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Tu2007 Prenatal Microbial Exposure Induces Epigenetic Changes and Modulates TLR-Signaling Pathway Associated Gene Expression in the Immature Intestine
AGA Abstracts Figure: Immunohistochemical analysis of EGFR expression in esophageal biopsies obtained from children with eosinophilic esophagitis (A and B) showing diffuse full thickness staining, and from controls (C and D) showing faint basal staining.
Severely thickened, erythematous and exudative gastric folds diffusely throughout the entire stomach. Tu2007
Tu2006
Prenatal Microbial Exposure Induces Epigenetic Changes and Modulates TLRSignaling Pathway Associated Gene Expression in the Immature Intestine Lei Lu, Yueyue Yu, Yana Filipovich, Hirsch Emmet, Erika Claud
A Case of Phlegmonous Gastritis in a 10-Year Old Child With Newly Diagnosed Ulcerative Colitis Jonathan Cordova, Tiffany Patton, Ruba Azzam, Barbara S. Kirschner, Ranjana R. Gokhale
Background: Many disorders of preterm infants are inflammatory in nature including neonatal necrotizing enterocolitis (NEC). NEC affects approximately 10% of premature infants <1500gm and is associated with an increased inflammatory response of the immature enterocyte to both commensal and pathogenic bacteria. At least 40% of preterm births are associated with intrauterine infection. Intrauterine infection results in maternal/fetal inflammatory responses that are to a large extent dependent upon toll-like receptor (TLR)mediated innate immune responses. Studies have demonstrated that when TLRs recognize pathogens and respond to systemic infections, epigenetic alterations reprogram distinct functional sets of genes to both activate and repress transcription of hundreds of other genes. We hypothesis that intrauterine microbial exposure induces epigenetic changes in TLR signaling molecules thus modulating postnatal inflammatory responses in the immature small intestine. Methods: Heat killed E. coli or PBS was administered into the gestational compartment of pregnant CD1 mice on E14.5. The resulting viable pups at term or nearterm that survived the neonatal period were subjected to further analysis. 10-day-old pup ileum genomic DNA and total RNA were extracted and used in the analysis of both TLRsignaling pathway-focused profiling of DNA methylation status (22 genes) and gene expression levels (84 genes) by qRT-PCR. Results: Intrauterine exposure to heat-killed E. coli resulted in changes in the DNA-methylation profile of TLR-signaling genes in the mouse ileum. Using a TLR-signaling pathway DNA methylation PCR Array system, we detected differential DNA methylation of major TLR-signaling molecules including Tlr-2, Irak-1, 2, CD14, Hspa1a (HSP70), Hspd1, Il-6ra, Irf-1 and Irf-3 genes (n = 6 per group). We also observed down-regulation of mRNA expression levels of many genes associated with TLRsignaling. The downregulated genes (≤ -2 fold) were TLRs: Tlr1, Tlr4, Tlr6, Tlr7, Tlr8, Tlr9, and to a lesser degree Tlr2, 3 and 5; TLR signaling molecules: Cd14, Irak1, 2, Ticam1, Tradd; proinflammatory genes: Il-1, Il-12a, Ifnb1, Ifng, Tnf, Ccl2; and transcription factors: Nfkb2, Ppara, and other genes involved in immunomodulatory functions: Btk, Il6ra, Il-10, Il-2, Cd80, Ly86, Ube2v1, Csf2, Clec4e. Intrauterine infection induced upregulation of Csf3 and Fos genes (≥ 2). Conclusions: Together, these data suggest that antenatal intrauterine inflammation induces DNA methylation changes as well as a downregulation of mRNA expressions in TLR-related genes in the small intestines of offspring. These changes may result in a tolerance/inhibition of innate immune/inflammatory responses in the immature gut upon subsequent postnatal infectious/inflammatory challenge.
Introduction Phlegmonous gastritis is a life-threatening condition described as a rapidly progressive suppurative bacterial infection of the stomach that can lead to necrotizing or gangrenous gastritis. We report a case of acute phlegmonous gastritis in a child who was newly diagnosed with ulcerative colitis. Case Description A.M. is a 10 year old female with no significant past medical history who presented to our emergency department with a ten day history of bloody diarrhea, emesis and abdominal pain. Initial labs revealed an elevated WBC 15.9 x103/μL and hemoglobin 8.7 g/dL requiring a transfusion. Stool studies were negative with a fecal calprotectin >2500 μg/g feces. She became febrile and was started on ampicillin, gentamicin and metronidazole. On day 3 of admission she underwent an ileocolonoscopy that was consistent with ulcerative colitis. An EGD showe chronic, mildly active antral gastritis. Solumedrol was started at 1 mg/kg twice daily. She remained febrile with worsening abdominal pain and emesis and, on day 4 of admission, a CT of the abdomen/ pelvis showed pan-colitis without evidence of an intra-abdominal abscess. Over the following 10 days, she developed persistent bloody emesis, severe worsening abdominal pain, hypotension, anemia and new onset pancreatitis. An ongoing fever (despite antibiotics) and an elevated WBC 34 x103/μL with coagulopathy (INR 1.5) led to a repeat CT of the abdomen. CT results showed pancreatitis (without pseudocyst or necrosis) as well as severe, diffuse gastritis with thickened gastric folds and scattered hypoechoic foci within the gastric wall concerning for phlegmonous gastritis. As a result, antibiotics were broadened to include vancomycin and meropenem and steroids were decreased to 0.5 mg/kg twice daily to improve the eradication of the infection while continuing to induce remission of ulcerative colitis. On day 15 of admission, A.M. underwent a repeat EGD due to persistent anemia and ongoing upper GI bleeding that showed severe and diffuse exudative gastritis, deep ulcerations and clots of adherent blood. Histological findings including severe neutrophilic inflammation further support a diagnosis of phlegmonous gastritis. Sub-mucosal gastric biopsies were collected without an identifiable organism isolated. A.M.'s clinical status improved dramatically on broad spectrum antibiotics, over the following few days, with resolution of the upper GI bleed. A 1-month course of antibiotics was completed as treatment of phlegmonous gastritis. At this time, patient remains in clinical remission. Conclusion Phlegmonous gastritis is a rare bacterial infection of the stomach that has a high level of mortality and should be on the differential diagnosis for any patient who develops severe abdominal pain, hematemesis and fever, particularly while on immunosuppressive therapy.
Tu2008 Severity of Hepatic Fibrosis in Children With Biliary Atresia Using Non Invasive Markers vs Liver Biopsy Teena Sebastian, Parvathi Mohan Biliary atresia (BA) is an idiopathic neonatal obstructive cholangiopathy characterized by a progressive obliteration of the large bile ducts that presents uniquely in the first few months of life. It is the most common cholestatic liver disorder requiring a liver transplantation in infants and children. Hepatic fibrosis is a universal and prominent feature of BA even after a portoenterostomy. Therefore assessing the stage of fibrosis is an important tool to predict the course of biliary atresia. A liver biopsy is the gold standard for diagnosis but is associated with certain risks. Currently available non-invasive markers for fibrosis are not validated in children. Several authors, using routine laboratory data have constructed a simple model -AST (aspartate transaminase) to platelet ratio index (APRI)- to predict fibrosis in chronic viral hepatitis and in BA (1,2). Our aim was to examine the spectrum of hepatic histopathology in patients with BA at our institution from 2008 to 2013 and to examine laboratory markers as correlates of fibrosis specifically APRI vs. liver histology. Methods: A retrospective chart review study of 15 patients with BA who had initial liver biopsies at diagnosis was performed. Age at liver biopsy, laboratory data including serum AST, total Bilirubin (TB), platelet count, INR at the time of biopsy were correlated with histological changes, specifically stage of fibrosis. Results: The mean age at biopsy 61.9 ± 30 days (Mean ± SD). The histologic changes in 15 biopsies included portal fibrosis (stage 1, 2) in 9, bridging fibrosis (stage 3) in 4 and cirrhosis (stage 4) in 2. At biopsy AST ranged from 61- 405U /L (mean ± SD 208.5 ± 117), Platelet count 203-762 (109/L) (487 ± 167 x 109/L), Total bilirubin 4.9-12.6mg/dL (8.27 ± 2.34) and APRI 1.21 ± 0.74. Correlation of total bilirubin with APRI was not significant (Pearson correlation coefficient = 0.22) (p = 0.41); Correlation of APRI with biopsy staging was also not significant (r = 0.24 and p = 0.44.) 8 of the 15 patients underwent liver
Thickened gastric folds with a ragged appearance; hypoechoic foci within gastric wall
AGA Abstracts
S-958
Severely thickened, erythematous and exudative gastric folds diffusely throughout the entire stomach. Tu2007
Tu2006
Prenatal Microbial Exposure Induces Epigenetic Changes and Modulates TLRSignaling Pathway Associated Gene Expression in the Immature Intestine Lei Lu, Yueyue Yu, Yana Filipovich, Hirsch Emmet, Erika Claud
A Case of Phlegmonous Gastritis in a 10-Year Old Child With Newly Diagnosed Ulcerative Colitis Jonathan Cordova, Tiffany Patton, Ruba Azzam, Barbara S. Kirschner, Ranjana R. Gokhale
Background: Many disorders of preterm infants are inflammatory in nature including neonatal necrotizing enterocolitis (NEC). NEC affects approximately 10% of premature infants <1500gm and is associated with an increased inflammatory response of the immature enterocyte to both commensal and pathogenic bacteria. At least 40% of preterm births are associated with intrauterine infection. Intrauterine infection results in maternal/fetal inflammatory responses that are to a large extent dependent upon toll-like receptor (TLR)mediated innate immune responses. Studies have demonstrated that when TLRs recognize pathogens and respond to systemic infections, epigenetic alterations reprogram distinct functional sets of genes to both activate and repress transcription of hundreds of other genes. We hypothesis that intrauterine microbial exposure induces epigenetic changes in TLR signaling molecules thus modulating postnatal inflammatory responses in the immature small intestine. Methods: Heat killed E. coli or PBS was administered into the gestational compartment of pregnant CD1 mice on E14.5. The resulting viable pups at term or nearterm that survived the neonatal period were subjected to further analysis. 10-day-old pup ileum genomic DNA and total RNA were extracted and used in the analysis of both TLRsignaling pathway-focused profiling of DNA methylation status (22 genes) and gene expression levels (84 genes) by qRT-PCR. Results: Intrauterine exposure to heat-killed E. coli resulted in changes in the DNA-methylation profile of TLR-signaling genes in the mouse ileum. Using a TLR-signaling pathway DNA methylation PCR Array system, we detected differential DNA methylation of major TLR-signaling molecules including Tlr-2, Irak-1, 2, CD14, Hspa1a (HSP70), Hspd1, Il-6ra, Irf-1 and Irf-3 genes (n = 6 per group). We also observed down-regulation of mRNA expression levels of many genes associated with TLRsignaling. The downregulated genes (≤ -2 fold) were TLRs: Tlr1, Tlr4, Tlr6, Tlr7, Tlr8, Tlr9, and to a lesser degree Tlr2, 3 and 5; TLR signaling molecules: Cd14, Irak1, 2, Ticam1, Tradd; proinflammatory genes: Il-1, Il-12a, Ifnb1, Ifng, Tnf, Ccl2; and transcription factors: Nfkb2, Ppara, and other genes involved in immunomodulatory functions: Btk, Il6ra, Il-10, Il-2, Cd80, Ly86, Ube2v1, Csf2, Clec4e. Intrauterine infection induced upregulation of Csf3 and Fos genes (≥ 2). Conclusions: Together, these data suggest that antenatal intrauterine inflammation induces DNA methylation changes as well as a downregulation of mRNA expressions in TLR-related genes in the small intestines of offspring. These changes may result in a tolerance/inhibition of innate immune/inflammatory responses in the immature gut upon subsequent postnatal infectious/inflammatory challenge.
Introduction Phlegmonous gastritis is a life-threatening condition described as a rapidly progressive suppurative bacterial infection of the stomach that can lead to necrotizing or gangrenous gastritis. We report a case of acute phlegmonous gastritis in a child who was newly diagnosed with ulcerative colitis. Case Description A.M. is a 10 year old female with no significant past medical history who presented to our emergency department with a ten day history of bloody diarrhea, emesis and abdominal pain. Initial labs revealed an elevated WBC 15.9 x103/μL and hemoglobin 8.7 g/dL requiring a transfusion. Stool studies were negative with a fecal calprotectin >2500 μg/g feces. She became febrile and was started on ampicillin, gentamicin and metronidazole. On day 3 of admission she underwent an ileocolonoscopy that was consistent with ulcerative colitis. An EGD showe chronic, mildly active antral gastritis. Solumedrol was started at 1 mg/kg twice daily. She remained febrile with worsening abdominal pain and emesis and, on day 4 of admission, a CT of the abdomen/ pelvis showed pan-colitis without evidence of an intra-abdominal abscess. Over the following 10 days, she developed persistent bloody emesis, severe worsening abdominal pain, hypotension, anemia and new onset pancreatitis. An ongoing fever (despite antibiotics) and an elevated WBC 34 x103/μL with coagulopathy (INR 1.5) led to a repeat CT of the abdomen. CT results showed pancreatitis (without pseudocyst or necrosis) as well as severe, diffuse gastritis with thickened gastric folds and scattered hypoechoic foci within the gastric wall concerning for phlegmonous gastritis. As a result, antibiotics were broadened to include vancomycin and meropenem and steroids were decreased to 0.5 mg/kg twice daily to improve the eradication of the infection while continuing to induce remission of ulcerative colitis. On day 15 of admission, A.M. underwent a repeat EGD due to persistent anemia and ongoing upper GI bleeding that showed severe and diffuse exudative gastritis, deep ulcerations and clots of adherent blood. Histological findings including severe neutrophilic inflammation further support a diagnosis of phlegmonous gastritis. Sub-mucosal gastric biopsies were collected without an identifiable organism isolated. A.M.'s clinical status improved dramatically on broad spectrum antibiotics, over the following few days, with resolution of the upper GI bleed. A 1-month course of antibiotics was completed as treatment of phlegmonous gastritis. At this time, patient remains in clinical remission. Conclusion Phlegmonous gastritis is a rare bacterial infection of the stomach that has a high level of mortality and should be on the differential diagnosis for any patient who develops severe abdominal pain, hematemesis and fever, particularly while on immunosuppressive therapy.
Tu2008 Severity of Hepatic Fibrosis in Children With Biliary Atresia Using Non Invasive Markers vs Liver Biopsy Teena Sebastian, Parvathi Mohan Biliary atresia (BA) is an idiopathic neonatal obstructive cholangiopathy characterized by a progressive obliteration of the large bile ducts that presents uniquely in the first few months of life. It is the most common cholestatic liver disorder requiring a liver transplantation in infants and children. Hepatic fibrosis is a universal and prominent feature of BA even after a portoenterostomy. Therefore assessing the stage of fibrosis is an important tool to predict the course of biliary atresia. A liver biopsy is the gold standard for diagnosis but is associated with certain risks. Currently available non-invasive markers for fibrosis are not validated in children. Several authors, using routine laboratory data have constructed a simple model -AST (aspartate transaminase) to platelet ratio index (APRI)- to predict fibrosis in chronic viral hepatitis and in BA (1,2). Our aim was to examine the spectrum of hepatic histopathology in patients with BA at our institution from 2008 to 2013 and to examine laboratory markers as correlates of fibrosis specifically APRI vs. liver histology. Methods: A retrospective chart review study of 15 patients with BA who had initial liver biopsies at diagnosis was performed. Age at liver biopsy, laboratory data including serum AST, total Bilirubin (TB), platelet count, INR at the time of biopsy were correlated with histological changes, specifically stage of fibrosis. Results: The mean age at biopsy 61.9 ± 30 days (Mean ± SD). The histologic changes in 15 biopsies included portal fibrosis (stage 1, 2) in 9, bridging fibrosis (stage 3) in 4 and cirrhosis (stage 4) in 2. At biopsy AST ranged from 61- 405U /L (mean ± SD 208.5 ± 117), Platelet count 203-762 (109/L) (487 ± 167 x 109/L), Total bilirubin 4.9-12.6mg/dL (8.27 ± 2.34) and APRI 1.21 ± 0.74. Correlation of total bilirubin with APRI was not significant (Pearson correlation coefficient = 0.22) (p = 0.41); Correlation of APRI with biopsy staging was also not significant (r = 0.24 and p = 0.44.) 8 of the 15 patients underwent liver
Thickened gastric folds with a ragged appearance; hypoechoic foci within gastric wall
AGA Abstracts
S-958