Exposure to early life adversity (ELA) during critical periods of prenatal and postnatal development is an important risk factor for the later life onset of highly prevalent gastrointestinal (GI) diseases, including irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). The precise mechanisms linking ELA and GI disease susceptibility are unknown and thus management and therapeutic targets and biomarkers are lacking. Our studies using a porcine model demonstrated that ELA alters the normal course of GI development resulting in lifelong intestinal barrier dysfunction or ?leaky gut', neuroimmune dysregulation and increased GI disease that recapitulates much of the pathophysiology and clinical features of human stress-related GI disorders. We recently identified two factors associated with ELA-induced GI disease susceptibility and severity in adulthood: (1) heightened and persistent intestinal mast cell hyper-activity and (2) biological sex with females at increased risk and males protected. Furthermore, we have identified novel sex-differences in the mast cell phenotype in that mast cell from female animals exhibit enhanced synthesis storage and stress-induced release of mediators such as histamine, proteases and serotonin which have known roles in GI neuroimmune disorders. Our hypothesis is that mast cells and biological sex interact to organize the development of GI barrier and neuroimmune systems, consequently determining the lifetime risk to disease following exposure to ELA. We have designed three specific aims to accomplish this objective.
Aim 1 will test the hypothesis that hyper-activation of GI mast cells during early postnatal development lead to GI barrier and neuroimmune dysfunction in adulthood.
Aim 2 will test the hypothesis that the heightened vulnerability of females to ELA-induced GI disease depends on androgens acting during early development.
Aim 3 will test the hypothesis that ELA and perinatal androgens program mast cells, via epigenetic and transcriptional mechanisms, resulting in mast cell hyperactivity which drives GI barrier and neuroimmune dysfunction into adulthood. Together, the studies proposed in the grant application are expected to result in a major paradigm shift in the understanding the origins of ELA-induced and sex-biased GI neuroimmune diseases which could ultimately unveil new therapeutic targets to protect the GI system during vulnerable periods of stress and to therapeutically modulate adult diseases in both sexes.

Public Health Relevance

The susceptibility to chronic, debilitating gastrointestinal and immune diseases in adulthood are profoundly influenced by adverse stressful influences occurring early in life. This research program seeks to understand how interactions between biological sex and innate immune signaling in early life shape the trajectory for GI barrier development and disease susceptibility into adulthood. These studies have the potential to yield critical information to explain why females are more prone, or males more resilient, to stress-related GI and immune disorders resulting in the future development and testing of new therapeutics and technologies for both sexes.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD072968-07
Application #
9988474
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Winer, Karen
Project Start
2013-07-01
Project End
2024-04-30
Budget Start
2020-05-01
Budget End
2021-04-30
Support Year
7
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Michigan State University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
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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