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Maltodextrin-induced intestinal injury in a neonatal mouse model.

ABSTRACT: Prematurity and enteral feedings are major risk factors for intestinal injury leading to necrotizing enterocolitis (NEC). An immature digestive system can lead to maldigestion of macronutrients and increased vulnerability to intestinal injury. The aim of this study was to test in neonatal mice the effect of maltodextrin, a complex carbohydrate, on the risk of intestinal injury. The goal was to develop a robust and highly reproducible murine model of intestinal injury that allows insight into the pathogenesis and therapeutic interventions of nutrient-driven intestinal injury. Five- to 6-day-old C57BL/6 mice were assigned to the following groups: dam fed (D); D+hypoxia+Klebsiella pneumoniae; maltodextrin-dominant human infant formula (M) only; M+hypoxia; and M+hypoxia+K. pneumoniae. The mice in all M groups were gavage fed five times a day for 4?days. Mice were exposed to hypoxia twice a day for 10?min prior to the first and last feedings, and K. pneumoniae was added to feedings as per group assignment. Mice in all M groups demonstrated reduced body weight, increased small intestinal dilatation and increased intestinal injury scores. Maltodextrin-dominant infant formula with hypoxia led to intestinal injury in neonatal mice accompanied by loss of villi, increased MUC2 production, altered expression of tight junction proteins, enhanced intestinal permeability, increased cell death and higher levels of intestinal inflammatory mediators. This robust and highly reproducible model allows for further interrogation of the effects of nutrients on pathogenic factors leading to intestinal injury and NEC in preterm infants.This article has an associated First Person interview with the first author of the paper.

SUBMITTER: Singh P

PROVIDER: S-EPMC7473650 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Maltodextrin-induced intestinal injury in a neonatal mouse model.

Singh Pratibha P Sanchez-Fernandez Lady Leidy LL Ramiro-Cortijo David D Ochoa-Allemant Pedro P Perides George G Liu Yan Y Medina-Morales Esli E Yakah William W Freedman Steven D SD Martin Camilia R CR

Disease models & mechanisms 20200827 8

Prematurity and enteral feedings are major risk factors for intestinal injury leading to necrotizing enterocolitis (NEC). An immature digestive system can lead to maldigestion of macronutrients and increased vulnerability to intestinal injury. The aim of this study was to test in neonatal mice the effect of maltodextrin, a complex carbohydrate, on the risk of intestinal injury. The goal was to develop a robust and highly reproducible murine model of intestinal injury that allows insight into the ...[more]

PMID: 32753526

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Project description:BackgroundNeonatal hypoxic-ischemic brain injury (HIBI) results in significant morbidity and mortality despite current standard therapies. MicroRNAs (miRNAs) are a promising therapeutic target; however, there is a paucity of data on endogenous miRNA expression of the brain after HIBI during the primary therapeutic window (6-72 h after injury).MethodsPostnatal day 9 mouse pups underwent unilateral carotid ligation+hypoxia (HIBI), sham surgery+hypoxia, or sham surgery+normoxia (controls). miRNA sequencing was performed on the ipsilateral brain of each of the three groups plus the contralateral HIBI brain at 24 and 72 h after injury. Findings were validated in eight key miRNAs by quantitative polymerase chain reaction.ResultsHypoxia resulted in significant differential expression of 38 miRNAs at both time points. Mir-2137, -335, -137, and -376c were significantly altered by neonatal HIBI at 24 and 72 h, with 3 of the 4 demonstrating multiphasic expression (different direction of differential expression at 24 versus 72 h).ConclusionsOur global assessment of subacute changes in brain miRNA expression after hypoxia or HIBI will advance research into targeted miRNA-based interventions. It will be important to consider the multiphasic miRNA expression patterns after HIBI to identify optimal timing for individual interventions.ImpactThis study is the first to comprehensively define endogenous brain microRNA expression changes outside of the first hours after neonatal hypoxic-ischemic brain injury (HIBI). Mir-2137, -335, -137, and -376c were significantly altered by neonatal HIBI and therefore deserve further investigation as possible therapeutic targets. The expression profiles described will support the design of future studies attempting to develop miRNA-based interventions for infants with HIBI. At 24 h after injury, contralateral HIBI miRNA expression patterns were more similar to ipsilateral HIBI than to controls, suggesting that the contralateral brain is not an appropriate "internal control" for miRNA studies in this model.

Project description:Cerebellum is involved in higher cognitive functions and plays important roles in neurological disorders. Cerebellar injury has been detected frequently in patients with preterm birth resulting in cognitive dysfunction later in life. Maternal infection and inflammation is associated with preterm birth and in neonatal brain injury. We have previously shown that intrauterine lipopolysaccharide (LPS) exposure induces white matter injury and microglial activation in the cerebral white matter tracts of neonatal rabbits, resulting in motor deficits consistent with the clinical findings of cerebral palsy (CP). Here we investigated whether intrauterine LPS exposure induced cerebellar inflammation and functional impairment. Timed-pregnant New Zealand white rabbits underwent a laparotomy on gestational day 28 (G28) and LPS (3200 EU, endotoxin group) was injected along the wall of the uterus as previously described. Controls did not receive surgical intervention. Kits born to control and endotoxin treated dams were euthanized on postnatal day (PND)1 (3 days post-injury) or PND5 (7 days post-injury) and cerebellum evaluated for presence of inflammation. The microglial morphology in cerebellar white matter areas was analyzed using Neurolucida and Neurolucida Explorer. mRNA expression of inflammatory cytokines was quantified by real-time-PCR. We found that intrauterine exposure to LPS induced intensive microglial activation in cerebellar white matter areas, as evidenced by increased numbers of activated microglia and morphological changes (amoeboid soma and retracted processes) that was accompanied by significant increases in pro-inflammatory cytokines. The Purkinje cell layer was less developed in endotoxin exposed kits than healthy controls. In kits that survived to PND 60, soma size and cell density of Purkinje cells were significantly decreased in endotoxin exposed kits compared to controls. The findings of altered Purkinje cell morphology were consistent with impaired cerebellar function as tested by eye-blink conditioning at 1 month of age. The results indicate that the cerebellum is vulnerable to perinatal insults and that therapies targeting cerebellar inflammation and injury may help in improving outcomes and function.

Project description:Despite limited regeneration capacity, partial injuries to the adult mammalian spinal cord can elicit variable degrees of functional recovery, mediated at least in part by reorganization of neuronal circuitry. Underlying mechanisms are believed to include synaptic plasticity and collateral sprouting of spared axons. Because plasticity is higher in young animals, we developed a spinal cord compression (SCC) injury model in the neonatal mouse to gain insight into the potential for reorganization during early life. The model provides a platform for high-throughput assessment of functional synaptic connectivity that is also suitable for testing the functional integration of human stem and progenitor cell-derived neurons being considered for clinical cell replacement strategies. SCC was generated at T9-T11 and functional recovery was assessed using an integrated approach including video kinematics, histology, tract tracing, electrophysiology, and high-throughput optical recording of descending inputs to identified spinal neurons. Dramatic degeneration of axons and synaptic contacts was evident within 24 hours of SCC, and loss of neurons in the injured segment was evident for at least a month thereafter. Initial hindlimb paralysis was paralleled by a loss of descending inputs to lumbar motoneurons. Within 4 days of SCC and progressively thereafter, hindlimb motility began to be restored and descending inputs reappeared, but with examples of atypical synaptic connections indicating a reorganization of circuitry. One to two weeks after SCC, hindlimb motility approached sham control levels, and weight-bearing locomotion was virtually indistinguishable in SCC and sham control mice. Genetically labeled human fetal neural progenitor cells injected into the injured spinal cord survived for at least a month, integrated into the host tissue and began to differentiate morphologically. This integrative neonatal mouse model provides opportunities to explore early adaptive plasticity mechanisms underlying functional recovery as well as the capacity for human stem cell-derived neurons to integrate functionally into spinal circuits.

Dataset Information

Maltodextrin-induced intestinal injury in a neonatal mouse model.

Publications

Maltodextrin-induced intestinal injury in a neonatal mouse model.

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