relevance

The susceptibility to adult onset of chronic, debilitating gastrointestinal diseases is profoundly influenced by environmental influences occurring early in life. We will study the mechanisms by which early life stress triggers long-lasting defects in intestinal epithelial barrier function, a primary causative factor in the development of GI diseases, including IBD, IBS, and food allergy. These studies have the potential to unravel the mechanisms of early life stress-induced GI disorders leading to the identification of novel therapeutic targets for the prevention and treatment of a number of GI diseases of humans and animals.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Grave, Gilman D
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Michigan State University
Veterinary Sciences
Schools of Veterinary Medicine
East Lansing
United States
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Pohl, Calvin S; Lennon, Elizabeth M; Li, Yihang et al. (2018) S. Typhimurium challenge in juvenile pigs modulates the expression and localization of enteric cholinergic proteins and correlates with mucosal injury and inflammation. Auton Neurosci 213:51-59
Gulledge, Travis V; Collette, Nicholas M; Mackey, Emily et al. (2018) Mast cell degranulation and calcium influx are inhibited by an Echinacea purpurea extract and the alkylamide dodeca-2E,4E-dienoic acid isobutylamide. J Ethnopharmacol 212:166-174
D'Costa, Susan; Ayyadurai, Saravanan; Gibson, Amelia J et al. (2018) Mast Cell CRF2 Suppresses Mast Cell Degranulation and Limits the Severity of Anaphylaxis and Stress-Induced Intestinal Permeability. J Allergy Clin Immunol :
Pohl, C S; Medland, J E; Mackey, E et al. (2017) Early weaning stress induces chronic functional diarrhea, intestinal barrier defects, and increased mast cell activity in a porcine model of early life adversity. Neurogastroenterol Motil 29:
Moeser, Adam J; Pohl, Calvin S; Rajput, Mrigendra (2017) Weaning stress and gastrointestinal barrier development: Implications for lifelong gut health in pigs. Anim Nutr 3:313-321
Ayyadurai, Saravanan; Gibson, Amelia J; D'Costa, Susan et al. (2017) Frontline Science: Corticotropin-releasing factor receptor subtype 1 is a critical modulator of mast cell degranulation and stress-induced pathophysiology. J Leukoc Biol 102:1299-1312
Choi, Hae Woong; Bowen, Samantha E; Miao, Yuxuan et al. (2016) Loss of Bladder Epithelium Induced by Cytolytic Mast Cell Granules. Immunity 45:1258-1269
Medland, J E; Pohl, C S; Edwards, L L et al. (2016) Early life adversity in piglets induces long-term upregulation of the enteric cholinergic nervous system and heightened, sex-specific secretomotor neuron responses. Neurogastroenterol Motil 28:1317-29
Li, Yihang; Hansen, Stephanie L; Borst, Luke B et al. (2016) Dietary Iron Deficiency and Oversupplementation Increase Intestinal Permeability, Ion Transport, and Inflammation in Pigs. J Nutr 146:1499-505
Mackey, Emily; Ayyadurai, Saravanan; Pohl, Calvin S et al. (2016) Sexual dimorphism in the mast cell transcriptome and the pathophysiological responses to immunological and psychological stress. Biol Sex Differ 7:60

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