Weaning stress and gastrointestinal barrier development: Implications for lifelong gut health in pigs

“…barrier, which is regulated predominantly by the tight junctions (TJs), which consist of numerous intracellular and apical intercellular membrane proteins (e.g., zonula occludens, occludin, and claudins) (Edelblum and Turner, 2009; Groschwitz and Hogan, 2009; Marchiando et al., 2010; Turner, 2009).”

“…receivedmuch attention as an important defense barrier through several proposed mechanisms, reviewing the body of microbiome studies is beyond the scope of this review, but we direct readers to other excellent reviews on the topic (Backhed et al., 2005; Honda and Littman, 2016; Kelly et al., 2015).”

“Mast cells are required for host defense and wound healing; however, excessive activation of mast cells is a central pathophysiologic mechanisms in inflammatory disease such as allergy and asthma and functional stress-related GI disorders including irritable bowel syndrome in humans (Boeckxstaens, 2015; Galli and Tsai…”

“…barrier, which is regulated predominantly by the tight junctions (TJs), which consist of numerous intracellular and apical intercellular membrane proteins (e.g., zonula occludens, occludin, and claudins) (Edelblum and Turner, 2009; Groschwitz and Hogan, 2009; Marchiando et al., 2010; Turner, 2009).”

“Similar to human IBS, Pohl et al. (2017) demonstrated that adult pigs that were previously early weaned (16 d wean age) exhibited enhanced co-localization of intestinal mast cells with enteric nerves, compared with late weaned pigs (weaned at 28 d of age) (Pohl et al., 2017).”

“…complete by 12 to 14 ity and shape the adult phenotype and function of the GI barrier. to a wide variety of antigen including self-antigen and bacteria, help in differentiating between self and non-self-antigen and further facilitate to achieve homeostasis (Martin et al., 2010; Wu and Wu, 2012).”

“Whereas the microbiome has receivedmuch attention as an important defense barrier through several proposed mechanisms, reviewing the body of microbiome studies is beyond the scope of this review, but we direct readers to other excellent reviews on the topic (Backhed et al., 2005; Honda and Littman, 2016; Kelly et al.,…”

“, IL-17A, IL-33, IL-23 and transforming growth factor-b), which have important immunomodulatory properties (Schiering et al., 2014).”

“, psychological trauma, inflammation, infection) are risk factors for GI inflammatory and functional diseases later in life (Bradford et al., 2012; Chaloner and Greenwood-Van Meerveld, 2013; Maccari et al., 2014; Park et al., 2016; Sanchez et al., 2001).”

“The proportion of ChAT neurons in postnatal life increases dramatically and can account for approximately 44% of all neurons in the submucosal plexus, and 62% in the myenteric plexus by maturity (Furness, 2000; Hao et al., 2013).”

“Similar to human IBS, Pohl et al. (2017) demonstrated that adult pigs that were previously early weaned (16 d wean age) exhibited enhanced co-localization of intestinal mast cells with enteric nerves, compared with late weaned pigs (weaned at 28 d of age) (Pohl et al., 2017).”

“…mast cells are also potent positive and negative modulators of immune responses (Abraham and St John, 2010; Chan et al., 2013; Choi et al., 2013; Galli et al., 2008) and enteric neurons (Barbara et al., 2004; Kirsch and Riddell, 2006; Kobayashi et al., 1999; Wouters et al., 2016), mast cells…”

“, zonula occludens, occludin, and claudins) (Edelblum and Turner, 2009; Groschwitz and Hogan, 2009; Marchiando et al., 2010; Turner, 2009).”

“…by sensory fibers beneath the epithelium, which in turn convey signals and activation of secretomotor neuron activation, mediated via release of neurochemicals vasoactive intestinal peptide and acetylcholine, which drive electrolyte and fluid secretion (Field, 2003; Lundgren, 2002; Wood, 2010).”

“Whereas a tight or resistant epithelium is critical for barrier function, the epitheliummust exhibit a normal physiologic degree of paracellular and transcellular permeability required for solutedriven water absorption and transcellular antigen uptake (Turner et al., 1997).”

“, 2007b) and develop a persistent intestinal mast cell hyperplasia that was evident at 9 weeks post-weaning (Smith et al., 2010) and into adulthood (Pohl et al.”

“Developmental processes occurring this time exhibit a high degree of plastic and colostrum and milk factors (Fawzy et al., 2011; Rogier et al., 2014).”

“In response to weaning there are a number of morphological, enzymatic, and inflammatory changes, which take place in the GI tract of pigs and have been reviewed previously (Boudry et al., 2004; Montagne et al., 2007; Wijtten et al., 2011).”

“Results of several studies have demonstrated that weaning in pigs induces a breakdown in intestinal barrier function characterized by a significant decline in intestinal transepithelial electrical resistance and increased permeability to paracellular probes in Ussing chamber experiments (Hu et al., 2013; Moeser et al.…”

“In response to weaning there are a number of morphological, enzymatic, and inflammatory changes, which take place in the GI tract of pigs and have been reviewed previously (Boudry et al., 2004; Montagne et al., 2007; Wijtten et al., 2011).”

“During postnatal life, major changes take place in the enteric nervous system including formation of functional neurocircuits, gangliogenesis, and changes in the neurochemical phenotype (Lake and Heuckeroth, 2013; Sasselli et al., 2012).”

“, psychological trauma, inflammation, infection) are risk factors for GI inflammatory and functional diseases later in life (Bradford et al., 2012; Chaloner and Greenwood-Van Meerveld, 2013; Maccari et al., 2014; Park et al., 2016; Sanchez et al., 2001).”

“to a wide variety of antigen including self-antigen and bacteria, help in differentiating between self and non-self-antigen and further facilitate to achieve homeostasis (Martin et al., 2010; Wu and Wu, 2012).”

“At the same time that epithelial barrier function is disrupted, an upregulation of proinflammatory cytokines has been reported indicating a robust activation of the GI immune system following weaning (Hu et al., 2013; McCracken et al., 1999).”

“, psychological trauma, inflammation, infection) are risk factors for GI inflammatory and functional diseases later in life (Bradford et al., 2012; Chaloner and Greenwood-Van Meerveld, 2013; Maccari et al., 2014; Park et al., 2016; Sanchez et al., 2001).”

“…barrier, which is regulated predominantly by the tight junctions (TJs), which consist of numerous intracellular and apical intercellular membrane proteins (e.g., zonula occludens, occludin, and claudins) (Edelblum and Turner, 2009; Groschwitz and Hogan, 2009; Marchiando et al., 2010; Turner, 2009).”

“More importantly, administration of CRF receptor antagonists to early weaned pigs at weaning, or 9 weeks post-weaning, reduced the early (Moeser et al., 2007a) and chronic (Smith et al., 2010) elevations in intestinal permeability thus demonstrating a central role for the intestinal CRF receptor…”

“…et al., 2013; Choi et al., 2013; Galli et al., 2008) and enteric neurons (Barbara et al., 2004; Kirsch and Riddell, 2006; Kobayashi et al., 1999; Wouters et al., 2016), mast cells might be major players regulating immune and ENS dysfunction observed in early weaned pigs, but the precise role of…”

“…nervous system in modulating immune responses, secretory diarrhea and the epithelial barrier (Dhawan et al., 2012; Hirota and McKay, 2006; Matteoli and Boeckxstaens, 2013), there are potential implications for an upregulated cholinergic system in early weaned pigs as a pathogenic…”

“More importantly, administration of CRF receptor antagonists to early weaned pigs at weaning, or 9 weeks post-weaning, reduced the early (Moeser et al., 2007a) and chronic (Smith et al., 2010) elevations in intestinal permeability thus demonstrating a central role for the intestinal CRF receptor…”

“coli challenge, early weaned pigs (15 to 16 d weaning age) had increased incidence of clinical disease (diarrhea and growth performance reductions) and increased intestinal permeability compared with later-weaned pigs (22 dweaning age) (McLamb et al., 2013).”

“In response to weaning there are a number of morphological, enzymatic, and inflammatory changes, which take place in the GI tract of pigs and have been reviewed previously (Boudry et al., 2004; Montagne et al., 2007; Wijtten et al., 2011).”

“The nervous system is also a major regulator of systemic and local GI immune responses via neuro-immune synapses, and can modulate bacterial toxin sensing and adherence (Dhawan et al., 2012; Downing and Miyan, 2000; Fernandez-Cabezudo et al., 2010).”

“Although species differences exist, in most animals the development of intestinal epithelial barrier function occurs within the first 2 to 3 weeks of postnatal life characterized by a decline in intestinal permeability (Catassi et al., 1995; De Quelen et al., 2011; Mackey et al., 2016; Patel et al., 2012).”

“In vivo and ex vivo studies demonstrated an interplay between the CRF receptor activation andmast cells as CRF applied to porcine intestinewas shown to increase intestinal permeability via a mechanism involving release of mast cell proteases and TNFa (Overman et al., 2012; Smith et al., 2010).”

“Moreover, a shorter complementarity-determining region 3 (CDR3), where binding of molecules to their specific antigen on T cell receptors (TcR) occur, makes neonatal T cells less reactive (Garcia et al., 2000).”

“Following neurogenesis and proliferation is a period of neuronal number decline, or “neuron pruning”, resulting in the adult neuronal phenotype (Aoki et al., 2007; Gabella, 1971; Medland et al., 2016; Schafer et al., 1999; Wester et al., 1999).”

“Given that mast cells are also potent positive and negative modulators of immune responses (Abraham and St John, 2010; Chan et al., 2013; Choi et al., 2013; Galli et al., 2008) and enteric neurons (Barbara et al., 2004; Kirsch and Riddell, 2006; Kobayashi et al., 1999; Wouters et al., 2016), mast…”

“An additional mechanism to prevent over-activation of the immune system during GI immune development, neonates are born with few lymphocytes and reduced co-stimulatory molecules expression (Nguyen et al., 2010; Upham et al., 2006).”

“, psychological trauma, inflammation, infection) are risk factors for GI inflammatory and functional diseases later in life (Bradford et al., 2012; Chaloner and Greenwood-Van Meerveld, 2013; Maccari et al., 2014; Park et al., 2016; Sanchez et al., 2001).”

“…et al. (2007a) demonstrated that, compared with age-matched, non-weaned littermate pigs, weaned pigs exhibited increased intestinal permeability that wasmost pronounced at 24 h post weaning and then gradually declined over the first 2 weeks post-weaning (Moeser et al., 2007a; Peace et al., 2011).”

“…the number of important diseases linked with “leaky gut” including chronic inflammatory, allergic, and functional disorders and life threatening conditions such as sepsis and multiple organ dysfunction (Barbara, 2006; Camilleri and Gorman, 2007; Edelblum and Turner, 2009; Marchiando et al., 2010).”

“Main et al. (2004) demonstrated in a commercial multisite swine production system that increases in weaning age from 12 to 21.5 d resulted in linear improvements in growth rate, feed efficiency and reductions in mortality to market (Main et al., 2004).”

“Given the role of the cholinergic nervous system in modulating immune responses, secretory diarrhea and the epithelial barrier (Dhawan et al., 2012; Hirota and McKay, 2006; Matteoli and Boeckxstaens, 2013), there are potential implications for an upregulated cholinergic system in early weaned pigs…”

“Several weeks after birth, neonates overcome the neonatal immunosuppressive stage when lymphocytes start developing functionally as well as structurally (Butler et al., 2000, 2009; Butler and Wertz, 2012).”

“…the number of important diseases linked with “leaky gut” including chronic inflammatory, allergic, and functional disorders and life threatening conditions such as sepsis and multiple organ dysfunction (Barbara, 2006; Camilleri and Gorman, 2007; Edelblum and Turner, 2009; Marchiando et al., 2010).”

“Similar to human IBS, Pohl et al. (2017) demonstrated that adult pigs that were previously early weaned (16 d wean age) exhibited enhanced co-localization of intestinal mast cells with enteric nerves, compared with late weaned pigs (weaned at 28 d of age) (Pohl et al., 2017).”

“Enteroendocrine cells play important roles in pathogen sensing and can synthesize and release neuropeptides such as serotonin and Peptide YY (PYY), which have a diverse range of physiologic functions from pathogen defense to metabolic regulation of appetite (Argenzio et al., 1997; Duca et al., 2013; Little and Feinle-…”

“…by sensory fibers beneath the epithelium, which in turn convey signals and activation of secretomotor neuron activation, mediated via release of neurochemicals vasoactive intestinal peptide and acetylcholine, which drive electrolyte and fluid secretion (Field, 2003; Lundgren, 2002; Wood, 2010).”

“Enteroendocrine cells play important roles in pathogen sensing and can synthesize and release neuropeptides such as serotonin and Peptide YY (PYY), which have a diverse range of physiologic functions from pathogen defense to metabolic regulation of appetite (Argenzio et al., 1997; Duca et al., 2013; Little and Feinle-…”

“Developmental processes occurring this time exhibit a high degree of plastic and colostrum and milk factors (Fawzy et al., 2011; Rogier et al., 2014).”

“The postnatal GI developmental aspects in the pig has been reviewed in detail previously (Pohl et al., 2015) but here we will cover some of the major concepts of postnatal GI barrier function development relevant to GI barrier components discussed above.”

“Although species differences exist, in most animals the development of intestinal epithelial barrier function occurs within the first 2 to 3 weeks of postnatal life characterized by a decline in intestinal permeability (Catassi et al., 1995; De Quelen et al., 2011; Mackey et al., 2016; Patel et al., 2012).”

“An additional mechanism to prevent over-activation of the immune system during GI immune development, neonates are born with few lymphocytes and reduced co-stimulatory molecules expression (Nguyen et al., 2010; Upham et al., 2006).”

“Mast cells are required for host defense and wound healing; however, excessive activation of mast cells is a central pathophysiologic mechanisms in inflammatory disease such as allergy and asthma and functional stress-related GI disorders including irritable bowel syndrome in humans (Boeckxstaens, 2015; Galli and Tsai…”

“Around the same time, secondary lymphoid organs such as jejunal and ileal Peyer's patches rapidly mature characterized by an infiltration of lymphocytes (Barman et al., 1997; Pabst et al., 1988).”

“Mast cells are required for host defense and wound healing; however, excessive activation of mast cells is a central pathophysiologic mechanisms in inflammatory disease such as allergy and asthma and functional stress-related GI disorders including irritable bowel syndrome in humans (Boeckxstaens, 2015; Galli and Tsai…”

“, 2015) and chronicmixing and crowding stress (Li et al., 2017), suggesting a potential common pathophysiologic mechanism underlying stress-induced gut dysfunction in pigs.”

“Several weeks after birth, neonates overcome the neonatal immunosuppressive stage when lymphocytes start developing functionally as well as structurally (Butler et al., 2000, 2009; Butler and Wertz, 2012).”

“Unweaned (nursing) piglets achieve a stable number of lymphocytes at about 6 weeks of age (Blikslager et al., 1997).”

“The ability to upregulate ion and fluid secretion is considered to be an important mechanism to flush out pathogens in response to stress and pathogenic challenges (Moeser and Blikslager, 2007).”

“In the same study, lower blood eosinophils were observed in 14 dweaned pigs at 44 d post-weaning whereas at 65 d post-weaning, 14-d weaned pigs had higher neutrophil percent but lower lymphocyte percent compared with 21-d weaned pigs (Davis et al., 2006).”

“…of immune responses (Abraham and St John, 2010; Chan et al., 2013; Choi et al., 2013; Galli et al., 2008) and enteric neurons (Barbara et al., 2004; Kirsch and Riddell, 2006; Kobayashi et al., 1999; Wouters et al., 2016), mast cells might be major players regulating immune and ENS dysfunction…”

“Stress neuroendocrine mediators such as catecholamines and adrenocorticotropic hormone (ACTH) can influence binding and adherence of important swine enteric pathogens to the intestinal mucosa (Brown and Price, 2008; Chen et al., 2006; Schreiber and Brown, 2005).”

“The proportion of ChAT neurons in postnatal life increases dramatically and can account for approximately 44% of all neurons in the submucosal plexus, and 62% in the myenteric plexus by maturity (Furness, 2000; Hao et al., 2013).”

“The proper interactions of lymphocytes with antigen also lead to their proliferation, immunoglobulins and balanced Th1/Th2 cytokine production (Blikslager et al., 1997; Frenyo et al., 1981; Pomorska-Mol and Markowska-Daniel, 2010).”

“In a study by Medland et al. (2016), early weaned pigs exhibited lasting phenotypic and functional changes in the enteric nervous system, compared with late weaned pigs.”

“…species differences exist, in most animals the development of intestinal epithelial barrier function occurs within the first 2 to 3 weeks of postnatal life characterized by a decline in intestinal permeability (Catassi et al., 1995; De Quelen et al., 2011; Mackey et al., 2016; Patel et al., 2012).”

“Significant alterations in the enteric nervous system phenotype and function can change in response to stressors such as weaning (Medland et al., 2016; Moeser et al., 2007a) and pathogenic challenges from Lawsonia intracellularis (Pidsudko et al., 2008; Wojtkiewicz et al., 2012).”

“In addition weaning-associated changes in the expression of the CRF system, we have also demonstrated that the CRF system is upregulated in pigs undergoing other stressors including Salmonella typhimurium challenge (Boyer et al., 2015) and chronicmixing and crowding stress (Li et al.”

“, 2008) and enteric neurons (Barbara et al., 2004; Kirsch and Riddell, 2006; Kobayashi et al., 1999; Wouters et al., 2016), mast cells might be major players regulating immune and ENS dysfunction observed in early weaned pigs, but the precise role of mast cells as immune modulators in pigs remains to be elucidated.”

“…by sensory fibers beneath the epithelium, which in turn convey signals and activation of secretomotor neuron activation, mediated via release of neurochemicals vasoactive intestinal peptide and acetylcholine, which drive electrolyte and fluid secretion (Field, 2003; Lundgren, 2002; Wood, 2010).”

“Several weeks after birth, neonates overcome the neonatal immunosuppressive stage when lymphocytes start developing functionally as well as structurally (Butler et al., 2000, 2009; Butler and Wertz, 2012).”

“The nervous system is also a major regulator of systemic and local GI immune responses via neuro-immune synapses, and can modulate bacterial toxin sensing and adherence (Dhawan et al., 2012; Downing and Miyan, 2000; Fernandez-Cabezudo et al., 2010).”

“Stress neuroendocrine mediators such as catecholamines and adrenocorticotropic hormone (ACTH) can influence binding and adherence of important swine enteric pathogens to the intestinal mucosa (Brown and Price, 2008; Chen et al., 2006; Schreiber and Brown, 2005).”

“Stress neuroendocrine mediators such as catecholamines and adrenocorticotropic hormone (ACTH) can influence binding and adherence of important swine enteric pathogens to the intestinal mucosa (Brown and Price, 2008; Chen et al., 2006; Schreiber and Brown, 2005).”

“The proper interactions of lymphocytes with antigen also lead to their proliferation, immunoglobulins and balanced Th1/Th2 cytokine production (Blikslager et al., 1997; Frenyo et al., 1981; Pomorska-Mol and Markowska-Daniel, 2010).”

“Significant alterations in the enteric nervous system phenotype and function can change in response to stressors such as weaning (Medland et al., 2016; Moeser et al., 2007a) and pathogenic challenges from Lawsonia intracellularis (Pidsudko et al., 2008; Wojtkiewicz et al., 2012).”

“Following neurogenesis and proliferation is a period of neuronal number decline, or “neuron pruning”, resulting in the adult neuronal phenotype (Aoki et al., 2007; Gabella, 1971; Medland et al., 2016; Schafer et al., 1999; Wester et al., 1999).”

“Additionally, neonatal T cells show hyper responsiveness to IL-4 and hypo-responsiveness to IL12, which further skews the immune response toward Th2 (Beverley, 1997).”

“004 absorptive, barrier and immune functions (e.g., Boudry et al., 2004; Cranwell, 1995; Hampson, 1986a, b; Lall es et al., 2004, 2007a, b; Moeser et al., 2017; Pluske, 2013, 2016; Pluske et al., 1996a, b; 1997, 2003).”