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Increases in adhesive and invasive commensal bacteria, such as Escherichia coli, and subsequent disruption of the epithelial barrier is implicated in the pathogenesis of inflammatory bowel disease (IBD). However, the protective systems against such barrier disruption are not fully understood. Here, we show that secretion of luminal glycoprotein 2 (GP2) from pancreatic acinar cells is induced in a TNF-dependent manner in mice with chemically induced colitis. Fecal GP2 concentration is also increased in Crohn's diease patients. Furthermore, pancreas-specific GP2-deficient colitis mice have more severe intestinal inflammation and a larger mucosal E. coli population than do intact mice, indicating that digestive-tract GP2 binds commensal E. coli, preventing epithelial attachment and penetration. Thus, the pancreas-intestinal barrier axis and pancreatic GP2 are important as a first line of defense against adhesive and invasive commensal bacteria during intestinal inflammation.

Transforming growth factor-β-activated kinase 1 (TAK1) plays a pivotal role in innate and adaptive immunity. TAK1 is essential for the activation of mitogen-activated protein kinases (MAPKs) and nuclear factor (NF)-κB pathways downstream of diverse immune receptors, including toll-like receptors (TLRs). Upon stimulation with TLR ligands, TAK1 is activated via recruitment to the lysine 63-linked polyubiquitin chain through TAK1-binding protein 2 (TAB2) and TAB3. However, the physiological importance of TAB2 and TAB3 in macrophages is still controversial. A previous study has shown that mouse bone marrow-derived macrophages (BMDMs) isolated from mice double deficient for TAB2 and TAB3 produced tumor necrosis factor (TNF)-α and interleukin (IL)-6 to the similar levels as control wild-type BMDMs in response to TLR ligands such as lipopolysaccharide (LPS) or Pam3CSK4, indicating that TAB2 and TAB3 are dispensable for TLR signaling. In this study, we revisited the role of TAB2 and TAB3 using an improved mouse model. We observed a significant impairment in the production of pro-inflammatory cytokines and chemokine in LPS- or Pam3CSK4-treated BMDMs deficient for both TAB2 and TAB3. Double deficiency of TAB2 and TAB3 resulted in the decreased activation of NF-κB and MAPK pathways as well as the slight decrease in TAK1 activation in response to LPS or Pam3CSK4. Notably, the TLR-mediated expression of inhibitor of NF-κB (IκB)ζ was severely compromised at the protein and messenger RNA (mRNA) levels in the TAB2/TAB3 double-deficient BMDMs, thereby impeding IL-6 production. Our results suggest that TAB2 and TAB3 play a redundant and indispensable role in the TLR signaling pathway. [ABSTRACT FROM AUTHOR]

Purpose: Colistin is classified by the World Health Organization (WHO) as a critically important and last-resort antibiotic for the treatment of infections caused by carbapenem-resistant bacteria. However, colistin resistance mediated by chromosomal mutations or plasmid-linked mobilized colistin resistance (mcr) genes has emerged. Methods: Thirteen mcr-positive Aeromonas species isolated from water samples collected in Eastern Ghana were analyzed using whole-genome sequencing (WGS). Antimicrobial susceptibility was tested using the broth microdilution method. Resistome analysis was performed in silico using a web-based platform. Results: The minimum inhibitory concentration (MIC) of colistin for all except three isolates was > 4 μg/mL. Nine new sequence types were identified and whole-genome analysis revealed that the isolates harbored genes (mcr-3-related genes) that code for Lipid A phosphoethanolamine transferases on their chromosomes. BLAST analysis indicated that the amino acid sequences of the mcr-3-related genes detected varied from those previously reported and shared 79.04– 99.86% nucleotide sequence identity with publicly available mcr-3 variants and mcr-3-related phosphoethanolamine transferases. Analysis of the genetic context of mcr-3-related genes revealed that the genetic environment surrounding mcr-3-related genes was diverse among the different species of Aeromonas but conserved among isolates of the same species. Mcr-3-related-gene-IS-mcr-3-related-gene segment was identified in three Aeromonas caviae strains. Conclusion: The presence of mcr-3-related genes close to insertion elements is important for continuous monitoring to better understand how to control the mobilization and dissemination of antibiotic resistance genes. [ABSTRACT FROM AUTHOR]

Introduction: The effects of hydrocortisone (HDC) administration to extremely low birth weight (ELBW) infants on later development remain unclear. This study examined the association between HDC dosage during neonatal period and neurodevelopmental outcomes in ELBW infants. Methods: This study was a retrospective cohort study conducted in eight centers in Japan. The subjects of this study were ELBW infants born between April 2015 and March 2017. The association between postnatal total HDC dosage up to 36 weeks postmenstrual age and the developmental quotient (DQ) at 3 years of age was examined. Multiple linear regression evaluated the association, adjusting for weeks of gestation, birth weight, and the presence of bronchopulmonary dysplasia, late-onset circulatory collapse, intracranial hemorrhage, necrotizing enterocolitis, and sepsis. Results: This study included 218 ELBW infants, of whom 144 underwent a developmental test at 3 years of age. Simple linear regression analysis revealed a significant association between total HDC dosage and DQ at 3 years of age (coefficients: −2.65, 95% CI: −3.73, −1.57). Multiple linear regression analysis adjusted for the presence of bronchopulmonary dysplasia and late-onset circulatory collapse also revealed a significant association between total HDC dosage and DQ at 3 years of age (coefficients: −2.66, 95% CI: −3.89, −1.42). Conclusion: Higher total HDC dosage up to 36 weeks postmenstrual age in ELBW infants was associated with impaired neurodevelopmental outcomes. Although HDC is often needed in the treatment of ELBW infants, clinicians should be aware that an increased dose of HDC may be associated with impaired neurodevelopmental outcomes. [ABSTRACT FROM AUTHOR]

Rotavirus (RVA) is a leading cause of childhood gastroenteritis. RVA vaccines have reduced the global disease burden; however, the emergence of intergenogroup reassortant strains is a growing concern. During surveillance in Ghana, we observed the emergence of G9P[4] RVA strains in the fourth year after RVA vaccine introduction. To investigate whether Ghanaian G9P[4] strains also exhibited the DS-1-like backbone, as seen in reassortant G1/G3/G8/G9 strains found in other countries in recent years, this study determined the whole genome sequences of fifteen G9P[4] and two G2P[4] RVA strains detected during 2015–2016. The results reveal that the Ghanaian G9P[4] strains exhibited a double-reassortant genotype, with G9-VP7 and E6-NSP4 genes on a DS-1-like backbone (G9-P[4]-I2-R2-C2-M2-A2-N2-T2-E6-H2). Although they shared a common ancestor with G9P[4] DS-1-like strains from other countries, further intra-reassortment events were observed among the original G9P[4] and co-circulating strains in Ghana. In the post-vaccine era, there were significant changes in the distribution of RVA genotype constellations, with unique strains emerging, indicating an impact beyond natural cyclical fluctuations. However, reassortant strains may exhibit instability and have a limited duration of appearance. Current vaccines have shown efficacy against DS-1-like strains; however, ongoing surveillance in fully vaccinated children is crucial for addressing concerns about long-term effectiveness. [ABSTRACT FROM AUTHOR]