Genome-wide Expression Profiles of Necrotizing Enterocolitis Versus Spontaneous Intestinal Perforation in Human Intestinal Tissues

Chan, Kathy Yuen Yee; Leung, Kam Tong; Tam, Yuk Him; Lam, Hugh Simon; Cheung, Hon Ming; Yuen, Terence Ping; Lee, Kim Hung; To, Ka Fai; Li, Karen; Ng, Pak Cheung

doi:10.1097/sla.0000000000000374

Cited by 67 publications

(63 citation statements)

References 42 publications

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“…Prevention of NEC with oral antibiotics downregulates CXCL8 and TLR2 (7- to 10-fold) [20], but TLR2 failed to be differentially regulated in this study. Upregulation of immune-related genes, including IL1B , IL6 , and CXCL8 , has also been observed in resected intestinal tissues from NEC patients [21]. Among the genes involved in the TLR4 complex and NFκB signaling pathways, we observed upregulation of CD14 (coreceptor for LPS recognition), IL10 , NFKBIA , and TNFAIP3 (NFκB inhibition factors).…”

Section: Discussionmentioning

confidence: 58%

“…In preterm pigs, NEC progression appears less dependent on TLR4 and NFκB signaling pathways [3,10,12], compared to rodents, where marked changes occur after NEC induction [22,23]. In infant NEC tissues, a moderate upregulation of CD14 (5-fold) and a slight upregulation of TLR4 (1.8-fold) have been observed [21]. Upregulation of IL1B in pigs with severe NEC was accompanied by an increased IL-1β level.…”

Section: Discussionmentioning

confidence: 99%

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Increased Intestinal Inflammation and Digestive Dysfunction in Preterm Pigs with Severe Necrotizing Enterocolitis

Støy

Heegaard²,

Skovgaard³

et al. 2016

Neonatology

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Background: The risk factors for necrotizing enterocolitis (NEC) are well known, but the factors involved in the different NEC presentations remain unclear. Objectives: We hypothesized that digestive dysfunction and intestinal inflammation are mainly affected by severe NEC lesions. Methods: In 48 preterm pigs, the association between the macroscopic NEC score (range 1-6) and the expression of 48 genes related to inflammation, morphological, and digestive parameters in the distal small intestine was investigated. Results: Only severe NEC cases (score of 5-6) were associated with the upregulation of genes involved in inflammation (CCL2, CCL3, CD14, CD163, CXCL8, HP, IL1B, IL1RN, IL6,IL10, NFKBIA, PTGS2 and TNFAIP3) compared to pigs that appeared healthy (score of 1-2) or showed mild NEC (score of 3-4). Pigs with a score of 5-6 had higher intestinal tissue IL-1β levels and a lower mucosal mass, villus height, and aminopeptidase N activity compared to pigs with a score of 1-4, and lower crypts and activities of lactase, dipeptidylpeptidase IV, and aminopeptidase A than pigs with a score of 1-2. Conclusions: The expression of a range of inflammation-related genes was increased only in pigs with severe NEC, concomitant with morphological changes and decreased hydrolase activity. A severe inflammatory response and digestive dysfunction are associated mainly with severe NEC. Still, it remains difficult to separate the initial causes of NEC and the later intestinal consequences of NEC in both infants and experimental models.

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Section: Discussionmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Increased Intestinal Inflammation and Digestive Dysfunction in Preterm Pigs with Severe Necrotizing Enterocolitis

Støy

Heegaard²,

Skovgaard³

et al. 2016

Neonatology

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“…Differentiation between the two entities is of critical importance for disease categorization in clinical studies, and may contribute to the reproducibility and clinical translatability issues that have persisted. Ng, et al, used genomics to differentiate the two entities, reporting both differentially expressed mRNA as well as micro-RNAs in the small bowel tissue of NEC and SIP compared with surgical control tissue (79, 80). Shah et al used a more clinically applicable serum biomarker to distinguish NEC from SIP, called inter-alpha inhibitor proteins (IaIps) (81).…”

Section: Biomarkers: Disease Discriminationmentioning

confidence: 99%

The Microbiome and Biomarkers for Necrotizing Enterocolitis: Are We Any Closer to Prediction?

Rusconi

Good

Warner

2017

The Journal of Pediatrics

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“…NEC patient microarray CEL files (GSE46619) were obtained from a previous study in which whole-genome microarray expression profiling was performed on bowel tissue from neonates diagnosed with NEC and surgical controls (Chan et al, 2014). We processed the CEL files using R Bioconductor with gcrma normalization (Wu et al, 2004) and the limma package (Smyth, 2004).…”

Section: Informatics Analysismentioning

confidence: 99%

“…We analyzed expression data from NEC patients compared with surgical control patients (Chan et al, 2014) using Gene Set Enrichment Analysis (GSEA). A strong correlation was observed between genes downregulated in NEC patients and genes downregulated upon YY1 loss (Fig.…”

Section: Yy1 Loss Leads To Mitochondrial Dysfunctionmentioning

confidence: 99%

A YY1-dependent increase in aerobic metabolism is indispensable for intestinal organogenesis

et al. 2016

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During late gestation, villi extend into the intestinal lumen to dramatically increase the surface area of the intestinal epithelium, preparing the gut for the neonatal diet. Incomplete development of the intestine is the most common gastrointestinal complication in neonates, but the causes are unclear. We provide evidence in mice that Yin Yang 1 (Yy1) is crucial for intestinal villus development. YY1 loss in the developing endoderm had no apparent consequences until late gestation, after which the intestine differentiated poorly and exhibited severely stunted villi. Transcriptome analysis revealed that YY1 is required for mitochondrial gene expression, and ultrastructural analysis confirmed compromised mitochondrial integrity in the mutant intestine. We found increased oxidative phosphorylation gene expression at the onset of villus elongation, suggesting that aerobic respiration might function as a regulator of villus growth. Mitochondrial inhibitors blocked villus growth in a fashion similar to Yy1 loss, thus further linking oxidative phosphorylation with late-gestation intestinal development. Interestingly, we find that necrotizing enterocolitis patients also exhibit decreased expression of oxidative phosphorylation genes. Our study highlights the still unappreciated role of metabolic regulation during organogenesis, and suggests that it might contribute to neonatal gastrointestinal disorders.

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Genome-wide Expression Profiles of Necrotizing Enterocolitis Versus Spontaneous Intestinal Perforation in Human Intestinal Tissues

Cited by 67 publications

References 42 publications

Increased Intestinal Inflammation and Digestive Dysfunction in Preterm Pigs with Severe Necrotizing Enterocolitis

Increased Intestinal Inflammation and Digestive Dysfunction in Preterm Pigs with Severe Necrotizing Enterocolitis

The Microbiome and Biomarkers for Necrotizing Enterocolitis: Are We Any Closer to Prediction?

A YY1-dependent increase in aerobic metabolism is indispensable for intestinal organogenesis

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