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Williamson CG, Rook JM, Curry J, Gollin G, Benharash P, Wagner JP. Necrotizing enterocolitis vs bowel ischemia of congenital heart disease: Apples and oranges. Am J Surg 2025; 242:116201. [PMID: 39854928 DOI: 10.1016/j.amjsurg.2025.116201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 12/16/2024] [Accepted: 01/13/2025] [Indexed: 01/27/2025]
Abstract
Necrotizing enterocolitis (NEC) is a devastating illness with mortality rates approaching 26 %, with 4 % of patients with congenital heart disease (CHD) receiving this diagnosis. In this retrospective cohort study, the Pediatric Health Information System database was used to compare outcomes among patients with NEC diagnoses between 2019 and 2021 by CHD. The association of clinical factors with the outcomes of interest were compared using multivariable logistic regression. Of 2415 pediatric patients diagnosed with NEC, 955 (39.5 %) had a diagnosis of CHD. Those with CHD were more frequently White and born at a later gestational age. Antibiotic courses were similar; however, CHD patients had lower rates of post-antibiotic operations (18.0 % vs 32.1 %, p < 0.001) and in-hospital mortality (11.1 % vs 15.5 %, p = 0.001). On adjusted analysis, patients without CHD were twice as likely to undergo an abdominal operation. Compared with patients without CHD, those with CHD had decreased rates of antibiotic failure for NEC diagnosis despite similar treatment courses. Distinct outcomes of bowel ischemia among infants with CHD warrant further study of treatment strategies that may differ from those of classical NEC. TYPE OF STUDY: Retrospective Cohort Study. LEVEL OF EVIDENCE: III.
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Affiliation(s)
- Catherine G Williamson
- David Geffen School of Medicine, University of California, Los Angeles, CA, USA; Massachusetts General Hospital, Boston, MA, USA
| | - Jordan M Rook
- David Geffen School of Medicine, University of California, Los Angeles, CA, USA; Geater Los Angeles Veterans Administration Healthcare System, Los Angeles CA, USA; Fielding School of Public Health, University of California, Los Angeles, CA, USA
| | - Joanna Curry
- David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Gerald Gollin
- Rady Children's Hospital, University of California, San Diego, CA, USA
| | - Peyman Benharash
- David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Justin P Wagner
- David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
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2
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DeVeaux AL, Hall-Moore C, Shaikh N, Wallace M, Burnham CAD, Schnadower D, Kuppermann N, Mahajan P, Ramilo O, Tarr PI, Dantas G, Schwartz DJ. Metagenomic signatures of extraintestinal bacterial infection in the febrile term infant gut microbiome. MICROBIOME 2025; 13:82. [PMID: 40128855 PMCID: PMC11931804 DOI: 10.1186/s40168-025-02079-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/25/2024] [Accepted: 03/04/2025] [Indexed: 03/26/2025]
Abstract
BACKGROUND Extraintestinal bacterial infections (EBIs), e.g., urinary tract infection, bacteremia, and meningitis, occur in approximately 10% of febrile infants younger than 60 days. Although many EBI-causing species commonly reside in the infant gut, proof that the digestive system is a pre-infection habitat remains unestablished. RESULTS We studied a cohort of febrile term infants < 60 days old who presented to one of thirteen US emergency departments in the Pediatric Emergency Care Applied Research Network from 2016 to 2019. Forty EBI cases and 74 febrile controls matched for age, sex, and race without documented EBIs were selected for analysis. Shotgun sequencing was performed of the gut microbiome and of strains cultured from the gut and extraintestinal site(s) of EBI cases, including blood, urine, and/or cerebrospinal fluid. Using a combination of EBI isolate genomics and fecal metagenomics, we detected an intestinal strain presumptively isogenic to the EBI pathogen (> 99.999% average nucleotide identity) in 63% of infants with EBIs. Although there was no difference in gut microbiome diversity between cases and controls, we observed significantly increased Escherichia coli relative abundance in the gut microbiome of infants with EBIs caused by E. coli. Infants with E. coli infections who were colonized by the putatively isogenic pathogen strain had significantly higher E. coli phylogroup B2 abundance in their gut, and their microbiome was more likely to contain virulence factor loci associated with adherence, exotoxin production, and nutritional/metabolic function. CONCLUSIONS The intestine plausibly serves as a reservoir for EBI pathogens in a subset of febrile term infants, prompting consideration of new opportunities for surveillance and EBI prevention among colonized, pre-symptomatic infants. Video Abstract.
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Affiliation(s)
- Anna L DeVeaux
- The Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO, USA
| | - Carla Hall-Moore
- Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA
| | - Nurmohammad Shaikh
- Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA
| | - Meghan Wallace
- Department of Pathology and Immunology, Division of Laboratory and Genomic Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Carey-Ann D Burnham
- Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA
- Department of Pathology and Immunology, Division of Laboratory and Genomic Medicine, Washington University School of Medicine, St. Louis, MO, USA
- Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, USA
| | - David Schnadower
- Division of Emergency Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Nathan Kuppermann
- Departments of Pediatrics and Emergency Medicine, The George Washington School of Medicine and Health Sciences, and Children'S National Hospital, Washington, DC, USA
| | - Prashant Mahajan
- Departments of Emergency Medicine and Pediatrics, University of Michigan, Ann Arbor, MI, USA
| | - Octavio Ramilo
- Department of Infectious Diseases, St. Jude Children'S Research Hospital, Memphis, TN, USA
| | - Phillip I Tarr
- Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA
- Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, USA
| | - Gautam Dantas
- The Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO, USA
- Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA
- Department of Pathology and Immunology, Division of Laboratory and Genomic Medicine, Washington University School of Medicine, St. Louis, MO, USA
- Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, USA
- Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, USA
| | - Drew J Schwartz
- Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA.
- Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, USA.
- Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO, USA.
- Center for Women's Infectious Disease Research, Washington University School of Medicine, St. Louis, MO, USA.
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Lee P, Sin E, Yip KT, Ng K. A 10-Year Study of Neonatal Sepsis from Tuen Mun Hospital, Hong Kong. Pathogens 2025; 14:276. [PMID: 40137761 PMCID: PMC11945203 DOI: 10.3390/pathogens14030276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2025] [Revised: 03/09/2025] [Accepted: 03/10/2025] [Indexed: 03/29/2025] Open
Abstract
BACKGROUND Neonatal sepsis is a major cause of infant mortality, and it accounts for a significant consumption of antimicrobials in paediatrics. This is the first comprehensive study on neonatal sepsis in Hong Kong. METHODS From 2014 to 2023, all neonates admitted to a single institution with culture-proven infections from the blood and/or cerebrospinal fluid were selected and reviewed retrospectively. The infecting organisms, their antibiotic nonsusceptibility pattern, and the concordance of empirical antimicrobial therapy with the microbiological profiles were described and were further compared between infants of normal/low birth weight (≥1.5 kg) and very low/extremely low birth weight (<1.5 kg), early-onset sepsis (<72 h), and late-onset sepsis (4-28 days), the first and the second 5-year periods (2014-2018 vs. 2019-2023). RESULTS After contaminants were excluded, there were 118 affected neonates with 125 organisms identified. Fifty-nine were male. Thirty-four were very low/extremely low birth weight infants, and twenty-eight infants had early-onset sepsis. Patient demographics and the microbiology findings did not differ between the first 5 years and the latter 5 years. However, the incidence of neonatal sepsis was significantly lower in the latter 5 years (3.23 vs. 1.61 per 1000 live births, p < 0.001), the period that coincided with the COVID-19 pandemic. Escherichia coli was the most common Gram-negative pathogen. Streptococcus agalactiae and Streptococcus bovis group infections were more common in early-onset sepsis, while coagulase-negative Staphylococcus and non-E. coli Gram-negative pathogens were more likely to occur in late-onset sepsis. In very low/extremely low birth weight infants, the rate of cefotaxime or ceftriaxone nonsusceptibility among Gram-negative isolates was higher (p = 0.01), and concordance of empirical antimicrobial therapy was lower (p = 0.006). CONCLUSIONS Management of neonatal sepsis remains challenging, and there is a need for optimising antimicrobial therapy, especially in preterm patients. Antepartum screening with intrapartum antibiotic prophylaxis is effective in reducing the risk of early-onset sepsis associated with S. agalactiae, while stringent infection control measures are important for the prevention of late-onset sepsis.
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Affiliation(s)
- Pascoe Lee
- Department of Clinical Pathology, Tuen Mun Hospital, Hospital Authority, Hong Kong, China
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McGann C, Phyu R, Bittinger K, Mukhopadhyay S. Role of the Microbiome in Neonatal Infection: Pathogenesis and Implications for Management. Clin Perinatol 2025; 52:147-166. [PMID: 39892949 DOI: 10.1016/j.clp.2024.10.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2025]
Abstract
The human microbiome refers to the collective genome of microorganisms, including bacteria, fungi, and viruses residing on human body surfaces that are in contact with the environment. Together these communities protect against invasive infections. Conversely, when disrupted, the microbiome can be the source of pathogens causing invasive infection. Interventions to manipulate it via probiotics, antibiotics, and fecal transplantation are available. The risk benefit of these interventions remains unclear. In this review, the authors discuss evidence linking the gut microbiome to neonatal sepsis and also discuss the challenges for translating this knowledge into better clinical care.
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Affiliation(s)
- Carolyn McGann
- Division of Neonatology, Department of Pediatrics, Children's Hospital of Philadelphia, 3401 Civic Center Boulevard, Philadelphia, PA 19104, USA; Perelman School of Medicine, University of Pennsylvania, 3401 Civic Center Boulevard, Philadelphia, PA 19104, USA
| | - Riley Phyu
- Department of Clinical Education and Assessment Center, Rown-Virtua School of Osteopathic Medicine, Rowan University, 1 Medical Center Drive Stratford, NJ 08084, USA
| | - Kyle Bittinger
- Perelman School of Medicine, University of Pennsylvania, 3401 Civic Center Boulevard, Philadelphia, PA 19104, USA; Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children's Hospital of Philadelphia, 3401 Civic Center Boulevard, Philadelphia, PA 19104, USA
| | - Sagori Mukhopadhyay
- Division of Neonatology, Department of Pediatrics, Children's Hospital of Philadelphia, 3401 Civic Center Boulevard, Philadelphia, PA 19104, USA; Perelman School of Medicine, University of Pennsylvania, 3401 Civic Center Boulevard, Philadelphia, PA 19104, USA.
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Nordsten MJB, Winther CL, Haugaard MM, Skovgaard K, Thymann T, Sangild PT. Enteral plasma feeding improves gut function and immunity in piglets after birth asphyxia. Pediatr Res 2025; 97:774-784. [PMID: 39034356 PMCID: PMC12014487 DOI: 10.1038/s41390-024-03376-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Revised: 05/17/2024] [Accepted: 06/17/2024] [Indexed: 07/23/2024]
Abstract
INTRODUCTION Birth asphyxia may negatively affect gut function and immunity in newborns. Conversely, immunomodulatory milk diets may protect the gut and immune system against damage caused by asphyxia. Using caesarean-derived pigs as models, we hypothesised that enteral feeding with plasma improves gut and immune functions in asphyxiated newborns. METHODS Near-term pig fetuses (98% gestation,) were delivered by caesarean section after 8 min umbilical cord occlusion, leading to transient birth asphyxia (ASP, n = 75) and compared with non-occluded controls (CON, n = 69). Piglets were further randomised to supplementation with/without porcine plasma (plasma, PLA/vehicle, VEH), into bovine colostrum (first 24 h) or formula (until 72 h). RESULTS Compared with CON, ASP piglets took longer to achieve stable respiration and showed reduced blood pH, weight gain and survival. Independent of asphyxia, plasma supplementation reduced gut haemorrhagic lesions, permeability and inflammatory cytokines together with improved villous morphology and brush-border enzyme activities. Asphyxia reduced blood cytokine responses to ex vivo bacterial stimulation, whereas plasma supplementation ameliorated this effect. CONCLUSION Dietary plasma supplementation improves survival, gut functions and immunity in both normal and asphyxiated newborns. The components in plasma that mediate gut-protective effects in piglets remain to be identified, but may benefit also birth-compromised newborn infants. IMPACT Complicated deliveries leading to birth asphyxia, may negatively affect gut, liver and immune adaptation in the first days after birth. Using a model of birth asphyxia in caesarean-derived piglets, we show that enteral feeding with maternal plasma exerts gut maturational and immunomodulatory effects in both control and asphyxiated animals in the first days of life. The mechanisms behind the gut-protective effects of plasma are unknown, but plasma components hold potential for new oral therapies for compromised newborn infants as well as piglets.
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Affiliation(s)
- Mads Jacob Bagi Nordsten
- Comparative Pediatrics and Nutrition, Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Christina L Winther
- Department of Pediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen, Denmark
| | - Maria Mathilde Haugaard
- Comparative Pediatrics and Nutrition, Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Kerstin Skovgaard
- Department of Biotechnology and Biomedicine, Technical University of Denmark, Lyngby, Denmark
| | - Thomas Thymann
- Comparative Pediatrics and Nutrition, Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
| | - Per T Sangild
- Comparative Pediatrics and Nutrition, Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Pediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen, Denmark
- Department of Pediatrics, Odense University Hospital, Odense, Denmark
- Faculty of Theology, University of Copenhagen, Copenhagen, Denmark
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Kontou A, Agakidou E, Chatziioannidis I, Chotas W, Thomaidou E, Sarafidis K. Antibiotics, Analgesic Sedatives, and Antiseizure Medications Frequently Used in Critically Ill Neonates: A Narrative Review. CHILDREN (BASEL, SWITZERLAND) 2024; 11:871. [PMID: 39062320 PMCID: PMC11275925 DOI: 10.3390/children11070871] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 07/09/2024] [Accepted: 07/11/2024] [Indexed: 07/28/2024]
Abstract
Antibiotic, analgesic sedative, and antiseizure medications are among the most commonly used medications in preterm/sick neonates, who are at high risk of nosocomial infections, central nervous system complications, and are exposed to numerous painful/stressful procedures. These severe and potentially life-threatening complications may have serious short- and long-term consequences and should be prevented and/or promptly treated. The reported variability in the medications used in neonates indicates the lack of adequate neonatal studies regarding their effectiveness and safety. Important obstacles contributing to inadequate studies in preterm/sick infants include difficulties in obtaining parental consent, physicians' unwillingness to recruit preterm infants, the off-label use of many medications in neonates, and other scientific and ethical concerns. This review is an update on the use of antimicrobials (antifungals), analgesics (sedatives), and antiseizure medications in neonates, focusing on current evidence or knowledge gaps regarding their pharmacokinetics, indications, safety, dosage, and evidence-based guidelines for their optimal use in neonates. We also address the effects of early antibiotic use on the intestinal microbiome and its association with long-term immune-related diseases, obesity, and neurodevelopment (ND). Recommendations for empirical treatment and the emergence of pathogen resistance to antimicrobials and antifungals are also presented. Finally, future perspectives on the prevention, modification, or reversal of antibiotic resistance are discussed.
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Affiliation(s)
- Angeliki Kontou
- Department of Neonatology and Neonatal Intensive Care, Faculty of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, Ippokrateion General Hospital, 54642 Thessaloniki, Greece; (E.A.); (I.C.); (K.S.)
| | - Eleni Agakidou
- Department of Neonatology and Neonatal Intensive Care, Faculty of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, Ippokrateion General Hospital, 54642 Thessaloniki, Greece; (E.A.); (I.C.); (K.S.)
| | - Ilias Chatziioannidis
- Department of Neonatology and Neonatal Intensive Care, Faculty of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, Ippokrateion General Hospital, 54642 Thessaloniki, Greece; (E.A.); (I.C.); (K.S.)
| | - William Chotas
- Department of Neonatology, University of Vermont, Burlington, VT 05405, USA
| | - Evanthia Thomaidou
- Department of Anesthesia and Intensive Care, Faculty of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, AHEPA University General Hospital of Thessaloniki, 54621 Thessaloniki, Greece;
| | - Kosmas Sarafidis
- Department of Neonatology and Neonatal Intensive Care, Faculty of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, Ippokrateion General Hospital, 54642 Thessaloniki, Greece; (E.A.); (I.C.); (K.S.)
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7
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Giugliano FP, Navis M, Ouahoud S, Garcia TM, Kreulen IA, Ferrantelli E, Meisner S, Vermeulen JL, van Roest M, Billaud JN, Koster J, Dawood Y, de Bakker BS, Picavet-Havik DI, Schimmel IM, van der Wel NN, Koelink PJ, Wildenberg ME, Derikx JP, de Jonge WJ, Renes IB, van Elburg RM, Muncan V. Pro-inflammatory T cells-derived cytokines enhance the maturation of the human fetal intestinal epithelial barrier. iScience 2024; 27:109909. [PMID: 38812539 PMCID: PMC11134877 DOI: 10.1016/j.isci.2024.109909] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 01/31/2024] [Accepted: 05/03/2024] [Indexed: 05/31/2024] Open
Abstract
Small intestine (SI) maturation during early life is pivotal in preventing the onset of gut diseases. In this study we interrogated the milestones of SI development by gene expression profiling and ingenuity pathway analyses. We identified a set of cytokines as main regulators of changes observed across different developmental stages. Upon cytokines stimulation, with IFNγ as the most contributing factor, human fetal organoids (HFOs) increase brush border gene expression and enzyme activity as well as trans-epithelial electrical resistance. Electron microscopy revealed developed brush border and loss of fetal cell characteristics in HFOs upon cytokine stimulation. We identified T cells as major source of IFNγ production in the fetal SI lamina propria. Co-culture of HFOs with T cells recapitulated the major effects of cytokine stimulation. Our findings underline pro-inflammatory cytokines derived from T cells as pivotal factors inducing functional SI maturation in vivo and capable of modulating the barrier maturation of HFOs in vitro.
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Affiliation(s)
- Francesca P. Giugliano
- Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Center (AUMC), University of Amsterdam, Amsterdam, the Netherlands
| | - Marit Navis
- Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Center (AUMC), University of Amsterdam, Amsterdam, the Netherlands
| | - Sarah Ouahoud
- Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Center (AUMC), University of Amsterdam, Amsterdam, the Netherlands
| | - Tânia Martins Garcia
- Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Center (AUMC), University of Amsterdam, Amsterdam, the Netherlands
| | - Irini A.M. Kreulen
- Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Center (AUMC), University of Amsterdam, Amsterdam, the Netherlands
| | - Evelina Ferrantelli
- Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Center (AUMC), University of Amsterdam, Amsterdam, the Netherlands
| | - Sander Meisner
- Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Center (AUMC), University of Amsterdam, Amsterdam, the Netherlands
| | - Jacqueline L.M. Vermeulen
- Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Center (AUMC), University of Amsterdam, Amsterdam, the Netherlands
| | - Manon van Roest
- Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Center (AUMC), University of Amsterdam, Amsterdam, the Netherlands
| | - Jean-Noël Billaud
- QIAGEN Digital Insights, 1001 Marshall Street, Redwood City, CA, USA
- DNAnexus, 204 El Camino Real, Mountain View, CA, USA
| | - Jan Koster
- Center for Experimental and Molecular Medicine (CEMM), Amsterdam University Medical Center (AUMC), University of Amsterdam, Amsterdam, the Netherlands
| | - Yousif Dawood
- Department of Obstetrics and Gynecology, Amsterdam University Medical Center (AUMC), University of Amsterdam, Amsterdam, the Netherlands
- Amsterdam Reproduction and Development research institute, Amsterdam University Medical Center (AUMC), University of Amsterdam, Amsterdam, the Netherlands
| | - Bernadette S. de Bakker
- Department of Obstetrics and Gynecology, Amsterdam University Medical Center (AUMC), University of Amsterdam, Amsterdam, the Netherlands
- Amsterdam Reproduction and Development research institute, Amsterdam University Medical Center (AUMC), University of Amsterdam, Amsterdam, the Netherlands
| | - Daisy I. Picavet-Havik
- Department of Medical Biology, Electron Microscopy Center Amsterdam, Amsterdam University Medical Center (AUMC), University of Amsterdam, Amsterdam, the Netherlands
| | - Irene M. Schimmel
- Department of Medical Biology, Electron Microscopy Center Amsterdam, Amsterdam University Medical Center (AUMC), University of Amsterdam, Amsterdam, the Netherlands
| | - Nicole N. van der Wel
- Department of Medical Biology, Electron Microscopy Center Amsterdam, Amsterdam University Medical Center (AUMC), University of Amsterdam, Amsterdam, the Netherlands
| | - Pim J. Koelink
- Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Center (AUMC), University of Amsterdam, Amsterdam, the Netherlands
| | - Manon E. Wildenberg
- Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Center (AUMC), University of Amsterdam, Amsterdam, the Netherlands
| | - Joep P.M. Derikx
- Department of Pediatric Surgery, Pediatric Surgery Center of Amsterdam, Amsterdam University Medical Center (AUMC), University of Amsterdam, Amsterdam, the Netherlands
| | - Wouter J. de Jonge
- Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Center (AUMC), University of Amsterdam, Amsterdam, the Netherlands
| | - Ingrid B. Renes
- Department of Pediatrics, Amsterdam University Medical Center (AUMC), Emma Children’s Hospital, Amsterdam, the Netherlands
- Danone Nutricia Research, Utrecht, the Netherlands
| | - Ruurd M. van Elburg
- Department of Pediatrics, Amsterdam University Medical Center (AUMC), Emma Children’s Hospital, Amsterdam, the Netherlands
| | - Vanesa Muncan
- Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Center (AUMC), University of Amsterdam, Amsterdam, the Netherlands
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8
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Lee CC, Chiu CH. Link between gut microbiota and neonatal sepsis. J Formos Med Assoc 2024; 123:638-646. [PMID: 37821302 DOI: 10.1016/j.jfma.2023.09.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 09/15/2023] [Accepted: 09/28/2023] [Indexed: 10/13/2023] Open
Abstract
In neonates, the gastrointestinal tract is rapidly colonized by bacteria after birth. Gut microbiota development is critical during the first few years of life. However, disruption of gut microbiota development in neonates can lead to gut dysbiosis, characterized by overcolonization by pathogenic bacteria and delayed or failed maturation toward increasing microbial diversity and Fermicutes dominance. Gut dysbiosis can predispose infants to sepsis. Pathogenic bacteria can colonize the gut prior to sepsis and cause sepsis through translocation. This review explores gut microbiota development in neonates, the evidence linking gut dysbiosis to neonatal sepsis, and the potential role of probiotics in gut microbiota modulation and sepsis prevention.
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Affiliation(s)
- Chien-Chung Lee
- Division of Neonatology, Department of Pediatrics, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Cheng-Hsun Chiu
- Division of Pediatric Infectious Diseases, Department of Pediatrics, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan; Molecular Infectious Disease Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
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9
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de Kroon RR, Frerichs NM, Struys EA, de Boer NK, de Meij TGJ, Niemarkt HJ. The Potential of Fecal Volatile Organic Compound Analysis for the Early Diagnosis of Late-Onset Sepsis in Preterm Infants: A Narrative Review. SENSORS (BASEL, SWITZERLAND) 2024; 24:3162. [PMID: 38794014 PMCID: PMC11124895 DOI: 10.3390/s24103162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 05/01/2024] [Accepted: 05/10/2024] [Indexed: 05/26/2024]
Abstract
Early diagnosis and treatment of late-onset sepsis (LOS) is crucial for survival, but challenging. Intestinal microbiota and metabolome alterations precede the clinical onset of LOS, and the preterm gut is considered an important source of bacterial pathogens. Fecal volatile organic compounds (VOCs), formed by physiologic and pathophysiologic metabolic processes in the preterm gut, reflect a complex interplay between the human host, the environment, and microbiota. Disease-associated fecal VOCs can be detected with an array of devices with various potential for the development of a point-of-care test (POCT) for preclinical LOS detection. While characteristic VOCs for common LOS pathogens have been described, their VOC profiles often overlap with other pathogens due to similarities in metabolic pathways, hampering the construction of species-specific profiles. Clinical studies have, however, successfully discriminated LOS patients from healthy individuals using fecal VOC analysis with the highest predictive value for Gram-negative pathogens. This review discusses the current advancements in the development of a non-invasive fecal VOC-based POCT for early diagnosis of LOS, which may potentially provide opportunities for early intervention and targeted treatment and could improve clinical neonatal outcomes. Identification of confounding variables impacting VOC synthesis, selection of an optimal detection device, and development of standardized sampling protocols will allow for the development of a novel POCT in the near future.
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Affiliation(s)
- Rimke R. de Kroon
- Department of Pediatric Gastroenterology, Emma Children’s Hospital, Amsterdam Gastroenterology Endocrinology Metabolism Research Institute, Amsterdam University Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
- Amsterdam Reproduction and Development Research Institute, Amsterdam University Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
| | - Nina M. Frerichs
- Department of Pediatric Gastroenterology, Emma Children’s Hospital, Amsterdam Gastroenterology Endocrinology Metabolism Research Institute, Amsterdam University Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
- Amsterdam Reproduction and Development Research Institute, Amsterdam University Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
| | - Eduard A. Struys
- Department of Laboratory Medicine, Amsterdam University Medical Center, Location AMC, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
| | - Nanne K. de Boer
- Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism Research Institute, Amsterdam University Medical Center, Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
| | - Tim G. J. de Meij
- Department of Pediatric Gastroenterology, Emma Children’s Hospital, Amsterdam Gastroenterology Endocrinology Metabolism Research Institute, Amsterdam University Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
| | - Hendrik J. Niemarkt
- Department of Neonatology, Maxima Medisch Centrum, De Run 4600, 5504 DB Veldhoven, The Netherlands
- Department of Electrical Engineering, TU Eindhoven, Eindhoven University of Technology, Postbus 513, 5600 MB Eindhoven, The Netherlands
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10
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VALENTINE GREGORYC, WALLEN LINDAD. Neonatal Bacterial Sepsis and Meningitis. AVERY'S DISEASES OF THE NEWBORN 2024:439-449.e5. [DOI: 10.1016/b978-0-323-82823-9.00033-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Wang H, Li QF, Xu XF, Hu XL. Effects of Sublingual Colostrum Application on Oral and Intestinal Flora of Extremely Low Birth Weight Infants. Endocr Metab Immune Disord Drug Targets 2024; 24:489-494. [PMID: 37711000 DOI: 10.2174/1871530323666230913105820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 07/26/2023] [Accepted: 07/28/2023] [Indexed: 09/16/2023]
Abstract
BACKGROUND The aim of this study is to analyze the effects of colostrum application on the establishment of normal flora in the intestinal tracts and oral cavities of extremely low birth weight infants (ELBWI). METHODS A prospective cohort study design was adopted following the STROBE guidelines (Supplementary File 1). Colostrum was administered immediately after obtaining maternal breast milk using a special sterile cotton swab. There were no specific treatments for infants who did not receive colostrum. This experiment was completed on day 5 post-birth and the patients were divided into the colostrum and control groups, corresponding to whether or not colostrum was administered. Throat swabs and stool samples were collected on days 1 and 5 post-birth. RESULTS Using the conventional bacteria cultivation technique, the detection rate of bacteria in 98 cases of meconium at birth was 15.31%. On day 5, the detection rates of Staphylococcus in the colostrum and control groups were 36.54% and 34.78%, with no significant difference between them (P = 0.856), and that of Enterococcus was 26.92% and 13.04%, respectively, with no statistically significant difference (P = 0.089). Likewise, at birth, the detection rate of bacteria in 98 cases of throat swabs was 27.55%. On day 5, the detection rate of Streptococcus in the colostrum and control groups was 78.85% and 50.00%, respectively, recording a statistically significant difference this time (P = 0.003). CONCLUSION Colostrum application had limited effects on intestinal flora colonization but contributes to physiological oral flora colonization.
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Affiliation(s)
- Hua Wang
- Department of NICU, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Qiu-Fang Li
- Department of nursing, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Xin-Fen Xu
- Department of nursing, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Xiao-Li Hu
- Department of obstetrics, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
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12
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Ogunbosi BO, Kigbu A, Tongo OO, Adepoju AA, Orimadegun AE, Odaibo GN, Olaleye DO, Akinyinka OO. Emergence of Raoultella ornithinolytica as a significant intestinal microbiota in Nigerian Neonates. AFRICAN JOURNAL OF MEDICINE AND MEDICAL SCIENCES 2023; 52:247-253. [PMID: 40093860 PMCID: PMC11907646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Subscribe] [Scholar Register] [Indexed: 03/19/2025]
Abstract
Background There are increasing reports of Raoultella ornithinolytica infection in humans. This study reports significant contribution of Raoultella ornithinolytica to neonatal gut microbiota. Methods Rectal swab samples were collected in 70 healthy neonates, within 6-12hours of birth, and days 3, 9, and 14 after birth. Colonization by R. ornithinolytica was evaluated against neonatal characteristics. Results Among the 70 neonates, R. ornithinolytica was the fourth most common bacteria isolated. R. ornithinolytica was part of gut microbiota at birth, and on Day 3, Day 9 and Day 14 after birth in 15%, 28.6%, 21.4% and 5.7% of neonates respectively. No factor was associated with R. ornithinolytica colonization, but a trend towards an increased likelihood of colonization among females, asphyxiated and neonates whose mothers had prolonged labour was observed. Conclusion R. ornithinolytica has emerged as an important part of gut microbiota among neonates in Nigeria, but its' role in neonatal dysbiosis and infection remains unclear.
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Affiliation(s)
- B O Ogunbosi
- Departments of Paediatrics, College of Medicine, University of Ibadan, Ibadan Nigeria
- Department of Paediatrics, University College Hospital, Ibadan, Nigeria
| | - A Kigbu
- Department of Paediatrics, University College Hospital, Ibadan, Nigeria
| | - O O Tongo
- Departments of Paediatrics, College of Medicine, University of Ibadan, Ibadan Nigeria
- Department of Paediatrics, University College Hospital, Ibadan, Nigeria
| | - A A Adepoju
- Departments of Paediatrics, College of Medicine, University of Ibadan, Ibadan Nigeria
- Department of Paediatrics, University College Hospital, Ibadan, Nigeria
| | - A E Orimadegun
- Department of Paediatrics, University College Hospital, Ibadan, Nigeria
- Institute of Child Health, College of Medicine, University of Ibadan, Ibadan Nigeria
| | - G N Odaibo
- Department of Virology, College of Medicine, University of Ibadan, Ibadan Nigeria
| | - D O Olaleye
- Department of Virology, College of Medicine, University of Ibadan, Ibadan Nigeria
| | - O O Akinyinka
- Departments of Paediatrics, College of Medicine, University of Ibadan, Ibadan Nigeria
- Department of Paediatrics, University College Hospital, Ibadan, Nigeria
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13
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Lin X, Wu C. Identification and evaluation of probiotic potential of Bifidobacterium breve AHC3 isolated from chicken intestines and its effect on necrotizing enterocolitis (NEC) in newborn SD rats. PLoS One 2023; 18:e0287799. [PMID: 37917716 PMCID: PMC10621988 DOI: 10.1371/journal.pone.0287799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Accepted: 06/13/2023] [Indexed: 11/04/2023] Open
Abstract
Necrotizing enterocolitis (NEC) is a severe intestinal disease of the newborn infants, associated with high morbidity and mortality. It has been reported that Bifidobacterium could protect the intestinal barrier function and reduce the risk of NEC. This study aimed to evaluate the probiotic potential of Bifidobacterium strains isolated from the chicken intestines and its effect on necrotizing enterocolitis in newborn SD rats. Out of 32 isolates, B. breve AHC3 not only exhibited excellent probiotic potential, including tolerance to artificial simulated gastric conditions, adhesion to HT-29 cells, antioxidant capacity and antibacterial activity, but also possessed reliable safety. Additionally, NEC model was established to further investigate the effect of B. breve AHC3 on necrotizing enterocolitis in newborn SD rats. It was illustrated that administration of B. breve AHC3 significantly not only reduced the incidence of NEC (from 81.25% to 34.38%) (P< 0.05), but also alleviated the severity of ileal injury (P< 0.05). Compared with NEC model, B. breve AHC3 could significantly decrease the level of proinflammatory factor TNF-α (P< 0.05) and increase the level of antiinflammatory factor IL-10 (P< 0.05) in the ileum of NEC rats. Through the intervention of B. breve AHC3, the gray value of inducible nitric oxide synthase (iNOS) in intestinal tissue of NEC rats was significantly reduced (P< 0.05). It was indicated that B. breve AHC3 exhibited prominent probiotic potential and reliable safety. In the neonatal SD rat model of NEC, B. breve AHC3 had an available protective effect on the intestinal injury of NEC, which might be related to reducing the inflammatory reaction in the ileum and inhibiting the expression of iNOS in intestinal tissue cells. B. breve AHC3 could be used as a potential treatment for human NEC.
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Affiliation(s)
- Xiaopei Lin
- Department of Pediatrics, Maternity and Child Health Care Hospital Affiliated to Anhui Medical University (Anhui Maternity and Child Health Care Hospital), Hefei, Anhui, China
| | - Changjun Wu
- Institute of Microbiology, Anhui Academy of Medical Sciences, Hefei, Anhui, China
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14
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Kartjito MS, Yosia M, Wasito E, Soloan G, Agussalim AF, Basrowi RW. Defining the Relationship of Gut Microbiota, Immunity, and Cognition in Early Life-A Narrative Review. Nutrients 2023; 15:2642. [PMID: 37375546 DOI: 10.3390/nu15122642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 05/22/2023] [Accepted: 06/02/2023] [Indexed: 06/29/2023] Open
Abstract
Recently, the immune system has been identified as one of the possible main bridges which connect the gut-brain axis. This review aims to examine available evidence on the microbiota-immunity-cognitive relationship and its possible effects on human health early in life. This review was assembled by compiling and analyzing various literature and publications that document the gut microbiota-immune system-cognition interaction and its implications in the pediatric population. This review shows that the gut microbiota is a pivotal component of gut physiology, with its development being influenced by a variety of factors and, in return, supports the development of overall health. Findings from current research focus on the complex relationship between the central nervous system, gut (along with gut microbiota), and immune cells, highlighting the importance of maintaining a balanced interaction among these systems for preserving homeostasis, and demonstrating the influence of gut microbes on neurogenesis, myelin formation, the potential for dysbiosis, and alterations in immune and cognitive functions. While limited, evidence shows how gut microbiota affects innate and adaptive immunity as well as cognition (through HPA axis, metabolites, vagal nerve, neurotransmitter, and myelination).
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Affiliation(s)
| | - Mikhael Yosia
- Faculty of Medicine, Universitas Indonesia, Jakarta 10430, Indonesia
| | - Erika Wasito
- Medical and Science Affairs Division, Danone Specialized Nutrition Indonesia, Jakarta 12950, Indonesia
| | - Garry Soloan
- Faculty of Medicine, Universitas Indonesia, Jakarta 10430, Indonesia
| | | | - Ray Wagiu Basrowi
- Medical and Science Affairs Division, Danone Specialized Nutrition Indonesia, Jakarta 12950, Indonesia
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15
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Cha T, Kim HH, Keum J, Kwak MJ, Park JY, Hoh JK, Kim CR, Jeon BH, Park HK. Gut microbiome profiling of neonates using Nanopore MinION and Illumina MiSeq sequencing. Front Microbiol 2023; 14:1148466. [PMID: 37256051 PMCID: PMC10225602 DOI: 10.3389/fmicb.2023.1148466] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 04/17/2023] [Indexed: 06/01/2023] Open
Abstract
This study aimed to evaluate the difference in gut microbiomes between preterm and term infants using third-generation long-read sequencing (Oxford Nanopore Technologies, ONT) compared with an established gold standard, Illumina (second-generation short-read sequencing). A total of 69 fecal samples from 51 term (T) and preterm (P) infants were collected at 7 and 28 days of life. Gut colonization profiling was performed by 16S rRNA gene sequencing using ONT. We used Illumina to validate and compare the patterns in 13 neonates. Using bioinformatic analysis, we identified features that differed between P and T. Both T1 and P1 microbiomes were dominated by Firmicutes (Staphylococcus and Enterococcus), whereas sequentially showed dominant transitions to Lactobacillus (p < 0.001) and Streptococcus in T2 (p = 0.001), and pathogenic bacteria (Klebsiella) in P2 (p = 0.001). The abundance of beneficial bacteria (Bifidobacterium and Lactobacillus) increased in T2 (p = 0.026 and p < 0.001, respectively). These assignments were correlated with the abundance at the species-level. Bacterial α-diversity increased in T (p = 0.005) but not in P (p = 0.156), and P2 showed distinct β-diversity clustering than T2 (p = 0.001). The ONT reliably identified pathogenic bacteria at the genus level, and taxonomic profiles were comparable to those identified by Illumina at the genus level. This study shows that ONT and Illumina are highly correlated. P and T had different microbiome profiles, and the α- and β-diversity varied. ONT sequencing has potential for pathogen detection in neonates in clinical settings.
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Affiliation(s)
- Teahyen Cha
- Department of Pediatrics, Hanyang University College of Medicine, Seoul, Republic of Korea
| | - Hoo Hugo Kim
- Department of Earth Resources and Environmental Engineering, Hanyang University, Seoul, Republic of Korea
| | - Jihyun Keum
- Department of Obstetrics and Gynecology, Hanyang University College of Medicine, Seoul, Republic of Korea
| | - Min-Jin Kwak
- Department of Agricultural Biotechnology and Research Institute of Agriculture and Life Sciences, Seoul National University, Seoul, Republic of Korea
| | - Jae Yong Park
- Division of Microbiome, Int-Gen Company, Seoul, Republic of Korea
| | - Jeong Kyu Hoh
- Department of Obstetrics and Gynecology, Hanyang University College of Medicine, Seoul, Republic of Korea
| | - Chang-Ryul Kim
- Department of Pediatrics, Hanyang University College of Medicine, Seoul, Republic of Korea
| | - Byong-Hun Jeon
- Department of Earth Resources and Environmental Engineering, Hanyang University, Seoul, Republic of Korea
| | - Hyun-Kyung Park
- Department of Pediatrics, Hanyang University College of Medicine, Seoul, Republic of Korea
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Parra-Llorca A, Pinilla-Gonzlez A, Torrejón-Rodríguez L, Lara-Cantón I, Kuligowski J, Collado MC, Gormaz M, Aguar M, Vento M, Serna E, Cernada M. Effects of Sepsis on Immune Response, Microbiome and Oxidative Metabolism in Preterm Infants. CHILDREN (BASEL, SWITZERLAND) 2023; 10:602. [PMID: 36980160 PMCID: PMC10046958 DOI: 10.3390/children10030602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 03/03/2023] [Accepted: 03/16/2023] [Indexed: 03/30/2023]
Abstract
This is a narrative review about the mechanisms involved in bacterial sepsis in preterm infants, which is an illness with a high incidence, morbidity, and mortality. The role of the innate immune response and its relationship with oxidative stress in the pathogenesis are described as well as their potential implementation as early biomarkers. Moreover, we address the impact that all the mechanisms triggered by sepsis have on the dysbiosis and the changes on neonatal microbiota.
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Affiliation(s)
- Anna Parra-Llorca
- Division of Neonatology, University and Polytechnic Hospital La Fe (HULAFE), 46026 Valencia, Spain
- Neonatal Research Group, Health Research Institute La Fe (IISLAFE), 46026 Valencia, Spain
| | - Alejandro Pinilla-Gonzlez
- Division of Neonatology, University and Polytechnic Hospital La Fe (HULAFE), 46026 Valencia, Spain
- Neonatal Research Group, Health Research Institute La Fe (IISLAFE), 46026 Valencia, Spain
| | - Laura Torrejón-Rodríguez
- Division of Neonatology, University and Polytechnic Hospital La Fe (HULAFE), 46026 Valencia, Spain
- Neonatal Research Group, Health Research Institute La Fe (IISLAFE), 46026 Valencia, Spain
| | - Inmaculada Lara-Cantón
- Division of Neonatology, University and Polytechnic Hospital La Fe (HULAFE), 46026 Valencia, Spain
- Neonatal Research Group, Health Research Institute La Fe (IISLAFE), 46026 Valencia, Spain
| | - Julia Kuligowski
- Neonatal Research Group, Health Research Institute La Fe (IISLAFE), 46026 Valencia, Spain
| | - María Carmen Collado
- Department of Biotechnology, Institute of Agrochemistry and Food Technology, National Research Council (IATA-CSIC), 46980 Valencia, Spain
| | - María Gormaz
- Division of Neonatology, University and Polytechnic Hospital La Fe (HULAFE), 46026 Valencia, Spain
- Neonatal Research Group, Health Research Institute La Fe (IISLAFE), 46026 Valencia, Spain
| | - Marta Aguar
- Division of Neonatology, University and Polytechnic Hospital La Fe (HULAFE), 46026 Valencia, Spain
- Neonatal Research Group, Health Research Institute La Fe (IISLAFE), 46026 Valencia, Spain
| | - Máximo Vento
- Division of Neonatology, University and Polytechnic Hospital La Fe (HULAFE), 46026 Valencia, Spain
- Neonatal Research Group, Health Research Institute La Fe (IISLAFE), 46026 Valencia, Spain
| | - Eva Serna
- Department of Physiology, University of Valencia, 46010 Valencia, Spain
| | - María Cernada
- Division of Neonatology, University and Polytechnic Hospital La Fe (HULAFE), 46026 Valencia, Spain
- Neonatal Research Group, Health Research Institute La Fe (IISLAFE), 46026 Valencia, Spain
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17
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Risk Factors, Diagnosis, and Treatment of Neonatal Fungal Liver Abscess: A Systematic Review of the Literature. LIFE (BASEL, SWITZERLAND) 2023; 13:life13010167. [PMID: 36676116 PMCID: PMC9864123 DOI: 10.3390/life13010167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 12/30/2022] [Accepted: 01/03/2023] [Indexed: 01/08/2023]
Abstract
(1) Background: Although invasive fungal infections are a major cause of neonatal morbidity and mortality, data on the incidence and outcomes of localized abscesses in solid organs due to fungal infections are scarce. The aim of this study was to consolidate evidence and enhance our understanding on neonatal liver abscesses due to invasive fungal infections. (2) Methods: An electronic search of the PubMed and Scopus databases was conducted, considering studies that evaluated fungal liver abscesses in the neonatal population. Data on the epidemiology, clinical course, treatment, and outcome of these infections were integrated in our study. (3) Results: Overall, 10 studies were included presenting data on 19 cases of neonatal fungal liver abscesses. Candida spp. were the most common causative pathogens (94.7%). Premature neonates constituted the majority of cases (93%), while umbilical venous catheter placement, broad spectrum antibiotics, and prolonged parenteral nutrition administration were identified as other common predisposing factors. Diagnosis was established primarily by abdominal ultrasonography. Medical therapy with antifungal agents was the mainstay of treatment, with Amphotericin B being the most common agent (47%). Abscess drainage was required in four cases (21%). Eradication of the infection was achieved in the majority of cases (80%). (4) Conclusions: Even though fungal liver abscess is a rare entity in the neonatal population, clinicians should keep it in mind in small, premature infants who fail to respond to conventional treatment for sepsis, particularly if an indwelling catheter is in situ. A high index of suspicion is necessary in order to achieve a timely diagnosis and the initiation of the appropriate treatment.
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18
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Khan A, Mi H, Gao F, Hu Q, Gu X, Ma F, Qu L, Li S, Dai Y, Hao H. Dynamic changes of the gut microbial colonization in preterm infants with different time points after birth. Front Microbiol 2023; 14:1078426. [PMID: 36876108 PMCID: PMC9983350 DOI: 10.3389/fmicb.2023.1078426] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Accepted: 01/12/2023] [Indexed: 02/19/2023] Open
Abstract
Risks associated with preterm birth are unevenly distributed across all gestations. At earlier gestational ages, complications such as necrotizing enterocolitis (NEC) and late-onset sepsis (LOS) conditions are significantly more common and are associated with a shift in the composition of the gut microbiome. Conventional bacterial culture techniques demonstrate that the colonization of the gut microbiota of preterm infants differs significantly from that of healthy-term infants. The current study aimed to investigate the impact of preterm infancy on the dynamic changes of fecal microbiota in preterm infants at different time points (1, 7, 14, 21, 28, and 42 days) after birth. We selected 12 preterm infants hospitalized in the Sixth Affiliated Hospital of Sun Yat-sen University from January 2017 to December 2017. A total of 130 fecal specimens from preterm infants were analyzed using 16S rRNA gene sequencing. We found that the colonization process of fecal microbiota in preterm infants is highly dynamic at different time points after birth, i.e., Exiguobacterium, Acinetobacter, and Citrobacter showed a declining abundance pattern with the advancement of age, while the bacterial groups of Enterococcus (Klebsiella and Escherichia coli) gradually grew and became the main microbiota during the development of fecal microbiota in preterm infants at the age of 42 days. Furthermore, the colonization of intestinal Bifidobacteria in preterm infants was relatively late and did not rapidly become the predominant microbiota. Moreover, the results also showed the presence of Chryseobacterium bacterial group, whose colonization was different in different time point groups. Conclusively, our findings deepen our comprehension and offer new perspectives on targeting particular bacteria in the treatment of preterm infants at different time points after birth.
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Affiliation(s)
- Adnan Khan
- Guangdong Laboratory of Lingnan Modern Agriculture, Genome Analysis Laboratory of the Ministry of Agriculture and Rural Affairs, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen, China
| | - Hongying Mi
- Department of Pediatric, The First People's Hospital of Yunnan Province, Kunming, Yunnan, China
| | - Fei Gao
- Guangdong Laboratory of Lingnan Modern Agriculture, Genome Analysis Laboratory of the Ministry of Agriculture and Rural Affairs, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen, China.,Section of Comparative Pediatrics and Nutrition, Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark
| | - Qi Hu
- NEOMICS Institute, Shenzhen, China
| | - Xia Gu
- Department of Pediatrics, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Fei Ma
- Department of Pediatrics, Zhuhai Women and Children's Hospital, Zhuhai, China
| | - LiuHong Qu
- Department of Neonatology, The Maternal and Child Health Care Hospital of HuaDu District, Guangzhou, China
| | - Sitao Li
- Department of Pediatrics, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Yiheng Dai
- Department of Neonatology, Affiliated Foshan Maternity and Child Healthcare Hospital, Southern Medical University, Foshan, Guangdong, China
| | - Hu Hao
- Department of Pediatrics, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
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Liu M, Chen C, Kang S, Kwon JI, Jin J, Che H. Effect of different feeding methods and gut microbiota on premature infants and clinical outcomes. Front Nutr 2022; 9:888304. [PMID: 35978959 PMCID: PMC9376281 DOI: 10.3389/fnut.2022.888304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 07/06/2022] [Indexed: 11/20/2022] Open
Abstract
Premature infants require special care, and clinical feeding methods for this patient group are generally divided into breastfeeding and formula milk. This retrospective study investigated the effects of these two feeding methods on premature infants admitted to the neonatal intensive care unit between 2017 and 2018. Data regarding the duration of complete enteral feeding, weight gain, and postnatal infections were collected, categorized, and compared. Pearson's correlation coefficient was used to determine the correlation between the intestinal flora and clinical outcomes. Results revealed no differences between the two feeding methods, and neither had significant effects on clinical indicators in premature infants, although the gut microbiota may be an important factor influencing many clinical indicators. Results of this study suggest an important role for the gut microbiota in the care of premature infants and provide a basis for promoting the healthy development of this patient population.
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Affiliation(s)
- Manman Liu
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
| | - Cheng Chen
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
| | - Songhao Kang
- College of Engineering, China Agricultural University, Beijing, China
| | - Jung-il Kwon
- Maeil Innovation Center, Maeil Dairies Co., Ltd., Seoul, South Korea
| | - Juan Jin
- Maeil Innovation Center, Maeil Dairies Co., Ltd., Seoul, South Korea
| | - Huilian Che
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
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20
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Romo JA, Arsenault AB, Laforce-Nesbitt SS, Bliss JM, Kumamoto CA. Minimal Effects of Medium-Chain Triglyceride Supplementation on the Intestinal Microbiome Composition of Premature Infants: A Single-Center Pilot Study. Nutrients 2022; 14:2159. [PMID: 35631300 PMCID: PMC9145469 DOI: 10.3390/nu14102159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 05/18/2022] [Accepted: 05/19/2022] [Indexed: 12/04/2022] Open
Abstract
Compared to term infants, the microbiota of preterm infants is less diverse and often enriched for potential pathogens (e.g., members of the family Enterobacteriaceae). Additionally, antibiotics are frequently given to preterm infants, further destabilizing the microbiota and increasing the risk of fungal infections. In a previous communication, our group showed that supplementation of the premature infant diet with medium-chain triglyceride (MCT) oil reduced the fungal burden of Candida spp. in the gastrointestinal tract. The objective of this study was to determine whether MCT supplementation impacts the bacterial component of the microbiome. Pre-term infants (n = 17) receiving enteral feedings of either infant formula (n = 12) or human milk (n = 5) were randomized to MCT supplementation (n = 9) or no supplementation (n = 8). Fecal samples were taken at randomization and prior to MCT supplementation (Week 0), on days 5-7 (Week 1) and day 21 (Week 3). After DNA extraction from samples, the QIIME2 pipeline was utilized to measure community diversity and composition (genera and phyla). Our findings show that MCT supplementation did not significantly alter microbiota diversity or composition in the gastrointestinal tract. Importantly, there were no significant changes in the family Enterobacteriaceae, suggesting that MCT supplementation did not enrich for potential pathogens. MCT holds promise as a therapeutic intervention for reducing fungal colonization without significant impact on the bacterial composition of the host gastrointestinal tract.
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Affiliation(s)
- Jesús A. Romo
- Department of Molecular Biology and Microbiology, Tufts University School of Medicine, 136 Harrison Ave., Boston, MA 02111, USA;
| | - Amanda B. Arsenault
- Department of Pediatrics, Women & Infants Hospital of Rhode Island, Providence, RI 02905, USA; (A.B.A.); (S.S.L.-N.); (J.M.B.)
- Warren Alpert Medical School, Brown University, Providence, RI 02903, USA
| | - Sonia S. Laforce-Nesbitt
- Department of Pediatrics, Women & Infants Hospital of Rhode Island, Providence, RI 02905, USA; (A.B.A.); (S.S.L.-N.); (J.M.B.)
- Warren Alpert Medical School, Brown University, Providence, RI 02903, USA
| | - Joseph M. Bliss
- Department of Pediatrics, Women & Infants Hospital of Rhode Island, Providence, RI 02905, USA; (A.B.A.); (S.S.L.-N.); (J.M.B.)
- Warren Alpert Medical School, Brown University, Providence, RI 02903, USA
| | - Carol A. Kumamoto
- Department of Molecular Biology and Microbiology, Tufts University School of Medicine, 136 Harrison Ave., Boston, MA 02111, USA;
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Pilarczyk-Zurek M, Majka G, Skowron B, Baranowska A, Piwowar M, Strus M. The Multi-Component Causes of Late Neonatal Sepsis-Can We Regulate Them? Nutrients 2022; 14:nu14020243. [PMID: 35057424 PMCID: PMC8780644 DOI: 10.3390/nu14020243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 12/30/2021] [Accepted: 01/04/2022] [Indexed: 12/10/2022] Open
Abstract
Elucidating the mechanisms of bacterial translocation is crucial for the prevention and treatment of neonatal sepsis. In the present study, we aimed to evaluate the potential of lactoferrin to inhibit the development of late-onset blood infection in neonates. Our investigation evaluates the role of key stress factors leading to the translocation of intestinal bacteria into the bloodstream and, consequently, the development of life-threatening sepsis. Three stress factors, namely weaning, intraperitoneal administration of Gram-positive cocci and oral intake of Gram-negative rods, were found to act synergistically. We developed a novel model of rat pups sepsis induced by bacterial translocation and observed the inhibition of this process by supplementation of various forms of lactoferrin: iron-depleted (apolactoferrin), iron-saturated (hololactoferrin) and manganese-saturated lactoferrin. Additionally, lactoferrin saturated with manganese significantly increases the Lactobacillus bacterial population, which contributes to the fortification of the intestinal barrier and inhibits the translocation phenomenon. The acquired knowledge can be used to limit the development of sepsis in newborns in hospital neonatal intensive care units.
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Affiliation(s)
- Magdalena Pilarczyk-Zurek
- Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-387 Cracow, Poland;
- Chair of Microbiology, Faculty of Medicine, Jagiellonian University Medical College, 31-121 Cracow, Poland;
| | - Grzegorz Majka
- Chair of Microbiology, Faculty of Medicine, Jagiellonian University Medical College, 31-121 Cracow, Poland;
- Chair of Immunology, Faculty of Medicine, Jagiellonian University Medical College, 31-121 Cracow, Poland
| | - Beata Skowron
- Medical Department Diagnostyka S.A., 31-864 Cracow, Poland;
| | - Agnieszka Baranowska
- Chair of Pathophysiology, Faculty of Medicine, Jagiellonian University Medical College, 31-121 Cracow, Poland;
| | - Monika Piwowar
- Department of Bioinformatics and Telemedicine, Faculty of Medicine, Jagiellonian University Medical College, 30-688 Cracow, Poland;
| | - Magdalena Strus
- Chair of Microbiology, Faculty of Medicine, Jagiellonian University Medical College, 31-121 Cracow, Poland;
- Correspondence: ; Tel.: +48-12-633-25-67; Fax: +48-12-423-39-24
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Zeinali LI, Giuliano S, Lakshminrusimha S, Underwood MA. Intestinal Dysbiosis in the Infant and the Future of Lacto-Engineering to Shape the Developing Intestinal Microbiome. Clin Ther 2021; 44:193-214.e1. [PMID: 34922744 DOI: 10.1016/j.clinthera.2021.11.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Revised: 11/06/2021] [Accepted: 11/12/2021] [Indexed: 12/16/2022]
Abstract
PURPOSE The goal of this study was to review the role of human milk in shaping the infant intestinal microbiota and the potential of human milk bioactive molecules to reverse trends of increasing intestinal dysbiosis and dysbiosis-associated diseases. METHODS This narrative review was based on recent and historic literature. FINDINGS Human milk immunoglobulins, oligosaccharides, lactoferrin, lysozyme, milk fat globule membranes, and bile salt-stimulating lipase are complex multifunctional bioactive molecules that, among other important functions, shape the composition of the infant intestinal microbiota. IMPLICATIONS The co-evolution of human milk components and human milk-consuming commensal anaerobes many thousands of years ago resulted in a stable low-diversity infant microbiota. Over the past century, the introduction of antibiotics and modern hygiene practices plus changes in the care of newborns have led to significant alterations in the intestinal microbiota, with associated increases in risk of dysbiosis-associated disease. A better understanding of mechanisms by which human milk shapes the intestinal microbiota of the infant during a vulnerable period of development of the immune system is needed to alter the current trajectory and decrease intestinal dysbiosis and associated diseases.
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Affiliation(s)
- Lida I Zeinali
- Department of Pediatrics, UC Davis School of Medicine, Sacramento, CA, USA
| | | | | | - Mark A Underwood
- Department of Pediatrics, UC Davis School of Medicine, Sacramento, CA, USA.
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Hanford J, Mannebach K, Ohler A, Patten M, Pardalos J. Rates of Comorbidities in Very Low Birth Weight Infants Fed an Exclusive Human Milk Diet Versus a Bovine Supplemented Diet. Breastfeed Med 2021; 16:814-820. [PMID: 34415775 DOI: 10.1089/bfm.2020.0345] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Background: Our level III neonatal intensive care unit (NICU) implemented the use of an exclusive human milk diet (EHD) and sought to determine its effect on the severe co-morbidities of preterm infants as well as the potential cost-savings due to the anticipated reduction in these co-morbidities. Methods: A retrospective cohort study was completed to determine if an EHD statistically decreased the rate of co-morbidities including length of stay (LOS), days on total parental nutrition (TPN), rates of late onset sepsis, necrotizing enterocolitis (NEC), bronchopulmonary dysplasia (BPD), and severe retinopathy of prematurity (ROP). Results: An EHD significantly decreased the odds of severe ROP (adjusted odds-ratio (aOR)=0.349; 95%CI [0.156, 0.739]; p=0.008) and late onset sepsis (aOR=0.323; 95%CI [0.123, 0.768]; p=0.014). Analysis of cost-effectiveness of an EHD relative to a BSD based on the incremental costs of these co-morbidities determined the net loss in direct hospital costs per patient were estimated to be $420 in 2016 US dollars; however, given the long-term health-care costs and non-pecuniary damages from the co-morbidities of severe ROP and sepsis this net loss appears negligible. Conclusion: This study found that an EHD significantly decreased the odds of severe ROP and late onset sepsis; though not significant, there was a positive trend in decreasing cases of medical NEC; our surgical NEC rates dropped to 0. The benefits of human milk are vital, and the costs are nominal.
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Affiliation(s)
- Jennifer Hanford
- Division of Neonatology, Department of Child Health, Women's and Children's Hospital, University of Missouri Health Care, Columbia, Missouri, USA
| | - Kimberly Mannebach
- Division of Neonatology, Department of Child Health, Women's and Children's Hospital, University of Missouri Health Care, Columbia, Missouri, USA
| | - Adrienne Ohler
- Division of Neonatology, Department of Child Health, Women's and Children's Hospital, University of Missouri Health Care, Columbia, Missouri, USA
| | - Michael Patten
- Division of Neonatology, Department of Child Health, Women's and Children's Hospital, University of Missouri Health Care, Columbia, Missouri, USA
| | - John Pardalos
- Division of Neonatology, Department of Child Health, Women's and Children's Hospital, University of Missouri Health Care, Columbia, Missouri, USA
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24
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Utomo MT, Sumitro KR, Etika R, Widodo ADW. Current-proven neonatal sepsis in Indonesian tertiary neonatal intensive care unit: a hematological and microbiological profile. IRANIAN JOURNAL OF MICROBIOLOGY 2021; 13:266-273. [PMID: 34540164 PMCID: PMC8416597 DOI: 10.18502/ijm.v13i3.6386] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Background and Objectives: Neonatal sepsis is the third leading cause of neonatal death in the world. The patterns of pathogens causing neonatal sepsis varies in many countries. This study was aimed to identify hematological and microbiological profile of culture-proven neonatal sepsis in Indonesian tertiary neonatal intensive care unit (NICU). Materials and Methods: Hospital based cross-sectional study was conducted in all inborn neonates that were suspected sepsis neonatal over a period of six months from April to September 2019. Complete blood count, c-reactive protein (CRP) and blood culture were examined before antibiotic administration. Statistical analysis were calculated based on Chi-Square’s Test and Mann-Whitney U test and p <0.05 considered significant. Results: One hundred four inborn neonates admitted to NICU and diagnosed with suspected neonatal sepsis were recruited. Culture-proven neonatal sepsis were confirmed in 52 (50%) neonates, 13 (25%) in early-onset neonatal sepsis (EONS) and 39 (75%) in late-onset neonatal sepsis (LONS). The most common abnormal hematological profile were anemia and thrombocytopenia, with amount of 61.5% and 75%, respectively. High CRP only detected in 36.4% and only 18.5% experienced leukopenia. Gram negative bacteria responsible in 75% from total isolated pathogens. Klebsiella pneumoniae accounted for 48.1% followed by coagulase negative staphylococci (CONS) for 17.3% and Enterobacter cloacae for 11.5%. Conclusion: Anemia and thrombocytopenia were the top two hematological profile of culture-proven neonatal sepsis. Most causes of culture-proven neonatal sepsis were Gram negative bacteria and the dominant pathogen was K. pneumoniae.
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Affiliation(s)
- Martono Tri Utomo
- Department of Child Health, School of Medicine, Universitas Airlangga, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Khadijah Rizky Sumitro
- Department of Child Health, School of Medicine, Universitas Airlangga, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Risa Etika
- Department of Child Health, School of Medicine, Universitas Airlangga, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Agung Dwi Wahyu Widodo
- Department of Clinical Microbiology, School of Medicine, Universitas Airlangga, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
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25
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Li T, Shen K, Li J, Leung SWS, Zhu T, Shi Y. Glomerular Endothelial Cells Are the Coordinator in the Development of Diabetic Nephropathy. Front Med (Lausanne) 2021; 8:655639. [PMID: 34222276 PMCID: PMC8249723 DOI: 10.3389/fmed.2021.655639] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 05/21/2021] [Indexed: 12/22/2022] Open
Abstract
The prevalence of diabetes is consistently rising worldwide. Diabetic nephropathy is a leading cause of chronic renal failure. The present study aimed to explore the crosstalk among the different cell types inside diabetic glomeruli, including glomerular endothelial cells, mesangial cells, podocytes, and immune cells, by analyzing an online single-cell RNA profile (GSE131882) of patients with diabetic nephropathy. Differentially expressed genes in the glomeruli were processed by gene enrichment and protein-protein interactions analysis. Glomerular endothelial cells, as well as podocytes, play a critical role in diabetic nephropathy. A subgroup of glomerular endothelial cells possesses characteristic angiogenesis genes, indicating that angiogenesis takes place in the progress of diabetic nephropathy. Immune cells such as macrophages, T lymphocytes, B lymphocytes, and plasma cells also contribute to the disease progression. By using iTALK, the present study reports complicated cellular crosstalk inside glomeruli. Dysfunction of glomerular endothelial cells and immature angiogenesis result from the activation of both paracrine and autocrine signals. The present study reinforces the importance of glomerular endothelial cells in the development of diabetic nephropathy. The exploration of the signaling pathways involved in aberrant angiogenesis reported in the present study shed light on potential therapeutic target(s) for diabetic nephropathy.
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Affiliation(s)
- Tingting Li
- Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China.,Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Kaiyuan Shen
- Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jiawei Li
- Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China.,Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Susan W S Leung
- Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Tongyu Zhu
- Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China.,Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yi Shi
- Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China.,Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai, China
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26
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Huang F, Huang S. Active vitamin D3 attenuates the severity of Salmonella colitis in mice by orchestrating innate immunity. Immun Inflamm Dis 2021; 9:481-491. [PMID: 33559391 PMCID: PMC8127544 DOI: 10.1002/iid3.408] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 01/02/2021] [Accepted: 01/19/2021] [Indexed: 12/12/2022] Open
Abstract
INTRODUCTION Salmonella spp. pose major public health problems worldwide. A better understanding of the pathogenesis of these foodborne pathogens is a prerequisite for the design of improved intervention strategies that could reduce the use of antimicrobial agents and drug-resistant Salmonellosis. Accumulating evidence indicates that vitamin D is involved in regulating innate immunity, and may, therefore, play a key role in human responses to infection. Studies have suggested 1,25-dihydroxyvitamin D3 (1,25D3), the active form of vitamin D, effectively ameliorates colitis. These findings have broad implications for the use of vitamin D compounds in colitis. This study investigated the effect of active vitamin D3 on the severity of Salmonella colitis. METHODS A Salmonella colitis model was established with 6-8-week-old male C57BL/6 mice: Streptomycin-pretreated C57BL/6 mice were infected orally with Salmonella enterica serova Typhimurium wild-type strain SL1344 for 48 h. The mice were randomly assigned to control, model, and 1,25(OH)2 D3 -treated groups. After the experiment, the mice were sacrificed, and intestinal, spleen, and liver tissue samples were removed to analyze bacterial colonization, western blot for protein levels, and real-time-polymer chain reaction for messenger RNA (mRNA) expression. RESULTS We observed that 1,25D3 reduced the severity of Salmonella colitis in C57BL/6 mice by reducing cecal mIL-1beta, mIL-6, mTNF-alpha, and mIL-8 mRNA expressions, bacterial colonization (CFU/mg tissue) in the liver and spleen, but increased the human β-defensin-2 mRNA and autophagy protein expression, compared to those of the SL1344 infection only. CONCLUSIONS Our results document that active vitamin D3 reduced Salmonella colitis by decreasing inflammation, and bacterial translocation via induction of killing and autophagic clearance of pathogenic organisms.
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Affiliation(s)
- Fu‐Chen Huang
- Department of Pediatrics, Kaohsiung Chang Gung Memorial HospitalChang Gung University College of MedicineKaohsiungTaiwan
| | - Shun‐Chen Huang
- Department of PathologyKaohsiung Chang Gung Memorial HospitalKaohsiungTaiwan
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27
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Wu H, Wang Y, Li H, Meng L, Zheng N, Wang J. Effect of Food Endotoxin on Infant Health. Toxins (Basel) 2021; 13:298. [PMID: 33922125 PMCID: PMC8143472 DOI: 10.3390/toxins13050298] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 04/12/2021] [Accepted: 04/20/2021] [Indexed: 01/07/2023] Open
Abstract
Endotoxin is a complex molecule derived from the outer membrane of Gram-negative bacteria, and it has strong thermal stability. The processing of infant food can kill pathogenic bacteria but cannot remove endotoxin. Because the intestinal structure of infants is not fully developed, residual endotoxin poses a threat to their health by damaging the intestinal flora and inducing intestinal inflammation, obesity, and sepsis, among others. This paper discusses the sources and contents of endotoxin in infant food and methods for preventing endotoxin from harming infants. However, there is no clear evidence that endotoxin levels in infant food cause significant immune symptoms or even diseases in infants. However, in order to improve the safety level of infant food and reduce the endotoxin content, this issue should not be ignored. The purpose of this review is to provide a theoretical basis for manufacturers and consumers to understand the possible harm of endotoxin content in infant formula milk powder and to explore how to reduce its level in infant formula milk powder. Generally, producers should focus on cleaning the milk source, securing the cold chain, avoiding long-distance transportation, and shortening the storage time of raw milk to reduce the level of bacteria and endotoxin. After production and processing, the endotoxin content should be measured as an important index to test the quality of infant formula milk powder so as to provide high-quality infant products for the healthy growth of newborns.
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Affiliation(s)
- Haoming Wu
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (H.W.); (H.L.); (L.M.); (N.Z.)
- Laboratory of Quality and Safety Risk Assessment for Dairy Products of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China
- Key Laboratory of Quality & Safety Control for Milk and Dairy Products of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China
| | - Yang Wang
- State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua University-Peking University Joint Center for Life Sciences, Tsinghua University, Beijing 100084, China;
| | - Huiying Li
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (H.W.); (H.L.); (L.M.); (N.Z.)
- Laboratory of Quality and Safety Risk Assessment for Dairy Products of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China
- Key Laboratory of Quality & Safety Control for Milk and Dairy Products of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China
| | - Lu Meng
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (H.W.); (H.L.); (L.M.); (N.Z.)
- Laboratory of Quality and Safety Risk Assessment for Dairy Products of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China
- Key Laboratory of Quality & Safety Control for Milk and Dairy Products of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China
| | - Nan Zheng
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (H.W.); (H.L.); (L.M.); (N.Z.)
- Laboratory of Quality and Safety Risk Assessment for Dairy Products of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China
- Key Laboratory of Quality & Safety Control for Milk and Dairy Products of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China
| | - Jiaqi Wang
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (H.W.); (H.L.); (L.M.); (N.Z.)
- Laboratory of Quality and Safety Risk Assessment for Dairy Products of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China
- Key Laboratory of Quality & Safety Control for Milk and Dairy Products of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China
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Shifting focus toward healthcare-associated bloodstream infections: The need for neonatal intensive care unit-specific NHSN definitions. Infect Control Hosp Epidemiol 2021; 41:181-186. [PMID: 31694731 DOI: 10.1017/ice.2019.310] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Healthcare-associated bloodstream infections (HABSIs) are a significant cause of mortality and morbidity in the neonatal intensive care unit (NICU) population. Our objectives were to review the epidemiology of HABSIs in our NICU and to examine the applicability of National Healthcare Safety Network (NHSN) definitions to the NICU population. METHODS We performed a retrospective review of all neonates admitted to the 54-bed, level IV NICU at Yale-New Haven Children's Hospital with a HABSI between January 1, 2013, and December 31, 2018. Clinical definitions per NICU team and NHSN site-specific definitions used for source identification were compared using the McNemar χ2 test. RESULTS We identified 86 HABSIs with an incidence rate of 0.80 per 1,000 patient days. Only 13% of these were CLABSIs. Both CLABSIs and non-catheter-related bloodstream infections occurred primarily in preterm neonates, but the latter were associated with a significantly higher incidence of comorbidities and the need for respiratory support. The NHSN definitions were less likely to identify a source compared to the clinical definitions agreed upon by our NICU treating team (P < .001). Furthermore, 50% of patients without an identified source of infection by NHSN definitions were bacteremic with a mucosal barrier injury organism, likely from gut translocation. CONCLUSIONS HABSIs occur primarily in premature infants with comorbidities, and CLABSIs account for a small proportion of these infections. With the increasing focus on HABSI prevention, there is a need for better NHSN site-specific definitions for the NICU population to prevent misclassification and direct prevention efforts.
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Hattori N, Yamashiro Y. The Gut-Brain Axis. ANNALS OF NUTRITION AND METABOLISM 2021; 77 Suppl 2:1-3. [PMID: 33406517 DOI: 10.1159/000512226] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Accepted: 09/17/2020] [Indexed: 12/25/2022]
Affiliation(s)
- Nobutaka Hattori
- Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan
| | - Yuichiro Yamashiro
- Probiotics Research Laboratory, Juntendo University Graduate School of Medicine, Tokyo, Japan,
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Mezu-Ndubuisi OJ, Maheshwari A. The role of integrins in inflammation and angiogenesis. Pediatr Res 2021; 89:1619-1626. [PMID: 33027803 PMCID: PMC8249239 DOI: 10.1038/s41390-020-01177-9] [Citation(s) in RCA: 195] [Impact Index Per Article: 48.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 08/18/2020] [Accepted: 09/10/2020] [Indexed: 02/06/2023]
Abstract
Integrins are heterodimeric transmembrane cell adhesion molecules made up of alpha (α) and beta (β) subunits arranged in numerous dimeric pairings. These complexes have varying affinities to extracellular ligands. Integrins regulate cellular growth, proliferation, migration, signaling, and cytokine activation and release and thereby play important roles in cell proliferation and migration, apoptosis, tissue repair, as well as in all processes critical to inflammation, infection, and angiogenesis. This review presents current evidence from human and animal studies on integrin structure and molecular signaling, with particular emphasis on signal transduction in infants. We have included evidence from our own laboratory studies and from an extensive literature search in databases PubMed, EMBASE, Scopus, and the electronic archives of abstracts presented at the annual meetings of the Pediatric Academic Societies. To avoid bias in identification of existing studies, key words were short-listed prior to the actual search both from anecdotal experience and from PubMed's Medical Subject Heading (MeSH) thesaurus. IMPACT: Integrins are a family of ubiquitous αβ heterodimeric receptors that interact with numerous ligands in physiology and disease. Integrins play a key role in cell proliferation, tissue repair, inflammation, infection, and angiogenesis. This review summarizes current evidence from human and animal studies on integrin structure and molecular signaling and promising role in diseases of inflammation, infection, and angiogenesis in infants. This review shows that integrin receptors and ligands are novel therapeutic targets of clinical interest and hold promise as novel therapeutic targets in the management of several neonatal diseases.
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Affiliation(s)
- Olachi J. Mezu-Ndubuisi
- grid.14003.360000 0001 2167 3675Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI USA
| | - Akhil Maheshwari
- grid.21107.350000 0001 2171 9311Department of Pediatrics, Johns Hopkins University, Baltimore, MD USA
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Lactoferrin Metal Saturation-Which Form Is the Best for Neonatal Nutrition? Nutrients 2020; 12:nu12113340. [PMID: 33143055 PMCID: PMC7692973 DOI: 10.3390/nu12113340] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Accepted: 10/28/2020] [Indexed: 01/04/2023] Open
Abstract
We evaluated the impact of metal saturation of lactoferrin (with iron and manganese) on population numbers of pathogenic species relevant for neonatal sepsis that commonly originates from the gut due to bacterial translocation. Little attention has been paid to how metal ions bound to the protein affect its activity. Several reference and clinical strains as well as probiotic strains were incubated with different forms of lactoferrin: metal-depleted (apolactoferrin), iron-saturated (hololactoferrin) and manganese-saturated lactoferrin. We also attempted to confirm the observed effects of lactoferrin forms in vivo using rat pups. The observed decrease in population numbers of Gram-negative rods could not be confirmed by quantitative plating—lactoferrin may regulate these populations diversely (e.g., by anti-biofilm activity) and contribute to the inhibition of inflammatory response. We did not see any effect of lactoferrin forms on staphylococci and bifidobacteria. However, we have noted a significant increase of population numbers of Lactobacillus strains upon incubation with manganese-saturated lactoferrin. These results were confirmed in vivo in a rat model. Metal saturation is an underestimated factor regulating lactoferrin activity. Some forms are more potent in the inhibition of pathogenic species while others, such as manganese-saturated lactoferrin, could contribute to the restoration of gut homeostasis.
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Pillai A, Tan J, Paquette V, Panczuk J. Does probiotic bacteremia in premature infants impact clinically relevant outcomes? A case report and updated review of literature. Clin Nutr ESPEN 2020; 39:255-259. [PMID: 32859326 DOI: 10.1016/j.clnesp.2020.05.020] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Revised: 05/13/2020] [Accepted: 05/17/2020] [Indexed: 01/26/2023]
Abstract
Prophylactic use of probiotics decreases the incidence of necrotizing enterocolitis (NEC) in premature infants. However, there are ongoing concerns related to the routine use of probiotics including inconsistent literature regarding optimal dose and strain, lack of regulatory standards in production and reports regarding potential side effects. There is limited data regarding the incidence of probiotic bacteremia and its impact on relevant clinical outcomes in the premature population. We report the first case of Bifidobacterium longum bacteremia in our center since the routine introduction of probiotics. The neonate had NEC with perforation on day of life 7, which likely led to translocation of the probiotic strain to the blood stream. The neonate did not have any hemodynamic instability and the repeat blood culture was negative after starting antibiotic therapy. We also conducted a literature review and found 13 other cases of probiotic bacteremia in premature or very low birth weight neonates. Although the incidence of probiotic bacteremia is low, it can impact several clinical outcomes including prolonged exposure to antibiotics, removal of central lines and additional laboratory testing such as lumbar puncture. There has been no mortality attributable to probiotic bacteremia and there is no data regarding long term neurodevelopmental outcomes.
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Affiliation(s)
- Anish Pillai
- Division of Neonatology, Surya Mother and Child Super Specialty Hospital, Mumbai, Maharashtra, India.
| | - Jason Tan
- Department of Pharmacy, British Columbia Women's and Children's Hospital, Vancouver, BC, Canada; Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada.
| | - Vanessa Paquette
- Department of Pharmacy, British Columbia Women's and Children's Hospital, Vancouver, BC, Canada; Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada.
| | - Julia Panczuk
- Neonatal-Perinatal Medicine, Department of Pediatrics, British Columbia Women's Hospital and Health Centre, University of British Columbia, Vancouver, BC Canada.
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Roodsant T, Navis M, Aknouch I, Renes IB, van Elburg RM, Pajkrt D, Wolthers KC, Schultsz C, van der Ark KCH, Sridhar A, Muncan V. A Human 2D Primary Organoid-Derived Epithelial Monolayer Model to Study Host-Pathogen Interaction in the Small Intestine. Front Cell Infect Microbiol 2020; 10:272. [PMID: 32656095 PMCID: PMC7326037 DOI: 10.3389/fcimb.2020.00272] [Citation(s) in RCA: 82] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Accepted: 05/07/2020] [Indexed: 12/12/2022] Open
Abstract
Gut organoids are stem cell derived 3D models of the intestinal epithelium that are useful for studying interactions between enteric pathogens and their host. While the organoid model has been used for both bacterial and viral infections, this is a closed system with the luminal side being inaccessible without microinjection or disruption of the organoid polarization. In order to overcome this and simplify their applicability for transepithelial studies, permeable membrane based monolayer approaches are needed. In this paper, we demonstrate a method for generating a monolayer model of the human fetal intestinal polarized epithelium that is fully characterized and validated. Proximal and distal small intestinal organoids were used to generate 2D monolayer cultures, which were characterized with respect to epithelial cell types, polarization, barrier function, and gene expression. In addition, viral replication and bacterial translocation after apical infection with enteric pathogens Enterovirus A71 and Listeria monocytogenes were evaluated, with subsequent monitoring of the pro-inflammatory host response. This human 2D fetal intestinal monolayer model will be a valuable tool to study host-pathogen interactions and potentially reduce the use of animals in research.
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Affiliation(s)
- Thomas Roodsant
- Department of Global Health-Amsterdam Institute for Global Health and Development, Amsterdam University Medical Center (UMC), University of Amsterdam, Amsterdam, Netherlands.,Department of Medical Microbiology, Amsterdam University Medical Center (UMC), University of Amsterdam, Amsterdam, Netherlands
| | - Marit Navis
- Tytgat Institute for Intestinal and Liver Research, Amsterdam Gastroenterology Endocrinology and Metabolism, Amsterdam University Medical Center (UMC), University of Amsterdam, Amsterdam, Netherlands
| | - Ikrame Aknouch
- Department of Medical Microbiology, Amsterdam University Medical Center (UMC), University of Amsterdam, Amsterdam, Netherlands.,Viroclinics Xplore, Schaijk, Netherlands
| | - Ingrid B Renes
- Danone Nutricia Research, Utrecht, Netherlands.,Department of Pediatrics, Amsterdam University Medical Center (UMC), Emma Children's Hospital, University of Amsterdam, Amsterdam, Netherlands
| | - Ruurd M van Elburg
- Department of Pediatrics, Amsterdam University Medical Center (UMC), Emma Children's Hospital, University of Amsterdam, Amsterdam, Netherlands
| | - Dasja Pajkrt
- Department of Pediatric Infectious Diseases, Amsterdam University Medical Center (UMC), Emma Children's Hospital, University of Amsterdam, Amsterdam, Netherlands
| | - Katja C Wolthers
- Department of Medical Microbiology, Amsterdam University Medical Center (UMC), University of Amsterdam, Amsterdam, Netherlands
| | - Constance Schultsz
- Department of Global Health-Amsterdam Institute for Global Health and Development, Amsterdam University Medical Center (UMC), University of Amsterdam, Amsterdam, Netherlands.,Department of Medical Microbiology, Amsterdam University Medical Center (UMC), University of Amsterdam, Amsterdam, Netherlands
| | - Kees C H van der Ark
- Department of Global Health-Amsterdam Institute for Global Health and Development, Amsterdam University Medical Center (UMC), University of Amsterdam, Amsterdam, Netherlands.,Department of Medical Microbiology, Amsterdam University Medical Center (UMC), University of Amsterdam, Amsterdam, Netherlands
| | - Adithya Sridhar
- Department of Medical Microbiology, Amsterdam University Medical Center (UMC), University of Amsterdam, Amsterdam, Netherlands
| | - Vanesa Muncan
- Tytgat Institute for Intestinal and Liver Research, Amsterdam Gastroenterology Endocrinology and Metabolism, Amsterdam University Medical Center (UMC), University of Amsterdam, Amsterdam, Netherlands
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Antecedents of Objectively Diagnosed Diffuse White Matter Abnormality in Very Preterm Infants. Pediatr Neurol 2020; 106:56-62. [PMID: 32139164 PMCID: PMC7500641 DOI: 10.1016/j.pediatrneurol.2020.01.011] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Revised: 01/22/2020] [Accepted: 01/26/2020] [Indexed: 12/25/2022]
Abstract
BACKGROUND Diffuse white matter abnormality (diffuse excessive high signal intensity) is the most common finding on structural brain magnetic resonance imaging (MRI) at term-equivalent age in very preterm infants. Yet, there remains a large gap in our understanding of the etiology of diffuse white matter abnormality. Our objective was to evaluate perinatal and neonatal inflammation-associated antecedents of diffuse white matter abnormality on MRI. METHODS We prospectively enrolled 110 very preterm infants born at ≤31 weeks gestational age and collected data on multiple perinatal/neonatal exposures, especially inflammation initiating-illnesses. We performed structural MRI at term-equivalent age and quantified the volume of diffuse white matter abnormality objectively. Multivariable regression was used to identify clinical antecedents of diffuse white matter abnormality. RESULTS The mean (S.D.) birth gestational age of the final study sample of 98 very preterm infants was 28.3 (2.5) weeks. Multiple inflammation initiating-illnesses were associated with diffuse white matter abnormality in univariate analyses. In multivariable linear regression analyses controlling for gestational age, severe retinopathy of prematurity (P < 0.001) and bronchopulmonary dysplasia (P = 0.006) were independent risk factors, whereas maternal treatment with 17-hydroxyprogesterone (P < 0.001) was protective of later development of objectively quantified diffuse white matter abnormality. CONCLUSIONS We identified several perinatal and neonatal antecedent clinical factors associated with diffuse white matter abnormality. Although we found some support for inflammation as a common underlying mechanism, larger studies are needed to validate inflammation as a potential common pathway to the development of diffuse white matter abnormality in very preterm infants.
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Preclinical Detection of Non-catheter Related Late-onset Sepsis in Preterm Infants by Fecal Volatile Compounds Analysis: A Prospective, Multi-center Cohort Study. Pediatr Infect Dis J 2020; 39:330-335. [PMID: 32032172 DOI: 10.1097/inf.0000000000002589] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Late onset sepsis (LOS) in preterm infants is preceded by fecal volatile organic compound (VOC) alterations, suggesting an etiologic role of gut microbiota in LOS rather than being primarily caused by central venous catheters (CVC). To increase our knowledge about the involvement of the gut microbiota in LOS, we analyzed fecal samples from septic infants without a CVC. METHODS In this prospective multicenter study, fecal samples were collected daily from all infants born at ≤30 weeks gestation. Fecal VOC profiles up to 3 days prior to sepsis onset from infants with non-catheter-related LOS were compared with profiles from non-septic controls by means of High-Field Asymmetric Waveform Ion Mobility Spectrometry. RESULTS In total, 104 fecal samples were analyzed. Fecal VOC profiles allowed for discrimination between non-catheter-related LOS cases (n = 24) and matched controls (n = 25). Discriminative accuracy increased after focusing on center of origin (area under the curve, sensitivity, specificity; 0.95, 100%, 83%) and after focusing on LOS cases caused by Staphylococcus epidermidis (0.95, 100%, 78%), the most cultured pathogen (n = 11). CONCLUSIONS Fecal VOC profiles of preterm LOS infants without a CVC differed from matched controls underlining the increasing notion that aberrations in gut microbiota composition and activity may play a role in LOS etiology.
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Van Belkum M, Mendoza Alvarez L, Neu J. Preterm neonatal immunology at the intestinal interface. Cell Mol Life Sci 2020; 77:1209-1227. [PMID: 31576423 PMCID: PMC11105006 DOI: 10.1007/s00018-019-03316-w] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Revised: 08/21/2019] [Accepted: 09/19/2019] [Indexed: 12/17/2022]
Abstract
Fetal and neonatal development represents a critical window for setting a path toward health throughout life. In this review, we focus on intestinal immunity, how it develops, and its implications for subsequent neonatal diseases. We discuss maternal nutritional and environmental exposures that dictate outcomes for the developing fetus. Although still controversial, there is evidence in support of an in utero microbiome. Specific well-intentioned and routine applications of antibiotics, steroids, and surgical interventions implemented before, during, and after birth skew the neonate towards pro-inflammatory dysbiosis. Shortly after birth, a consortium of maternal and environmentally derived bacteria, through cross-talk with the developing host immune system, takes center stage in developing or disrupting immune homeostasis at the intestinal interface. We also examine subsequent immunological cross-talks, which involve neonatal myeloid and lymphoid responses, and their potential impacts on health and disease such as necrotizing enterocolitis and sepsis, especially critical disease entities for the infant born preterm.
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Affiliation(s)
- Max Van Belkum
- Division of Neonatology, Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL, 32610, USA
| | - Lybil Mendoza Alvarez
- Division of Neonatology, Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL, 32610, USA
| | - Josef Neu
- Division of Neonatology, Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL, 32610, USA.
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Chen C, Yin Q, Wu H, Cheng L, Kwon JI, Jin J, Han T, Che H. Different Effects of Premature Infant Formula and Breast Milk on Intestinal Microecological Development in Premature Infants. Front Microbiol 2020; 10:3020. [PMID: 32010090 PMCID: PMC6978717 DOI: 10.3389/fmicb.2019.03020] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Accepted: 12/17/2019] [Indexed: 01/07/2023] Open
Abstract
Intestinal microecology has been shown to participate in the pathogenesis of many diseases through different pathways, and the intestinal microecology of premature infants is significantly different from full-term infants. Intestinal microecology in premature infants is affected by various factors such as gestational age, diet, antibiotic use. However, there are few studies focus on the effects of diet on intestinal microecological development in premature infants. This study explored the different effects of the formula milk (FM) and breast milk (BM) for the development of intestinal microecology in premature infants. The results showed that BM feeding increases the alpha diversity of the intestinal flora, however, FM feeding contributes to the increase in short-chain fatty acids (SCFAs) in the gut of preterm infants. The growth environment has an important influence on the β diversity of intestinal microecology, the genomic function, and the evolution of intestinal microecology in premature infants. The intestinal microecology in premature infants is significantly associated with gestational age and weight gain. This study explored the effects of feeding methods and growth environment on intestinal microecology in premature infants, and provided a basis for promoting the healthy development of premature infants.
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Affiliation(s)
- Cheng Chen
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
| | - Qiuyue Yin
- Department of Neonatology, Nanpi County People's Hospital, Cangzhou, China
| | - Hui Wu
- Department of Neonatology, Peking University Third Hospital, Beijing, China
| | - Lei Cheng
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
| | - Jung-Il Kwon
- Maeil Innovation Center, Maeil Dairies Co., Ltd., Seoul, South Korea
| | - Juan Jin
- Maeil Innovation Center, Maeil Dairies Co., Ltd., Seoul, South Korea
| | - Tongyan Han
- Department of Neonatology, Peking University Third Hospital, Beijing, China
| | - Huilian Che
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
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Assessment of bioactivities of the human milk lactoferrin–osteopontin complex in vitro. J Nutr Biochem 2019; 69:10-18. [DOI: 10.1016/j.jnutbio.2019.03.016] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Revised: 01/28/2019] [Accepted: 03/14/2019] [Indexed: 02/02/2023]
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Srugo SA, Bloise E, Nguyen TTTN, Connor KL. Impact of Maternal Malnutrition on Gut Barrier Defense: Implications for Pregnancy Health and Fetal Development. Nutrients 2019; 11:nu11061375. [PMID: 31248104 PMCID: PMC6628366 DOI: 10.3390/nu11061375] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2019] [Revised: 05/31/2019] [Accepted: 06/10/2019] [Indexed: 12/16/2022] Open
Abstract
Small intestinal Paneth cells, enteric glial cells (EGC), and goblet cells maintain gut mucosal integrity, homeostasis, and influence host physiology locally and through the gut-brain axis. Little is known about their roles during pregnancy, or how maternal malnutrition impacts these cells and their development. Pregnant mice were fed a control diet (CON), undernourished by 30% vs. control (UN), or fed a high fat diet (HF). At day 18.5 (term = 19), gut integrity and function were assessed by immunohistochemistry and qPCR. UN mothers displayed reduced mRNA expression of Paneth cell antimicrobial peptides (AMP; Lyz2, Reg3g) and an accumulation of villi goblet cells, while HF had reduced Reg3g and mucin (Muc2) mRNA and increased lysozyme protein. UN fetuses had increased mRNA expression of gut transcription factor Sox9, associated with reduced expression of maturation markers (Cdx2, Muc2), and increased expression of tight junctions (TJ; Cldn-7). HF fetuses had increased mRNA expression of EGC markers (S100b, Bfabp, Plp1), AMP (Lyz1, Defa1, Reg3g), and TJ (Cldn-3, Cldn-7), and reduced expression of an AMP-activator (Tlr4). Maternal malnutrition altered expression of genes that maintain maternal gut homeostasis, and altered fetal gut permeability, function, and development. This may have long-term implications for host-microbe interactions, immunity, and offspring gut-brain axis function.
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Affiliation(s)
- Sebastian A Srugo
- Department of Health Sciences, Carleton University, Ottawa, ON K1S 5B6, Canada.
| | - Enrrico Bloise
- Department of Morphology, Federal University of Minas Gerais, Belo Horizonte 31270-901, Brazil.
| | | | - Kristin L Connor
- Department of Health Sciences, Carleton University, Ottawa, ON K1S 5B6, Canada.
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
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40
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Shimasaki T, Seekatz A, Bassis C, Rhee Y, Yelin RD, Fogg L, Dangana T, Cisneros EC, Weinstein RA, Okamoto K, Lolans K, Schoeny M, Lin MY, Moore NM, Young VB, Hayden MK. Increased Relative Abundance of Klebsiella pneumoniae Carbapenemase-producing Klebsiella pneumoniae Within the Gut Microbiota Is Associated With Risk of Bloodstream Infection in Long-term Acute Care Hospital Patients. Clin Infect Dis 2019; 68:2053-2059. [PMID: 30239622 PMCID: PMC6541703 DOI: 10.1093/cid/ciy796] [Citation(s) in RCA: 79] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2018] [Accepted: 09/10/2018] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND An association between increased relative abundance of specific bacterial taxa in the intestinal microbiota and bacteremia has been reported in some high-risk patient populations. METHODS We collected weekly rectal swab samples from patients at 1 long-term acute care hospital (LTACH) in Chicago from May 2015 to May 2016. Samples positive for Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) by polymerase chain reaction and culture underwent 16S rRNA gene sequence analysis; relative abundance of the operational taxonomic unit containing KPC-Kp was determined. Receiver operator characteristic (ROC) curves were constructed using results from the sample with highest relative abundance of KPC-Kp from each patient admission, excluding samples collected after KPC-Kp bacteremia. Cox regression analysis was performed to evaluate risk factors associated with time to achieve KPC-Kp relative abundance thresholds calculated by ROC curve analysis. RESULTS We collected 2319 samples from 562 admissions (506 patients); KPC-Kp colonization was detected in 255 (45.4%) admissions and KPC-Kp bacteremia in 11 (4.3%). A relative abundance cutoff of 22% predicted KPC-Kp bacteremia with sensitivity 73%, specificity 72%, and relative risk 4.2 (P = .01). In a multivariable Cox regression model adjusted for age, Charlson comorbidity index, and medical devices, carbapenem receipt was associated with achieving the 22% relative abundance threshold (P = .044). CONCLUSION Carbapenem receipt was associated with increased hazard for high relative abundance of KPC-Kp in the gut microbiota. Increased relative abundance of KPC-Kp was associated with KPC-Kp bacteremia. Whether bacteremia arose directly from bacterial translocation or indirectly from skin contamination followed by bloodstream invasion remains to be determined.
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Affiliation(s)
- Teppei Shimasaki
- Department of Internal Medicine, Division of Infectious Diseases, Rush University Medical Center, Chicago, Illinois
| | - Anna Seekatz
- Department of Internal Medicine, Division of Infectious Diseases, University of Michigan Medical School, Ann Arbor
| | - Christine Bassis
- Department of Internal Medicine, Division of Infectious Diseases, University of Michigan Medical School, Ann Arbor
| | - Yoona Rhee
- Department of Internal Medicine, Division of Infectious Diseases, Rush University Medical Center, Chicago, Illinois
| | - Rachel D Yelin
- Department of Internal Medicine, Division of Infectious Diseases, Rush University Medical Center, Chicago, Illinois
| | - Louis Fogg
- Department of Nursing, Rush University Medical Center, Chicago, Illinois
| | - Thelma Dangana
- Department of Internal Medicine, Division of Infectious Diseases, Rush University Medical Center, Chicago, Illinois
| | - Enrique Cornejo Cisneros
- Department of Internal Medicine, Division of Infectious Diseases, Rush University Medical Center, Chicago, Illinois
- Hospital Nacional Cayetano Heredia, Lima, Peru
| | - Robert A Weinstein
- Department of Internal Medicine, Division of Infectious Diseases, Rush University Medical Center, Chicago, Illinois
| | - Koh Okamoto
- Department of Internal Medicine, Division of Infectious Diseases, Rush University Medical Center, Chicago, Illinois
- University of Tokyo Hospital, Japan
| | - Karen Lolans
- Department of Internal Medicine, Division of Infectious Diseases, Rush University Medical Center, Chicago, Illinois
| | - Michael Schoeny
- Department of Nursing, Rush University Medical Center, Chicago, Illinois
| | - Michael Y Lin
- Department of Internal Medicine, Division of Infectious Diseases, Rush University Medical Center, Chicago, Illinois
| | - Nicholas M Moore
- Department of Internal Medicine, Division of Infectious Diseases, Rush University Medical Center, Chicago, Illinois
| | - Vincent B Young
- Department of Internal Medicine, Division of Infectious Diseases, University of Michigan Medical School, Ann Arbor
| | - Mary K Hayden
- Department of Internal Medicine, Division of Infectious Diseases, Rush University Medical Center, Chicago, Illinois
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Schüller SS, Kramer BW, Villamor E, Spittler A, Berger A, Levy O. Immunomodulation to Prevent or Treat Neonatal Sepsis: Past, Present, and Future. Front Pediatr 2018; 6:199. [PMID: 30073156 PMCID: PMC6060673 DOI: 10.3389/fped.2018.00199] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Accepted: 06/25/2018] [Indexed: 12/12/2022] Open
Abstract
Despite continued advances in neonatal medicine, sepsis remains a leading cause of death worldwide in neonatal intensive care units. The clinical presentation of sepsis in neonates varies markedly from that in older children and adults, and distinct acute inflammatory responses results in age-specific inflammatory and protective immune response to infection. This review first provides an overview of the neonatal immune system, then covers current mainstream, and experimental preventive and adjuvant therapies in neonatal sepsis. We also discuss how the distinct physiology of the perinatal period shapes early life immune responses and review strategies to reduce neonatal sepsis-related morbidity and mortality. A summary of studies that characterize immune ontogeny and neonatal sepsis is presented, followed by discussion of clinical trials assessing interventions such as breast milk, lactoferrin, probiotics, and pentoxifylline. Finally, we critically appraise future treatment options such as stem cell therapy, other antimicrobial protein and peptides, and targeting of pattern recognition receptors in an effort to prevent and/or treat sepsis in this highly vulnerable neonatal population.
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Affiliation(s)
- Simone S. Schüller
- Division of Neonatology, Pediatric Intensive Care & Neuropediatrics, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria
- Precision Vaccines Program, Division of Infectious Diseases, Department of Medicine, Boston Children's Hospital, Boston, MA, United States
- Harvard Medical School, Boston, MA, United States
| | - Boris W. Kramer
- Department of Pediatrics, Maastricht University Medical Centre (MUMC+), Maastricht, Netherlands
- School for Oncology and Developmental Biology (GROW), Maastricht University, Maastricht, Netherlands
| | - Eduardo Villamor
- Department of Pediatrics, Maastricht University Medical Centre (MUMC+), Maastricht, Netherlands
- School for Oncology and Developmental Biology (GROW), Maastricht University, Maastricht, Netherlands
| | - Andreas Spittler
- Department of Surgery, Research Labs & Core Facility Flow Cytometry, Medical University of Vienna, Vienna, Austria
| | - Angelika Berger
- Division of Neonatology, Pediatric Intensive Care & Neuropediatrics, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria
| | - Ofer Levy
- Precision Vaccines Program, Division of Infectious Diseases, Department of Medicine, Boston Children's Hospital, Boston, MA, United States
- Harvard Medical School, Boston, MA, United States
- Broad Institute of MIT and Harvard, Boston, MA, United States
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The premature infant gut microbiome during the first 6 weeks of life differs based on gestational maturity at birth. Pediatr Res 2018; 84:71-79. [PMID: 29795209 PMCID: PMC6082716 DOI: 10.1038/s41390-018-0022-z] [Citation(s) in RCA: 91] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Revised: 03/11/2018] [Accepted: 04/04/2018] [Indexed: 12/28/2022]
Abstract
BACKGROUND The impact of degree of prematurity at birth on premature infant gut microbiota has not been extensively studied in comparison to term infants in large cohorts. METHODS To determine the effect of gestational age at birth and postnatal exposures on gut bacterial colonization in infants, we analyzed 65 stool samples from 17 premature infants in the neonatal intensive care unit, as well as 13 samples from 13 mostly moderate-to-late premature infants and 189 samples from 176 term infants in the New Hampshire Birth Cohort Study. Gut colonization patterns were determined with 16S rDNA microbiome profiling. RESULTS Gut bacterial alpha-diversity differed between premature and term infants at 6 weeks of age, after adjusting for exposures (p = 0.027). Alpha-diversity varied between extremely premature (<28 weeks gestation) and very premature infants (≥28 but <32 weeks, p = 0.011), as well as between extremely and moderate-to-late premature infants (≥32 and <37 weeks, p = 0.004). Newborn antibiotic use among premature infants was associated with lower Bifidobacterium and Bacteroides abundance (p = 0.015 and p = 0.041). CONCLUSION Gestational age at birth and early antibiotic exposure have significant effects on the premature infant gut microbiota.
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43
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Gengaimuthu K. The Cross Contamination (Cross Colonization) Phenomenon of Probiotic Use in Neonatal Intensive Care Units: Putative Mechanisms and Clinical and Research Implications. Cureus 2018; 10:e2691. [PMID: 30050746 PMCID: PMC6059533 DOI: 10.7759/cureus.2691] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Accepted: 05/24/2018] [Indexed: 01/21/2023] Open
Abstract
In studies of probiotic use in neonates the phenomenon of cross contamination (cross colonization) of the control group neonates with the probiotics administered to the study group was observed and a hypothetical reanalysis of the presented data after statistically controlling this phenomenon unveils significant benefits resulting from probiotic therapy. This article discusses the putative pathogenesis of this phenomenon and its clinical and research implications.
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Khasbiullina NR, Shilova NV, Navakouski ME, Nokel AY, Knirel YA, Blixt O, Bovin NV. Repertoire of Abs primed by bacteria in gnotobiotic mice. Innate Immun 2018; 24:180-187. [PMID: 29546786 PMCID: PMC6852387 DOI: 10.1177/1753425918763524] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Revised: 01/27/2018] [Accepted: 02/13/2018] [Indexed: 11/16/2022] Open
Abstract
Innate immunity natural Abs (NAbs) execute a number of functions, including protection and surveillance. Despite active research, the stimuli that induce the formation of NAbs are still described only hypothetically. Here, we compared repertoires of anti-glycan Abs in the peripheral blood of mice that received per os various bacteria. The repertoires of Abs of mice primed in this way were compared using a microarray that included about 350 glycans, as well as 150 bacterial polysaccharides. Sterile mice did not possess anti-glycan Abs. Oral inoculation of a single strain or combination of two to four strains of bacteria, as well as putting the animals on short-term nutrition with non-sterile food, did not contribute significantly to the formation of Abs, whereas a single gavage of digested food of non-sterile mice induced the formation of a repertoire close to the natural ones. Interestingly, the priming with polysaccharide Ags (in a composition of the bacterial cell envelope), that is, dominant Ags of bacteria, led to the induction of Abs against typical glycans of mammalian glycoproteins and glycolipids (e.g. Abs of the ABH blood group system) that do not have a structural similarity to the polysaccharides. The results support the importance of early contact with a naïve immune system with microorganisms of the environment to form a normal NAbs repertoire.
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Affiliation(s)
- Nailia R Khasbiullina
- Shemyakin-Ovchinnikov Institute of
Bioorganic Chemistry, Russian Academy of Sciences, Russia
- Zelinsky Institute of Organic Chemistry,
Russian Academy of Sciences, Russia
| | - Nadezhda V Shilova
- Shemyakin-Ovchinnikov Institute of
Bioorganic Chemistry, Russian Academy of Sciences, Russia
| | - Maxim E Navakouski
- Shemyakin-Ovchinnikov Institute of
Bioorganic Chemistry, Russian Academy of Sciences, Russia
| | - Alexey Yu Nokel
- Shemyakin-Ovchinnikov Institute of
Bioorganic Chemistry, Russian Academy of Sciences, Russia
| | - Yuri A Knirel
- Zelinsky Institute of Organic Chemistry,
Russian Academy of Sciences, Russia
| | - Ola Blixt
- University of Copenhagen, Department of
Chemistry, Denmark
| | - Nicolai V Bovin
- Shemyakin-Ovchinnikov Institute of
Bioorganic Chemistry, Russian Academy of Sciences, Russia
- Auckland University of Technology, New
Zealand
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Moschopoulos C, Kratimenos P, Koutroulis I, Shah BV, Mowes A, Bhandari V. The Neurodevelopmental Perspective of Surgical Necrotizing Enterocolitis: The Role of the Gut-Brain Axis. Mediators Inflamm 2018; 2018:7456857. [PMID: 29686534 PMCID: PMC5866871 DOI: 10.1155/2018/7456857] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2017] [Revised: 01/22/2018] [Accepted: 02/05/2018] [Indexed: 02/07/2023] Open
Abstract
This state-of-the-art review article aims to highlight the most recent evidence about the therapeutic options of surgical necrotizing enterocolitis, focusing on the molecular basis of the gut-brain axis in relevance to the neurodevelopmental outcomes of primary peritoneal drainage and primary laparotomy. Current evidence favors primary laparotomy over primary peritoneal drainage as regards neurodevelopment in the surgical treatment of necrotizing enterocolitis. The added exposure to inhalational anesthesia in infants undergoing primary laparotomy is an additional confounding variable but requires further study. The concept of the gut-brain axis suggests that bowel injury initiates systemic inflammation potentially affecting the developing central nervous system. Signals about microbes in the gut are transduced to the brain and the limbic system via the enteric nervous system, autonomic nervous system, and hypothalamic-pituitary axis. Preterm infants with necrotizing enterocolitis have significant differences in the diversity of the microbiome compared with preterm controls. The gut bacterial flora changes remarkably prior to the onset of necrotizing enterocolitis with a predominance of pathogenic organisms. The type of initial surgical approach correlates with the length of functional gut and microbiome equilibrium influencing brain development and function through the gut-brain axis. Existing data favor patients who were treated with primary laparotomy over those who underwent primary peritoneal drainage in terms of neurodevelopmental outcomes. We propose that this is due to the sustained injurious effect of the remaining diseased and necrotic bowel on the developing newborn brain, in patients treated with primary peritoneal drainage, through the gut-brain axis and probably not due to the procedure itself.
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Affiliation(s)
- Chariton Moschopoulos
- 1Department of Pediatrics, Flushing Hospital Medical Center, SUNY-Stonybrook School of Medicine, Flushing, NY, USA
| | - Panagiotis Kratimenos
- 2Division of Neonatology and Center for Research in Neuroscience, Children's National Medical Center, George Washington University School of Medicine, Washington, DC, USA
| | - Ioannis Koutroulis
- 3Department of Emergency Medicine, Children's National Medical Center, George Washington University School of Medicine, Washington, DC, USA
| | - Bhairav V. Shah
- 4Division of Pediatric Surgery, Palmetto Health Children's Hospital, University of South Carolina School of Medicine, Columbia, SC, USA
| | - Anja Mowes
- 5St. Christopher's Hospital for Children, Drexel University College of Medicine, Philadelphia, PA, USA
| | - Vineet Bhandari
- 5St. Christopher's Hospital for Children, Drexel University College of Medicine, Philadelphia, PA, USA
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Qian T, Zhang R, Zhu L, Shi P, Yang J, Yang CY, Chen DM, Shi JY, Zhou XG, Qiu YP, Yang Y, He L, He SR, Cao YT, Wei QF, Kumar M, Chen C. Necrotizing enterocolitis in low birth weight infants in China: Mortality risk factors expressed by birth weight categories. Pediatr Neonatol 2017; 58:509-515. [PMID: 28528756 DOI: 10.1016/j.pedneo.2016.10.004] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2016] [Revised: 09/21/2016] [Accepted: 10/14/2016] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND We retrospectively investigated incidence, morbidity, and mortality of neonatal necrotizing enterocolitis in China, with special emphasis on determining the predictors of necrotizing enterocolitis associated mortality. METHODS We identified neonates as having necrotizing enterocolitis if they met the accepted diagnostic criterion. Data pertaining to antenatal period, labor and birth, and the postnatal course of illness were collected. Multivariate analysis and logistic regression were used to analyze the risk factors. RESULTS There were 1167 cases of necrotizing enterocolitis identified from the 95 participating NICUs in mainland China in 2011, with the incidence of 2.50% and 4.53% in LBW (birth weight <2500 g) and VLBW (birth weight <1500 g) infants, respectively. Stage 1, 2 and 3 diseases were noted in 51.1%, 30.3% and 18.6% of cases respectively. The mortality from stage 2 and 3 necrotizing enterocolitis in this cohort was 41.7%. In VLBW infants, the important risk factors for mortality were small for gestation age (OR: 5.02, 95% CI 1.73-14.6; P = 0.003) and stage 3 NEC (OR: 8.09, 95% CI 2.80-23.3, P < 0.001). In moderate LBW infants (birth weight 1500-2499 g), the risk factors identified for mortality were sepsis during hospitalization (OR: 2.59, 95% CI 1.57-4.28, P < 0.001) and stage 3 NEC (OR: 5.37, 95% CI 3.24-8.90; P < 0.001). CONCLUSIONS Necrotizing enterocolitis remains an important cause of morbidity and mortality in prematurely born neonates in Chinese neonatal units. Awareness of the associated risk factors and appropriate interventions may improve the outcome of necrotizing enterocolitis in different birth weight subgroup.
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Affiliation(s)
- Tian Qian
- Children's Hospital of Fudan University and the Laboratory of Neonatal Diseases of Ministry of Health, Shanghai, China
| | - Rong Zhang
- Children's Hospital of Fudan University and the Laboratory of Neonatal Diseases of Ministry of Health, Shanghai, China
| | - Li Zhu
- Children's Hospital of Fudan University and the Laboratory of Neonatal Diseases of Ministry of Health, Shanghai, China
| | - Peng Shi
- Children's Hospital of Fudan University and the Laboratory of Neonatal Diseases of Ministry of Health, Shanghai, China
| | - Jie Yang
- Guangdong Provincial Maternity Hospital, Guangzhou, China
| | | | | | - Jing-Yun Shi
- Gansu Provincial Maternity Hospital, Lanzhou, China
| | - Xiao-Guang Zhou
- Nanjing Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Yin-Ping Qiu
- General Hospital of Ningxia Medical University, Yinchuan, China
| | - Yong Yang
- Dongguan Maternity Hospital, Dongguan, China
| | - Ling He
- Jiangxi Provincial Children's Hospital, Nanchang, China
| | - Shao-Ru He
- Guangdong Provincial People's Hospital, Guangzhou, China
| | - Yun-Tao Cao
- Affiliated Hospital of Zunyi Medical College, Zunyi, China
| | - Qiu-Fen Wei
- Maternal and Child Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | | | - Chao Chen
- Children's Hospital of Fudan University and the Laboratory of Neonatal Diseases of Ministry of Health, Shanghai, China.
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Role of HIV exposure and infection in relation to neonatal GBS disease and rectovaginal GBS carriage: a systematic review and meta-analysis. Sci Rep 2017; 7:13820. [PMID: 29062060 PMCID: PMC5653843 DOI: 10.1038/s41598-017-13218-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2017] [Accepted: 09/20/2017] [Indexed: 12/31/2022] Open
Abstract
Streptococcus agalactiae (GBS) is the leading cause worldwide of neonatal sepsis. We sought to assess to which extent HIV exposure of neonates is associated with GBS neonatal disease. Furthermore, we assessed to which extent HIV infection in women is associated with maternal rectovaginal GBS carriage, the single most important risk factor for GBS neonatal disease. We searched Pubmed, Embase, and Web of Science for studies assessing the association between neonatal GBS disease and HIV-status of the mother and studies that assessed the association between rectovaginal GBS colonization and HIV status in women. HIV-exposed uninfected neonates were more than twice as likely to have neonatal GBS disease compared to unexposed neonates. HIV-exposed neonates were not at increased risk for early-onset neonatal disease, but were 4.43 times more likely to have late-onset neonatal GBS disease. There was no significant association between HIV infection status and rectovaginal GBS carriage. Public health interventions preventing neonatal GBS disease are urgently needed for the increasing group of HIV-exposed neonates. A framework integrating and explaining our findings highlights opportunities for the clinical practice and global health policy to prevent disease. Well-designed studies should clarify the relation between HIV-status and GBS carriage.
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48
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Detection of Sepsis in Preterm Infants by Fecal Volatile Organic Compounds Analysis: A Proof of Principle Study. J Pediatr Gastroenterol Nutr 2017; 65:e47-e52. [PMID: 27846067 DOI: 10.1097/mpg.0000000000001471] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
OBJECTIVES Several studies associated altered gut microbiota composition in preterm infants with late-onset sepsis (LOS), up to days before clinical onset of sepsis. Microbiota analysis as early diagnostic biomarker is, however, in clinical practice currently not feasible because of logistic aspects and high costs. Therefore, we hypothesized that analysis of fecal volatile organic compounds (VOCs) may serve as noninvasive biomarker to predict LOS at a preclinical stage, because VOC reflect the composition and activity of intestinal microbial communities. METHODS In a prospective multicenter study, fecal samples were collected daily from infants with a gestational age of <30 weeks. VOC signatures of fecal samples from infants with LOS, collected up to 5 days before diagnosis, were analyzed by means of an electronic nose technology (Cyranose 320) and compared to matched controls. RESULTS Fecal VOC profiles of infants with LOS (n = 36) could be discriminated from controls (n = 40) at 3 days (area under the curve [±95% confidence interval], P value, sensitivity, specificity; 70.2 [52.2-88.3], 0.033, 57.1%, 61.5%), 2 days (77.7 [62.7-92.7], 0.050, 75.0%, 70.8%), and 1 day (70.4 [49.6-91.3], 0.037, 64.3%, 64.3%) before the onset of LOS. CONCLUSIONS Fecal VOC profiles of preterm infants with LOS could be discriminated from matched controls, up to 3 days before clinical onset of the disease, underlining the hypothesis that intestinal microbiota may play an etiological role in LOS. Notably, VOC profiling is clinically feasible and the potential of this technique in the early detection of LOS needs to be confirmed in future studies.
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49
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Embleton ND, Berrington JE, Dorling J, Ewer AK, Juszczak E, Kirby JA, Lamb CA, Lanyon CV, McGuire W, Probert CS, Rushton SP, Shirley MD, Stewart CJ, Cummings SP. Mechanisms Affecting the Gut of Preterm Infants in Enteral Feeding Trials. Front Nutr 2017; 4:14. [PMID: 28534028 PMCID: PMC5420562 DOI: 10.3389/fnut.2017.00014] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2017] [Accepted: 04/18/2017] [Indexed: 12/20/2022] Open
Abstract
Large randomized controlled trials (RCTs) in preterm infants offer unique opportunities for mechanistic evaluation of the risk factors leading to serious diseases, as well as the actions of interventions designed to prevent them. Necrotizing enterocolitis (NEC) a serious inflammatory gut condition and late-onset sepsis (LOS) are common feeding and nutrition-related problems that may cause death or serious long-term morbidity and are key outcomes in two current UK National Institutes for Health Research (NIHR) trials. Speed of increasing milk feeds trial (SIFT) randomized preterm infants to different rates of increases in milk feeds with a primary outcome of survival without disability at 2 years corrected age. Enteral lactoferrin in neonates (ELFIN) randomizes infants to supplemental enteral lactoferrin or placebo with a primary outcome of LOS. This is a protocol for the mechanisms affecting the gut of preterm infants in enteral feeding trials (MAGPIE) study and is funded by the UK NIHR Efficacy and Mechanistic Evaluation programme. MAGPIE will recruit ~480 preterm infants who were enrolled in SIFT or ELFIN. Participation in MAGPIE does not change the main trial protocols and uses non-invasive sampling of stool and urine, along with any residual resected gut tissue if infants required surgery. Trial interventions may involve effects on gut microbes, metabolites (e.g., short-chain fatty acids), and aspects of host immune function. Current hypotheses suggest that NEC and/or LOS are due to a dysregulated immune system in the context of gut dysbiosis, but mechanisms have not been systematically studied within large RCTs. Microbiomic analysis will use next-generation sequencing, and metabolites will be assessed by mass spectrometry to detect volatile organic and other compounds produced by microbes or the host. We will explore differences between disease cases and controls, as well as exploring the actions of trial interventions. Impacts of this research are multiple: translation of knowledge of mechanisms promoting gut health may explain outcomes or suggest alternate strategies to improve health. Results may identify new non-invasive diagnostic or monitoring techniques, preventative or treatment strategies for NEC or LOS, or provide data useful for risk stratification in future studies. Mechanistic evaluation might be especially informative where there are not clear effects on the primary outcome (ISRCTN 12554594).
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Affiliation(s)
- Nicholas D Embleton
- Newcastle Neonatal Service, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.,Institute of Health and Society, Newcastle University, Newcastle upon Tyne, UK
| | - Janet E Berrington
- Newcastle Neonatal Service, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.,Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
| | - Jon Dorling
- School of Medicine, University of Nottingham, Nottingham, UK
| | - Andrew K Ewer
- College of Medical and Dental Sciences, Institute of Metabolism and Systems Research, Birmingham University, Birmingham, UK
| | | | - John A Kirby
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
| | - Christopher A Lamb
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
| | - Clare V Lanyon
- Department for Biomedical Sciences, School of Life Sciences, Northumbria University, Newcastle upon Tyne, UK
| | - William McGuire
- Centre for Reviews and Dissemination, University of York, York, UK
| | - Christopher S Probert
- Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | | | - Mark D Shirley
- School of Biology, Newcastle University, Newcastle upon Tyne, UK
| | - Christopher J Stewart
- Department for Biomedical Sciences, School of Life Sciences, Northumbria University, Newcastle upon Tyne, UK.,Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA
| | - Stephen P Cummings
- School of Science and Engineering, Teesside University, Middlesbrough, UK
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50
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Galvão M, Bastos R, Acurcio L, Nascimento B, Sandes S, Arantes R, Souza M, Martins F, Vieira L, Nicoli J. Evaluation of colonisation resistance in stool of human donors using ex vivo, in vitro and in vivo assays. Benef Microbes 2017; 8:217-230. [DOI: 10.3920/bm2016.0027] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
The indigenous microbiota is the population of microorganisms normally present on the surface and mucosa of an individual, where it performs essential health functions, including the colonisation resistance (CR) against pathogens. To identify the bacteria responsible and the mechanisms involved in the CR, the germ-free (GF) animal model has been used, because in vitro studies cannot always be extrapolated to what occurs in vivo. In this study, ex vivo antagonism assays against seven enteropathogenic bacteria using stools from 15 healthy human donors confirmed that the CR showed individual variation. Using in vitro antagonism assays, 14 strains isolated from dominant faecal microbiota of donors with elevated CR were selected for mono-association in GF mice to test the in vivo antagonism against Salmonella enterica ser. Typhimurium. Mice mono-associated with Enterococcus hirae strain 8.2, Bacteroides thetaiotaomicron strain 16.2 and Lactobacillus ruminis strain 18.1 had significant reductions in faecal counts of the pathogen during the challenge. After five days of infection, the group associated with E. hirae 8.2 showed a reduction in the translocation of S. Typhimurium to the spleen, while the group associated with L. ruminis 18.1 presented an increased translocation to the liver. The histological data confirmed these results and revealed that the mice associated with E. hirae 8.2 showed fewer lesions on ileum and liver, compared to the damage caused by S. Typhimurium alone, while in mice associated with L. ruminis 18.1 there was significantly worse lesions. Concluding, from the dominant faecal microbiota from healthy human with high CR, through ex vivo, in vitro and in vivo assays, a bacterium was characterised for its high CR potential, being a candidate for probiotic use.
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Affiliation(s)
- M.F. Galvão
- Departamento de Microbiologia, Universidade Federal de Minas Gerais, Avenida Antônio Carlos 6627, C.P. 486, Belo Horizonte, MG 31270-901, Brazil
| | - R.W. Bastos
- Departamento de Microbiologia, Universidade Federal de Minas Gerais, Avenida Antônio Carlos 6627, C.P. 486, Belo Horizonte, MG 31270-901, Brazil
| | - L.B. Acurcio
- Departamento de Microbiologia, Universidade Federal de Minas Gerais, Avenida Antônio Carlos 6627, C.P. 486, Belo Horizonte, MG 31270-901, Brazil
| | - B.B. Nascimento
- Departamento de Patologia Geral, Universidade Federal de Minas Gerais, Avenida Antonio Carlos 6627, C.P. 486, Belo Horizonte, MG 31270-901, Brazil
| | - S.H.C. Sandes
- Departamento de Biologia Geral, Universidade Federal de Minas Gerais, Avenida Antônio Carlos 6627, Belo Horizonte, MG 31270-901, Brazil
| | - R.M.E. Arantes
- Departamento de Patologia Geral, Universidade Federal de Minas Gerais, Avenida Antonio Carlos 6627, C.P. 486, Belo Horizonte, MG 31270-901, Brazil
| | - M.R. Souza
- Escola de Veterinária, Inspeção e Tecnologia de Produtos de Origem Animal, Universidade Federal de Minas Gerais, Avenida Antônio Carlos 6627, Belo Horizonte, MG 30123-970, Brazil
| | - F.S. Martins
- Departamento de Microbiologia, Universidade Federal de Minas Gerais, Avenida Antônio Carlos 6627, C.P. 486, Belo Horizonte, MG 31270-901, Brazil
| | - L.Q. Vieira
- Departamento de Imunologia-Bioquímica, Universidade Federal de Minas Gerais, Avenida Antônio Carlos 6627, Belo Horizonte, MG 30123-970, Brazil
| | - J.R. Nicoli
- Departamento de Microbiologia, Universidade Federal de Minas Gerais, Avenida Antônio Carlos 6627, C.P. 486, Belo Horizonte, MG 31270-901, Brazil
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