Publications by authors named "Adam J Moeser"

52 Publications

Effects of a multi-strain -based direct-fed microbial on weanling pig growth performance and nutrient digestibility.

Transl Anim Sci 2021 Jul 20;5(3):txab058. Epub 2021 Mar 20.

Department of Animal Science, Michigan State University, East Lansing, MI 48824, USA.

A study was conducted to evaluate the effects of a multi-strain -based direct-fed microbial (DFM) on growth performance and apparent nutrient digestibility of nursery pigs. Eighty pigs, of equal number of barrows and gilts (initial body weight: 7.0 ± 0.60 kg), were weaned at 21 ± 1 d and randomly allotted to 1 of the 16 pens, with 5 pigs per pen. Two dietary treatments were implemented, a basal control (CON) and a control plus DFM (CDFM). Both diets were corn, soybean meal, and distillers dried grains based. Diets were fed for 42 d and growth performance measures were recorded weekly. On days 21 and 42 of the experiment, one pig per pen, with equal number of males and females, was randomly selected and euthanized. Digestibility of nitrogen (N), amino acids (AA), and energy were evaluated within the duodenum, jejunum, ileum, and ascending and distal colon. Relative to CON, CDFM tended to increase ADG during week 2 ( 0.08) and significantly increased ADFI during week 2 ( 0.04) and week 3 ( 0.02). In addition, CDFM decreased the gain to feed ratio (G:F) during week 6 relative to CON ( 0.04). Within the jejunum, pigs fed the DFM had greater digestibility of tryptophan ( 0.04) and cysteine ( 0.04) and tended to have greater digestibility of lysine ( 0.07), methionine ( 0.06), and threonine ( 0.08), relative to CON. The content pH in the ascending colon did not differ between CDFM and CON. Compared with CON, apparent total tract digestibility (ATTD) of energy did not differ from CDFM, whereas ATTD of nitrogen of CDFM was lower ( 0.05). The addition of a multi-strain -based DFM appears to impact growth performance, AA, and N digestibility depending upon the location in the gastrointestinal tract, with primary AA differences occurring within the mid-jejunum.
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http://dx.doi.org/10.1093/tas/txab058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8281103PMC
July 2021

Loss of histone methyltransferase ASH1L in the developing mouse brain causes autistic-like behaviors.

Commun Biol 2021 06 18;4(1):756. Epub 2021 Jun 18.

Department of Biochemistry and Molecular Biology, College of Natural Science, Michigan State University, East Lansing, MI, USA.

Autism spectrum disorder (ASD) is a neurodevelopmental disease associated with various gene mutations. Recent genetic and clinical studies report that mutations of the epigenetic gene ASH1L are highly associated with human ASD and intellectual disability (ID). However, the causality and underlying molecular mechanisms linking ASH1L mutations to genesis of ASD/ID remain undetermined. Here we show loss of ASH1L in the developing mouse brain is sufficient to cause multiple developmental defects, core autistic-like behaviors, and impaired cognitive memory. Gene expression analyses uncover critical roles of ASH1L in regulating gene expression during neural cell development. Thus, our study establishes an ASD/ID mouse model revealing the critical function of an epigenetic factor ASH1L in normal brain development, a causality between Ash1L mutations and ASD/ID-like behaviors in mice, and potential molecular mechanisms linking Ash1L mutations to brain functional abnormalities.
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http://dx.doi.org/10.1038/s42003-021-02282-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213741PMC
June 2021

Neuroimmunology of depression.

Adv Pharmacol 2021 26;91:259-292. Epub 2021 Apr 26.

Department of Physiology, Michigan State University, East Lansing, MI, United States. Electronic address:

Depression is one of the leading causes of disability worldwide and a major contributor to the global burden of disease, yet the cellular and molecular etiology of depression remain largely unknown. Major Depressive Disorder (MDD) is associated with a variety of chronic physical inflammatory and autoimmune disorders, and mood disorders may act synergistically with other medical disorders to worsen patient outcomes. Here, we outline the neuroimmune complement, explore the evidence for altered immune system function in MDD, and present some of the potential mechanisms by which immune cells and molecules may drive the onset and course of MDD. These include pro-inflammatory signaling, alterations in the hypothalamic-pituitary-adrenal axis, dysregulation of the serotonergic and noradrenergic neurotransmitter systems, neuroinflammation, and meningeal immune dysfunction. Finally, we discuss the interactions between current antidepressants and the immune system and propose the possibility of immunomodulatory drugs as potential novel antidepressant treatments.
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http://dx.doi.org/10.1016/bs.apha.2021.03.004DOI Listing
April 2021

Sex differences in viral entry protein expression, host responses to SARS-CoV-2, and in vitro responses to sex steroid hormone treatment in COVID-19.

Res Sq 2020 Nov 4. Epub 2020 Nov 4.

Epidemiological studies suggest that men exhibit a higher mortality rate to COVID-19 than women, yet the underlying biology is largely unknown. Here, we seek to delineate sex differences in the expression of entry genes and , host responses to SARS-CoV-2, and in vitro responses to sex steroid hormone treatment. Using over 220,000 human gene expression profiles covering a wide range of age, tissues, and diseases, we found that male samples show higher expression levels of and , especially in the older group (>60 years) and in the kidney. Analysis of 6,031 COVID-19 patients at Mount Sinai Health System revealed that men have significantly higher creatinine levels, an indicator of impaired kidney function. Further analysis of 782 COVID-19 patient gene expression profiles taken from upper airway and blood suggested men and women present profound expression differences in responses to SARS-CoV-2. Computational deconvolution analysis of these profiles revealed male COVID-19 patients have enriched kidney-specific mesangial cells in blood compared to healthy patients. Finally, we observed selective estrogen receptor modulators, but not other hormone drugs (agonists/antagonists of estrogen, androgen, and progesterone), could reduce SARS-CoV-2 infection in vitro.
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http://dx.doi.org/10.21203/rs.3.rs-100914/v1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654875PMC
November 2020

Histamine-dependent interactions between mast cells, glia, and neurons are altered following early-life adversity in mice and humans.

Am J Physiol Gastrointest Liver Physiol 2020 12 30;319(6):G655-G668. Epub 2020 Sep 30.

Department of Physiology, Michigan State University, East Lansing, Michigan.

Early-life adversity contributes to the development of functional bowel disorders later in life through unresolved mechanisms. Here, we tested the hypothesis that early-life adversity alters anatomical and functional interactions between mast cells and enteric glia. The effects of early-life stress were studied using the neonatal maternal separation (NMS) stress mouse model. Anatomical relationships between mast cells and enteric glia were assessed using immunohistochemistry and mast cell reporter mice (;). Immunohistochemistry was used to assess the expression of histamine, histamine 1 (H1) receptors, and glial fibrillary acidic protein. Functional responses of glia to mast cell mediators were assessed in calcium imaging experiments using ; mice and cultured human enteric glial cells. NMS increases mast cell numbers at the level of the myenteric plexus and their proximity to myenteric ganglia. Myenteric glia respond to mediators released by activated mast cells that are blocked by H1 receptor antagonists in mice and humans and by blocking neuronal activity with tetrodotoxin in mouse tissue. Histamine replicates the effects of mast cell supernatants on enteric glia, and NMS increases histamine production by mast cells. NMS reduces glial responses to mast cell mediators in mouse tissue, while potentiating responses in cultured human enteric glia. NMS increases myenteric glial fibrillary acidic protein expression and reduces glial process length but does not cause neurodegeneration. Histamine receptor expression is not altered by NMS and is localized to neurons in mice, but glia in humans. Early-life stress increases the potential for interactions between enteric glia and mast cells, and histamine is a potential mediator of mast cell-glial interactions through H1 receptors. We propose that glial-mast cell signaling is a mechanism that contributes to enteric neuroplasticity driven by early-life adversity. Early-life adversity places an individual at risk for developing functional gastrointestinal disorders later in life through unknown mechanisms. Here, we show that interactions between mast cells and glia are disrupted by early-life stress in mice and that histamine is a potential mediator of mast cell-glial interactions.
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http://dx.doi.org/10.1152/ajpgi.00041.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792668PMC
December 2020

Perinatal androgens organize sex differences in mast cells and attenuate anaphylaxis severity into adulthood.

Proc Natl Acad Sci U S A 2020 09 11;117(38):23751-23761. Epub 2020 Sep 11.

Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824;

Mast cell (MC)-associated diseases, including allergy/anaphylaxis and neuroinflammatory pain disorders, exhibit a sex bias, with females at increase risk. While much attention has been directed toward adult sex hormones as drivers of sex differences, that female sex bias in MC-associated diseases is evident in prepubertal children, suggesting early-life origins of sex differences which have yet to be explored. Utilizing rodent models of MC-mediated anaphylaxis, our data here reveal that, 1) compared with females, males exhibit significantly reduced severity of MC-mediated anaphylactic responses that emerge prior to puberty and persist into adulthood, 2) reduced severity of MC-mediated anaphylaxis in males is linked with the naturally high level of perinatal androgens and can be recapitulated in females by perinatal exposure to testosterone proprionate, 3) perinatal androgen exposure guides bone marrow MC progenitors toward a masculinized tissue MC phenotype characterized by decreased concentration of prestored MC granule mediators (e.g., histamine, serotonin, and proteases) and reduced mediator release upon degranulation, and 4) engraftment of MC-deficient Kit mice with adult male, female, or perinatally androgenized female MCs results in MC-mediated anaphylaxis response that reflects the MC sex and not host sex. Together, these data present evidence that sex differences in MC phenotype and resulting disease severity are established in early life by perinatal androgens. Thus, factors affecting levels of perinatal androgens could have a significant impact on MC development and MC-associated disease risk across the life span.
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http://dx.doi.org/10.1073/pnas.1915075117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519313PMC
September 2020

Perivascular Adipocytes Store Norepinephrine by Vesicular Transport.

Arterioscler Thromb Vasc Biol 2019 02;39(2):188-199

From the Department of Pharmacology and Toxicology (M.F.A., D.F., E.D., J.T., A.I., R.B., S.W.W.), Michigan State University, East Lansing.

Objective- Perivascular adipose tissue (PVAT) contains an independent adrenergic system that can take up, metabolize, release, and potentially synthesize the vasoactive catecholamine norepinephrine. Norepinephrine has been detected in PVAT, but the mechanism of its protection within this tissue is unknown. Here, we investigate whether PVAT adipocytes can store norepinephrine using VMAT (vesicular monoamine transporter). Approach and Results- High-performance liquid chromatography identified norepinephrine in normal male Sprague Dawley rat aortic, superior mesenteric artery, and mesenteric resistance vessel PVATs, and retroperitoneal fat. Real-time polymerase chain reaction revealed VMAT1 and VMAT2 mRNA expression in the adipocytes and stromal vascular fraction of mesenteric resistance vessel PVAT. Immunofluorescence demonstrated the presence of VMAT1 and VMAT2, and the colocalization of VMAT2 with norepinephrine, in the cytoplasm of adipocytes in mesenteric resistance vessel PVAT. A protocol was developed to capture real-time uptake of Mini 202-a functional and fluorescent VMAT probe-in live rat PVAT adipocytes. Mini 202 was taken up by freshly isolated and differentiated adipocytes from mesenteric resistance vessel PVAT and adipocytes from thoracic aortic and superior mesenteric artery PVATs. In adipocytes freshly isolated from mesenteric resistance vessel PVAT, addition of rose bengal (VMAT inhibitor), nisoxetine (norepinephrine transporter inhibitor), or corticosterone (organic cation 3 transporter inhibitor) significantly reduced Mini 202 signal. Immunofluorescence supports that neither VMAT1 nor VMAT2 is present in retroperitoneal adipocytes, suggesting that PVAT adipocytes may be unique in storing norepinephrine. Conclusions- This study supports a novel function of PVAT adipocytes in storing amines in a VMAT-dependent manner. It provides a foundation for future studies exploring the purpose and mechanisms of norepinephrine storage by PVAT in normal physiology and obesity-related hypertension.
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http://dx.doi.org/10.1161/ATVBAHA.118.311720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6344267PMC
February 2019

Mast cell corticotropin-releasing factor subtype 2 suppresses mast cell degranulation and limits the severity of anaphylaxis and stress-induced intestinal permeability.

J Allergy Clin Immunol 2019 05 12;143(5):1865-1877.e4. Epub 2018 Nov 12.

Gastrointestinal Stress Biology Laboratory, Department of Large Animal Clinical Sciences, College of Veterinary Medicine, East Lansing, Mich; Department of Physiology, Michigan State University, East Lansing, Mich. Electronic address:

Background: Psychological stress and heightened mast cell (MC) activation are linked with important immunologic disorders, including allergy, anaphylaxis, asthma, and functional bowel diseases, but the mechanisms remain poorly defined. We have previously demonstrated that activation of the corticotropin-releasing factor (CRF) system potentiates MC degranulation responses during IgE-mediated anaphylaxis and psychological stress through corticotropin-releasing factor receptor subtype 1 (CRF) expressed on MCs.

Objective: In this study we investigated the role of corticotropin-releasing factor receptor subtype 2 (CRF) as a modulator of stress-induced MC degranulation and associated disease pathophysiology.

Methods: In vitro MC degranulation assays were performed with bone marrow-derived mast cells (BMMCs) derived from wild-type (WT) and CRF-deficient (CRF) mice and RBL-2H3 MCs transfected with CRF-overexpressing plasmid or CRF small interfering RNA. In vivo MC responses and associated pathophysiology in IgE-mediated passive systemic anaphylaxis and acute psychological restraint stress were measured in WT, CRF, and MC-deficient Kit knock-in mice.

Results: Compared with WT mice, CRF mice exhibited greater serum histamine levels and exacerbated IgE-mediated anaphylaxis and colonic permeability. In addition, CRF mice exhibited increased serum histamine levels and colonic permeability after acute restraint stress. Experiments with BMMCs and RBL-2H3 MCs demonstrated that CRF expressed on MCs suppresses store-operated Ca entry signaling and MC degranulation induced by diverse MC stimuli. Experiments with MC-deficient Kit mice systemically engrafted with WT and CRF BMMCs demonstrated the functional importance of MC CRF in modulating stress-induced pathophysiology.

Conclusions: MC CRF is a negative global modulator of stimuli-induced MC degranulation and limits the severity of IgE-mediated anaphylaxis and stress-related disease pathogenesis.
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http://dx.doi.org/10.1016/j.jaci.2018.08.053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6802741PMC
May 2019

S. Typhimurium challenge in juvenile pigs modulates the expression and localization of enteric cholinergic proteins and correlates with mucosal injury and inflammation.

Auton Neurosci 2018 09 8;213:51-59. Epub 2018 Jun 8.

Gastrointestinal Stress Biology Laboratory, Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI, USA; Neuroscience Program, Michigan State University, East Lansing, MI, USA. Electronic address:

The cholinergic system plays a central role in regulating critical gastrointestinal functions, including motility, secretion, barrier and immune function. In rodent models of acute, non-infectious gastrointestinal injury, the cholinergic system functions to inhibit inflammation; however, during inflammation local expression and regulation of the cholinergic system is not well known, particularly during infectious enteritis. The objective of this study was to determine the intrinsic expression of the enteric cholinergic system in pig ileum following an acute challenge with Salmonella enterica serovar Typhimurium DT104 (S. Typhimurium). At 2 d post-challenge, a three-fold reduction in ileal acetylcholine (ACh) levels was observed in challenged animals, compared with controls. Ileal acetylcholinesterase (AChE) activity was decreased (by four-fold) while choline acetyltransferase (ChAT) expression was increased in both the ileum and mesenteric lymph nodes. Elevated ChAT found to localize preferentially to mucosa overlying lymphoid follicles of the Peyers patch in challenged pigs, with more intense labeling for ChAT in S. Typhimurium challenged pigs compared to controls. Ileal mRNA gene expression of muscarinic receptor 1 and 3 was also increased in challenged pigs, while muscarinic receptor 2 and the nicotinic receptor alpha 7 subunit gene expression were unaffected. A positive correlation was observed between ChAT protein expression in the ileum, rectal temperature, and histopathological severity in challenged animals. These data show that inflammation from S. Typhimurium challenge alters enteric cholinergic expression by down-regulating acetylcholine concentration and acetylcholine degrading enzymes while increasing acetylcholine synthesis proteins and receptors. Given the known anti-inflammatory role of the cholinergic system, the divergent expression of cholinergic genes may represent an attempt to limit tissue damage by preserving cholinergic signaling in the face of low ligand availability.
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http://dx.doi.org/10.1016/j.autneu.2018.05.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6090566PMC
September 2018

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

Anim Nutr 2017 Dec 29;3(4):313-321. Epub 2017 Jun 29.

Gastrointestinal Stress Biology Laboratory, Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824, USA.

The gastrointestinal (GI) barrier serves a critical role in survival and overall health of animals and humans. Several layers of barrier defense mechanisms are provided by the epithelial, immune and enteric nervous systems. Together they act in concert to control normal gut functions (e.g., digestion, absorption, secretion, immunity, etc.) whereas at the same time provide a barrier from the hostile conditions in the luminal environment. Breakdown of these critical GI functions is a central pathophysiological mechanism in the most serious GI disorders in pigs. This review will focus on the development and functional properties of the GI barrier in pigs and how common early life production stressors, such as weaning, can alter immediate and long-term barrier function and disease susceptibility. Specific stress-related pathophysiological mechanisms responsible for driving GI barrier dysfunction induced by weaning and the implications to animal health and performance will be discussed.
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http://dx.doi.org/10.1016/j.aninu.2017.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5941262PMC
December 2017

Mast cell degranulation and calcium influx are inhibited by an Echinacea purpurea extract and the alkylamide dodeca-2E,4E-dienoic acid isobutylamide.

J Ethnopharmacol 2018 Feb 14;212:166-174. Epub 2017 Oct 14.

Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695, United States; Comparative Medicine Institute, North Carolina State University, Raleigh, NC 27695, United States. Electronic address:

Ethnopharmacological Relevance: Native Americans used plants from the genus Echinacea to treat a variety of different inflammatory conditions including swollen gums, sore throats, skin inflammation, and gastrointestinal disorders. Today, various Echinacea spp. preparations are used primarily to treat upper respiratory infections.

Aim Of The Study: The goal of this study was to evaluate the effects of an ethanolic E. purpurea (L) Moench root extract and the alkylamide dodeca-2E,4E-dienoic acid isobutylamide (A15) on mast cells, which are important mediators of allergic and inflammatory responses. Inhibition of mast cell activation may help explain the traditional use of Echinacea.

Materials And Methods: A15 was evaluated for its effects on degranulation, calcium influx, cytokine and lipid mediator production using bone marrow derived mast cells (BMMCs) and the transformed rat basophilic leukemia mast cell line RBL-2H3. Methods included enzymatic assays, fluorimetry, ELISAs, and microscopy. A root extract of E. purpurea, and low and high alkylamide-containing fractions prepared from this extract, were also tested for effects on mast cell function. Finally, we tested A15 for effects on calcium responses in RAW 264.7 macrophage and Jurkat T cell lines.

Results: A15 inhibited ß-hexosaminidase release from BMMCs and RBL-2H3 cells after treatment with the calcium ionophore A23187 by 83.5% and 48.4% at 100µM, respectively. Inhibition also occurred following stimulation with IgE anti-DNP/DNP-HSA. In addition, A15 inhibited 47% of histamine release from A23187-treated RBL-2H3 cells. A15 prevented the rapid rise in intracellular calcium following FcεRI crosslinking and A23187 treatment suggesting it acts on the signals controlling granule release. An E. purpurea root extract and a fraction with high alkylamide content derived from this extract also displayed these activities while fractions with little to no detectable amounts of alkylamide did not. A15 mediated inhibition of calcium influx was not limited to mast cells as A23187-stimulated calcium influx was blocked in both RAW 264.7 and Jurkat cell lines with 60.2% and 43.6% inhibition at 1min post-stimulation, respectively. A15 also inhibited the release of TNF-α, and PGE to a lesser degree, following A23187 stimulation indicating its broad activity on mast cell mediator production.

Conclusions: These findings suggest that Echinacea extracts and alkylamides may be useful for treating allergic and inflammatory responses mediated by mast cells. More broadly, since calcium is a critical second messenger, the inhibitory effects of alkylamides on calcium uptake would be predicted to dampen a variety of pathological responses, suggesting new uses for this plant and its constituents.
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http://dx.doi.org/10.1016/j.jep.2017.10.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5818717PMC
February 2018

Frontline Science: Corticotropin-releasing factor receptor subtype 1 is a critical modulator of mast cell degranulation and stress-induced pathophysiology.

J Leukoc Biol 2017 12 6;102(6):1299-1312. Epub 2017 Jul 6.

Gastrointestinal Stress Biology Laboratory, Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, Michigan, USA;

Life stress is a major risk factor in the onset and exacerbation of mast cell-associated diseases, including allergy/anaphylaxis, asthma, and irritable bowel syndrome. Although it is known that mast cells are highly activated upon stressful events, the mechanisms by which stress modulates mast cell function and disease pathophysiology remains poorly understood. Here, we investigated the role of corticotropin-releasing factor receptor subtype 1 (CRF) in mast cell degranulation and associated disease pathophysiology. In a mast cell-dependent model of IgE-mediated passive systemic anaphylaxis (PSA), prophylactic administration of the CRF-antagonist antalarmin attenuated mast cell degranulation and hypothermia. Mast cell-deficient mice engrafted with CRF bone marrow-derived mast cells (BMMCs) exhibited attenuated PSA-induced serum histamine, hypothermia, and clinical scores compared with wild-type BMMC-engrafted mice. mice engrafted with CRF BMMCs also exhibited suppressed in vivo mast cell degranulation and intestinal permeability in response to acute restraint stress. Genetic and pharmacologic experiments with murine BMMCs, rat RBL-2H3, and human LAD2 mast cells demonstrated that although CRF activation did not directly induce MC degranulation, CRF signaling potentiated the degranulation responses triggered by diverse mast cell stimuli and was associated with enhanced release of Ca from intracellular stores. Taken together, our results revealed a prominent role for CRF signaling in mast cells as a positive modulator of stimuli-induced degranulation and in vivo pathophysiologic responses to immunologic and psychologic stress.
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http://dx.doi.org/10.1189/jlb.2HI0317-088RRDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5669636PMC
December 2017

Chronic social stress in pigs impairs intestinal barrier and nutrient transporter function, and alters neuro-immune mediator and receptor expression.

PLoS One 2017 7;12(2):e0171617. Epub 2017 Feb 7.

Gastrointestinal Stress Biology Laboratory, Michigan State University, East Lansing, Michigan, United States of America.

Psychosocial stress is a major factor driving gastrointestinal (GI) pathophysiology and disease susceptibility in humans and animals. The mechanisms governing susceptibility to stress-induced GI disease remain poorly understood. In the present study, we investigated the influence of chronic social stress (CSS) in pigs, induced by 7 d of chronic mixing/crowding stress, on intestinal barrier and nutrient transport function, corticotropin releasing factor (CRF) signaling and immunological responses. Results from this study showed that CSS resulted in a significant impairment of ileal and colonic barrier function indicated by reduced transepithelial electrical resistance (TER) in the ileum and increased FD4 flux in the ileum (by 0.8 fold) and colon (by 0.7 fold). Ileal sodium glucose linked transporter 1 (SGLT-1) function, measured as glucose-induced changes in short-circuit current (Isc), was diminished (by 52%) in CSS pigs, associated with reduced body weight gain and feed efficiency. Although reductions in SGLT-1 function were observed in CSS pigs, mRNA expression for SGLT-1, villus heights were increased in CSS pigs. Corticotropin releasing factor (CRF) mRNA was upregulated (by 0.9 fold) in the ileum of CSS pigs but not in the colon. Urocortin 2 (Ucn2) mRNA was upregulated (by 1.5 fold) in the colon of CSS pigs, but not in the ileum. In CSS pigs, a downregulation of pro-inflammatory cytokines mRNA (IL1B, TNFA, IL8, and IL6) was observed in both ileum and colon, compared with controls. In contrast CSS induced a marked upregulation of mRNA for IL10 and mast cell chymase gene (CMA1) in the ileum and colon. Together, these data demonstrate that chronic stress in pigs results in significant alterations in intestinal barrier and nutrient transport function and neuro-immune mediator and receptor expression.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0171617PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5295718PMC
August 2017

Loss of Bladder Epithelium Induced by Cytolytic Mast Cell Granules.

Immunity 2016 12 6;45(6):1258-1269. Epub 2016 Dec 6.

Department of Pathology, Duke University, Durham, NC 27710, USA; Department of Molecular Genetics and Microbiology, Duke University, Durham, NC 27710, USA; Department of Immunology, Duke University, Durham, NC 27710, USA; Program in Emerging Infectious Diseases, Duke-National University of Singapore, Singapore 169857, Singapore.

Programmed death and shedding of epithelial cells is a powerful defense mechanism to reduce bacterial burden during infection but this activity cannot be indiscriminate because of the critical barrier function of the epithelium. We report that during cystitis, shedding of infected bladder epithelial cells (BECs) was preceded by the recruitment of mast cells (MCs) directly underneath the superficial epithelium where they docked and extruded their granules. MCs were responding to interleukin-1β (IL-1β) secreted by BECs after inflammasome and caspase-1 signaling. Upon uptake of granule-associated chymase (mouse MC protease 4 [mMCPT4]), BECs underwent caspase-1-associated cytolysis and exfoliation. Thus, infected epithelial cells require a specific cue for cytolysis from recruited sentinel inflammatory cells before shedding.
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http://dx.doi.org/10.1016/j.immuni.2016.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5177478PMC
December 2016

Sexual dimorphism in the mast cell transcriptome and the pathophysiological responses to immunological and psychological stress.

Biol Sex Differ 2016 22;7:60. Epub 2016 Nov 22.

Gastrointestinal Stress Biology Laboratory, Michigan State University, East Lansing, MI 48824 USA ; Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824 USA ; Neuroscience Program, Michigan State University, East Lansing, MI 48824 USA ; Department of Physiology, Michigan State University, East Lansing, MI 48824 USA.

Background: Biological sex plays a prominent role in the prevalence and severity of a number of important stress-related gastrointestinal and immune-related diseases including IBS and allergy/anaphylaxis. Despite the establishment of sex differences in these diseases, the underlying mechanisms contributing to sex differences remain poorly understood. The objective of this study was to define the role of biological sex on mast cells (MCs), an innate immune cell central to the pathophysiology of many GI and allergic disorders.

Methods: Twelve-week-old C57BL/6 male and female mice were exposed to immunological stress (2 h of IgE-mediated passive systemic anaphylaxis (PSA)) or psychological stress (1 h of restraint stress (RS)) and temperature, clinical scores, serum histamine, and intestinal permeability (for RS) were measured. Primary bone marrow-derived MCs (BMMCs) were harvested from male and female mice and analyzed for MC degranulation, signaling pathways, mediator content, and RNA transcriptome analysis.

Results: Sexually dimorphic responses were observed in both models of PSA and RS and in primary MCs. Compared with male mice, female mice exhibited increased clinical scores, hypothermia, and serum histamine levels in response to PSA and had greater intestinal permeability and serum histamine responses to RS. Primary BMMCs from female mice exhibited increased release of β-hexosaminidase, histamine, tryptase, and TNF-α upon stimulation with IgE/DNP and A23187. Increased mediator release in female BMMCs was not associated with increased upstream phospho-tyrosine signaling pathways or downstream Ca mobilization. Instead, increased mediator release in female MCs was associated with markedly increased capacity for synthesis and storage of MC granule-associated immune mediators as determined by MC mediator content and RNA transcriptome analysis.

Conclusions: These results provide a new understanding of sexual dimorphic responses in MCs and have direct implications for stress-related diseases associated with a female predominance and MC hyperactivity including irritable bowel syndrome, allergy, and anaphylaxis.
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http://dx.doi.org/10.1186/s13293-016-0113-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5120457PMC
November 2016

Dietary Iron Deficiency and Oversupplementation Increase Intestinal Permeability, Ion Transport, and Inflammation in Pigs.

J Nutr 2016 08 29;146(8):1499-505. Epub 2016 Jun 29.

Gastrointestinal Stress Biology Laboratory, Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI;

Background: Understanding the influence of dietary iron deficiency and dietary iron oversupplementation on intestinal health is important for both animal production and human health.

Objective: The aim of this study was to determine whether dietary iron concentration influences intestinal physiology, morphology, and inflammation in the porcine duodenum.

Methods: Twenty-four male pigs (21 d old) were fed diets containing either 20 mg Fe/kg [low dietary iron (L-Fe)], 120 mg Fe/kg [adequate dietary iron (A-Fe); control], or 520 mg Fe/kg [high dietary iron (H-Fe)] by FeSO4 supplement (dry matter basis). After 32-36 d, the duodenum was harvested from pigs and mounted in Ussing chambers for the measurement of transepithelial electrical resistance (TER), short-circuit current, and (3)H-mannitol permeability. Intestinal morphology and inflammation were assessed by histologic examination, and proinflammatory gene expression was assessed by real-time polymerase chain reaction.

Results: Compared with A-Fe-fed pigs, pigs fed L-Fe diets exhibited reduced TER (by 30%; P < 0.05). Compared with that of A-Fe-fed controls, the paracellular flux of (3)H-mannitol across the duodenal mucosa was higher (P < 0.05) in L-Fe-fed (>100%) and H-Fe-fed (∼4-fold) pigs; the L-Fe-fed and H-Fe-fed groups did not differ significantly from one another. Compared with the L-Fe-fed pigs, the A-Fe-fed and H-Fe-fed pigs had malondialdehyde concentrations 1.4- and 2.5-fold higher in the duodenum and 4.4- and 6.6-fold higher in the liver, respectively (P < 0.05). Neutrophil counts were higher in both the L-Fe-fed (by 3-fold) and H-Fe-fed (by 3.3-fold) groups than in the A-Fe-fed group; the L-Fe-fed and H-Fe-fed groups did not significantly differ from one another. Duodenal mucosal tumor necrosis factor α (TNFA), interleukin (IL) 1β, and IL6 relative gene expression was upregulated by 36%, 28%, and 45%, respectively, in H-Fe pigs (P < 0.05), but not in L-Fe pigs, compared with A-Fe pigs.

Conclusion: These data suggest that adequate but not oversupplementation of dietary iron in pigs is required to maintain intestinal barrier health and function.
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http://dx.doi.org/10.3945/jn.116.231621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4958291PMC
August 2016

Cromolyn-mediated improvement of intestinal barrier function is associated with enhanced piglet performance after weaning.

BMC Vet Res 2015 Oct 28;11:274. Epub 2015 Oct 28.

Lucta S.A., Can Parellada 28, 08170, Montornés del Vallés, Barcelona, Spain.

Background: Previous work showed that weaning stress causes gut barrier dysfunction partly by triggering the release of corticotropin releasing factor (CRF) and thereby inducing the degranulation of intestinal mast cell (MC). This study investigated the hypothesis that attenuating the weaning-induced activation of the CRF-MC axis via administration of a MC stabilizing agent (cromolyn) may improve gut permeability and piglet performance after weaning.

Results: To test the hypothesis twenty piglets were weaned (20 ± 1.0 d of age; 6.4 ± 0.4 kg of BW) and injected intraperitoneally with saline (control, n = 10) or 20 mg/kg BW of sodium cromolyn (cromolyn, n = 10) at - 0.5, 8 and 16 h relative to weaning. Piglets were housed individually and fed ad libitum a pre-starter diet from one to 15 d post-weaning followed by a starter diet until the end of the study on d 36. Cromolyn improved intestinal permeability as indicated by the reduced recovery of cobalt and mannitol in plasma samples. Cromolyn treated pigs consumed more feed (369 vs. 313 g/d; P < 0.009), gained more BW (283 vs. 238 g/d; P < 0.006), and grew more efficiently (0.60 vs. 0.40; P < 0.042) than their control counterparts. As a result, cromolyn treated pigs were 1.4 kg heavier than those in the control group by d 36 after weaning (16.5 vs. 17.9 kg; P < 0.002).

Conclusions: In agreement with our hypothesis, present data indicate that the cromolyn-mediated improvement of intestinal permeability is associated with enhanced pig performance after weaning.
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http://dx.doi.org/10.1186/s12917-015-0588-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4624645PMC
October 2015

Early-life stress origins of gastrointestinal disease: animal models, intestinal pathophysiology, and translational implications.

Am J Physiol Gastrointest Liver Physiol 2015 Dec 8;309(12):G927-41. Epub 2015 Oct 8.

Department of Large Animal Clinical Sciences, Michigan State University, East Lansing, Michigan; Gastrointestinal Stress Biology Laboratory, College of Veterinary Medicine, Michigan State University, East Lansing, Michigan; and

Early-life stress and adversity are major risk factors in the onset and severity of gastrointestinal (GI) disease in humans later in life. The mechanisms by which early-life stress leads to increased GI disease susceptibility in adult life remain poorly understood. Animal models of early-life stress have provided a foundation from which to gain a more fundamental understanding of this important GI disease paradigm. This review focuses on animal models of early-life stress-induced GI disease, with a specific emphasis on translational aspects of each model to specific human GI disease states. Early postnatal development of major GI systems and the consequences of stress on their development are discussed in detail. Relevant translational differences between species and models are highlighted.
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http://dx.doi.org/10.1152/ajpgi.00206.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4683303PMC
December 2015

Peroxidised dietary lipids impair intestinal function and morphology of the small intestine villi of nursery pigs in a dose-dependent manner.

Br J Nutr 2015 Dec 6;114(12):1985-92. Epub 2015 Oct 6.

1Department of Animal Science,North Carolina State University,Raleigh,NC 27695,USA.

The objective of this study was to investigate the effect of increasing degrees of lipid peroxidation on structure and function of the small intestine of nursery pigs. A total of 216 pigs (mean body weight was 6·5 kg) were randomly allotted within weight blocks and sex and fed one of five experimental diets for 35 d (eleven pens per treatment with three to four pigs per pen). Treatments included a control diet without added lipid, and diets supplemented with 6 % soyabean oil that was exposed to heat (80°C) and constant oxygen flow (1 litre/min) for 0, 6, 9 and 12 d. Increasing lipid peroxidation linearly reduced feed intake (P<0·001) and weight gain (P=0·024). Apparent faecal digestibility of gross energy (P=0·001) and fat (P<0·001) decreased linearly as the degree of peroxidation increased. Absorption of mannitol (linear, P=0·097) and d-xylose (linear, P=0·089), measured in serum 2 h post gavage with a solution containing 0·2 g/ml of d-xylose and 0·3 g/ml of mannitol, tended to decrease progressively as the peroxidation level increased. Increasing peroxidation also resulted in increased villi height (linear, P<0·001) and crypt depth (quadratic, P=0·005) in the jejunum. Increasing peroxidation increased malondialdehyde concentrations (quadratic, P=0·035) and reduced the total antioxidant capacity (linear, P=0·044) in the jejunal mucosa. In conclusion, lipid peroxidation progressively diminished animal performance and modified the function and morphology of the small intestine of nursery pigs. Detrimental effects were related with the disruption of redox environment of the intestinal mucosa.
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http://dx.doi.org/10.1017/S000711451500392XDOI Listing
December 2015

MARCKS-dependent mucin clearance and lipid metabolism in ependymal cells are required for maintenance of forebrain homeostasis during aging.

Aging Cell 2015 Oct 25;14(5):764-73. Epub 2015 May 25.

Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, 27607, USA.

Ependymal cells (ECs) form a barrier responsible for selective movement of fluids and molecules between the cerebrospinal fluid and the central nervous system. Here, we demonstrate that metabolic and barrier functions in ECs decline significantly during aging in mice. The longevity of these functions in part requires the expression of the myristoylated alanine-rich protein kinase C substrate (MARCKS). Both the expression levels and subcellular localization of MARCKS in ECs are markedly transformed during aging. Conditional deletion of MARCKS in ECs induces intracellular accumulation of mucins, elevated oxidative stress, and lipid droplet buildup. These alterations are concomitant with precocious disruption of ependymal barrier function, which results in the elevation of reactive astrocytes, microglia, and macrophages in the interstitial brain tissue of young mutant mice. Interestingly, similar alterations are observed during normal aging in ECs and the forebrain interstitium. Our findings constitute a conceptually new paradigm in the potential role of ECs in the initiation of various conditions and diseases in the aging brain.
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http://dx.doi.org/10.1111/acel.12354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4568964PMC
October 2015

Impact of dietary organic acids and botanicals on intestinal integrity and inflammation in weaned pigs.

BMC Vet Res 2015 Apr 16;11:96. Epub 2015 Apr 16.

North Carolina State University, Department of Population Health and Pathobiology, Raleigh, NC, 27695, USA.

Background: Organic acids, such as citric and sorbic acid, and pure plant-derived constituents, like monoterpens and aldehydes, have a long history of use in pig feeding as alternatives to antibiotic growth promoters. However, their effects on the intestinal barrier function and inflammation have never been investigated. Therefore, aim of this study was to assess the impact of a microencapsulated mixture of citric acid and sorbic acid (OA) and pure botanicals, namely thymol and vanillin, (PB) on the intestinal integrity and functionality of weaned pigs and in vitro on Caco-2 cells. In the first study 20 piglets were divided in 2 groups and received either a basal diet or the basal diet supplemented with OA + PB (5 g/kg) for 2 weeks post-weaning at the end of which ileum and jejunum samples were collected for Ussing chambers analysis of trans-epithelial electrical resistance (TER), intermittent short-circuit current (I SC), and dextran flux. Scrapings of ileum mucosa were also collected for cytokine analysis (n = 6). In the second study we measured the effect of these compounds directly on TER and permeability of Caco-2 monolayers treated with either 0.2 or 1 g/l of OA + PB.

Results: Pigs fed with OA + PB tended to have reduced I SC in the ileum (P = 0.07) and the ileal gene expression of IL-12, TGF-β, and IL-6 was down regulated. In the in vitro study on Caco-2 cells, TER was increased by the supplementation of 0.2 g/l at 4, 6, and 14 days of the experiment, whereas 1 g/l increased TER at 10 and 12 days of treatment (P < 0.05). Dextran flux was not significantly affected though a decrease was observed at 7 and 14 days (P = 0.10 and P = 0.09, respectively).

Conclusions: Overall, considering the results from both experiments, OA + PB improved the maturation of the intestinal mucosa by modulating the local and systemic inflammatory pressure ultimately resulting in a less permeable intestine, and eventually improving the growth of piglets prematurely weaned.
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http://dx.doi.org/10.1186/s12917-015-0410-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4483210PMC
April 2015

Porcine models of digestive disease: the future of large animal translational research.

Transl Res 2015 Jul 13;166(1):12-27. Epub 2015 Jan 13.

Department of Clinical Sciences, Center for Comparative Medicine and Translational Research, North Carolina State University, Raleigh, North Carolina.

There is increasing interest in nonrodent translational models for the study of human disease. The pig, in particular, serves as a useful animal model for the study of pathophysiological conditions relevant to the human intestine. This review assesses currently used porcine models of gastrointestinal physiology and disease and provides a rationale for the use of these models for future translational studies. The pig has proven its utility for the study of fundamental disease conditions such as ischemia-reperfusion injury, stress-induced intestinal dysfunction, and short bowel syndrome. Pigs have also shown great promise for the study of intestinal barrier function, surgical tissue manipulation and intervention, as well as biomaterial implantation and tissue transplantation. Advantages of pig models highlighted by these studies include the physiological similarity to human intestine and mechanisms of human disease. Emerging future directions for porcine models of human disease include the fields of transgenics and stem cell biology, with exciting implications for regenerative medicine.
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http://dx.doi.org/10.1016/j.trsl.2015.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4458388PMC
July 2015

Animal models of ischemia-reperfusion-induced intestinal injury: progress and promise for translational research.

Am J Physiol Gastrointest Liver Physiol 2015 Jan 20;308(2):G63-75. Epub 2014 Nov 20.

Department of Clinical Sciences, Center for Comparative Medicine and Translational Research, North Carolina State University, Raleigh, North Carolina; and

Research in the field of ischemia-reperfusion injury continues to be plagued by the inability to translate research findings to clinically useful therapies. This may in part relate to the complexity of disease processes that result in intestinal ischemia but may also result from inappropriate research model selection. Research animal models have been integral to the study of ischemia-reperfusion-induced intestinal injury. However, the clinical conditions that compromise intestinal blood flow in clinical patients ranges widely from primary intestinal disease to processes secondary to distant organ failure and generalized systemic disease. Thus models that closely resemble human pathology in clinical conditions as disparate as volvulus, shock, and necrotizing enterocolitis are likely to give the greatest opportunity to understand mechanisms of ischemia that may ultimately translate to patient care. Furthermore, conditions that result in varying levels of ischemia may be further complicated by the reperfusion of blood to tissues that, in some cases, further exacerbates injury. This review assesses animal models of ischemia-reperfusion injury as well as the knowledge that has been derived from each to aid selection of appropriate research models. In addition, a discussion of the future of intestinal ischemia-reperfusion research is provided to place some context on the areas likely to provide the greatest benefit from continued research of ischemia-reperfusion injury.
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http://dx.doi.org/10.1152/ajpgi.00112.2013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4297854PMC
January 2015

Effects of quaternary benzo(c)phenanthridine alkaloids on growth performance, shedding of organisms, and gastrointestinal tract integrity in pigs inoculated with multidrug-resistant Salmonella spp.

Am J Vet Res 2013 Dec;74(12):1530-5

Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27695.

Objective: To evaluate effects of quaternary benzo(c)phenanthridine alkaloids (QBAs) against Salmonella spp and determine effects on growth performance, organism shedding, and gastrointestinal tract integrity in pigs inoculated with Salmonella enterica serovar Typhimurium.

Sample: 36 Salmonella isolates and twenty 5-week-old pigs.

Procedures: Minimum inhibitory concentration of QBAs against the Salmonella isolates was determined. Pigs were allocated to 4 groups and inoculated with Salmonella organisms. Pigs received diets supplemented with 1.5 g of QBAs/1,000 kg of feed, 0.75 g of QBAs/1,000 kg of feed, or 59.4 g of chlortetracycline/1,000 kg of feed or a nonsupplemented (control) diet. Pigs were weighed on day 0 and then weekly for 40 days. Fecal samples were collected to quantify Salmonella organisms. Gastrointestinal tract integrity was evaluated by measuring transepithelial resistance.

Results: In vitro, 9 of 36 (25%) Salmonella isolates were inhibited at 90 μg of QBAs/mL; all 36 were inhibited at 179 μg of QBAs/mL. Diets containing QBAs significantly decreased Salmonella spp shedding; shedding was lower 40 days after inoculation for pigs fed diets containing QBAs or chlortetracycline than for pigs fed the control diet. Growth performance was similar for pigs fed diets containing QBA or chlortetracycline. Gastrointestinal tract integrity was improved in pigs fed the diet containing 1.5 g of QBAs/1,000 kg of feed.

Conclusions And Clinical Relevance: QBAs and chlortetracycline decreased Salmonella spp shedding but did not differ with regard to growth performance. Gastrointestinal tract integrity was better, albeit not significantly, in pigs fed diets containing QBAs. Further investigation into the role of QBAs and their mechanism as an immunomodulator is necessary.
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http://dx.doi.org/10.2460/ajvr.74.12.1530DOI Listing
December 2013

Acute effects of rotavirus and malnutrition on intestinal barrier function in neonatal piglets.

World J Gastroenterol 2013 Aug;19(31):5094-102

Laboratory of Developmental Nutrition, College of Agriculture and Life Sciences, North Carolina State University, Raleigh, NC 27695, USA.

Aim: To investigate the effect of protein-energy malnutrition on intestinal barrier function during rotavirus enteritis in a piglet model.

Methods: Newborn piglets were allotted at day 4 of age to the following treatments: (1) full-strength formula (FSF)/noninfected; (2) FSF/rotavirus infected; (3) half-strength formula (HSF)/noninfected; or (4) HSF/rotavirus infected. After one day of adjustment to the feeding rates, pigs were infected with rotavirus and acute effects on growth and diarrhea were monitored for 3 d and jejunal samples were collected for Ussing-chamber analyses.

Results: Piglets that were malnourished or infected had lower body weights on days 2 and 3 post-infection (P < 0.05). Three days post-infection, marked diarrhea and weight loss were accompanied by sharp reductions in villus height (59%) and lactase activity (91%) and increased crypt depth (21%) in infected compared with non-infected pigs (P < 0.05). Malnutrition also increased crypt depth (21%) compared to full-fed piglets. Villus:crypt ratio was reduced (67%) with viral infection. There was a trend for reduction in transepithelial electrical resistance with rotavirus infection and malnutrition (P = 0.1). (3)H-mannitol flux was significantly increased (50%; P < 0.001) in rotavirus-infected piglets compared to non-infected piglets, but there was no effect of nutritional status. Furthermore, rotavirus infection reduced localization of the tight junction protein, occludin, in the cell membrane and increased localization in the cytosol.

Conclusion: Overall, malnutrition had no additive effects to rotavirus infection on intestinal barrier function at day 3 post-infection in a neonatal piglet model.
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http://dx.doi.org/10.3748/wjg.v19.i31.5094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3746381PMC
August 2013

Effects of creep feeding and supplemental glutamine or glutamine plus glutamate (Aminogut) on pre- and post-weaning growth performance and intestinal health of piglets.

J Anim Sci Biotechnol 2013 Aug 3;4(1):29. Epub 2013 Aug 3.

Laboratory of Developmental Nutrition, Department of Animal Science, North Carolina State University, 101 Polk Hall, North Carolina State University, Raleigh, NC 27695, USA.

Background: Creep feeding is used to stimulate piglet post-weaning feed consumption. L-Glutamine (GLN) is an important source of fuel for intestinal epithelial cells. The objective of this study was to determine the impact of creep feeding and adding GLN or AminoGut (AG; containing glutamine + glutamate) to pre- and post-weaning diets on pig performance and intestinal health. Litters (N = 120) were allotted to four treatments during 14-21 d of lactation: 1) No creep feed (NC, n = 45); 2) creep fed control diet (CFCD, n = 45); 3) creep fed 1% GLN (CFGLN, n = 15); 4) creep fed .88% AG (CFAG, n = 15). After weaning, the NC and CFCD groups were sub-divided into three groups (n = 15 each), receiving either a control nursery diet (NC-CD, CFCD-CD) or a diet supplemented with either GLN (NC-GLN, CFCD-GLN) or with AG (NC-AG, CFCD-AG). Litters that were creep fed with diets containing GLN or AG also were supplemented with those amino acids in the nursery diets (CFGLN-GLN, CFAG-AG). Glutamine was added at 1% in all three post-weaning diet phases and AG was added at .88% in phase 1 and 2 and at .66% in phase 3.

Results: Feed conversion (feed/gain) showed means among treatment means close to significance (P = 0.056) and Tukey's test for pairwise mean comparisons showed that Pigs in the CFGLN-GLN group had the best feed conversion (feed/gain) in the first three-week period post-weaning, exceeding (P = 0.044) controls (CFCD-CD) by 34%. The NC-AG group had (P = 0.02) the greatest feed intake in the last three week of the study, exceeding controls (CFCD-CD) by 12%. CFGLN-GLN, CFCD-GLN and sow reared (SR) pigs had the greatest (P = 0.049) villi height exceeding the CFCD-AG group by 18%, 20% and 19% respectively. The CFAG-AG group had the deepest (P = 0.001) crypts among all treatments. CFGLN-GLN, CFCD-GLN and SR groups had the greatest (P = 0.001) number of cells proliferating (PCNA) exceeding those in the NC-CD group by 43%, 54% and 63% respectively. Sow reared pigs showed the greatest (P = 0.001) intestinal absorption capacity for xylose and mannitol.

Conclusion: Supplementation of creep feed and nursery diets with GLN and/or AminoGut in the first three week improved feed conversion possibly due to improved intestinal health.
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http://dx.doi.org/10.1186/2049-1891-4-29DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3765720PMC
August 2013

Early weaning stress in pigs impairs innate mucosal immune responses to enterotoxigenic E. coli challenge and exacerbates intestinal injury and clinical disease.

PLoS One 2013 24;8(4):e59838. Epub 2013 Apr 24.

Department of Population Health and Pathobiology, North Carolina State University College of Veterinary Medicine, Raleigh, North Carolina, United States of America.

Background And Aims: The clinical onset and severity of intestinal disorders in humans and animals can be profoundly impacted by early life stress. Here we investigated the impact of early weaning stress in pigs on intestinal physiology, clinical disease, and immune response to subsequent challenge with enterotoxigenic F18 E. coli (ETEC).

Methodology: Pigs weaned from their dam at 16 d, 18 d, and 20 d of age were given a direct oral challenge of F18 ETEC at 26 d of age. Pigs were monitored from days 0 to 4 post-infection for clinical signs of disease. On Day 4 post-ETEC challenge, ileal barrier function, histopathologic and inflammatory cytokine analysis were performed on ileal mucosa.

Results: Early weaned pigs (16 d and 18 d weaning age) exhibited a more rapid onset and severity of diarrhea and reductions in weight gain in response to ETEC challenge compared with late weaned pigs (20 d weaning age). ETEC challenge induced intestinal barrier injury in early weaned pigs, indicated by reductions in ileal transepithelial electrical resistance (TER) and elevated FD4 flux rates, in early weaned pig ileum but not in late weaned pigs. ETEC-induced marked elevations in IL-6 and IL-8, neutrophil recruitment, and mast cell activation in late-weaned pigs; these responses were attenuated in early weaned pigs. TNF levels elevated in ETEC challenged ileal mucosa from early weaned pigs but not in other weaning age groups.

Conclusions: These data demonstrate the early weaning stress can profoundly alter subsequent immune and physiology responses and clinical outcomes to subsequent infectious pathogen challenge. Given the link between early life stress and gastrointestinal diseases of animals and humans, a more fundamental understanding of the mechanisms by which early life stress impacts subsequent pathophysiologic intestinal responses has implications for the prevention and management of important GI disorders in humans and animals.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0059838PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3634819PMC
December 2013

Intestinal mast cells mediate gut injury and systemic inflammation in a rat model of deep hypothermic circulatory arrest.

Crit Care Med 2013 Sep;41(9):e200-10

Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USA.

Objective: Cardiac surgery, especially when employing cardiopulmonary bypass and deep hypothermic circulatory arrest, is associated with systemic inflammatory responses that significantly affect morbidity and mortality. Intestinal perfusion abnormalities have been implicated in such responses, but the mechanisms linking local injury and systemic inflammation remain unclear. Intestinal mast cells are specialized immune cells that secrete various preformed effectors in response to cellular stress. We hypothesized that mast cells are activated in a microenvironment shaped by intestinal ischemia/reperfusion, and investigated local and systemic consequences.

Design: Rat model of deep hypothermic circulatory arrest.

Setting: University research laboratory.

Subjects: Twelve- to 14-week-old male Sprague-Dawley rats.

Interventions: Rats were anesthetized and cooled to 16°C to 18°C on cardiopulmonary bypass before instituting deep hypothermic circulatory arrest for 45 minutes. Specimens were harvested following rewarming and 2 hours of recovery.

Measurements And Main Results: Significant intestinal barrier disruption was found, together with macro- and microscopic evidence of ischemia/reperfusion injury in ileum and colon, but not in the lungs or kidneys. Immunofluorescence and toluidine blue staining revealed increased numbers of mast cells and their activation in the gut. In animals pretreated with the mast cell stabilizer, cromolyn sodium, mast cell degranulation was blocked, and intestinal morphology and barrier function were preserved following deep hypothermic circulatory arrest. Furthermore, cromolyn sodium treatment was associated with reduced intestinal neutrophil influx and blunted systemic release of proinflammatory cytokines.

Conclusion: Our data provide primary evidence that intestinal ischemia/reperfusion is a leading pathophysiologic process in a rat model of deep hypothermic circulatory arrest, and that intestinal injury, and local and systemic inflammatory responses are critically dependent on mast cell activation. This identifies intestinal mast cells as central players in deep hypothermic circulatory arrest-associated responses, and opens novel therapeutic possibilities for patients undergoing this procedure.
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http://dx.doi.org/10.1097/CCM.0b013e31827cac7aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5756097PMC
September 2013

Infection with feline immunodeficiency virus alters intestinal epithelial transport and mucosal immune responses to probiotics.

Vet Immunol Immunopathol 2013 May 8;153(1-2):146-52. Epub 2013 Feb 8.

Center for Comparative Medicine and Translational Research, College of Veterinary Medicine, North Carolina State University, 1060 William Moore Dr., Raleigh, NC 27607, United States.

HIV infection is associated with intestinal mucosal dysfunction and probiotics offer the therapeutic potential to enhance the mucosal barrier in HIV+ patients. To evaluate the response of immunocompromised hosts to probiotics, we orally administered Lactobacillus acidophilus to cats with chronic feline immunodeficiency virus (FIV) infection. FIV infection significantly affected transcellular, but not paracellular, transport of small molecules across the intestinal epithelium. Additionally, probiotic treatment of FIV+ cats resulted in changes in cytokine release and mucosal leukocyte percentages that were not paralleled in FIV- cats. These results suggest a novel role for FIV in upregulating transcellular transport across the gastrointestinal epithelial barrier and demonstrate the potential therapeutic use of probiotic bacteria to restore intestinal homeostasis.
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http://dx.doi.org/10.1016/j.vetimm.2013.01.017DOI Listing
May 2013

Early life stress triggers persistent colonic barrier dysfunction and exacerbates colitis in adult IL-10-/- mice.

Inflamm Bowel Dis 2013 Mar-Apr;19(4):712-9

Department of Population Health and Pathobiology, North Carolina State University, College of Veterinary Medicine, Raleigh, NC 27607, USA.

Background: It has become increasingly evident that disease flares in the human inflammatory bowel diseases are influenced by life stress. It is known that life stress can trigger disturbances in intestinal barrier function and activate proinflammatory signaling pathways, which are important contributors to intestinal inflammation and clinical disease; however, the exact mechanisms of stress-induced inflammatory bowel disease exacerbations remain to be elucidated. Here, we presented a model of early life stress-induced exacerbation of colitis in interleukin (IL)-10 mice.

Methods: C57Bl/6 wild-type and IL-10 mice were exposed to neonatal maternal separation (NMS) stress on postnatal days 1 to 18 and reared under normal conditions until 10 to 12 weeks of age. At this time, histopathology, colitis scores, intestinal barrier function, proinflammatory cytokine expression, and mast cell activity were evaluated.

Results: NMS increased the severity of colitis IL-10 mice indicated by greater colitis scores and colonic proinflammatory cytokine concentrations. NMS and IL-10 increased colonic permeability; however, NMS alone did not induce colitis. Increased mast cell activation and colonic tryptase release were observed in IL-10 mice exposed to NMS, indicating mast cell activation.

Conclusions: This study demonstrates that colitis in IL-10 mice can be exacerbated by NMS stress. The precise mechanisms of enhanced colitis severity in NMS IL10 mice are unclear but persistent defects in intestinal barrier function likely play a contributing role. NMS serves as a novel model to investigate the mechanisms by which early life stress influences the development and course of inflammatory bowel disease in adulthood.
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http://dx.doi.org/10.1097/MIB.0b013e3182802a4eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4114389PMC
September 2013
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