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Co-bedding of Preterm Newborn Pigs Reduces Necrotizing Enterocolitis Incidence Independent of Vital Functions and Cortisol Levels.

ABSTRACT: Background: Preterm infants are born with immature organs, leading to morbidities such as necrotizing enterocolitis (NEC), a gut inflammatory disease associated with adverse feeding responses but also hemodynamic and respiratory instability. Skin-to-skin contact including "kangaroo care" may improve infant survival and health via improved vital functions (e.g., pulmonary, cardiovascular) and endocrine influences by adrenal glucocorticoids. Clinical effects of skin-to-skin contact for newborn siblings ("co-bedding") are not known. Using NEC-susceptible Preterm pigs as models, we hypothesized that co-bedding and exogenous glucocorticoids improve vital functions and NEC resistance. Methods: In experiment 1, cesarean-delivered, formula-fed Preterm pigs were reared in incubators with (co-bedding, COB, n = 30) or without (single-bedding, SIN, n = 29) a sibling until euthanasia and tissue collection on day four. In experiment 2, single-bedded Preterm pigs were treated postnatally with a tapering dose of hydrocortisone (HC, n = 19, 1-3 mg/kg/d) or saline (CON, n = 19). Results: Co-bedding reduced NEC incidence (38 vs. 65%, p < 0.05) and increased the density of colonic goblet cells (+20%, p < 0.05) but had no effect on pulmonary and cardiovascular functions (respiration, blood pressure, heart rate, blood gases) or cortisol levels. There were limited differences in intestinal villous architecture and digestive enzyme activities. In experiment 2, HC treatment increased NEC lesions in the small intestine without any effects on pulmonary or cardiovascular functions. Conclusion: Co-bedding may improve gut function and NEC resistance independently of cardiorespiratory function and cortisol levels, but pharmacological cortisol treatment predispose to NEC. Preterm pigs may be a useful tool to better understand the physiological effects of co-bedding, neonatal stressors and their possible interactions with morbidities in Preterm neonates.

SUBMITTER: Brunse A

PROVIDER: S-EPMC8049114 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Necrotizing enterocolitis (NEC) is an acute gut inflammatory disorder that occurs in preterm infants in the first weeks after birth. Infants surviving NEC often show impaired neurodevelopment. The mechanisms linking NEC lesions with later neurodevelopment are poorly understood but may include proinflammatory signaling in the immature brain. Using preterm pigs as a model for preterm infants, we hypothesized that severe intestinal NEC lesions are associated with acute effects on the developing hippocampus. METHODS:Cesarean-delivered preterm pigs (n?=?117) were reared for 8 days and spontaneously developed variable severity of NEC lesions. Neonatal arousal, physical activity, and in vitro neuritogenic effects of cerebrospinal fluid (CSF) were investigated in pigs showing NEC lesions in the colon (Co-NEC) or in the small intestine (Si-NEC). Hippocampal transcriptome analysis and qPCR were used to assess gene expressions and their relation to biological processes, including neuroinflammation, and neural plasticity. Microglia activation was quantified by stereology. The neuritogenic response to selected proteins was investigated in primary cultures of hippocampal neurons. RESULTS:NEC development rapidly reduced the physical activity of pigs, especially when lesions occurred in the small intestine. Si-NEC and Co-NEC were associated with 27 and 12 hippocampal differentially expressed genes (DEGs), respectively. These included genes related to neuroinflammation (i.e., S100A8, S100A9, IL8, IL6, MMP8, SAA, TAGLN2) and hypoxia (i.e., PDK4, IER3, TXNIP, AGER), and they were all upregulated in Si-NEC pigs. Genes related to protection against oxidative stress (HBB, ALAS2) and oligodendrocytes (OPALIN) were downregulated in Si-NEC pigs. CSF collected from NEC pigs promoted neurite outgrowth in vitro, and the S100A9 and S100A8/S100A9 proteins may mediate the neuritogenic effects of NEC-related CSF on hippocampal neurons. NEC lesions did not affect total microglial cell number but markedly increased the proportion of Iba1-positive amoeboid microglial cells. CONCLUSIONS:NEC lesions, especially when present in the small intestine, are associated with changes to hippocampal gene expression that potentially mediate neuroinflammation and disturbed neural circuit formation via enhanced neuronal differentiation. Early brain-protective interventions may be critical for preterm infants affected by intestinal NEC lesions to reduce their later neurological dysfunctions.

Project description:Background: Recombinant human IGF-1/binding protein-3 (rhIGF-1/BP-3) is currently tested as a therapy in preterm infants but possible effects on the gut, including necrotizing enterocolitis (NEC), have not been tested. The aim of this study was to evaluate if rhIGF-1/BP-3 supplementation in the first days after birth negatively affects clinical variables like growth, physical activity, blood chemistry and hematology and gut maturation (e.g., intestinal permeability, morphology, enzyme activities, cytokine levels, enterocyte proliferation, NEC lesions), using NEC-sensitive preterm pigs as a model for preterm infants. Methods: Preterm pigs were given twice daily subcutaneous injections of rhIGF-1/BP-3 or vehicle. Blood was collected for IGF-1 measurements and gut tissue for NEC evaluation and biochemical analyses on day 5. Results: Baseline circulating IGF-1 levels were low in preterm pigs compared with near-term pigs reared by their mother (<20 vs. 70 ng/ml). Injection with rhIGF-1/BP-3 resulted in increased plasma IGF-1 levels for up to 6 h after injection (>40 ng/mL). rhIGF-1/BP-3 treatment reduced the incidence of severe NEC lesions (7/24 vs.16/24, p = 0.01) and overall NEC severity (1.8 ± 0.2 vs. 2.6 ± 0.3, p < 0.05, with most lesions occurring in colon). In the small intestine, villi length (405 ± 25 vs. 345 ± 33 ?m) and activities of the brush border peptidases aminopeptidase N and dipeptidylpeptidase IV were increased in rhIGF-1/BP-3 treated pigs, relative to control pigs (+31-44%, both p < 0.05). The treatment had no effects on body weight, blood chemistry or hematology, except for an increase in blood leucocyte and neutrophil counts (p < 0.05, i.e., reduced neonatal neutropenia). Likewise, rhIGF-1/BP-3 treatment did not affect intestinal tissue cytokine levels (IL-1?, IL-6, IL-8, TNF?,), enterocyte proliferation, goblet cell density, permeability or bacterial translocation to the bone marrow. Conclusion: Supplemental rhIGF-1/BP-3 did not negatively affect any of the measured variables of clinical status or gut maturation in preterm pigs. Longer-term safety and efficacy of exogenous rhIGF-1/BP-3 to support maturation of the gut and other critical organs in preterm newborns remain to be investigated in both pigs and infants.

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Co-bedding of Preterm Newborn Pigs Reduces Necrotizing Enterocolitis Incidence Independent of Vital Functions and Cortisol Levels.

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