Early life adversity has been established as a major risk factor for the development of inflammatory disease as well as increased mortality in humans. In swine production, weaning is a necessary practice, but is also the most stressful life event that a piglet will endure. Weaning stress-induced increases in inflammation and intestinal permeability occur during the window of developmental plasticity, which has been demonstrated to cause persistent detrimental effects on the gut, including chronic inflammation and epithelial barrier permeability. Despite efforts to improve growth performance and overall health, the lack of targeted interventions is a significant issue. The critical problem regarding the limited understanding of the mechanisms driving early responses to weaning stress urgently needs to be addressed. The objective of this dissertation is to investigate the role of histamine receptors as a potential mechanism and target to mitigate the inflammatory response and gut dysfunction induced by weaning stress.First, we sought to characterize the inflammatory response to weaning stress and the role of histamine receptors. As histamine has been shown to be upregulated in response to stress and histamine receptors are well known to be critical in allergic inflammation, we hypothesized that histamine receptors are responsible for early gastrointestinal (GI) inflammation. To test this, we utilized a porcine weaning model of early life stress and administration of pharmacological histamine receptor antagonists.Next, we investigated the role of histamine receptors in early changes in gut function, including epithelial barrier permeability, nutrient transport, and neural-evoked secretions. Through the employment of Using Chambers analyses, we were able to make ex vivo assessments of the aforementioned gut functions in response to weaning stress, as well as in response to selective inhibition of histamine receptors.Together, our data indicate that histamine receptor subtypes play critical, yet distinct roles in mediating early weaning stress responses in pigs. This provides evidence that histamine and histamine receptors are novel biological targets in mitigating early inflammatory and functional responses to stress in the gut. Future studies should focus on long-term effects of histamine receptors in GI development post weaning stress, as well as determining their role in secondary immune challenges.
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