Gut Mechanics During Stress: How Feed Efficiency and Growth Can be Influenced
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1 Gut Mechanics During Stress: How Feed Efficiency and Growth Can be Influenced Adam Moeser, DVM PhD Associate Professor Matilda R. Wilson Endowed Chair College of Veterinary Medicine
2 Focus of Talk: Gut Health Components of gut health How gut health is impacted by stressors Specific production stressors Pathophysiology Implications for feed efficiency
3 Poor Gut Health is a Major Contributor to Economic Losses in Animal Production Suboptimal feed efficiency GI Disease Infectious Enteric disease subclinical clinical
4 Factors Influencing Gut Health Environment Pathogen GI Disease Stress Host
5 Stressors in Animal Production Crowding stress Transport stress Nutrition stress Cold Stress Heat Stress Weaning Antigen Toxin Stress Mixing Stress
6 Stress is a Major Factor in the Onset and Exacerbation of GI Disease in Animals and People Weight gain Feed efficiency GI Infections Inflammatory and functional Gut Disease The biological mechanisms by which stress adversely impacts gut health is poorly understood
7 Gastrointestinal Stress Biology Laboratory GSL Objectives: To gain a fundamental understanding of how stress causes GI disease and to optimize GI Health in animals and people through basic science discovery, management and nutrition. Early Life stress and GI development Mechanisms of Stress-induced disruption of GI immune and epithelial barriers Interaction between nutrition, stress, and GI disease
8 The Gastrointestinal Barrier: The Largest Interface Between Us and the Outside World
9 Components of The Intestinal Barrier Intestinal Lumen HCO 3 - Cl- Antimicrobial peptides Mucus H 2 0 Nutrients Antigens Pathogens Toxins Microbiota Tight Junctions IgA Epithelial Cells Lamina Propria Enteric nervous system Circulation Immune System
10 Consequences of Intestinal Barrier Breakdown Intestinal Lumen Cl- Fluid Loss H 2 0 HCO 3 - Nutrients Antigens Pathogens Toxins Epithelial Cells Lamina Propria
11 Mechanisms of Intestinal Absorption and Secretion: Importance of Barrier Function
12 Impaired Barrier Function and Disease Pathogenesis Infectious Disease Pathogenesis Endotoxemia Sepsis Inflammatory Bowel Diseases Feed Efficiency Food Allergy/ Anaphylaxis Endocrine/ Metabolic Diseases Microbiome Dysbiosis
13 What is the Impact of Stress on the Intestinal Barrier?
14 Measurement of Barrier Function: Ussing Chamber Method Intestinal Mucosa
15 Measurement of Barrier Function: Ussing Chamber Method 3 H-Mannitol 14 C-Inulin FITC Dextran Mucosal 3 H-Mannitol 14 C-Inulin FITC Dextran Serosal High Flux Rate Low Flux Rate Impaired Barrier Function Intact Barrier Function
16 Impact of Heat and Mixing Stress on Feed:Gain Control Mixing crowding stress Control Chronic Heat Stress Feed intake: Not significant (P=0.6) ADG: p<0.01 Feed intake: Not significant (restricted feed intake) ADG: p<0.01 Manuscripts in preparation
17 Impact of Chronic Crowding Stress on Intestinal Barrier and Absorptive Function Intestinal Permeability Intestinal Glucose Absorptive Response Control Crowding + Mixing Stress Control Crowding + Mixing Stress d of mixing and crowding stress
18 Impact of Chronic Heat Stress on Intestinal Barrier and Absorptive Function Intestinal Permeability Intestinal Glucose Absorptive Response Control Chronic Heat Stress Control Chronic Heat Stress d of Heat stress
19 Weaning Stress
20 Weaning Stress is Linked with Impaired Gut Function and Enteric Disease Does weaning impact intestinal barrier function?
21 Weaning Induces Breakdown of the Intestinal Barrier 3 H-mannitol flux, mol.cm 2.h Moeser et al. Am J Physiol Gastrointest Liver Physiol. 292:G173-81
22 Intestinal Serum Cortisol Barrier Response to to Weaning Stress: Effects of of Wean Age d LW 18 d EWS Moeser et al. Am J Physiol Gastrointest Liver Physiol. 293:G413-21
23 Long-Term Effects of Early Weaning Stress on Intestinal Permeability 3 H-mannitol flux, mol.cm 2.h * * * * Time (Days Post-weaning)
24 Does Early Weaning Stress Impact Subsequent GI Stress Responses? 54d Post-Weaning Mixing Stress Mixing Stress EWS LWC Barrier function measured 3hr post stress Wean 16d Wean 28d Pohl et al. Manuscript in preparation
25 Early Weaning Stress Leads to Exacerbated Intestinal Injury Responses to Subsequent Stressors Control Mixing Stress 3 H-mannitol flux, mol.cm 2.h LW EWS Pohl et al. Manuscript in preparation
26 What is the Impact of Early Weaning Stress on Intestinal Responses to Subsequent Infectious Challenges?
27 Early Weaning Stress Leads to Heightened Clinical Disease in Response to Subsequent Enterotoxigenic E. coli Challenge 4 EWS Control EWS + ETEC Challenge LW Control LW + ETEC Challenge Control ETEC Challenge Fecal Score Days Post-ETEC Challenge LW EWS McLamb et al., 2013 PLoS One. 8:e59838
28 Early Weaned Pigs Exhibit Dampened Mucosal Immune Response to ETEC challenge Neutrophils/hpf IL-6, pg/mg protein McLamb et al., 2013 PLoS One. 8:e59838
29 Impact of Production Stressors on Gut Barrier Health in Pigs Impaired feed efficiency Independent of feed intake Immediate and long-lasting disturbances in intestinal barrier function Impaired nutrient transport mechanisms Not associated with changes in absorptive are or morphology Heightened responses to later life stress challenges Heightened responses to later life infectious challenges Suppressed immune response to later life infectious challenges
30 Mechanisms of Stress-Induced Intestinal Dysfunction
31 Histopathological Analysis of the Early Weaned Pig Intestine No Differences in H&E Histology LW EWS
32 Increased Mast Cell Numbers and Activation in EWS Pigs * LW Mast Cell Tryptase LW EWS Smith et al. Am J Physiol Gastrointest Liver Physiol 2010;298:G352-G363 EWS Pohl et al, manuscript in preparation
33 Mast Cell Release Preformed and Synthesized Mediators Histamine Cytokines Proteases Chemokines TNF Neuropeptides Lipid Mediators
34 Heightened Mast Cell Degranulation is a Driving Mechanism in GI Disease Inflammation/Colitis Mast Cell Secretion/diarrhea Association with and Activation of enteric neurons Increased Intestinal permeability (Barbara et al 2004, Gastroenterology) correlation with visceral hypersensitivity/abdominal pain in IBS patients
35 Does Inhibition of Mast Cells Improve Intestinal Barrier Function in EWS Pigs? 3 H-mannitol flux, mol.cm 2.h LW EWS EWS + Sodium Cromolyn Smith et al. Am J Physiol Gastrointest Liver Physiol 2010;298:G352-G363
36 How does stress induce intestinal mast cell activation and intestinal barrier dysfunction?
37 The Corticotropin Releasing Factor (CRF) System is a Major Regulator of the Stress Response Front. Psychiatry, 18 April 2011 doi: /fpsyt
38 Early Weaning Stress and Intestinal Permeability is Mediated by Activation of the CRF System Intestinal CRF receptor expression CRF 1/2 UW EWS Unweaned EWS + PBS EWS + Astressin B Overman et al., PLoS One 2012;7:e39935 Smith et al. Am J Physiol Gastrointest Liver Physiol 2010;298:G352-G363
39 CRF Receptor Activation in Linked with Intestinal Barrier Function and Mast Cell Activity Activated Mast Cell Early Weaning Stress Overman et al., PLoS One 2012;7:e39935 Smith et al. Am J Physiol Gastrointest Liver Physiol 2010;298:G352-G363 Stable Mast Cell Early Weaning Stress + Astressin B
40 How do Mast Cells Increase Intestinal Permeability in Response to Stress? Increased Intestinal Permeability Proteases TNFα Corticotropin Releasing Factor (CRF) Overman EL, Rivier JER, and Moeser AJ. CRF Induces Intestinal Epithelial Barrier Injury via the Release of Mast Cell Proteases and TNFα PLoS One. 7(6):e39935
41 The Mechanistic Link Between Stress and GI Disease Activation of the CRF system Intestinal Mast Cell Activation Intestinal Permeability LIFESPAN Early Life Stress (e.g. EWS, gut challenges) Pohl, Medland, and Moeser 2015; Am J Physiol-GI
42 Implications: Stress, GI Function, and FE Common production stressors have a marked, deleterious influence on intestinal barrier function Increased intestinal permeability Immune cell activation hypersecretion Stress and impaired intestinal barrier function can negatively influence FE Impaired digestive and absorptive processes Persistent GI immune system activation Changes in microbiota Further elucidation of the mechanisms of stress-induced regulation of gut health and barrier function could have important implications for improving FE Impaired digestive absorptive processes Stress Increased Intestinal Permeability FE Microbiome changes Persistent GI immune system activation
43 Moeser GI Stress Biology Laboratory Acknowledgements Saru Ayyadurai, Research Associate Kristen Bagley Susan D Costa, Research Associate Laura Edwards RLATG Shellsea Frandsen BS Amelia Gibson PhD Liz Lennon, DVM DACVIM Julia Medland MS Emily Mackey, DVM/PhD student Beth Overman, PhD Calvin Pohl DVM, PhD student Ashwin Poopal, MS Mrigendra Rajput, PhD Laura Sommerville, Post Doc Yihang Li, Post Doc Vandana Zaman, PhD Collaborators Soman Abraham PhD, Duke University (Mast Cell Biology) Jean Rivier PhD, The Salk Institute, La Jolla, CA (CRF receptor compounds) Aditi Bhargava PhD, UCSF (CRF 2 -/- mice) Richard Neubig MD PhD, MSU (GPCR mechanisms American Gastroenterological Association (AGA) National Institutes of Health grants NIH R01 HD NIH R03 DK NIH K08 DK Lab Funding National Pork Board NC Pork Council USDA UNC Chapel Hill Center for Gastrointestinal Biology and Disease Contact: Adam Moeser: moeserad@cvm.msu.edu
44 Implications: Stress, GI Function, and FE Common production stressors have a marked, deleterious influence on intestinal barrier function Increased intestinal permeability Immune cell activation hypersecretion Stress and impaired intestinal barrier function can negatively influence FE Impaired digestive and absorptive processes Persistent GI immune system activation Changes in microbiota Further elucidation of the mechanisms of stress-induced regulation of gut health and barrier function could have important implications for improving FE Impaired digestive absorptive processes Stress Increased Intestinal Permeability FE Microbiome changes Persistent GI immune system activation
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