1
|
Hackam DJ. A developmental role for toll like receptor 4 in the neonatal intestine. Pediatr Res 2025:10.1038/s41390-025-03900-w. [PMID: 39910350 DOI: 10.1038/s41390-025-03900-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Accepted: 12/31/2024] [Indexed: 02/07/2025]
Affiliation(s)
- David J Hackam
- Division of Pediatric Surgery, Johns Hopkins University, Baltimore, USA.
| |
Collapse
|
2
|
DeVette CI, Sugino K, Wilson A, Fuller K, Friedman JE, Burge KY, Chaaban H. Genomic interrogation of commercial infant probiotic products for label accuracy. Pediatr Res 2025:10.1038/s41390-025-03831-6. [PMID: 39856233 DOI: 10.1038/s41390-025-03831-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 12/09/2024] [Accepted: 12/16/2024] [Indexed: 01/27/2025]
Abstract
OBJECTIVE To evaluate the label accuracy of commercial infant probiotic products and identify potential microbial contamination. METHODS DNA was extracted from seventeen infant probiotic products purchased from a large online vendor. Samples underwent 16S ribosomal RNA gene sequencing, QIIME analysis, and bacterial taxonomic classification. Identified bacterial species were compared with product labels for label accuracy and potential contaminants. Additionally, fungal DNA was amplified using qPCR with universal 18S fungal primers, and cultures were performed to assess viability. RESULTS Over 82% of bacterial DNA extracted from samples corresponded to species listed on product labels. Contaminating bacteria were closely related species. Lot-to-lot variation in bacterial species abundance was greater in multi-strain products compared with single-strain products. Fungal DNA was detected in some samples, but culture results indicated these organisms were not viable. CONCLUSIONS This pilot study highlights that most bacterial species in commercial infant probiotic products are accurately represented on labels. Single-strain products reliably match product labels whereas multi-strain products were more prone to variation of species abundance and species omission. Additionally, fungal contamination of limited samples was not viable. These findings emphasize the need for improved regulatory guidelines and standardization of probiotic products, particularly those marketed for infants. IMPACT Commercial infant probiotic products were interrogated for label accuracy using 16S ribosomal RNA sequencing. Most bacterial species in commercial infant probiotic products are accurately represented on labels without pathogenic bacterial contamination. Live fungal contamination is absent. To date, no studies have interrogated infant probiotic products on this scale (other studies have been limited to single or dual strain infant probiotics). Since probiotics lack FDA regulation, this pilot study provides important information for pediatricians and consumers, further highlighting the need for improved quality control and standardization of probiotics.
Collapse
Affiliation(s)
- Christa I DeVette
- Department of Pediatrics, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
- Oklahoma Children's Hospital, Oklahoma City, OK, USA.
| | - Kameron Sugino
- Harold Hamm Diabetes Center, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Adam Wilson
- Department of Pediatrics, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Kevin Fuller
- Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Department of Microbiology & Immunology, The University of Oklahoma Health Sciences Center, Oklahoma City, USA
| | - Jacob E Friedman
- Harold Hamm Diabetes Center, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Kathryn Y Burge
- Department of Pediatrics, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Hala Chaaban
- Department of Pediatrics, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Oklahoma Children's Hospital, Oklahoma City, OK, USA
| |
Collapse
|
3
|
De Bernardo G, Ziello C, Parisi G, Vecchione C, Fattorusso V, Spadarella S, Giordano M, Buonocore G, Perrone S. Clinical Picture, Diagnosis, Management of NEC, and Effects of Probiotics on its Prevention: A Narrative Review. Curr Pediatr Rev 2025; 21:104-110. [PMID: 39129157 DOI: 10.2174/0115733963317134240801113609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2024] [Revised: 06/19/2024] [Accepted: 06/25/2024] [Indexed: 08/13/2024]
Abstract
Preterm newborns represent a population at risk of developing intestinal dysbiosis as well as being predisposed to sepsis and Necrotizing Enterocolitis. Necrotizing Enterocolitis is a condition burdened by many complications and mortality due to an alteration of the intestinal barrier, an immaturity of the immune system, and intestinal dysbiosis. Low gestational age at birth, low birth weight, and early use of antibiotics are other predisposing factors. Instead, breast milk and probiotics are protective factors in providing intestinal homeostasis and microbiome regulation. In this mini-review, we analysed the protective role of probiotics in the onset of Necrotizing Enterocolitis in preterm populations.
Collapse
MESH Headings
- Humans
- Probiotics/therapeutic use
- Enterocolitis, Necrotizing/prevention & control
- Enterocolitis, Necrotizing/diagnosis
- Enterocolitis, Necrotizing/therapy
- Infant, Newborn
- Infant, Premature
- Gastrointestinal Microbiome
- Infant, Premature, Diseases/prevention & control
- Infant, Premature, Diseases/therapy
- Infant, Premature, Diseases/diagnosis
- Infant, Premature, Diseases/microbiology
- Milk, Human/microbiology
- Dysbiosis
Collapse
Affiliation(s)
- Giuseppe De Bernardo
- Department of Woman and Child, Buon Consiglio Fatebenefratelli Hospital, Naples, Italy
| | - Carla Ziello
- Division of Pediatrics, Department of Transaltional Medical Sciences, University of Naples Federico II, Naples, Italy
| | - Grazia Parisi
- Division of Pediatrics, Department of Transaltional Medical Sciences, University of Naples Federico II, Naples, Italy
| | - Carolina Vecchione
- Division of Pediatrics, Department of Transaltional Medical Sciences, University of Naples Federico II, Naples, Italy
| | - Valentina Fattorusso
- Department of Woman and Child, Buon Consiglio Fatebenefratelli Hospital, Naples, Italy
| | - Simona Spadarella
- Department of Woman and Child, Buon Consiglio Fatebenefratelli Hospital, Naples, Italy
| | - Maurizio Giordano
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Giuseppe Buonocore
- Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy
| | - Serafina Perrone
- Neonatology Unit, Department of Medicine and Surgery, University of Parma, Pietro Barilla Children's Hospital, Parma, Italy
| |
Collapse
|
4
|
Shah S. The "pro" and "con" of probiotics, regulation and preterm infant health. Pediatr Res 2024:10.1038/s41390-024-03766-4. [PMID: 39633020 DOI: 10.1038/s41390-024-03766-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Accepted: 11/04/2024] [Indexed: 12/07/2024]
Affiliation(s)
- Shetal Shah
- Division of Neonatology, Department of Pediatrics, Maria Fareri Children's Hospital, New York Medical College, Valhalla, NY, USA.
| |
Collapse
|
5
|
Verhoeven R, Kupers T, Brunsch CL, Hulscher JBF, Kooi EMW. Using Vital Signs for the Early Prediction of Necrotizing Enterocolitis in Preterm Neonates with Machine Learning. CHILDREN (BASEL, SWITZERLAND) 2024; 11:1452. [PMID: 39767881 PMCID: PMC11674918 DOI: 10.3390/children11121452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 11/22/2024] [Accepted: 11/27/2024] [Indexed: 01/11/2025]
Abstract
BACKGROUND/OBJECTIVES Necrotizing enterocolitis (NEC), a devastating neonatal gastrointestinal disease mostly seen in preterm infants, lacks accurate prediction despite known risk factors. This hinders the possibility of applying targeted preventive therapies. This study explores the use of vital signs, including cerebral and splanchnic oxygenation, measured with near-infrared spectroscopy in early NEC prediction. METHODS Several machine learning algorithms were trained on data from very preterm patients (<30 weeks gestational age). Time Series FeatuRe Extraction on the basis of scalable hypothesis tests (TSFRESH) extracted significant features from the vital signs of the first 5 postnatal days. We present the F1-scores and area under the precision-recall curve (AUC-PR) of the models. The contribution of separate vital signs to the selected TSFRESH features was also determined. RESULTS Among 267 patients, 32 developed NEC Bell's stage > 1. Using a 1:4 NEC:control ratio, support vector machine and logistic regression predicted NEC better than extreme gradient boosting regarding the F1-score (0.82, 0.82, 0.76, resp., p = 0.001) and AUC-PR (0.82, 0.83, 0.77, resp., p < 0.001). Splanchnic and cerebral oxygenation contributed most to the prediction (40.1% and 24.8%, resp.). CONCLUSIONS Using vital signs, we predicted NEC in the first 5 postnatal days with an F1-score up to 0.82. Splanchnic and cerebral oxygenation were the most contributing vital predictors. This pioneering effort in early NEC prediction using vital signs underscores the potential for targeted preventive measures and also emphasizes the need for additional data in future studies.
Collapse
Affiliation(s)
- Rosa Verhoeven
- Department of Surgery, Division of Pediatric Surgery, University Medical Center Groningen, University of Groningen, Hanzeplein 1, P.O. Box 30.001, 9700 RB Groningen, The Netherlands; (R.V.); (J.B.F.H.)
- Department of Neonatology, Beatrix Children’s Hospital, University Medical Center Groningen, University of Groningen, Hanzeplein 1, P.O. Box 30.001, 9700 RB Groningen, The Netherlands (C.L.B.)
| | - Thijmen Kupers
- Department of Neonatology, Beatrix Children’s Hospital, University Medical Center Groningen, University of Groningen, Hanzeplein 1, P.O. Box 30.001, 9700 RB Groningen, The Netherlands (C.L.B.)
- Researchable, Zernikepad 12, 9747 AN Groningen, The Netherlands
| | - Celina L. Brunsch
- Department of Neonatology, Beatrix Children’s Hospital, University Medical Center Groningen, University of Groningen, Hanzeplein 1, P.O. Box 30.001, 9700 RB Groningen, The Netherlands (C.L.B.)
| | - Jan B. F. Hulscher
- Department of Surgery, Division of Pediatric Surgery, University Medical Center Groningen, University of Groningen, Hanzeplein 1, P.O. Box 30.001, 9700 RB Groningen, The Netherlands; (R.V.); (J.B.F.H.)
| | - Elisabeth M. W. Kooi
- Department of Neonatology, Beatrix Children’s Hospital, University Medical Center Groningen, University of Groningen, Hanzeplein 1, P.O. Box 30.001, 9700 RB Groningen, The Netherlands (C.L.B.)
| |
Collapse
|
6
|
Klerk DH, Moore H, Scheese DJ, Tragesser C, Raouf Z, Duess JW, Tsuboi K, Sampah ME, Lopez CM, Williams-McLeod S, El Baassiri MG, Jang HS, Prindle T, Wang S, Wang M, Fulton WB, Sodhi CP, Hackam DJ. Multi-strain probiotic administration decreases necrotizing enterocolitis severity and alters the epigenetic profile in mice. Pediatr Res 2024:10.1038/s41390-024-03716-0. [PMID: 39562735 DOI: 10.1038/s41390-024-03716-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2024] [Revised: 09/29/2024] [Accepted: 10/14/2024] [Indexed: 11/21/2024]
Abstract
BACKGROUND Probiotic administration may decrease the incidence of necrotizing enterocolitis (NEC) through mechanisms that are largely unknown. We investigated the effects of probiotics on intestinal epigenetics and assessed their effects on intestinal inflammation and motility using both ileum-predominant and combined ileo-colitis mouse NEC models. METHODS C57BL/6 J mice were gavage-fed a multi-strain probiotic from postnatal days 3-11, consisting of B. infantis, B. lactis, and S. thermophilus. From p8, mice were exposed to ileo-colitis NEC involving formula containing NEC bacteria and 0.5% DSS. DNA methylation was measured using the Infinium Methylation Assay. Gastrointestinal motility was assessed by 70 Kd FITC-dextran transit time. Probiotic colonization was measured in probiotic-fed mice by qPCR. RESULTS Probiotic administration caused significant changes in the small intestine's epigenetic signature, a reduction in NEC severity, and improved intestinal motility. The effects of probiotics were more pronounced in the ileo-colitis NEC model. CONCLUSIONS These findings shed light on the role of probiotics in two clinically relevant models of NEC, add additional insights into their underlying mechanism of action, and reveal unanticipated epigenetic modifications to the intestinal mucosa after their use. IMPACT These findings shed light on the role of multi-strain probiotics in two clinically relevant animal models of NEC, and add additional insights into their underlying mechanism of action This study provides a new, clinically relevant model for the study of NEC including administration of 0.5% DSS, to include ileal dominant and ileo-colonic dominant phenotypes of the disease. These results reveal that clinically relevant strains of probiotic bacteria can exert epigenetic effects on the small intestine in mice, and can attenuate the epigenetic changes induced by NEC.
Collapse
Affiliation(s)
- Daphne H Klerk
- Division of Pediatric Surgery, Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Division of Neonatology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Hannah Moore
- Division of Pediatric Surgery, Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Daniel J Scheese
- Division of Pediatric Surgery, Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Cody Tragesser
- Division of Pediatric Surgery, Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Zachariah Raouf
- Division of Pediatric Surgery, Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Johannes W Duess
- Division of Pediatric Surgery, Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Koichi Tsuboi
- Division of Pediatric Surgery, Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Maame E Sampah
- Division of Pediatric Surgery, Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Carla M Lopez
- Division of Pediatric Surgery, Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Sierra Williams-McLeod
- Division of Pediatric Surgery, Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Mahmoud G El Baassiri
- Division of Pediatric Surgery, Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Hee-Seong Jang
- Division of Pediatric Surgery, Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Thomas Prindle
- Division of Pediatric Surgery, Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Sanxia Wang
- Division of Pediatric Surgery, Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Menghan Wang
- Division of Pediatric Surgery, Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - William B Fulton
- Division of Pediatric Surgery, Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Chhinder P Sodhi
- Division of Pediatric Surgery, Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
| | - David J Hackam
- Division of Pediatric Surgery, Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
| |
Collapse
|
7
|
Sallam M, Breuer R, Wrotniak B, Alibrahim O. Necrotizing Enterocolitis Complicating Severe RSV Bronchiolitis in PICU Settings. Clin Pediatr (Phila) 2024; 63:1544-1550. [PMID: 38303673 DOI: 10.1177/00099228241227763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2024]
Abstract
This retrospective study aims to analyze the baseline characteristics and factors associated with poor outcomes in patients with necrotizing enterocolitis (NEC) complicating respiratory syncytial virus (RSV) infection. Using the Virtual Pediatric Systems data registry, patients under 2 years admitted to the pediatric intensive care unit (PICU) were screened. Patients with documented RSV infection and NEC, intestinal perforation, noninfectious gastroenteritis/colitis, or pneumatosis intestinalis occurring around the timing of RSV bronchiolitis diagnosis were included. Out of the screened patients, 41 were analyzed. Most patients (93%) were aged 30 days to 2 years, one-third had baseline anatomical cardiac defects, and 20% history of prematurity. Median PICU length of stay was 11.7 days. Seven patients died before hospital discharge. While not statistically significant, nonsurvivors tended to exhibit higher PRISM-3 scores, more acidemia, and lower systolic blood pressure. These findings emphasize the need for cautious assessment of gastrointestinal symptoms in critically ill patients with RSV infection.
Collapse
Affiliation(s)
- Mohammad Sallam
- University at Buffalo, Buffalo, NY, USA
- Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA
| | | | | | | |
Collapse
|
8
|
Provitera L, Tomaselli A, Algieri F, Tripodi M, Raffaeli G, Amodeo I, Raymo L, Bronzoni CV, Fumagalli M, Garrido F, Cavallaro G. Gut Microbiota-Derived Metabolites and Their Role in the Pathogenesis of Necrotizing Enterocolitis in Preterm Infants: A Narrative Review. Metabolites 2024; 14:570. [PMID: 39590806 PMCID: PMC11596930 DOI: 10.3390/metabo14110570] [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: 09/29/2024] [Revised: 10/18/2024] [Accepted: 10/21/2024] [Indexed: 11/28/2024] Open
Abstract
Background: Necrotizing enterocolitis (NEC) is a severe gastrointestinal disease that occurs predominantly in premature infants and is characterized by the inflammation and necrosis of the intestine, showing high morbidity and mortality rates. Despite decades of research efforts, a specific treatment is currently lacking, and preventive strategies are the mainstays of care. This review aims to help understand the complex interplay between gut microbiota and their metabolites in NEC pathogenesis. In particular, we focused on how these factors can influence gut health, immune responses, and intestinal barrier integrity. Discussion: Current research has increasingly focused on the role of the gut microbiota and their metabolites in NEC pathogenesis, thanks to their involvement in modulating gut health, immune responses, and intestinal barrier integrity. Conclusions: A deeper understanding of the interplay between gut microbiota and their metabolites is essential for developing personalized strategies to prevent NEC. By targeting these microbial interactions, new therapeutic approaches may emerge that offer improved outcomes for preterm infants at a high risk of NEC.
Collapse
Affiliation(s)
- Livia Provitera
- Neonatal Intensive Care Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; (A.T.); (M.T.); (G.R.); (I.A.); (L.R.); (C.V.B.); (M.F.); (G.C.)
| | - Andrea Tomaselli
- Neonatal Intensive Care Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; (A.T.); (M.T.); (G.R.); (I.A.); (L.R.); (C.V.B.); (M.F.); (G.C.)
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milan, Italy
| | - Francesca Algieri
- Research and Development Unit, Postbiotica S.R.L., 20123 Milan, Italy;
| | - Matteo Tripodi
- Neonatal Intensive Care Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; (A.T.); (M.T.); (G.R.); (I.A.); (L.R.); (C.V.B.); (M.F.); (G.C.)
| | - Genny Raffaeli
- Neonatal Intensive Care Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; (A.T.); (M.T.); (G.R.); (I.A.); (L.R.); (C.V.B.); (M.F.); (G.C.)
| | - Ilaria Amodeo
- Neonatal Intensive Care Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; (A.T.); (M.T.); (G.R.); (I.A.); (L.R.); (C.V.B.); (M.F.); (G.C.)
| | - Ludovica Raymo
- Neonatal Intensive Care Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; (A.T.); (M.T.); (G.R.); (I.A.); (L.R.); (C.V.B.); (M.F.); (G.C.)
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milan, Italy
| | - Carolina Vittoria Bronzoni
- Neonatal Intensive Care Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; (A.T.); (M.T.); (G.R.); (I.A.); (L.R.); (C.V.B.); (M.F.); (G.C.)
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milan, Italy
| | - Monica Fumagalli
- Neonatal Intensive Care Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; (A.T.); (M.T.); (G.R.); (I.A.); (L.R.); (C.V.B.); (M.F.); (G.C.)
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milan, Italy
| | - Felipe Garrido
- Department of Pediatrics, Clínica Universidad de Navarra, 28027 Madrid, Spain;
| | - Giacomo Cavallaro
- Neonatal Intensive Care Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; (A.T.); (M.T.); (G.R.); (I.A.); (L.R.); (C.V.B.); (M.F.); (G.C.)
| |
Collapse
|
9
|
Bianco I, Ferrara C, Romano F, Loperfido F, Sottotetti F, El Masri D, Vincenti A, Cena H, De Giuseppe R. The Influence of Maternal Lifestyle Factors on Human Breast Milk Microbial Composition: A Narrative Review. Biomedicines 2024; 12:2423. [PMID: 39594990 PMCID: PMC11592219 DOI: 10.3390/biomedicines12112423] [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: 09/16/2024] [Revised: 10/17/2024] [Accepted: 10/18/2024] [Indexed: 11/28/2024] Open
Abstract
Human breast milk (HBM) is considered the gold standard for infant nutrition due to its optimal nutrient profile and complex composition of cellular and non-cellular components. Breastfeeding positively influences the newborn's gut microbiota and health, reducing the risk of conditions like gastrointestinal infections and chronic diseases (e.g., allergies, asthma, diabetes, and obesity). Research has revealed that HBM contains beneficial microbes that aid gut microbiota maturation through mechanisms like antimicrobial production and pathogen exclusion. The HBM microbiota composition can be affected by several factors, including gestational age, delivery mode, medical treatments, lactation stage, as well as maternal lifestyle habits (e.g., diet, physical activity, sleep quality, smoking, alcohol consumption, stress level). Particularly, lifestyle factors can play a significant role in shaping the HBM microbiota by directly modulating the microbial composition or influencing the maternal gut microbiota and influencing the HBM microbes through the enteromammary pathway. This narrative review of current findings summarized how maternal lifestyle influences HBM microbiota. While the influence of maternal diet on HBM microbiota is well-documented, indicating that dietary patterns, especially those rich in plant-based proteins and complex carbohydrates, can positively influence HBM microbiota, the impact of other lifestyle factors is poorly investigated. Maintaining a healthy lifestyle during pregnancy and breastfeeding is crucial for the health of both mother and baby. Understanding how maternal lifestyle factors influence microbial colonization of HBM, along with their interactions and impact, is key to developing new strategies that support the beneficial maturation of the infant's gut microbiota.
Collapse
Affiliation(s)
- Irene Bianco
- Laboratory of Dietetics and Clinical Nutrition, Department of Public Health, Experimental and Forensic Medicine, University of Pavia, 27100 Pavia, Italy; (I.B.); (C.F.); (F.R.); (F.L.); (D.E.M.); (A.V.); (H.C.); (R.D.G.)
| | - Chiara Ferrara
- Laboratory of Dietetics and Clinical Nutrition, Department of Public Health, Experimental and Forensic Medicine, University of Pavia, 27100 Pavia, Italy; (I.B.); (C.F.); (F.R.); (F.L.); (D.E.M.); (A.V.); (H.C.); (R.D.G.)
| | - Francesca Romano
- Laboratory of Dietetics and Clinical Nutrition, Department of Public Health, Experimental and Forensic Medicine, University of Pavia, 27100 Pavia, Italy; (I.B.); (C.F.); (F.R.); (F.L.); (D.E.M.); (A.V.); (H.C.); (R.D.G.)
| | - Federica Loperfido
- Laboratory of Dietetics and Clinical Nutrition, Department of Public Health, Experimental and Forensic Medicine, University of Pavia, 27100 Pavia, Italy; (I.B.); (C.F.); (F.R.); (F.L.); (D.E.M.); (A.V.); (H.C.); (R.D.G.)
| | - Francesca Sottotetti
- Laboratory of Dietetics and Clinical Nutrition, Department of Public Health, Experimental and Forensic Medicine, University of Pavia, 27100 Pavia, Italy; (I.B.); (C.F.); (F.R.); (F.L.); (D.E.M.); (A.V.); (H.C.); (R.D.G.)
| | - Dana El Masri
- Laboratory of Dietetics and Clinical Nutrition, Department of Public Health, Experimental and Forensic Medicine, University of Pavia, 27100 Pavia, Italy; (I.B.); (C.F.); (F.R.); (F.L.); (D.E.M.); (A.V.); (H.C.); (R.D.G.)
| | - Alessandra Vincenti
- Laboratory of Dietetics and Clinical Nutrition, Department of Public Health, Experimental and Forensic Medicine, University of Pavia, 27100 Pavia, Italy; (I.B.); (C.F.); (F.R.); (F.L.); (D.E.M.); (A.V.); (H.C.); (R.D.G.)
| | - Hellas Cena
- Laboratory of Dietetics and Clinical Nutrition, Department of Public Health, Experimental and Forensic Medicine, University of Pavia, 27100 Pavia, Italy; (I.B.); (C.F.); (F.R.); (F.L.); (D.E.M.); (A.V.); (H.C.); (R.D.G.)
- Clinical Nutrition Unit, General Medicine, Istituti Clinici Scientifici (ICS) Maugeri, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 27100 Pavia, Italy
| | - Rachele De Giuseppe
- Laboratory of Dietetics and Clinical Nutrition, Department of Public Health, Experimental and Forensic Medicine, University of Pavia, 27100 Pavia, Italy; (I.B.); (C.F.); (F.R.); (F.L.); (D.E.M.); (A.V.); (H.C.); (R.D.G.)
| |
Collapse
|
10
|
Sha C, Jin Z, Ku SY, Kogosov AS, Yu S, Bergese SD, Hsieh H. Necrotizing Enterocolitis and Neurodevelopmental Impairments: Microbiome, Gut, and Brain Entanglements. Biomolecules 2024; 14:1254. [PMID: 39456187 PMCID: PMC11505939 DOI: 10.3390/biom14101254] [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: 08/15/2024] [Revised: 09/27/2024] [Accepted: 09/30/2024] [Indexed: 10/28/2024] Open
Abstract
There is significant communication and interdependence among the gut, the microbiome, and the brain during development. Diseases, such as necrotizing enterocolitis (NEC), highlight how injury to the immature gastrointestinal tract leads to long-term neurological consequences, due to vulnerabilities of the brain in the early stages of life. A better understanding of the developing gut-microbiota-brain axis is needed to both prevent and treat the devastating consequences of these disease processes. The gut-microbiota-brain axis is a bidirectional communication pathway that includes metabolic, nervous, endocrine, and immune components. In this review, we discuss gut development, microbiome colonization and maturation, and the interactions that influence neurodevelopment in the context of NEC. We describe the components of the gut-brain axis and how the microbiome is an integral member of this relationship. Finally, we explore how derangements within the microbiome and gut-microbiota-brain axis affect the normal development and function of the other systems and long-term neurodevelopmental consequences for patients.
Collapse
Affiliation(s)
- Cuilee Sha
- Department of Pharmacological Sciences, Stony Brook University, 100 Nicolls Road, Stony Brook, NY 11794, USA;
- Center for Nervous System Disorders, Stony Brook University, 100 Nicolls Road, Stony Brook, NY 11794, USA
| | - Zhaosheng Jin
- Department of Anesthesiology, Stony Brook Medicine, 101 Nicolls Road, Stony Brook, NY 11794, USA;
| | - Stella Y. Ku
- Stony Brook University, 100 Nicolls Road, Stony Brook, NY 11794, USA
| | - Ann S. Kogosov
- Renaissance School of Medicine, Stony Brook University, 100 Nicolls Road, Stony Brook, NY 11794, USA
| | - Sun Yu
- Department of Surgery, Stony Brook Medicine, 101 Nicolls Road, Stony Brook, NY 11794, USA
| | - Sergio D. Bergese
- Department of Anesthesiology, Stony Brook Medicine, 101 Nicolls Road, Stony Brook, NY 11794, USA;
| | - Helen Hsieh
- Center for Nervous System Disorders, Stony Brook University, 100 Nicolls Road, Stony Brook, NY 11794, USA
- Department of Surgery, Stony Brook Medicine, 101 Nicolls Road, Stony Brook, NY 11794, USA
| |
Collapse
|
11
|
Cuna A, Kumar N, Sampath V. Understanding necrotizing enterocolitis endotypes and acquired intestinal injury phenotypes from a historical and artificial intelligence perspective. Front Pediatr 2024; 12:1432808. [PMID: 39398415 PMCID: PMC11466774 DOI: 10.3389/fped.2024.1432808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Accepted: 09/13/2024] [Indexed: 10/15/2024] Open
Abstract
Necrotizing enterocolitis (NEC) remains a devastating disease in preterm and term neonates. Despite significant progress made in understanding NEC pathogenesis over the last 50 years, the inability of current definitions to discriminate the various pathophysiological processes underlying NEC has led to an umbrella term that limits clinical and research progress. In this mini review, we provide a historical perspective on how NEC definitions and pathogenesis have evolved to our current understanding of NEC endotypes. We also discuss how artificial intelligence-based approaches are influencing our knowledge of risk-factors, classification and prognosis of NEC and other neonatal intestinal injury phenotypes.
Collapse
Affiliation(s)
- Alain Cuna
- Division of Neonatology, Children’s Mercy Kansas City, Kansas City, MO, United States
- School of Medicine, University of Missouri-Kansas City, Kansas City, MO, United States
| | - Navin Kumar
- Division of Neonatology, Hurley Medical Center, Flint, MI, United States
| | - Venkatesh Sampath
- Division of Neonatology, Children’s Mercy Kansas City, Kansas City, MO, United States
- School of Medicine, University of Missouri-Kansas City, Kansas City, MO, United States
| |
Collapse
|
12
|
Kropp C, Tambosco K, Chadi S, Langella P, Claus SP, Martin R. Christensenella minuta protects and restores intestinal barrier in a colitis mouse model by regulating inflammation. NPJ Biofilms Microbiomes 2024; 10:88. [PMID: 39294159 PMCID: PMC11411060 DOI: 10.1038/s41522-024-00540-6] [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: 11/30/2023] [Accepted: 07/23/2024] [Indexed: 09/20/2024] Open
Abstract
Christensenella minuta DSM 22607 has recently been suggested as a potential microbiome-based therapy for inflammatory bowel disease (IBD) because it displays strong anti-inflammatory effects both in vitro and in vivo. Here, we aimed to decipher the mechanism(s) underlying the DSM 22607-mediated beneficial effects on the host in a mouse model of chemically induced acute colitis. We observed that C. minuta plays a key role in the preservation of the epithelial barrier and the management of DNBS-induced inflammation by inhibiting interleukin (IL)-33 and Tumor necrosis factor receptor superfamily member 8 (Tnfrsf8) gene expression. We also showed that DSM 22607 abundance was positively correlated with Akkermansia sp. and Dubosiella sp. and modulated microbial metabolites in the cecum. These results offer new insights into the biological and molecular mechanisms underlying the beneficial effects of C. minuta DSM 22607 by protecting the intestinal barrier integrity and regulating inflammation.
Collapse
Affiliation(s)
- Camille Kropp
- Micalis Institute, AgroParisTech, INRAE, Université Paris-Saclay, 68350, Jouy-en-Josas, France
- YSOPIA Bioscience, 33076, Bordeaux, France
| | - Kevin Tambosco
- Micalis Institute, AgroParisTech, INRAE, Université Paris-Saclay, 68350, Jouy-en-Josas, France
| | - Sead Chadi
- Micalis Institute, AgroParisTech, INRAE, Université Paris-Saclay, 68350, Jouy-en-Josas, France
| | - Philippe Langella
- Micalis Institute, AgroParisTech, INRAE, Université Paris-Saclay, 68350, Jouy-en-Josas, France
| | | | - Rebeca Martin
- Micalis Institute, AgroParisTech, INRAE, Université Paris-Saclay, 68350, Jouy-en-Josas, France.
| |
Collapse
|
13
|
Ullah S, Khan I, Lnu A, Ullah Khan J, Syed A, Shafiq F, Khan M, Khan FR. Probiotics vs. Placebo: Preventing Necrotizing Enterocolitis in a Premature Infant. Cureus 2024; 16:e68848. [PMID: 39376813 PMCID: PMC11456835 DOI: 10.7759/cureus.68848] [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] [Accepted: 09/03/2024] [Indexed: 10/09/2024] Open
Abstract
BACKGROUND Necrotizing enterocolitis (NEC) is a severe gastrointestinal condition primarily affecting preterm newborns, leading to significant morbidity and mortality. OBJECTIVE This prospective cohort study aimed to evaluate the effectiveness of probiotics in preventing NEC in premature infants. Secondary objectives included assessing the impact on mortality, late-onset sepsis, duration of hospital stay, and weight gain. METHODS The study was conducted at Lady Reading Hospital Medical Teaching Institute, Peshawar, from April 1, 2023, to March 31, 2024, involving 102 preterm infants. Participants were randomly assigned to receive daily oral probiotics (Lactobacillus and Bifidobacterium species) or a placebo. RESULTS The incidence of NEC was significantly lower in the probiotic group (7.8%) compared to the placebo group (21.6%; p = 0.04). The probiotic group also showed significant reductions in late-onset sepsis (13.7% vs. 29.4%; p = 0.03), shorter hospital stays (42.5 vs. 48.1 days; p = 0.02), and greater weight gain (15.3 vs. 13.4 grams/day; p = 0.01). CONCLUSION These findings support the integration of probiotics into neonatal care, particularly in resource-limited settings.
Collapse
Affiliation(s)
- Sami Ullah
- Pediatric Medicine, Lady Reading Hospital Medical Teaching Institute, Peshawar, PAK
| | - Inayatullah Khan
- Pediatric Medicine, Lady Reading Hospital Medical Teaching Institute, Peshawar, PAK
| | - Ayesha Lnu
- Pediatric Medicine, Peshawar Institute of Medical Sciences, Peshawar, PAK
| | - Jabran Ullah Khan
- Pediatric Medicine, Lady Reading Hospital Medical Teaching Institute, Peshawar, PAK
| | - Annam Syed
- Pediatric Medicine, Lady Reading Hospital Medical Teaching Institute, Peshawar, PAK
| | - Fatima Shafiq
- Pediatric Medicine, Lady Reading Hospital Medical Teaching Institute, Peshawar, PAK
| | - Muhammad Khan
- Pediatric Medicine, Lady Reading Hospital Medical Teaching Institute, Peshawar, PAK
| | - Fahad R Khan
- Cardiology, Lady Reading Hospital Medical Teaching Institute, Peshawar, PAK
| |
Collapse
|
14
|
Dermitzaki N, Baltogianni M, Tsekoura E, Giapros V. Invasive Candida Infections in Neonatal Intensive Care Units: Risk Factors and New Insights in Prevention. Pathogens 2024; 13:660. [PMID: 39204260 PMCID: PMC11356907 DOI: 10.3390/pathogens13080660] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 07/25/2024] [Accepted: 08/05/2024] [Indexed: 09/03/2024] Open
Abstract
Invasive Candida infections represent a significant cause of morbidity and mortality in neonatal intensive care units (NICUs), with a particular impact on preterm and low-birth-weight neonates. In addition to prematurity, several predisposing factors for Candida colonization and dissemination during NICU hospitalization have been identified, including prolonged exposure to broad-spectrum antibiotics, central venous catheters, parenteral nutrition, corticosteroids, H2 antagonist administration, and poor adherence to infection control measures. According to the literature, the implementation of antifungal prophylaxis, mainly fluconazole, in high-risk populations has proven to be an effective strategy in reducing the incidence of fungal infections. This review aims to provide an overview of risk factors for invasive Candida infections and current perspectives regarding antifungal prophylaxis use. Recognizing and reducing people's exposure to these modifiable risk factors, in conjunction with the administration of antifungal prophylaxis, has been demonstrated to be an effective method for preventing invasive candidiasis in susceptible neonatal populations.
Collapse
Affiliation(s)
- Niki Dermitzaki
- Neonatal Intensive Care Unit, School of Medicine, University of Ioannina, 45500 Ioannina, Greece; (N.D.); (M.B.)
| | - Maria Baltogianni
- Neonatal Intensive Care Unit, School of Medicine, University of Ioannina, 45500 Ioannina, Greece; (N.D.); (M.B.)
| | - Efrosini Tsekoura
- Paediatric Department, Asklepieion Voula’s General Hospital, 16673 Athens, Greece;
| | - Vasileios Giapros
- Neonatal Intensive Care Unit, School of Medicine, University of Ioannina, 45500 Ioannina, Greece; (N.D.); (M.B.)
| |
Collapse
|
15
|
Roberts AG, Younge N, Greenberg RG. Neonatal Necrotizing Enterocolitis: An Update on Pathophysiology, Treatment, and Prevention. Paediatr Drugs 2024; 26:259-275. [PMID: 38564081 DOI: 10.1007/s40272-024-00626-w] [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] [Accepted: 03/11/2024] [Indexed: 04/04/2024]
Abstract
Necrotizing enterocolitis (NEC) is a life-threatening disease predominantly affecting premature and very low birth weight infants resulting in inflammation and necrosis of the small bowel and colon and potentially leading to sepsis, peritonitis, perforation, and death. Numerous research efforts have been made to better understand, treat, and prevent NEC. This review explores a variety of factors involved in the pathogenesis of NEC (prematurity, low birth weight, lack of human breast milk exposure, alterations to the microbiota, maternal and environmental factors, and intestinal ischemia) and reports treatment modalities surrounding NEC, including pain medications and common antibiotic combinations, the rationale for these combinations, and recent antibiotic stewardship approaches surrounding NEC treatment. This review also highlights the effect of early antibiotic exposure, infections, proton pump inhibitors (PPIs), and H2 receptor antagonists on the microbiota and how these risk factors can increase the chances of NEC. Finally, modern prevention strategies including the use of human breast milk and standardized feeding regimens are discussed, as well as promising new preventative and treatment options for NEC including probiotics and stem cell therapy.
Collapse
|
16
|
Siddiqui A, Haider R, Aaqil SI, Vohra LI, Qamar K, Jawed A, Fatima N, Adnan A, Parikh V, Ochani S, Hasibuzzaman MA. Probiotic formulations and gastro-intestinal diseases in the paediatric population: a narrative review. Ann Med Surg (Lond) 2024; 86:2836-2847. [PMID: 38694362 PMCID: PMC11060255 DOI: 10.1097/ms9.0000000000002007] [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: 09/07/2023] [Accepted: 03/17/2024] [Indexed: 05/04/2024] Open
Abstract
Background/Aim Probiotics are live microbial supplements that improve the microbial balance in the host animal when administered in adequate amounts. They play an important role in relieving symptoms of many diseases associated with gastrointestinal tract, for example, in necrotizing enterocolitis (NEC), antibiotic-associated diarrhea, relapsing Clostridium difficile colitis, Helicobacter pylori infections, and inflammatory bowel disease (IBD). In this narrative review, the authors aim to evaluate the role of different probiotic formulations in treating gastrointestinal diseases in pediatric population aged 18 years or younger and highlight the main considerations for selecting probiotic formulations for use in this population. Methodology The authors searched PubMed and Clinicaltrials.gov from inception to 24th July 2022, without any restrictions. Using an iterative process, the authors subsequently added papers through hand-searching citations contained within retrieved articles and relevant systematic reviews and meta-analyses. Results The effectiveness of single-organism and composite probiotics in treating gastrointestinal disorders in pediatric patients aged 18 or under were analyzed and compared in this study. A total of 39 studies were reviewed and categorized based on positive and negative outcomes, and compared with a placebo, resulting in 25 studies for single-organism and 14 studies for composite probiotics. Gastrointestinal disorders studied included NEC, acute gastroenteritis (AGE), Acute Diarrhea, Ulcerative Colitis (UC), and others. The results show that probiotics are effective in treating various gastrointestinal disorders in children under 18, with single-organism probiotics demonstrating significant positive outcomes in most studies, and composite probiotics showing positive outcomes in all studies analyzed, with a low incidence of negative outcomes for both types. Conclusion This study concludes that single-organism and composite probiotics are effective complementary therapies for treating gastrointestinal disorders in the pediatric population. Hence, healthcare professionals should consider using probiotics in standard treatment regimens, and educating guardians can enhance the benefits of probiotic therapy. Further research is recommended to identify the optimal strains and dosages for specific conditions and demographics. The integration of probiotics in clinical practice and ongoing research can contribute to reducing the incidence and severity of gastrointestinal disorders in pediatric patients.
Collapse
Affiliation(s)
- Amna Siddiqui
- Department of Medicine, Karachi Medical and Dental College
| | - Ramsha Haider
- Department of Medicine, Karachi Medical and Dental College
| | | | | | - Khulud Qamar
- Department of Medicine, Dow University of Health and Sciences, Karachi
| | - Areesha Jawed
- Department of Medicine, Dow University of Health and Sciences, Karachi
| | - Nabeela Fatima
- Mentor, International Society of Chronic Illnesses, India
| | - Alishba Adnan
- Department of Medicine, Karachi Medical and Dental College
| | - Vidhi Parikh
- Parul Institute of Medical Sciences and Research, Parul University, Vadodara
| | - Sidhant Ochani
- Department of Medicine, Khairpur Medical College, Khairpur Mir’s, Pakistan
| | - Md. Al Hasibuzzaman
- Institute of Nutrition and Food Sciences, University of Dhaka, Dhaka, Bangladesh
| |
Collapse
|
17
|
Zhao S, Jiang H, Miao Y, Liu W, Li Y, Liu H, Wang A, Cui X, Zhang Y. Factors influencing necrotizing enterocolitis in premature infants in China: a systematic review and meta-analysis. BMC Pediatr 2024; 24:148. [PMID: 38418993 PMCID: PMC10903018 DOI: 10.1186/s12887-024-04607-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Accepted: 01/31/2024] [Indexed: 03/02/2024] Open
Abstract
BACKGROUND Necrotizing enterocolitis (NEC) is a multifactorial gastrointestinal disease with high morbidity and mortality among premature infants. However, studies with large samples on the factors of NEC in China have not been reported. This meta-analysis aims to systematically review the literature to explore the influencing factors of necrotizing enterocolitis in premature infants in China and provide a reference for the prevention of NEC. METHODS PubMed, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI), China Biomedical Literature Database (CBM), Wanfang and VIP databases were systematically searched from inception to February 2023. We used Stata14.0 software to perform the systematic review and meta-analysis. We used fixed or random effects models with combined odds ratios (ORs) and 95% confidence intervals (CIs), and quality was evaluated using the Newcastle‒Ottawa Scale (NOS). RESULTS The total sample was 8616 cases, including 2456 cases in the intervention group and 6160 cases in the control group. It was found that 16 risk factors and 3 protective factors were related to necrotizing enterocolitis in premature infants. Septicemia (OR = 3.91), blood transfusion (OR = 2.41), neonatal asphyxia (OR = 2.46), pneumonia (OR = 6.17), infection (OR = 5.99), congenital heart disease (OR = 4.80), intrahepatic cholestasis of pregnancy (ICP) (OR = 2.71), mechanical ventilation (OR = 1.44), gestational diabetes mellitus (GDM) (OR = 3.08), respiratory distress syndrome (RDS) (OR = 3.28), hypoalbuminemia (OR = 2.80), patent ductus arteriosus (PDA) (OR = 3.10), respiratory failure (OR = 7.51), severe anemia (OR = 2.86), history of antibiotic use (OR = 2.12), and meconium-stained amniotic fluid (MSAF) (OR = 3.14) were risk factors for NEC in preterm infants in China. Breastfeeding (OR = 0.31), oral probiotics (OR = 0.36), and prenatal use of glucocorticoids (OR = 0.38) were protective factors for NEC in preterm infants. CONCLUSIONS Septicemia, blood transfusion, neonatal asphyxia, pneumonia, infection, congenital heart disease, ICP, GDM, RDS, hypoproteinemia, PDA, respiratory failure, severe anemia, history of antibiotic use and MSAF will increase the risk of NEC in premature infants, whereas breastfeeding, oral probiotics and prenatal use of glucocorticoids reduce the risk. Due to the quantity and quality of the included literature, the above findings need to be further validated by more high-quality studies.
Collapse
Affiliation(s)
- Shuliang Zhao
- School of Nursing, Shandong Second Medical University, Weifang, 261053, China
- Nursing Department Affiliated Hospital of Shandong Second Medical University, Weifang, 261031, China
| | - Huimin Jiang
- School of Nursing, Shandong Second Medical University, Weifang, 261053, China
| | - Yiqun Miao
- School of Nursing, Capital Medical University, Beijing, 100071, China
| | - Wenwen Liu
- Xiangya School of Nursing, Central South University, Changsha, 410000, China
| | - Yanan Li
- School of Nursing, Shandong Second Medical University, Weifang, 261053, China
| | - Hui Liu
- School of Nursing, Shandong Second Medical University, Weifang, 261053, China
| | - Aihua Wang
- School of Nursing, Shandong Second Medical University, Weifang, 261053, China.
| | - Xinghui Cui
- Nursing Department Affiliated Hospital of Shandong Second Medical University, Weifang, 261031, China.
| | - Yuanyuan Zhang
- School of Nursing, Shandong Second Medical University, Weifang, 261053, China
| |
Collapse
|
18
|
Liu J, Joseph S, Manohar K, Lee J, Brokaw JP, Shelley WC, Markel TA. Role of innate T cells in necrotizing enterocolitis. Front Immunol 2024; 15:1357483. [PMID: 38390341 PMCID: PMC10881895 DOI: 10.3389/fimmu.2024.1357483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Accepted: 01/16/2024] [Indexed: 02/24/2024] Open
Abstract
Necrotizing enterocolitis (NEC) is a destructive gastrointestinal disease primarily affecting preterm babies. Despite advancements in neonatal care, NEC remains a significant cause of morbidity and mortality in neonatal intensive care units worldwide and the etiology of NEC is still unclear. Risk factors for NEC include prematurity, very low birth weight, feeding with formula, intestinal dysbiosis and bacterial infection. A review of the literature would suggest that supplementation of prebiotics and probiotics prevents NEC by altering the immune responses. Innate T cells, a highly conserved subpopulation of T cells that responds quickly to stimulation, develops differently from conventional T cells in neonates. This review aims to provide a succinct overview of innate T cells in neonates, encompassing their phenotypic characteristics, functional roles, likely involvement in the pathogenesis of NEC, and potential therapeutic implications.
Collapse
Affiliation(s)
- Jianyun Liu
- Department of Surgery, Section of Pediatric Surgery, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Sharon Joseph
- Department of Surgery, Section of Pediatric Surgery, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Krishna Manohar
- Department of Surgery, Section of Pediatric Surgery, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Jasmine Lee
- Department of Surgery, Section of Pediatric Surgery, Indiana University School of Medicine, Indianapolis, IN, United States
| | - John P. Brokaw
- Department of Surgery, Section of Pediatric Surgery, Indiana University School of Medicine, Indianapolis, IN, United States
| | - W. Christopher Shelley
- Department of Surgery, Section of Pediatric Surgery, Indiana University School of Medicine, Indianapolis, IN, United States
- Riley Hospital for Children at Indiana University Health, Indianapolis, IN, United States
| | - Troy A. Markel
- Department of Surgery, Section of Pediatric Surgery, Indiana University School of Medicine, Indianapolis, IN, United States
- Riley Hospital for Children at Indiana University Health, Indianapolis, IN, United States
| |
Collapse
|
19
|
Trivedi A, Teo E, Walker KS. Probiotics for the postoperative management of term neonates after gastrointestinal surgery. Cochrane Database Syst Rev 2024; 1:CD012265. [PMID: 38258877 PMCID: PMC10804440 DOI: 10.1002/14651858.cd012265.pub2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/24/2024]
Abstract
BACKGROUND The intestinal microflora has an essential role in providing a barrier against colonisation of pathogens, facilitating important metabolic functions, stimulating the development of the immune system, and maintaining intestinal motility. Probiotics are live microorganisms that can be administered to supplement the gut flora. Neonates who have undergone gastrointestinal surgery are particularly susceptible to infectious complications in the postoperative period. This may be partly due to a disruption of the integrity of the gut and its intestinal microflora. There may be a role for probiotics in reducing the incidence of sepsis and improving intestinal motility, thus reducing morbidity and mortality and improving enteral feeding in neonates in the postoperative period. OBJECTIVES To evaluate the efficacy and safety of administering probiotics after gastrointestinal surgery for the postoperative management of neonates born from 35 weeks of gestation. SEARCH METHODS We searched CENTRAL, MEDLINE, Embase, and trial registries in August 2023. We checked reference lists of included studies and relevant systematic reviews for additional studies. SELECTION CRITERIA We included randomised controlled trials (RCTs) that investigated the postoperative administration of oral probiotics versus placebo or no treatment in neonates born from 35 weeks of gestation who had one or more gastrointestinal surgical procedures. We applied no restrictions regarding the type or dosage of probiotics or the duration of treatment. DATA COLLECTION AND ANALYSIS We used standard Cochrane methods, and we used GRADE to assess the certainty of evidence. MAIN RESULTS We identified one RCT that recruited 61 neonates with a gestational age of 35 weeks or more. All infants were admitted to a neonatal intensive care unit and had surgery for gastrointestinal pathologies. There may be little or no difference in proven sepsis (positive bacterial culture, local or systemic) between infants who receive probiotics compared with those who receive placebo (odds ratio (OR) 0.64, 95% confidence interval (CI) 0.16 to 2.55; 61 infants; low-certainty evidence). Probiotics compared to placebo may have little or no effect on time to full enteral feeds (mean difference (MD) 0.63 days, 95% CI -4.02 to 5.28; 61 infants; low-certainty evidence). There were no reported deaths prior to discharge from hospital in either study arm. Two weeks after supplementation, the infants who received probiotics had a substantially higher relative abundance of non-pathogenic intestinal microflora (Bifidobacteriaceae) than those who received placebo (MD 38.22, 95% CI 28.40 to 48.04; 39 infants; low-certainty evidence). AUTHORS' CONCLUSIONS This review provides low-certainty evidence from one small RCT that probiotics compared to placebo have little or no effect on the risk of proven sepsis (positive bacterial culture, local or systemic) or time to full-enteral feeds in neonates who have undergone gastrointestinal surgery. Probiotics may substantially increase the abundance of beneficial bacterial in the intestine of these neonates, but the clinical implications of this finding are unknown. There is a need for adequately powered RCTs to assess the role of probiotics in this population. We identified two ongoing studies. As neither reported the gestational age of prospective study participants, we are unsure if they will be eligible for inclusion in this review.
Collapse
Affiliation(s)
- Amit Trivedi
- Grace Centre for Newborn Intensive Care, The Children's Hospital at Westmead, Sydney, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
| | - Edward Teo
- Emergency Department, Concord Repatriation General Hospital, Sydney, Australia
| | - Karen S Walker
- Neonatal intensive Care Unit, Royal Prince Alfred hospital, Sydney, Australia
| |
Collapse
|
20
|
Samarra A, Flores E, Bernabeu M, Cabrera-Rubio R, Bäuerl C, Selma-Royo M, Collado MC. Shaping Microbiota During the First 1000 Days of Life. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1449:1-28. [PMID: 39060728 DOI: 10.1007/978-3-031-58572-2_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/28/2024]
Abstract
Given that the host-microbe interaction is shaped by the immune system response, it is important to understand the key immune system-microbiota relationship during the period from conception to the first years of life. The present work summarizes the available evidence concerning human reproductive microbiota, and also, the microbial colonization during early life, focusing on the potential impact on infant development and health outcomes. Furthermore, we conclude that some dietary strategies including specific probiotics and other-biotics could become potentially valuable tools to modulate the maternal-neonatal microbiota during this early critical window of opportunity for targeted health outcomes throughout the entire lifespan.
Collapse
Affiliation(s)
- Anna Samarra
- Department of Biotechnology, Institute of Agrochemistry and Food Technology-National Research Council (IATA-CSIC), Paterna-Valencia, Spain
| | - Eduard Flores
- Department of Biotechnology, Institute of Agrochemistry and Food Technology-National Research Council (IATA-CSIC), Paterna-Valencia, Spain
| | - Manuel Bernabeu
- Department of Biotechnology, Institute of Agrochemistry and Food Technology-National Research Council (IATA-CSIC), Paterna-Valencia, Spain
| | - Raul Cabrera-Rubio
- Department of Biotechnology, Institute of Agrochemistry and Food Technology-National Research Council (IATA-CSIC), Paterna-Valencia, Spain
| | - Christine Bäuerl
- Department of Biotechnology, Institute of Agrochemistry and Food Technology-National Research Council (IATA-CSIC), Paterna-Valencia, Spain
| | - Marta Selma-Royo
- Department of Biotechnology, Institute of Agrochemistry and Food Technology-National Research Council (IATA-CSIC), Paterna-Valencia, Spain
| | - Maria Carmen Collado
- Department of Biotechnology, Institute of Agrochemistry and Food Technology-National Research Council (IATA-CSIC), Paterna-Valencia, Spain.
| |
Collapse
|
21
|
Bruno MA, Galletti MF, Brener Dik PH, Mariani GL, Gonzalez Á, Nieto R. Prevalence and risk factors associated with the need for surgical intervention due to necrotizing enterocolitis in very low birth weight infants. Early Hum Dev 2024; 188:105917. [PMID: 38096735 DOI: 10.1016/j.earlhumdev.2023.105917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2023] [Revised: 12/05/2023] [Accepted: 12/07/2023] [Indexed: 01/08/2024]
Abstract
INTRODUCTION Necrotizing enterocolitis (NEC) is one of the most common gastrointestinal emergencies affecting very low birth weight (VLBW) infants with an incidence of 6-15 %. Early recognition is crucial. Mortality is high and variable (30-50 %). Those requiring surgical intervention have a higher mortality rate than those who receive medical treatment. OBJECTIVES 1) To assess the prevalence of surgical NEC and associated risk factors 2) To compare outcomes based on the type of treatment required 3) To estimate the mortality associated with NEC and surgical NEC. METHODS A multicentre retrospective cohort study was designed (level II), including VLBW infants born between 2011 and 2020 in Centers of the Neocosur Network. A multivariate logistic regression analysis was performed to evaluate risk factors associated with the need for surgery. RESULTS NEC was diagnosed in 1679 (10.4 %) of 16,131 births in this period. The prevalence of surgery was 25 % (95 % CI 23-27 %). In multivariable analysis, variables associated with an increased risk of surgery requirement were birth weight <750 g (aOR 1.73-95%CI 1.2-2.5) and receiving antenatal antibiotics (aOR 1.54-95%CI 1.09-2.74). Those requiring surgery had significantly higher morbidity and mortality than the ones receiving medical treatment. CONCLUSION In VLBW infants with NEC, lower birth weight and antenatal antibiotics administration were independently associated with the need for surgical intervention.
Collapse
Affiliation(s)
- Maria Ailen Bruno
- Neonatology, Hospital Italiano de Buenos Aires, Perón 4190, Buenos Aires, Argentina.
| | - Maria Fernanda Galletti
- Magister in Clinical Research, Neonatology Division, Department of Pediatrics, Hospital Italiano de Buenos Aires, Argentina
| | - Pablo H Brener Dik
- Magister in Clinical Research, Neonatology Division, Department of Pediatrics, Hospital Italiano de Buenos Aires, Argentina
| | - Gonzalo L Mariani
- Magister in Bioethics, Neonatology Division, Department of Pediatrics, Hospital Italiano de Buenos Aires, Argentina
| | - Álvaro Gonzalez
- Neonatology Division, Department of Pediatrics, Pontificia Universidad Católica, Santiago de Chile, Chile
| | - Ricardo Nieto
- Neonatology Division, Maternidad Ramón Sardá, Buenos Aires, Argentina
| |
Collapse
|
22
|
Aneja A, Johnson J, Prochaska EC, Milstone AM. Microbiome dysbiosis: a modifiable state and target to prevent Staphylococcus aureus infections and other diseases in neonates. J Perinatol 2024; 44:125-130. [PMID: 37904005 PMCID: PMC10842217 DOI: 10.1038/s41372-023-01810-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 10/06/2023] [Accepted: 10/18/2023] [Indexed: 11/01/2023]
Abstract
Bacterial infections present a significant threat to neonates. Increasingly, studies demonstrate associations between human diseases and the microbiota, the communities of microorganisms on or in the body. A "healthy" microbiota with a great diversity and balance of microorganisms can resist harmful pathogens and protect against infections, whereas a microbiota suffering from dysbiosis, can predispose to pathogen colonization and subsequent infection. For decades, strategies such as bacterial interference, decolonization, prebiotics, and probiotics have been tested to reduce Staphylococcus aureus disease and other infections in neonates. More recently, microbiota transplant has emerged as a strategy to broadly correct dysbiosis, promote colonization resistance, and prevent infections. This paper discusses the benefits of a healthy neonate's microbiota, exposures that alter the microbiota, associations of dysbiosis and neonatal disease, strategies to prevent dysbiosis, such as microbiota transplantation, and presents a framework of microbiome manipulation to reduce Staphylococcus aureus (S. aureus) and other infections in neonates.
Collapse
Affiliation(s)
- Anushree Aneja
- Department of Pediatrics, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Julia Johnson
- Department of Pediatrics, Division of Neonatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Erica C Prochaska
- Department of Pediatrics, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Aaron M Milstone
- Department of Pediatrics, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
| |
Collapse
|
23
|
Iijima S. Clinical Dilemma Involving Treatments for Very Low-Birth-Weight Infants and the Potential Risk of Necrotizing Enterocolitis: A Narrative Literature Review. J Clin Med 2023; 13:62. [PMID: 38202069 PMCID: PMC10780023 DOI: 10.3390/jcm13010062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 12/18/2023] [Accepted: 12/20/2023] [Indexed: 01/12/2024] Open
Abstract
Necrotizing enterocolitis (NEC) is a critical gastrointestinal emergency with substantial morbidity and mortality risks, especially for very low-birth-weight (VLBW) infants, and unclear multifactorial pathophysiology. Whether common treatments for VLBW infants increase the NEC risk remains controversial. Indomethacin (utilized for patent ductus arteriosus) offers benefits but is concerning because of its vasoconstrictive impact on NEC susceptibility. Similarly, corticosteroids used to treat bronchopulmonary dysplasia may increase vulnerability to NEC by compromising immunity and altering the mesenteric blood flow. Histamine-2 receptor blockers (used to treat gastric bleeding) may inadvertently promote NEC by affecting bacterial colonization and translocation. Doxapram (used to treat apnea) poses a risk of gastrointestinal disturbance via gastric acid hypersecretion and circulatory changes. Glycerin enemas aid meconium evacuation but disrupt microbial equilibrium and trigger stress-related effects associated with the NEC risk. Prolonged antibiotic use may unintentionally increase the NEC risk. Blood transfusions for anemia can promote NEC via interactions between the immune response and ischemia-reperfusion injury. Probiotics for NEC prevention are associated with concerns regarding sepsis and bacteremia. Amid conflicting evidence, this review unveils NEC risk factors related to treatments for VLBW infants, offers a comprehensive overview of the current research, and guides personalized management strategies, thereby elucidating this clinical dilemma.
Collapse
Affiliation(s)
- Shigeo Iijima
- Department of Regional Neonatal-Perinatal Medicine, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan
| |
Collapse
|
24
|
Beharry KD, Latkowska M, Valencia AM, Allana A, Soto J, Cai CL, Golombek S, Hand I, Aranda JV. Factors Influencing Neonatal Gut Microbiome and Health with a Focus on Necrotizing Enterocolitis. Microorganisms 2023; 11:2528. [PMID: 37894186 PMCID: PMC10608807 DOI: 10.3390/microorganisms11102528] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 09/21/2023] [Accepted: 10/06/2023] [Indexed: 10/29/2023] Open
Abstract
Maturational changes in the gut start in utero and rapidly progress after birth, with some functions becoming fully developed several months or years post birth including the acquisition of a full gut microbiome, which is made up of trillions of bacteria of thousands of species. Many factors influence the normal development of the neonatal and infantile microbiome, resulting in dysbiosis, which is associated with various interventions used for neonatal morbidities and survival. Extremely low gestational age neonates (<28 weeks' gestation) frequently experience recurring arterial oxygen desaturations, or apneas, during the first few weeks of life. Apnea, or the cessation of breathing lasting 15-20 s or more, occurs due to immature respiratory control and is commonly associated with intermittent hypoxia (IH). Chronic IH induces oxygen radical diseases of the neonate, including necrotizing enterocolitis (NEC), the most common and devastating gastrointestinal disease in preterm infants. NEC is associated with an immature intestinal structure and function and involves dysbiosis of the gut microbiome, inflammation, and necrosis of the intestinal mucosal layer. This review describes the factors that influence the neonatal gut microbiome and dysbiosis, which predispose preterm infants to NEC. Current and future management and therapies, including the avoidance of dysbiosis, the use of a human milk diet, probiotics, prebiotics, synbiotics, restricted antibiotics, and fecal transplantation, for the prevention of NEC and the promotion of a healthy gut microbiome are also reviewed. Interventions directed at boosting endogenous and/or exogenous antioxidant supplementation may not only help with prevention, but may also lessen the severity or shorten the course of the disease.
Collapse
Affiliation(s)
- Kay D. Beharry
- Department of Pediatrics, Division of Neonatal-Perinatal Medicine, State University of New York Downstate Health Sciences University, Brooklyn, NY 11203, USA; (M.L.); (C.L.C.); (S.G.); (J.V.A.)
| | - Magdalena Latkowska
- Department of Pediatrics, Division of Neonatal-Perinatal Medicine, State University of New York Downstate Health Sciences University, Brooklyn, NY 11203, USA; (M.L.); (C.L.C.); (S.G.); (J.V.A.)
| | - Arwin M. Valencia
- Department of Pediatrics, Division of Neonatal-Perinatal Medicine, Saddleback Memorial Medical Center, Laguna Hills, CA 92653, USA;
| | - Ahreen Allana
- Department of Pediatrics, State University of New York Downstate Health Sciences University, Brooklyn, NY 11203, USA; (A.A.); (J.S.)
| | - Jatnna Soto
- Department of Pediatrics, State University of New York Downstate Health Sciences University, Brooklyn, NY 11203, USA; (A.A.); (J.S.)
| | - Charles L. Cai
- Department of Pediatrics, Division of Neonatal-Perinatal Medicine, State University of New York Downstate Health Sciences University, Brooklyn, NY 11203, USA; (M.L.); (C.L.C.); (S.G.); (J.V.A.)
| | - Sergio Golombek
- Department of Pediatrics, Division of Neonatal-Perinatal Medicine, State University of New York Downstate Health Sciences University, Brooklyn, NY 11203, USA; (M.L.); (C.L.C.); (S.G.); (J.V.A.)
| | - Ivan Hand
- Department of Pediatrics, Division of Neonatal-Perinatal Medicine, Kings County Hospital Center, Brooklyn, NY 11203, USA;
| | - Jacob V. Aranda
- Department of Pediatrics, Division of Neonatal-Perinatal Medicine, State University of New York Downstate Health Sciences University, Brooklyn, NY 11203, USA; (M.L.); (C.L.C.); (S.G.); (J.V.A.)
| |
Collapse
|
25
|
Bui A, Johnson E, Epshteyn M, Schumann C, Schwendeman C. Utilization of a High Potency Probiotic Product for Prevention of Necrotizing Enterocolitis in Preterm Infants at a Level IV NICU. J Pediatr Pharmacol Ther 2023; 28:473-475. [PMID: 38130501 PMCID: PMC10731933 DOI: 10.5863/1551-6776-28.5.473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Accepted: 12/06/2022] [Indexed: 12/23/2023]
Abstract
Necrotizing enterocolitis (NEC) is a serious gastrointestinal disease that can be seen in premature infants with high risk for morbidity and mortality. There is currently no US Food and Drug Administration (FDA) medication approved for the prevention of NEC. Despite great heterogeneity among available studies, large meta-analyses of clinical trials have demonstrated the efficacy of multiple-strain probiotics in reducing NEC and all-cause mortality. In 2020, Medical City Dallas's Level IV neonatal intensive care unit (NICU) implemented a probiotic protocol for NEC prevention. As a result, a reduction in NEC was observed, with no occurrence of probiotic-related sepsis.
Collapse
Affiliation(s)
- Annie Bui
- Department of Pharmacy (AB, EJ, ME), Medical City Dallas Hospital, Dallas, TX
| | - Emory Johnson
- Department of Pharmacy (AB, EJ, ME), Medical City Dallas Hospital, Dallas, TX
| | - Michael Epshteyn
- Department of Pharmacy (AB, EJ, ME), Medical City Dallas Hospital, Dallas, TX
| | - Caitlin Schumann
- Department of Nursing (C. Schumann), Medical City Dallas Hospital, Dallas, TX
| | - Clair Schwendeman
- Department of Neonatology (C. Schwendeman), Pediatrix Medical Group, North Dallas Practice, Dallas, TX
| |
Collapse
|
26
|
Bethell GS, Hall NJ. Recent advances in our understanding of NEC diagnosis, prognosis and surgical approach. Front Pediatr 2023; 11:1229850. [PMID: 37583622 PMCID: PMC10424793 DOI: 10.3389/fped.2023.1229850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2023] [Accepted: 07/21/2023] [Indexed: 08/17/2023] Open
Abstract
Necrotising enterocolitis (NEC) remains a devasting condition that has seen limited improvement in outcomes in recent years. The incidence of the disease is increasing as more extremely premature infants survive. NEC is responsible for 1 in 10 neonatal deaths and up to 61% of survivors have significant neurodevelopmental delay. The aim of this review is to highlight recent advances in diagnosis, prognosis and surgical approach in this condition. Many recent studies have reported novel methods of diagnosis of NEC with the aim of earlier and more accurate identification. These include imaging and machine learning techniques. Prognostication of NEC is particularly important to allow earlier escalation of therapy. Around 25% of infants with NEC will require surgery and recent data has shown that time from disease onset to surgery is greater in infants whose indication for surgery is failed medical management, rather than pneumoperitoneum. This indication was also associated with worse outcomes compared to pneumoperitoneum. Ongoing research has highlighted several new methods of disease prognostication which includes differentiating surgical from medical NEC. Finally, recent randomised controlled trials in surgical technique are discussed along with the implications of these for practice. Further, high quality research utilising multi-centre collaborations and high fidelity data from electronic patient records is needed to address the issues discussed and ultimately improve outcomes in NEC.
Collapse
Affiliation(s)
- George S Bethell
- University Surgical Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - Nigel J Hall
- University Surgical Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| |
Collapse
|
27
|
Sharif S, Meader N, Oddie SJ, Rojas-Reyes MX, McGuire W. Probiotics to prevent necrotising enterocolitis in very preterm or very low birth weight infants. Cochrane Database Syst Rev 2023; 7:CD005496. [PMID: 37493095 PMCID: PMC10370900 DOI: 10.1002/14651858.cd005496.pub6] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/27/2023]
Abstract
BACKGROUND Intestinal dysbiosis may contribute to the pathogenesis of necrotising enterocolitis (NEC) in very preterm or very low birth weight (VLBW) infants. Dietary supplementation with probiotics to modulate the intestinal microbiome has been proposed as a strategy to reduce the risk of NEC and associated mortality and morbidity in very preterm or VLBW infants. OBJECTIVES To determine the effect of supplemental probiotics on the risk of NEC and associated mortality and morbidity in very preterm or very low birth weight infants. SEARCH METHODS We searched CENTRAL, MEDLINE, Embase, the Maternity and Infant Care database, and CINAHL from inception to July 2022. We searched clinical trials databases and conference proceedings, and examined the reference lists of retrieved articles. SELECTION CRITERIA We included randomised controlled trials (RCTs) and quasi-RCTs comparing probiotics with placebo or no probiotics in very preterm infants (born before 32 weeks' gestation) and VLBW infants (weighing less than 1500 g at birth). DATA COLLECTION AND ANALYSIS Two review authors independently evaluated risk of bias of the trials, extracted data, and synthesised effect estimates using risk ratios (RRs), risk differences (RDs), and mean differences (MDs), with associated 95% confidence intervals (CIs). The primary outcomes were NEC and all-cause mortality; secondary outcome measures were late-onset invasive infection (more than 48 hours after birth), duration of hospitalisation from birth, and neurodevelopmental impairment. We used the GRADE approach to assess the certainty of the evidence. MAIN RESULTS We included 60 trials with 11,156 infants. Most trials were small (median sample size 145 infants). The main potential sources of bias were unclear reporting of methods for concealing allocation and masking caregivers or investigators in about half of the trials. The formulation of the probiotics varied across trials. The most common preparations contained Bifidobacterium spp., Lactobacillus spp., Saccharomyces spp., andStreptococcus spp., alone or in combination. Very preterm or very low birth weight infants Probiotics may reduce the risk of NEC (RR 0.54, 95% CI 0.46 to 0.65; I² = 17%; 57 trials, 10,918 infants; low certainty). The number needed to treat for an additional beneficial outcome (NNTB) was 33 (95% CI 25 to 50). Probiotics probably reduce mortality slightly (RR 0.77, 95% CI 0.66 to 0.90; I² = 0%; 54 trials, 10,484 infants; moderate certainty); the NNTB was 50 (95% CI 50 to 100). Probiotics probably have little or no effect on the risk of late-onset invasive infection (RR 0.89, 95% CI 0.82 to 0.97; I² = 22%; 49 trials, 9876 infants; moderate certainty). Probiotics may have little or no effect on neurodevelopmental impairment (RR 1.03, 95% CI 0.84 to 1.26; I² = 0%; 5 trials, 1518 infants; low certainty). Extremely preterm or extremely low birth weight infants Few data were available for extremely preterm or extremely low birth weight (ELBW) infants. In this population, probiotics may have little or no effect on NEC (RR 0.92, 95% CI 0.69 to 1.22, I² = 0%; 10 trials, 1836 infants; low certainty), all-cause mortality (RR 0.92, 95% CI 0.72 to 1.18; I² = 0%; 7 trials, 1723 infants; low certainty), or late-onset invasive infection (RR 0.93, 95% CI 0.78 to 1.09; I² = 0%; 7 trials, 1533 infants; low certainty). No trials provided data for measures of neurodevelopmental impairment in extremely preterm or ELBW infants. AUTHORS' CONCLUSIONS Given the low to moderate certainty of evidence for the effects of probiotic supplements on the risk of NEC and associated morbidity and mortality for very preterm or VLBW infants, and particularly for extremely preterm or ELBW infants, there is a need for further large, high-quality trials to provide evidence of sufficient validity and applicability to inform policy and practice.
Collapse
Key Words
- female
- humans
- infant
- infant, newborn
- enterocolitis, necrotizing
- enterocolitis, necrotizing/epidemiology
- fetal growth retardation
- infant, extremely premature
- infant, premature, diseases
- infant, premature, diseases/etiology
- infant, premature, diseases/prevention & control
- infant, very low birth weight
- probiotics
Collapse
Affiliation(s)
- Sahar Sharif
- Centre for Reviews and Dissemination, University of York, York, UK
| | - Nicholas Meader
- Centre for Reviews and Dissemination, University of York, York, UK
| | - Sam J Oddie
- Centre for Reviews and Dissemination, University of York, York, UK
- Bradford Neonatology, Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK
| | - Maria X Rojas-Reyes
- Institut d'Recerca Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
- Evaluation Unit of the Canary Islands Health Service (SESCS), Tenerife, Spain
| | - William McGuire
- Centre for Reviews and Dissemination, University of York, York, UK
| |
Collapse
|
28
|
Liu ZS, Chen PW. Featured Prebiotic Agent: The Roles and Mechanisms of Direct and Indirect Prebiotic Activities of Lactoferrin and Its Application in Disease Control. Nutrients 2023; 15:2759. [PMID: 37375663 DOI: 10.3390/nu15122759] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 06/13/2023] [Accepted: 06/14/2023] [Indexed: 06/29/2023] Open
Abstract
Lactoferrin (LF) is a glycoprotein found in mammalian milk, and lactoferricin is a peptide derived from LF hydrolysate. Both LF and lactoferricin (LFcin) have diverse functions that could benefit mammals. Bovine LF (BLF) and BLFcin exhibit a wide range of antimicrobial activities, but most probiotic strains are relatively resistant to their antibacterial effects. BLF and BLF hydrolysate can promote the growth of specific probiotics depending on the culture conditions, the dose of BLF or BLF-related peptides, and the probiotic strains used. BLF supplementation has been shown to modulate several central molecular pathways or genes in Lacticaseibacillus rhamnosus GG under cold conditions, which may explain the prebiotic roles of BLF. LF alone or in combination with selected probiotics can help control bacterial infections or metabolic disorders, both in animal studies and in human clinical trials. Various LF-expressing probiotics, including those expressing BLF, human LF, or porcine LF, have been developed to facilitate the combination of LFs with specific probiotics. Supplementation with LF-expressing probiotics has positive effects in animal studies. Interestingly, inactivated LF-expressing probiotics significantly improved diet-induced nonalcoholic fatty liver disease (NAFLD) in a mouse model. This review highlights the accumulated evidence supporting the use of LF in combination with selected LF-resistant probiotics or LF-expressing probiotics in the field.
Collapse
Affiliation(s)
- Zhen-Shu Liu
- Chronic Diseases and Health Promotion Research Center, Chang Gung University of Science and Technology, Chiayi 61363, Taiwan
- Department of Safety, Health and Environmental Engineering, Ming Chi University of Technology, New Taipei City 24301, Taiwan
| | - Po-Wen Chen
- Department of Veterinary Medicine, National Chung Hsing University, Taichung 40249, Taiwan
| |
Collapse
|
29
|
Scheese DJ, Sodhi CP, Hackam DJ. New insights into the pathogenesis of necrotizing enterocolitis and the dawn of potential therapeutics. Semin Pediatr Surg 2023; 32:151309. [PMID: 37290338 PMCID: PMC10330774 DOI: 10.1016/j.sempedsurg.2023.151309] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Necrotizing enterocolitis (NEC) is a devastating gastrointestinal disorder in premature infants that causes significant morbidity and mortality. Research efforts into the pathogenesis of NEC have discovered a pivotal role for the gram-negative bacterial receptor, Toll-like receptor 4 (TLR4), in its development. TLR4 is activated by dysbiotic microbes within the intestinal lumen, which leads to an exaggerated inflammatory response within the developing intestine, resulting in mucosal injury. More recently, studies have identified that the impaired intestinal motility that occurs early in NEC has a causative role in disease development, as strategies to enhance intestinal motility can reverse NEC in preclinical models. There has also been broad appreciation that NEC also contributes to significant neuroinflammation, which we have linked to the effects of gut-derived pro-inflammatory molecules and immune cells which activate microglia in the developing brain, resulting in white matter injury. These findings suggest that the management of the intestinal inflammation may secondarily be neuroprotective. Importantly, despite the significant burden of NEC on premature infants, these and other studies have provided a strong rationale for the development of small molecules with the capability of reducing NEC severity in pre-clinical models, thus guiding the development of specific anti-NEC therapies. This review summarizes the roles of TLR4 signaling in the premature gut in the pathogenesis of NEC, and provides insights into optimal clinical management strategies based upon findings from laboratory studies.
Collapse
Affiliation(s)
- Daniel J Scheese
- Division of Pediatric Surgery, Johns Hopkins University School of Medicine, 1800 Orleans St, Baltimore, MD 21287, USA
| | - Chhinder P Sodhi
- Division of Pediatric Surgery, Johns Hopkins University School of Medicine, 1800 Orleans St, Baltimore, MD 21287, USA
| | - David J Hackam
- Division of Pediatric Surgery, Johns Hopkins University School of Medicine, 1800 Orleans St, Baltimore, MD 21287, USA.
| |
Collapse
|
30
|
Oshima K, Hinoki A, Uchida H, Tanaka Y, Okuno Y, Go Y, Shirota C, Tainaka T, Sumida W, Yokota K, Makita S, Takimoto A, Kano Y, Sawa S. Single-cell RNA sequencing of intestinal immune cells in neonatal necrotizing enterocolitis. Pediatr Surg Int 2023; 39:179. [PMID: 37041419 DOI: 10.1007/s00383-023-05461-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/03/2023] [Indexed: 04/13/2023]
Abstract
PURPOSE Necrotizing enterocolitis (NEC) causes fatal intestinal necrosis in neonates, but its etiology is unknown. We analyzed the intestinal immune response to NEC. METHODS Using single-cell RNA sequencing (scRNA-seq), we analyzed the gene expression profiles of intestinal immune cells from four neonates with intestinal perforation (two with NEC and two without NEC). Target mononuclear cells were extracted from the lamina propria of the resected intestines. RESULTS In all four cases, major immune cells, such as T cells (15.1-47.7%), B cells (3.1-19.0%), monocytes (16.5-31.2%), macrophages (1.6-17.4%), dendritic cells (2.4-12.2%), and natural killer cells (7.5-12.8%), were present in similar proportions to those in the neonatal cord blood. Gene set enrichment analysis showed that the MTOR, TNF-α, and MYC signaling pathways were enriched in T cells of the NEC patients, suggesting upregulated immune responses related to inflammation and cell proliferation. In addition, all four cases exhibited a bias toward cell-mediated inflammation, based on the predominance of T helper 1 cells. CONCLUSION Intestinal immunity in NEC subjects exhibited stronger inflammatory responses compared to non-NEC subjects. Further scRNA-seq and cellular analysis may improve our understanding of the pathogenesis of NEC.
Collapse
Affiliation(s)
- Kazuo Oshima
- Department of Pediatric Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Department of Pediatric Surgery, Saitama Medical University, Saitama, Japan
| | - Akinari Hinoki
- Department of Pediatric Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hiroo Uchida
- Department of Pediatric Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yujiro Tanaka
- Department of Pediatric Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Department of Pediatric Surgery, Saitama Medical University, Saitama, Japan
| | - Yusuke Okuno
- Department of Virology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Yasuhiro Go
- Cognitive Genomics Research Group, Exploratory Research Center on Life and Living Systems (ExCELLS), National Institutes of Natural Sciences, Okazaki, Japan
- Department of System Neuroscience, National Institute for Physiological Science, Okazaki, Japan
- Department of Physiological Science, School of Life Science, SOKENDAI (The Graduate University for Advanced Studies), Okazaki, Japan
| | - Chiyoe Shirota
- Department of Pediatric Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takahisa Tainaka
- Department of Pediatric Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Wataru Sumida
- Department of Pediatric Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kazuki Yokota
- Department of Pediatric Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Satoshi Makita
- Department of Pediatric Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Aitaro Takimoto
- Department of Pediatric Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoko Kano
- Department of Pediatric Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Shinichiro Sawa
- Division of Mucosal Immunology, Research Center for Systems Immunology, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
| |
Collapse
|
31
|
Abstract
The last decade has witnessed a meteoric rise in research focused on characterizing the human microbiome and identifying associations with disease risk. The advent of sequencing technology has all but eradicated gel-based fingerprinting approaches for studying microbial ecology, while at the same time traditional microbiological culture is undergoing a renaissance. Although multiplexed high-throughput sequencing is relatively new, the discoveries leading to this are nearly 50 years old, coinciding with the inaugural Microbiology Society Fleming Prize lecture. It was an honour to give the 2022 Fleming Prize lecture and this review will cover the topics from that lecture. The focus will be on the bacterial community in early life, beginning with term infants before moving on to infants delivered prematurely. The review will discuss recent work showing how human milk oligosaccharides (HMOs), an abundant but non-nutritious component of breast milk, can modulate infant microbiome and promote the growth of Bifidobacterium spp. This has important connotations for preterm infants at risk of necrotizing enterocolitis, a devastating intestinal disease representing the leading cause of death and long-term morbidity in this population. With appropriate mechanistic studies, it may be possible to harness the power of breast milk bioactive factors and infant gut microbiome to improve short- and long-term health in infants.
Collapse
|
32
|
Chiruvolu A, Hendrikson H, Hanson R, Reedy A, Reis J, Desai S, Suterwala M. Effects of prophylactic probiotics supplementation on infants born very preterm or very low birth weight. J Perinatol 2023; 43:635-641. [PMID: 36997802 DOI: 10.1038/s41372-023-01657-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Revised: 03/08/2023] [Accepted: 03/20/2023] [Indexed: 04/01/2023]
Abstract
OBJECTIVE To evaluate the effects of guideline-driven prophylactic supplementation of a multi-strain neonatal intensive care unit-specific probiotic product on infants born very preterm (VP) or very low birth weight (VLBW). STUDY DESIGN A prospective cohort of 125 infants born in one year after implementation who received probiotics were compared to a retrospective cohort of eligible 126 VP or VLBW infants who did not receive probiotics. The primary outcome of interest was necrotizing enterocolitis (NEC). RESULT The incidence of NEC decreased from 6.3 to 1.6%. After adjusting for multiple variables, there were no significant differences in primary or other outcomes of interest; odds ratio (95% confidence interval) NEC 0.27 (0.05-1.33), death 0.76 (0.26-2.21) and late-onset sepsis 0.54 (0.18-1.63). No adverse effects related to probiotics supplementation were observed. CONCLUSION Although nonsignificant, prophylactic probiotics supplementation in infants born VP or VLBW was associated with reduction of NEC.
Collapse
Affiliation(s)
- Arpitha Chiruvolu
- Division of Neonatology, Department of Pediatrics, Baylor University Medical Center at Dallas, Dallas, TX, USA.
- Pediatrix Medical Group of Dallas, Dallas, TX, USA.
- Department of Medical Education, Texas A&M University School of Medicine, Bryan, TX, USA.
- Department of Women and Infants, Baylor Scott and White Medical Center-McKinney, McKinney, TX, USA.
| | - Heather Hendrikson
- Division of Neonatology, Department of Pediatrics, Baylor University Medical Center at Dallas, Dallas, TX, USA
- Aramark Corporation, Houston, TX, USA
| | - Rachael Hanson
- Department of Medical Education, Texas A&M University School of Medicine, Bryan, TX, USA
| | - Amy Reedy
- Department of Women and Infants, Baylor Scott and White Medical Center-McKinney, McKinney, TX, USA
| | - Jordan Reis
- Division of Neonatology, Department of Pediatrics, Baylor University Medical Center at Dallas, Dallas, TX, USA
- Pediatrix Medical Group of Dallas, Dallas, TX, USA
- Department of Women and Infants, Baylor Scott and White Medical Center-McKinney, McKinney, TX, USA
| | - Sujata Desai
- Division of Neonatology, Department of Pediatrics, Baylor University Medical Center at Dallas, Dallas, TX, USA
- Pediatrix Medical Group of Dallas, Dallas, TX, USA
| | - Mustafa Suterwala
- Division of Neonatology, Department of Pediatrics, Baylor University Medical Center at Dallas, Dallas, TX, USA
- Pediatrix Medical Group of Dallas, Dallas, TX, USA
| |
Collapse
|
33
|
Sajankila N, Wala SJ, Ragan MV, Volpe SG, Dumbauld Z, Purayil N, Mihi B, Besner GE. Current and future methods of probiotic therapy for necrotizing enterocolitis. Front Pediatr 2023; 11:1120459. [PMID: 36937955 PMCID: PMC10017871 DOI: 10.3389/fped.2023.1120459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Accepted: 01/31/2023] [Indexed: 03/06/2023] Open
Abstract
Necrotizing enterocolitis (NEC) is a complex intestinal disease that primarily affects premature neonates. Given its significant mortality and morbidity, there is an urgent need to develop improved prophylactic measures against the disease. One potential preventative strategy for NEC is the use of probiotics. Although there has been significant interest for decades in probiotics in neonatal care, no clear guidelines exist regarding which probiotic to use or for which patients, and no FDA-approved products exist on the market for NEC. In addition, there is lack of agreement regarding the benefits of probiotics in neonates, as well as some concerns about the safety and efficacy of available products. We discuss currently available probiotics as well as next-generation probiotics and novel delivery strategies which may offer an avenue to capitalize on the benefits of probiotics, while minimizing the risks. Thus, probiotics may still prove to be an effective prevention strategy for NEC, although further product development and research is needed to support use in the preterm population.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | - Gail E. Besner
- Department of Pediatric Surgery, Center for Perinatal Research, Nationwide Children’s Hospital, Columbus, OH, United States
| |
Collapse
|
34
|
Molecular Mechanisms of Hyperoxia-Induced Neonatal Intestinal Injury. Int J Mol Sci 2023; 24:ijms24054366. [PMID: 36901800 PMCID: PMC10002283 DOI: 10.3390/ijms24054366] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 02/15/2023] [Accepted: 02/20/2023] [Indexed: 02/25/2023] Open
Abstract
Oxygen therapy is important for newborns. However, hyperoxia can cause intestinal inflammation and injury. Hyperoxia-induced oxidative stress is mediated by multiple molecular factors and leads to intestinal damage. Histological changes include ileal mucosal thickness, intestinal barrier damage, and fewer Paneth cells, goblet cells, and villi, effects which decrease the protection from pathogens and increase the risk of necrotizing enterocolitis (NEC). It also causes vascular changes with microbiota influence. Hyperoxia-induced intestinal injuries are influenced by several molecular factors, including excessive nitric oxide, the nuclear factor-κB (NF-κB) pathway, reactive oxygen species, toll-like receptor-4, CXC motif ligand-1, and interleukin-6. Nuclear factor erythroid 2-related factor 2 (Nrf2) pathways and some antioxidant cytokines or molecules including interleukin-17D, n-acetylcysteine, arginyl-glutamine, deoxyribonucleic acid, cathelicidin, and health microbiota play a role in preventing cell apoptosis and tissue inflammation from oxidative stress. NF-κB and Nrf2 pathways are essential to maintain the balance of oxidative stress and antioxidants and prevent cell apoptosis and tissue inflammation. Intestinal inflammation can lead to intestinal damage and death of the intestinal tissue, such as in NEC. This review focuses on histologic changes and molecular pathways of hyperoxia-induced intestinal injuries to establish a framework for potential interventions.
Collapse
|
35
|
Cuna A, Morowitz MJ, Sampath V. Early antibiotics and risk for necrotizing enterocolitis in premature infants: A narrative review. Front Pediatr 2023; 11:1112812. [PMID: 36865691 PMCID: PMC9971631 DOI: 10.3389/fped.2023.1112812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 01/24/2023] [Indexed: 02/16/2023] Open
Abstract
While prompt initiation of antibiotics at birth due to concerns for early onset sepsis is common, it often leads to many preterm infants being exposed to treatment despite negative blood cultures. Such exposure to early antibiotics can impact the developing gut microbiome putting infants at increased risk of several diseases. Necrotizing enterocolitis (NEC), a devastating inflammatory bowel disease that affects preterm infants, is among the most widely studied neonatal disease that has been linked to early antibiotics. While some studies have demonstrated an increased risk of NEC, other studies have demonstrated seemingly contrary findings of decreased NEC with early antibiotics. Studies using animal models have also yielded differing findings of benefit vs. harm of early antibiotic exposure on subsequent NEC susceptibility. We thus sought to conduct this narrative review to help clarify the relationship between early antibiotics exposure and future risk of NEC in preterm infants. Our objectives are to: (1) summarize findings from human and animal studies that investigated the relationship between early antibiotics and NEC, (2) highlight important limitations of these studies, (3) explore potential mechanisms that can explain why early antibiotics may increase or decrease NEC risk, and (4) identify future directions for research.
Collapse
Affiliation(s)
- Alain Cuna
- Division of Neonatology, Children's Mercy Kansas City, Kansas City, MOUnited States
- School of Medicine, University of Missouri-Kansas City, Kansas City, MOUnited States
| | - Michael J. Morowitz
- Division of Pediatric General and Thoracic Surgery, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PAUnited States
- School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
| | - Venkatesh Sampath
- Division of Neonatology, Children's Mercy Kansas City, Kansas City, MOUnited States
- School of Medicine, University of Missouri-Kansas City, Kansas City, MOUnited States
| |
Collapse
|
36
|
Barbian ME, Patel RM. Probiotics for prevention of necrotizing enterocolitis: Where do we stand? Semin Perinatol 2023; 47:151689. [PMID: 36621416 PMCID: PMC10201375 DOI: 10.1016/j.semperi.2022.151689] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
In this review, we provide a historical perspective on probiotic use in preterm infants. We review recent data on the treatment effects of probiotics on necrotizing enterocolitis, sepsis, and mortality. We highlight guidance statements from professional societies and organizations, discussing key points within the context of the currently available evidence from both randomized trials and cohort studies. Finally, we summarize experiences from several North American centers that have reported on the routine use of probiotics, including our center. Our goal is to highlight some of the considerations and complexities surrounding routine probiotics use in preterm infants.
Collapse
Affiliation(s)
- Maria Estefania Barbian
- Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, 2015 Uppergate Dr. NE, Atlanta, GA 30322, United States
| | - Ravi Mangal Patel
- Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, 2015 Uppergate Dr. NE, Atlanta, GA 30322, United States.
| |
Collapse
|
37
|
Ganapathy Y, Muthusamy Sridhar N, Dhandapani P. Probiotics: A Healthy Treasure. ROLE OF MICROBES IN SUSTAINABLE DEVELOPMENT 2023:89-97. [DOI: 10.1007/978-981-99-3126-2_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
|
38
|
Prebiotic activity of chitooligosaccharides and their ability to alleviate necrotizing enterocolitis in newborn rats. Carbohydr Polym 2023; 299:120156. [PMID: 36876780 DOI: 10.1016/j.carbpol.2022.120156] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 09/14/2022] [Accepted: 09/22/2022] [Indexed: 11/07/2022]
Abstract
Chitooligosaccharides (COS) have many bioactive functions and favorable prospects in the fields of biomedicine and functional foods. In this study, COS was found to significantly improve the survival rate of neonatal necrotizing enterocolitis (NEC) model rats, alter the composition of the intestinal microbiota, inhibit the expression of inflammatory cytokines, and alleviate intestinal pathological injury. In addition, COS also increased the abundance of Akkermansia, Bacteroides, and Clostridium sensu stricto 1 in the intestines of normal rats (the normal rat model is more universal). The in vitro fermentation results found that COS was degraded by the human gut microbiota to promote the abundance of Clostridium sensu stricto 1 and produced numerous short-chain fatty acids (SCFAs). In vitro metabolomic analysis revealed that COS catabolism was associated with significant increases in 3-hydroxybutyrate acid and γ-aminobutyric acid. This study provides evidence for the potential of COS as a prebiotic in food products and to ameliorate NEC development in neonatal rats.
Collapse
|
39
|
Ghorbanian F, Seo H, Tajdozian H, Lee Y, Rahim MDA, Kim S, Jung IY, Lee S, Song HY. In Vivo Efficacy of Bacillus velezensis Isolated from Korean Gochang Bokbunja Vinegar against Carbapenem-Resistant Klebsiella pneumoniae Infections. Pol J Microbiol 2022; 71:553-562. [PMID: 36515501 PMCID: PMC9944968 DOI: 10.33073/pjm-2022-051] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Accepted: 11/03/2022] [Indexed: 12/15/2022] Open
Abstract
Outbreaks of carbapenem-resistant Enterobacteriaceae (CRE), especially Klebsiella pneumoniae (CRKP), are commonly reported as severe infections in hospitals and long-term care settings, and their occurrence is increasing globally. Conventional antibiotics used for treating CRE have become ineffective due to resistance development. Furthermore, their safety issues restrict their availability and use for CRE treatment. Therefore, developing new drugs different from existing drugs to combat this deadly menace is urgently needed. Probiotics can be a potential option in this context, as probiotics' efficacy against a variety of infectious illnesses has already been well established. Here, we report the effect of the Bacillus velezensis strain isolated from Gochang Bokbunja vinegar in Korea on CRE infection using two mouse models. Data showed that pretreatment with B. velezensis significantly reduced body weight loss and mortality of CRKP-infected mice in the preventive model. The oral administration of B. velezensis in a therapeutic model also decreased the mortality and illness severity in CRKP-infected mice. Moreover, a two-week oral acute toxicity assay in guinea pigs did not reveal any aberrant clinical signs. Our findings demonstrate the potential effectiveness of our candidate probiotic strain, B. velezensis, against CRKP, suggesting that it could be used as an antimicrobial agent for treating CRKP-related infections.
Collapse
Affiliation(s)
- Fatemeh Ghorbanian
- Department of Microbiology and Immunology, School of Medicine, Soonchunhyang University, Cheonan, Chungnam, Republic of Korea,Probiotics Microbiome Convergence Center, Soonchunhyang University, Asan, Chungnam, Republic of Korea
| | - Hoonhee Seo
- Department of Microbiology and Immunology, School of Medicine, Soonchunhyang University, Cheonan, Chungnam, Republic of Korea,Probiotics Microbiome Convergence Center, Soonchunhyang University, Asan, Chungnam, Republic of Korea
| | - Hanieh Tajdozian
- Department of Microbiology and Immunology, School of Medicine, Soonchunhyang University, Cheonan, Chungnam, Republic of Korea,Probiotics Microbiome Convergence Center, Soonchunhyang University, Asan, Chungnam, Republic of Korea
| | - Youngkyoung Lee
- Department of Microbiology and Immunology, School of Medicine, Soonchunhyang University, Cheonan, Chungnam, Republic of Korea,Probiotics Microbiome Convergence Center, Soonchunhyang University, Asan, Chungnam, Republic of Korea
| | - MD Abdur Rahim
- Department of Microbiology and Immunology, School of Medicine, Soonchunhyang University, Cheonan, Chungnam, Republic of Korea,Probiotics Microbiome Convergence Center, Soonchunhyang University, Asan, Chungnam, Republic of Korea
| | - Sukyung Kim
- Probiotics Microbiome Convergence Center, Soonchunhyang University, Asan, Chungnam, Republic of Korea
| | - Il-Yun Jung
- Korea Balsamic Vinegar Association, Gochang, Jeonbuk, Republic of Korea
| | - Saebim Lee
- Department of Microbiology and Immunology, School of Medicine, Soonchunhyang University, Cheonan, Chungnam, Republic of Korea,Probiotics Microbiome Convergence Center, Soonchunhyang University, Asan, Chungnam, Republic of Korea
| | - Ho-Yeon Song
- Department of Microbiology and Immunology, School of Medicine, Soonchunhyang University, Cheonan, Chungnam, Republic of Korea,Probiotics Microbiome Convergence Center, Soonchunhyang University, Asan, Chungnam, Republic of Korea, H.-Y. Song, Department of Microbiology and Immunology, School of Medicine, Soonchunhyang University, Cheonan, Chungnam, Republic of Korea; Probiotics Microbiome Convergence Center, Soonchunhyang University, Asan, Chungnam, Republic of Korea
| |
Collapse
|
40
|
Finkelstein SD, Sistrunk JW, Malchoff C, Thompson DV, Kumar G, Timmaraju VA, Repko B, Mireskandari A, Evoy-Goodman LA, Massoll NA, Lupo MA. A Retrospective Evaluation of the Diagnostic Performance of an Interdependent Pairwise MicroRNA Expression Analysis with a Mutation Panel in Indeterminate Thyroid Nodules. Thyroid 2022; 32:1362-1371. [PMID: 35943886 PMCID: PMC9700378 DOI: 10.1089/thy.2022.0124] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Background: The addition of genetic analysis to the evaluation of thyroid nodule fine-needle aspiration biopsy samples improves diagnostic accuracy of cytologically indeterminate thyroid nodules (ITNs) with Bethesda III or IV cytopathology. We previously reported the performance of a multiplatform molecular test, referred to in this study as MPTXv1, that includes a mutation panel (ThyGeNEXT®) plus an algorithmic microRNA (miRNA) risk classifier (ThyraMIR®). Complex interactions of growth-promoting and -suppressing miRNAs affect the phenotype. We previously demonstrated that accounting for these interactions with pairwise miRNA expression analysis improves the diagnosis of medullary thyroid carcinoma. In this study, we assess the impact of pairwise miRNA expression analysis on risk stratification of ITNs. Methods: Pairwise expression analysis of 11 miRNAs was performed on a training cohort of histopathology-proven benign nodules (n = 50) to define the mean and standard deviation of each pairwise analysis and create a Benign/Malignant Profiler (MPTXv2), deviations from which predicted the malignancy risk. Clinical validation of MPTXv2 was assessed using a cohort of 178 ITN (Bethesda III and IV) samples from a multicentered, blinded retrospective study, previously evaluated by MPTXv1. Results: Compared with MPTXv1, MPTXv2 significantly improved the test performance. The receiver operating characteristic (ROC) areas under the curve (AUC) increased from 0.85 to 0.97 (p < 0.001), and the diagnostic accuracy at the positive threshold increased significantly (p < 0.05) from 83% [95% confidence interval (CI) = 76-88] to 93% [CI = 89-96]. The significant improvement in the ROC AUC and the diagnostic accuracy was due to a strong statistical trend for improvement in specificity at the positive threshold. At the positive threshold, the specificity for MPTXv1 was 90% [CI = 84-95] and improved to 98% [CI = 94-99] for MPTXv2. Using the MPTXv2, the Moderate-Risk cohort decreased from 50 samples (28% of the cohort) to 24 samples (13% of the cohort). This 52% decrease is statistically significant (p < 0.001) and clinically meaningful. Conclusion: As compared with MPTXv1, pairwise miRNA expression analysis used in MPTXv2 significantly improved the diagnostic accuracy of ITN risk stratification and reduced the size of the Moderate-Risk group. Prospective trials are indicated to confirm these findings in a clinical practice setting.
Collapse
Affiliation(s)
- Sydney D. Finkelstein
- Interpace Diagnostics, Parsippany, New Jersey, USA
- Address correspondence to: Sydney D. Finkelstein, MD, Interpace Diagnostics, 300 Interpace Parkway, Parsippany, NJ 07054, USA
| | | | - Carl Malchoff
- UConn Health, Neag Comprehensive Cancer Center, Farmington, Connecticut, USA
| | | | | | | | | | | | | | - Nicole A. Massoll
- University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Mark A. Lupo
- Thyroid and Endocrine Center of Florida, Sarasota, Florida, USA
| |
Collapse
|
41
|
Oba S, Yildirim T, Karataş ŞM. Probiotics Safety Aspect of Functional Foods. JOURNAL OF CULINARY SCIENCE & TECHNOLOGY 2022. [DOI: 10.1080/15428052.2022.2135156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Affiliation(s)
- Sirin Oba
- Department of Food Processing, Suluova Vocational School, Amasya University, Amasya, Turkey
| | - Tugce Yildirim
- Department of Biotechnology, Institution of Science, Amasya University, Amasya, Turkey
| | | |
Collapse
|
42
|
Larke JA, Kuhn-Riordon K, Taft DH, Sohn K, Iqbal S, Underwood MA, Mills DA, Slupsky CM. Preterm Infant Fecal Microbiota and Metabolite Profiles Are Modulated in a Probiotic Specific Manner. J Pediatr Gastroenterol Nutr 2022; 75:535-542. [PMID: 35881967 PMCID: PMC9489674 DOI: 10.1097/mpg.0000000000003570] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVES To compare the impact of two probiotic supplements on fecal microbiota and metabolites, as well as on gut inflammation in human milk-fed preterm infants. METHODS In this single-center observational cohort study, we assessed the effects of Bifidobacterium longum subsp. infantis or Lactobacillus reuteri supplementation on the infant gut microbiota by 16S rRNA gene sequencing and fecal metabolome by 1 H nuclear magnetic resonance spectroscopy. Fecal calprotectin was measured as a marker of enteric inflammation. Aliquots of human or donor milk provided to each infant were also assessed to determine human milk oligosaccharide (HMO) content. RESULTS As expected, each probiotic treatment was associated with increased proportions of the respective bacterial taxon. Fecal HMOs were significantly higher in L. reuteri fed babies despite similar HMO content in the milk consumed. Fecal metabolites associated with bifidobacteria fermentation products were significantly increased in B. infantis supplemented infants. Fecal calprotectin was lower in infants receiving B. infantis relative to L. reuteri ( P < 0.01, Wilcoxon rank-sum test) and was negatively associated with the microbial metabolite indole-3-lactate (ILA). CONCLUSIONS This study demonstrates that supplementing an HMO-catabolizing Bifidobacterium probiotic results in increased microbial metabolism of milk oligosaccharides and reduced intestinal inflammation relative to a noncatabolizing Lactobacillus probiotic in human milk-fed preterm infants. In this context, Bifidobacterium may provide greater benefit in human milk-fed infants via activation of the microbiota-metabolite-immune axis.
Collapse
Affiliation(s)
| | - Kara Kuhn-Riordon
- Department of Pediatrics, UC Davis School of Medicine, Sacramento, CA, USA
| | - Diana H. Taft
- Department of Food Science and Technology, UC Davis, Davis, CA, USA
| | - Kristin Sohn
- Department of Pediatrics, UC Davis School of Medicine, Sacramento, CA, USA
| | - Sameeia Iqbal
- 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
| | - David A. Mills
- Department of Food Science and Technology, UC Davis, Davis, CA, USA
| | - Carolyn M. Slupsky
- Department of Nutrition, UC Davis, Davis, CA, USA
- Department of Food Science and Technology, UC Davis, Davis, CA, USA
| |
Collapse
|
43
|
Zuiderwijk MO, van der Burg M, Bekker V, Schoenaker MHD. Regulatory T Cells in Development and Prediction of Necrotizing Enterocolitis in Preterm Neonates: A Scoping Review. Int J Mol Sci 2022; 23:10903. [PMID: 36142816 PMCID: PMC9504949 DOI: 10.3390/ijms231810903] [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: 08/19/2022] [Revised: 09/11/2022] [Accepted: 09/14/2022] [Indexed: 11/17/2022] Open
Abstract
Necrotizing enterocolitis (NEC) is a leading cause of mortality in premature infants. However, the pathophysiology and influence of regulatory T cells (Tregs) have not been sufficiently elucidated. We performed a scoping review to investigate current knowledge on the influence of Tregs in NEC, and to investigate the predictive value of Treg number in NEC development. Pubmed, Embase, Prospero and Cochrane Library were searched during December 2020. Primary research articles discussing Tregs and NEC development written in English were selected. Two reviewers screened title and abstract for relevance, after which full-text screening was performed. A total of 20 articles were selected-13 of the articles discussed studies performed in animal models, while 8 used human neonate data. One study discussed both animal and human data. It was shown that after NEC diagnosis or induction, Treg levels were decreased while Th17 levels were increased. No studies were found which investigated the predictive value of Treg number in NEC development. A reduced Treg level is found in animals and neonates with NEC. The question remains whether this effect is a factor on the causal pathway of NEC development or a bystander effect. Future research focusing on the pathophysiological timeline of NEC and the involvement of Tregs is required for better understanding of this disease.
Collapse
Affiliation(s)
- Mara O. Zuiderwijk
- Willem Alexander Children’s Hospital, Division of Neonatology, Department of Pediatrics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
| | - Mirjam van der Burg
- Willem Alexander Children’s Hospital, Laboratory for Pediatric Immunology, Department of Pediatrics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
| | - Vincent Bekker
- Willem Alexander Children’s Hospital, Division of Neonatology, Department of Pediatrics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
| | - Michiel H. D. Schoenaker
- Willem Alexander Children’s Hospital, Division of Neonatology, Department of Pediatrics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
- Willem Alexander Children’s Hospital, Laboratory for Pediatric Immunology, Department of Pediatrics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
| |
Collapse
|
44
|
An L, Li J, Liu B, Hui J, Zhang Q, Zhang X, Wang Q. Knockdown of TRPM7 attenuates apoptosis and inflammation in neonatal necrotizing enterocolitis model cell IEC-6 via modulating TLR4/NF-κB and MEK/ERK pathways. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2022; 25:947-953. [PMID: 36159330 PMCID: PMC9464344 DOI: 10.22038/ijbms.2022.62113.13742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 06/13/2022] [Indexed: 11/25/2022]
Abstract
OBJECTIVES Neonatal necrotizing enterocolitis (NEC) is the most common gastrointestinal critical illness in neonatal infants. TRPM7 reportedly plays a role in human inflammatory bowel disease (IBD) and colorectal cancer, but the role of TRPM7 in the pathogenesis of NEC remains vague. MATERIALS AND METHODS The expression of TRPM7 was determined in intestinal tissues of NEC patients and lipopolysaccharide (LPS)-induced IEC-6 cells. Subsequently, a loss-of-function assay was performed to assess the effects of TRPM7 on cell apoptosis and inflammatory response in IEC-6 cells after LPS induction. Furthermore, the modulation of TRPM7 on TLR4/NF-κB and MEK/ERK signaling pathways was validated. RESULTS The expression of TRPM7 was higher in the intestinal tissues of NEC patients compared with the normal human intestinal tissues. Moreover, the expression level of TRPM7 was elevated in LPS stimulation IEC-6 cells. Knockdown of TRPM7 enhanced cell viability and suppressed apoptosis, accompanied by the decreased Bax/Bcl-1 ratio and cleaved-caspase3 expression in LPS-induced IEC-6 cells. Additionally, TRPM7 silencing attenuated LPS-induced expressions and secretions of proinflammatory cytokines. Mechanistically, TRPM7 knockdown inhibited the TLR4/NF-κB activation, while enhancing the MEK/ERK activation in LPS-treated IEC-6 cells. Overexpression of TLR4 or inhibition of MEK attenuated the inhibitory effects of TRPM7 knockdown on LPS-induced apoptosis and inflammation in IEC-6 cells. CONCLUSION Knockdown of TRPM7 attenuated LPS-induced IEC-6 cell apoptosis and inflammation by modulating TLR4/NF-κB and MEK/ERK pathways.
Collapse
Affiliation(s)
- Lu An
- Department of Pathology, Xi’an Children’s Hospital, Xi’an 710003, Shaanxi Province, China
| | - Juan Li
- Department of Pathology, Xi’an Children’s Hospital, Xi’an 710003, Shaanxi Province, China
| | - Bing Liu
- Department of Pathology, Xi’an Children’s Hospital, Xi’an 710003, Shaanxi Province, China
| | - Junpeng Hui
- Department of Pathology, Xi’an Children’s Hospital, Xi’an 710003, Shaanxi Province, China
| | - Qiang Zhang
- Department of Pathology, Xi’an Children’s Hospital, Xi’an 710003, Shaanxi Province, China
| | - Xin Zhang
- Department of Pathology, Xi’an Children’s Hospital, Xi’an 710003, Shaanxi Province, China
| | - Qi Wang
- Department of Neonatal Surgery, Xi’an Children’s Hospital, Xi’an 710003, Shaanxi Province, China,Corresponding author: Qi Wang. Department of Neonatal Surgery, Xi’an Children’s Hospital, No. 69, Xijuyuan Lane, Lianhu District, Xi’an 710003, Shaanxi Province, China.
| |
Collapse
|
45
|
Peixoto RS, Voolstra CR, Sweet M, Duarte CM, Carvalho S, Villela H, Lunshof JE, Gram L, Woodhams DC, Walter J, Roik A, Hentschel U, Thurber RV, Daisley B, Ushijima B, Daffonchio D, Costa R, Keller-Costa T, Bowman JS, Rosado AS, Reid G, Mason CE, Walke JB, Thomas T, Berg G. Harnessing the microbiome to prevent global biodiversity loss. Nat Microbiol 2022; 7:1726-1735. [PMID: 35864220 DOI: 10.1038/s41564-022-01173-1] [Citation(s) in RCA: 85] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Accepted: 06/14/2022] [Indexed: 01/21/2023]
Abstract
Global biodiversity loss and mass extinction of species are two of the most critical environmental issues the world is currently facing, resulting in the disruption of various ecosystems central to environmental functions and human health. Microbiome-targeted interventions, such as probiotics and microbiome transplants, are emerging as potential options to reverse deterioration of biodiversity and increase the resilience of wildlife and ecosystems. However, the implementation of these interventions is urgently needed. We summarize the current concepts, bottlenecks and ethical aspects encompassing the careful and responsible management of ecosystem resources using the microbiome (termed microbiome stewardship) to rehabilitate organisms and ecosystem functions. We propose a real-world application framework to guide environmental and wildlife probiotic applications. This framework details steps that must be taken in the upscaling process while weighing risks against the high toll of inaction. In doing so, we draw parallels with other aspects of contemporary science moving swiftly in the face of urgent global challenges.
Collapse
Affiliation(s)
- Raquel S Peixoto
- Red Sea Research Center (RSRC), Division of Biological and Environmental Science and Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia.
| | - Christian R Voolstra
- Red Sea Research Center (RSRC), Division of Biological and Environmental Science and Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia.,Department of Biology, University of Konstanz, Konstanz, Germany
| | - Michael Sweet
- Aquatic Research Facility, Environmental Sustainability Research Centre, University of Derby, Derby, UK
| | - Carlos M Duarte
- Red Sea Research Center (RSRC), Division of Biological and Environmental Science and Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia.,Computational Bioscience Research Center (CBRC), Division of Biological and Environmental Science and Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia
| | - Susana Carvalho
- Red Sea Research Center (RSRC), Division of Biological and Environmental Science and Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia
| | - Helena Villela
- Red Sea Research Center (RSRC), Division of Biological and Environmental Science and Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia
| | - Jeantine E Lunshof
- Department of Global Health and Social Medicine, Center for Bioethics, Harvard Medical School, Boston, MA, USA.,Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA
| | - Lone Gram
- Department of Biotechnology and Biomedicine, Technical University of Denmark, Kongens Lyngby, Denmark
| | - Douglas C Woodhams
- Department of Biology, University of Massachusetts Boston, Boston, MA, USA.,Smithsonian Tropical Research Institute, Panama City, Panama
| | - Jens Walter
- APC Microbiome Ireland, School of Microbiology, and Department of Medicine, University College Cork, Cork, Ireland
| | - Anna Roik
- Helmholtz Institute for Functional Marine Biodiversity (HIFMB), Oldenburg, Germany
| | - Ute Hentschel
- RD3 Marine Symbioses, GEOMAR Helmholtz Centre for Ocean Research Kiel, Kiel, Germany
| | | | - Brendan Daisley
- Lawson Health Research Institute, University of Western Ontario, London, Ontario, Canada
| | - Blake Ushijima
- Department of Biology and Marine Biology, University of North Carolina Wilmington, Wilmington, NC, USA
| | - Daniele Daffonchio
- Red Sea Research Center (RSRC), Division of Biological and Environmental Science and Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia
| | - Rodrigo Costa
- Institute for Bioengineering and Biosciences, Instituto Superior Técnico, University of Lisbon, Lisbon, Portugal
| | - Tina Keller-Costa
- Institute for Bioengineering and Biosciences, Instituto Superior Técnico, University of Lisbon, Lisbon, Portugal
| | - Jeff S Bowman
- Scripps Institution of Oceanography, University of California San Diego, San Diego, CA, USA
| | - Alexandre S Rosado
- Red Sea Research Center (RSRC), Division of Biological and Environmental Science and Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia
| | - Gregor Reid
- Lawson Health Research Institute, University of Western Ontario, London, Ontario, Canada
| | | | - Jenifer B Walke
- Department of Biology, Eastern Washington University, Cheney, WA, USA
| | - Torsten Thomas
- Centre for Marine Science and Innovation and School of Biological, Earth and Environmental Sciences, University of New South Wales, Sydney, Australia
| | - Gabriele Berg
- Institute of Environmental Biotechnology, Graz University of Technology, Graz, Austria.,University of Postdam and Leibniz Institute for Agricultural Engineering and Bioeconomy (ATB), Potsdam, Germany
| |
Collapse
|
46
|
Rao K, Cuna A, Chavez-Bueno S, Menden H, Yu W, Ahmed I, Srinivasan P, Umar S, Sampath V. Effect of Various Preterm Infant Milk Formulas on NEC-Like Gut Injury in Mice. Front Pediatr 2022; 10:902798. [PMID: 35874567 PMCID: PMC9299064 DOI: 10.3389/fped.2022.902798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Accepted: 06/10/2022] [Indexed: 11/13/2022] Open
Abstract
Formula feeding is an important risk factor for the development of necrotizing enterocolitis in preterm infants. The potential harmful effects of different preterm formulas on the developing intestinal tract remain incompletely understood. Here we demonstrate that feeding newborn mouse pups with various preterm formulas resulted in differing effects on intestinal inflammation, apoptosis, and activation of the pro-inflammatory transcription factor NFκB. 16S rRNA sequencing revealed that each preterm formula resulted in significant gut microbial alterations that were different from dam-fed controls. Formula feeding with EleCare and Similac Special Care caused greater intestinal injury compared to NeoSure. Pre-treatment with Lactobacillus rhamnosus GG ameliorated severity of intestinal injury from EleCare and Similac Special Care. Our findings indicate that not all preterm formulas are the same, and different formulations can have varying effects on intestinal inflammation, apoptosis, and microbiome composition.
Collapse
Affiliation(s)
- Karishma Rao
- Division of Neonatology, Children’s Mercy Hospital, Kansas City, MO, United States
- School of Medicine, University of Missouri-Kansas City, Kansas City, MO, United States
| | - Alain Cuna
- Division of Neonatology, Children’s Mercy Hospital, Kansas City, MO, United States
- School of Medicine, University of Missouri-Kansas City, Kansas City, MO, United States
| | - Susana Chavez-Bueno
- School of Medicine, University of Missouri-Kansas City, Kansas City, MO, United States
- Division of Infectious Disease, Children’s Mercy Hospital, Kansas City, MO, United States
| | - Heather Menden
- Division of Neonatology, Children’s Mercy Hospital, Kansas City, MO, United States
| | - Wei Yu
- Division of Neonatology, Children’s Mercy Hospital, Kansas City, MO, United States
| | - Ishfaq Ahmed
- Department of Biology, Kansas City Kansas Community College, Kansas City, KS, United States
| | - Pugazhendhi Srinivasan
- Department of Urology, University of Kansas Medical Center, Kansas City, KS, United States
| | - Shahid Umar
- Department of Surgery, University of Kansas Medical Center, Kansas City, KS, United States
| | - Venkatesh Sampath
- Division of Neonatology, Children’s Mercy Hospital, Kansas City, MO, United States
- School of Medicine, University of Missouri-Kansas City, Kansas City, MO, United States
| |
Collapse
|
47
|
Gandecha H, Kaur A, Sanghera R, Preece J, Pillay T. Nutrition and Immunity in Perinatal Hypoxic-Ischemic Injury. Nutrients 2022; 14:nu14132747. [PMID: 35807927 PMCID: PMC9269416 DOI: 10.3390/nu14132747] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 06/23/2022] [Accepted: 06/28/2022] [Indexed: 02/01/2023] Open
Abstract
Perinatal hypoxia ischaemia (PHI), acute and chronic, may be associated with considerable adverse outcomes in the foetus and neonate. The molecular and cellular mechanisms of injury and repair associated with PHI in the perinate are not completely understood. Increasing evidence is mounting for the role of nutrients and bioactive food components in immune development, function and repair in PHI. In this review, we explore current concepts around the neonatal immune response to PHI with a specific emphasis on the impact of nutrition in the mother, foetus and neonate.
Collapse
Affiliation(s)
- Hema Gandecha
- Department of Neonatology, University Hospitals Leicester NHS Trust, Leicester LE1 5WW, UK
- East Midlands Deanery, Health Education England, Leicester LE3 5DR, UK
| | - Avineet Kaur
- Department of Neonatology, University Hospitals Leicester NHS Trust, Leicester LE1 5WW, UK
- East Midlands Deanery, Health Education England, Leicester LE3 5DR, UK
| | - Ranveer Sanghera
- Department of Neonatology, University Hospitals Leicester NHS Trust, Leicester LE1 5WW, UK
- East Midlands Deanery, Health Education England, Leicester LE3 5DR, UK
| | - Joanna Preece
- Department of Neonatology, University Hospitals Leicester NHS Trust, Leicester LE1 5WW, UK
| | - Thillagavathie Pillay
- Department of Neonatology, University Hospitals Leicester NHS Trust, Leicester LE1 5WW, UK
- Faculty of Science and Engineering, Research Institute for Healthcare Sciences, University of Wolverhampton, Wolverhampton WV1 1LY, UK
- College of Life Sciences, University of Leicester, Leicester LE5 4PW, UK
| |
Collapse
|
48
|
Probiotics for Prevention of Necrotizing Enterocolitis: Where Are We Now? J Perinat Neonatal Nurs 2022; 36:231-232. [PMID: 35894718 DOI: 10.1097/jpn.0000000000000674] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
|
49
|
Antibacterial and anti-inflammatory effects of Lactobacillus reuteri in its biofilm state contribute to its beneficial effects in a rat model of experimental necrotizing enterocolitis. J Pediatr Surg 2022; 57:1382-1390. [PMID: 34657737 DOI: 10.1016/j.jpedsurg.2021.09.001] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 08/25/2021] [Accepted: 09/02/2021] [Indexed: 01/26/2023]
Abstract
INTRODUCTION Necrotizing enterocolitis (NEC) remains a significant surgical emergency in neonates. We have demonstrated the efficacy of Lactobacillus reuteri (Lr) in protecting against experimental NEC when administered as a biofilm by incubation with maltose loaded dextranomer microspheres. Lr possesses antimicrobial and anti-inflammatory properties. We developed mutant strains of Lr to examine the importance of its antimicrobial and anti-inflammatory properties in protecting the intestines from NEC. METHODS Premature rat pups were exposed to hypoxia/hypothermia/hypertonic feeds to induce NEC. To examine the importance of antimicrobial reuterin and anti-inflammatory histamine, pups received either native or mutant forms of Lr, in either its planktonic or biofilm states, prior to induction of NEC. Intestinal histology was examined upon sacrifice. RESULTS Compared to no treatment, administration of a single dose of Lr in its biofilm state significantly decreased the incidence of NEC (67% vs. 18%, p < 0.0001), whereas Lr in its planktonic state had no significant effect. Administration of reuterin-deficient or histamine-deficient forms of Lr, in either planktonic or biofilm states, resulted in significant loss of efficacy. CONCLUSION Antimicrobial and anti-inflammatory effects of Lr contribute to its beneficial effects against NEC. This suggests that both infectious and inflammatory components contribute to the etiology of NEC.
Collapse
|
50
|
Abstract
Extremely preterm infants are particularly vulnerable to systemic infections secondary to their immature immune defenses, prolonged hospitalizations, delays in enteral feeding, early antibiotic exposure, and need for life-sustaining invasive interventions. There have been several evidence-based practices for infection prevention in this population, such as human milk feedings, utilization of "bundle checklists" and decolonization of pathogenic organisms. Other practices, such as the use of probiotics, human milk-derived fortifiers, and antifungal prophylaxis are more controversial and require further investigation regarding the risks and benefits of such interventions. This chapter examines the susceptibility of the preterm newborn infant to invasive infections and describes several strategies for infection prevention, along with the associated limitations of such practices. It also addresses the various gaps in our understanding of preventing infections in this population, and the need for additional large multi-center randomized controlled trials. Additionally, the role of the SARs-CoV-2 global pandemic and associated strategies for infection prevention in the NICU are discussed.
Collapse
|