Progress 01/15/24 to 01/14/25
Outputs
Target Audience:Early weaning is necessary management practice for profictable pork production. However, early weaning is stressful on the piglest and results in long-lasting inefficencies in growth performance and increased disease risk. It is known that the gut of the young piglet at weaning is highly sensitive to weaning stressors demonstrated by leaky gut and increased inflammation, whcih together can have long-lasting negative impacts on gut development and overall pig health. Currently, there are no targeted, effective strategies to mitigate leaky gut and inflammation at weaning. This proposed research will investigate the role of histamine, a substance released primarily by immune cells in response to stress, as a cause of leaky gut and inflammation in weaned pigs. if histamine is established as a target for leaky gut and inflammation, future strategies can be focused on controlling histamines levels as a novel approach to optimize pig health. Changes/Problems:
Nothing Reported
What opportunities for training and professional development has the project provided?Our project provided continued training opportunities for graduate and undergraduate researchers. The lead Ph.D. student received extensive training in molecular techniques including RNA-seq data analysis, ELISA, immunoblotting, and histology. She also contributed to manuscript development and abstract preparation for conference submissions. Training Initiatives: Continued one-on-one mentorship of graduate and undergraduate students. Student trainee attended regular GI physiology seminars and completed coursework in bioinformatics. The graduate student submitted an abstract to the American Society of Animal Science and will present findings at the 2025 conference. How have the results been disseminated to communities of interest?Preliminary results were presented in the College of Veterinary Medicine's internal seminar series and Phi Zeta Research Symposium. Data have also been included in a manuscript currently under revision to American Journal of Physiology-Gastrointestinal and Liver Physiology. We plan to disseminate final findings through conference presentations and peer-reviewed publication in the coming year. What do you plan to do during the next reporting period to accomplish the goals?In Year 3, we will complete additional RNA-seq analyses to assess sex-specific responses to early weaning and histamine blockade. We also plan to: Validate top differentially expressed genes using qPCR. Assess long-term gut and immune outcomes in pigs treated with histamine receptor antagonists. Test additional pharmacologic interventions targeting mast cell and histamine pathways. Finalize manuscript(s) and present our findings at national meetings. These activities will complete the mechanistic arc of the project and move us closer to implementing practical strategies to support pig health during the critical weaning transition.
Impacts
What was accomplished under these goals?
Conducted detailed molecular and immunological profiling of the ileum following early weaning stress, with or without histamine receptor blockade. Performed RNA sequencing on ileal mucosa samples from early-weaned pigs treated with vehicle or histamine receptor antagonists. Performed ELISAs and western blotting for key inflammatory markers (e.g., IL-6, TNF-α), tight junction proteins (e.g., occludin, claudin-1), and mast cell activation markers. Conducted histopathological scoring of intestinal injury and mast cell presence using histological staining and image analysis. Data Collected: RNA-seq transcriptome datasets (differential expression and pathway analysis). Protein quantification of cytokines and tight junction markers by ELISA and western blot. Histological data: villus height, crypt depth, mast cell counts, and inflammation scores. Results and Discussion: Our molecular and cellular analyses have begun to unravel the mechanisms by which early weaning leads to gut dysfunction. RNA-seq results revealed robust activation of inflammatory and immune-related pathways, including TNF signaling, IL-17 pathway, and mast cell-related gene networks. These changes were significantly blunted by histamine receptor antagonist treatment, suggesting a critical role for histaminergic signaling in driving post-weaning gut inflammation. Protein assays corroborated transcriptomic findings, showing reduced IL-6 and TNF-α protein levels in treated animals. Histological scoring showed reduced mucosal damage and fewer degranulating mast cells in antagonist-treated pigs. Key Outcomes: Identified transcriptomic signatures of gut injury following early weaning and demonstrated that histamine receptor antagonism modifies these signatures. Defined early weaning-induced immune activation in the gut, with histamine receptor blockade significantly attenuating this response. Provided the first multi-layered evidence (mRNA, protein, histology) that histamine signaling directly contributes to post-weaning gut barrier dysfunction. Impact of the Project: These findings validate histamine receptors as novel targets to mitigate early weaning stress and enhance intestinal resilience in pigs. The work expands the mechanistic understanding of how immune-epithelial interactions drive gut injury and highlights a pharmacological pathway with practical implications for swine health management. These results lay the groundwork for future translational strategies and nutritional/pharmaceutical interventions in commercial pig production.
Publications
- Type:
Conference Papers and Presentations
Status:
Other
Year Published:
2024
Citation:
Stressed from the start: Implications of early life stress for lifelong health and disease resistance. AAVI Featured Speaker, CRWAD, Chicago. IL. Presented on January 2024.
- Type:
Conference Papers and Presentations
Status:
Other
Year Published:
2024
Citation:
Early Life Adversity and Sex: Interactive Factors Shaping Health Across the Lifespan. Presented at the Swine in Biomedical Research Conference, Aging Session, University of Wisconsin-Madison, Presented on June 17th, 2024
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Progress 01/15/23 to 01/14/24
Outputs
Target Audience:University faculty, students, and swine industry professionals (nutritionists, animal scientists, veterinarians). Changes/Problems:
Nothing Reported
What opportunities for training and professional development has the project provided?Our project has not only advanced scientific understanding in the field of veterinary science but has also significantly contributed to professional growth and training. Throughout the year, several opportunities were provided to both the research team and associated professionals. Training Initiatives: Mentorship Program: New graduate student and technicians working on the project received hands-on training in research and data analysis. This one-on-one mentorship helped them develop specific technical skills necessary for conducting the research described in this grant.Lab team mambers working on this research participated in monthlyseminars of the MSU GI group whcih consistes of faculty and trainees across MSU focusing on intestinal health research. The student trainee is in her first year, she has not attened scientific meetings to present her research but this in planned for next year to present at an Animal Science or Immunology meeting. How have the results been disseminated to communities of interest?
Nothing Reported
What do you plan to do during the next reporting period to accomplish the goals?The first year of funding focused on Aim 2 where we have extensivel characterized the impact of histamine receptor blockers and thus teh role of histamine, on gut function in weaned pigs. Despite the significant advancements, the complete mechanistic understanding of how histamine receptors contribute to early gut injury remains incomplete. The next phase will focus on detailed genetic, molecular, immunolgical studies to to elucidate these pathways. Specifically we will define the immune response induced by weaning stress in the gut using a variety of tools including RNA seq, Histology, ELISA, Western Blotting, etc, and determine how these measurments and pathways are inmpacted by Histamine receptor antagonism.
Impacts
What was accomplished under these goals?
Problem Addressed: Early weaning is a crucial practice for maintaining high reproductive efficiency and profitability in pork production. Unfortunately, it's also associated with significant challenges, including gut injury and inflammation in young pigs. These early injuries can have lasting effects on their gastrointestinal (GI) and immune systems, ultimately affecting their health and productivity throughout their lives. Intended Impact: Our research directly benefits piglets subjected to early weaning, aiming to improve their health and well-being, which in turn enhances farm productivity and profitability. By addressing these early-life challenges, our work also supports farmers, the pork industry, and communities dependent on agriculture by fostering more resilient and healthier livestock. Year 1 Achievements: Major Activities: Conducted experiments using a porcine model to explore how early weaning stress affects young pigs. Administered histamine receptor antagonists to study their potential protective effects against weaning-related stress. Data Collected: Measured changes in intestinal permeability using flux of FITC-dextran. Assessed nutrient transport and neural-evoked secretory functions. Results and Discussion: Our findings indicate that using histamine receptor antagonists significantly reduces intestinal damage and dysfunction caused by early weaning. Specifically, these treatments lowered the permeability of the intestine shortly after weaning, suggesting a protective effect against gut injury. At 24 hours post-weaning, the treatments also significantly improved the gut's ability to transport nutrients and reduced excessive secretion triggered by neural stimuli. Key Outcomes: During this reporting period, our project has made promising strides in mitigating the negative impacts of early weaning on piglets. By identifying and targeting histamine receptors, we have developed potential strategies to prevent early gut injury and inflammation. These interventions could lead to improved GI health and immune function in piglets, enhancing their overall growth and reducing their susceptibility to diseases later in life. Impact of the Project: Our research is paving the way for a major shift in managing early weaning stress in piglets. The outcomes not only promise to enhance animal welfare but also propose a new approach to increasing the long-term health and economic viability of pigs. By improving early life conditions, we can potentially reduce veterinary costs and losses due to diseases, benefiting farmers and the agricultural community at large.
Publications
- Type:
Journal Articles
Status:
Published
Year Published:
2023
Citation:
Fardisi M, Thelen K, Groenendal A, Rajput M, Sebastian K, Contreras GA, Moeser AJ*. Early weaning and biological sex shape long-term immune and metabolic responses in pigs. Sci Rep. 2023 Sep 23;13(1):15907. doi: 10.1038/s41598-023-42553-9. PMID: 37741873; PMCID: PMC10517948.
- Type:
Conference Papers and Presentations
Status:
Published
Year Published:
2023
Citation:
3. Thelen, K., Wilson, N., Fardisi, M., Garcia, C., Moeser, A.J. 2023. Mast cell histamine mediates intestinal inflammation to early weaning in piglets via histamine 2 receptor (H2R). Michigan State University. Presented at Immunology Session 2 of the Conference of Research Workers in Animal Diseases (CRWAD). January 22.
- Type:
Conference Papers and Presentations
Status:
Other
Year Published:
2023
Citation:
Invited Talk: Investigating the Impact of Weaning and Biological Sex on Gut Development: Discovering New Targets for Gut Inflammation. Invited speaker, Midwest Animal Science Meeting, Madison, WI March,11.2023.
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