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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.
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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.
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Waller ME, Eichhorn CJ, Gutierrez A, Baatz JE, Wagner CL, Chetta KE, Engevik MA. Analyzing the Responses of Enteric Bacteria to Neonatal Intensive Care Supplements. Int J Microbiol 2024; 2024:3840327. [PMID: 39220439 PMCID: PMC11364479 DOI: 10.1155/2024/3840327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 07/25/2024] [Accepted: 07/26/2024] [Indexed: 09/04/2024] Open
Abstract
In the neonatal intensive care unit, adequate nutrition requires various enteral products, including human milk and formula. Human milk is typically fortified to meet increased calorie goals, and infants commonly receive vitamin mixes, iron supplements, and less frequently, thickening agents. We examined the growth of 16 commensal microbes and 10 pathobionts found in the premature infant gut and found that formula, freshly pasteurized milk, and donated banked milk generally increased bacterial growth. Fortification of human milk significantly elevated the growth of all microbes. Supplementation with thickeners or NaCl in general did not stimulate additional growth. Vitamin mix promoted the growth of several commensals, while iron promoted growth of pathobionts. These data indicate that pathobionts in the preterm gut have significant growth advantage with preterm formula, fortified donor milk, and supplemented iron and suggest that the choice of milk and supplements may impact the infant gut microbiota.
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Affiliation(s)
- Megan E. Waller
- Department of Regenerative Medicine and Cell BiologyMedical University of South Carolina, Charleston, USA
| | - Caroline J. Eichhorn
- Department of Regenerative Medicine and Cell BiologyMedical University of South Carolina, Charleston, USA
| | - Alyssa Gutierrez
- Department of Regenerative Medicine and Cell BiologyMedical University of South Carolina, Charleston, USA
| | - John E. Baatz
- Department of PediatricsC.P. Darby Children's Research InstituteMedical University of South Carolina, Charleston, USA
- Department of PediatricsDivision of Neonatal-Perinatal MedicineMedical University of South CarolinaShawn Jenkins Children's Hospital, 10 McClennan Banks Drive, MSC 915, Charleston, SC 29425, USA
| | - Carol L. Wagner
- Department of PediatricsC.P. Darby Children's Research InstituteMedical University of South Carolina, Charleston, USA
- Department of PediatricsDivision of Neonatal-Perinatal MedicineMedical University of South CarolinaShawn Jenkins Children's Hospital, 10 McClennan Banks Drive, MSC 915, Charleston, SC 29425, USA
| | - Katherine E. Chetta
- Department of PediatricsC.P. Darby Children's Research InstituteMedical University of South Carolina, Charleston, USA
- Department of PediatricsDivision of Neonatal-Perinatal MedicineMedical University of South CarolinaShawn Jenkins Children's Hospital, 10 McClennan Banks Drive, MSC 915, Charleston, SC 29425, USA
| | - Melinda A. Engevik
- Department of Regenerative Medicine and Cell BiologyMedical University of South Carolina, Charleston, USA
- Department of Microbiology and ImmunologyMedical University of South Carolina, Charleston, USA
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3
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Boel L, Gallacher DJ, Marchesi JR, Kotecha S. The Role of the Airway and Gut Microbiome in the Development of Chronic Lung Disease of Prematurity. Pathogens 2024; 13:472. [PMID: 38921770 PMCID: PMC11206380 DOI: 10.3390/pathogens13060472] [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: 04/29/2024] [Revised: 05/24/2024] [Accepted: 05/25/2024] [Indexed: 06/27/2024] Open
Abstract
Chronic lung disease (CLD) of prematurity, a common cause of morbidity and mortality in preterm-born infants, has a multifactorial aetiology. This review summarizes the current evidence for the effect of the gut and airway microbiota on the development of CLD, highlighting the differences in the early colonisation patterns in preterm-born infants compared to term-born infants. Stool samples from preterm-born infants who develop CLD have less diversity than those who do not develop CLD. Pulmonary inflammation, which is a hallmark in the development of CLD, may potentially be influenced by gut bacteria. The respiratory microbiota is less abundant than the stool microbiota in preterm-born infants. There is a lack of clear evidence for the role of the respiratory microbiota in the development of CLD, with results from individual studies not replicated. A common finding is the presence of a single predominant bacterial genus in the lungs of preterm-born infants who develop CLD. Probiotic preparations have been proposed as a potential therapeutic strategy to modify the gut or lung microbiota with the aim of reducing rates of CLD but additional robust evidence is required before this treatment is introduced into routine clinical practice.
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Affiliation(s)
- Lieve Boel
- Neonatal Unit, University Hospital of Wales, Cardiff CF14 4XW, UK; (L.B.); (D.J.G.)
| | - David J. Gallacher
- Neonatal Unit, University Hospital of Wales, Cardiff CF14 4XW, UK; (L.B.); (D.J.G.)
| | - Julian R. Marchesi
- Division of Digestive Diseases, Faculty of Medicine, Imperial College, London W2 1NY, UK;
| | - Sailesh Kotecha
- Department of Child Health, Cardiff University School of Medicine, Cardiff CF14 4XN, UK
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4
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Li S, You X, Rani A, Özcan E, Sela DA. Bifidobacterium infantis utilizes N-acetylglucosamine-containing human milk oligosaccharides as a nitrogen source. Gut Microbes 2023; 15:2244721. [PMID: 37609905 PMCID: PMC10448974 DOI: 10.1080/19490976.2023.2244721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 07/26/2023] [Accepted: 08/01/2023] [Indexed: 08/24/2023] Open
Abstract
Bifidobacterium longum subsp. infantis (B. infantis) utilizes oligosaccharides secreted in human milk as a carbohydrate source. These human milk oligosaccharides (HMOs) integrate the nitrogenous residue N-acetylglucosamine (NAG), although HMO nitrogen utilization has not been described to date. Herein, we characterize the B. infantis nitrogen utilization phenotype on two NAG-containing HMO species, LNT and LNnT. This was characterized through in vitro growth kinetics, incorporation of isotopically labeled NAG nitrogen into the proteome, as well as modulation of intracellular 2-oxoglutarate levels while utilizing HMO nitrogen. Further support is provided by comparative transcriptomics and proteomics that identified global regulatory networks deployed during HMO nitrogen utilization. The aggregate data demonstrate that B. infantis strains utilize HMO nitrogen with the potential to significantly impact fundamental and clinical studies, as well as enable applications.
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Affiliation(s)
- Shuqi Li
- Department of Food Science, University of Massachusetts, Amherst, MA, USA
| | - Xiaomeng You
- Department of Food Science, University of Massachusetts, Amherst, MA, USA
| | - Asha Rani
- Department of Food Science, University of Massachusetts, Amherst, MA, USA
| | - Ezgi Özcan
- Department of Food Science, University of Massachusetts, Amherst, MA, USA
| | - David A. Sela
- Department of Food Science, University of Massachusetts, Amherst, MA, USA
- Department of Microbiology, University of Massachusetts Amherst, Amherst, MA, USA
- Department of Nutrition, University of Massachusetts Amherst, Amherst, MA, USA
- Department of Microbiology & Physiological Systems and Center for Microbiome Research, University of Massachusetts Medical School, Worcester, MA, USA
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van der Toorn M, Chatziioannou AC, Pellis L, Haandrikman A, van der Zee L, Dijkhuizen L. Biological Relevance of Goat Milk Oligosaccharides to Infant Health. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2023; 71:13935-13949. [PMID: 37691562 PMCID: PMC10540210 DOI: 10.1021/acs.jafc.3c02194] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 08/21/2023] [Accepted: 08/22/2023] [Indexed: 09/12/2023]
Abstract
Milk is often regarded as the gold standard for the nourishment of all mammalian offspring. The World Health Organization (WHO) recommends exclusive breastfeeding for the first 6 months of the life of the infant, followed by a slow introduction of complementary foods to the breastfeeding routine for a period of approximately 2 years, whenever this is possible ( Global Strategy for Infant and Young Child Feeding; WHO, 2003). One of the most abundant components in all mammals' milk, which is associated with important health benefits, is the oligosaccharides. The milk oligosaccharides (MOS) of humans and other mammals differ in terms of their concentration and diversity. Among those, goat milk contains more oligosaccharides (gMOS) than other domesticated dairy animals, as well as a greater range of structures. This review summarizes the biological functions of MOS found in both human and goat milk to identify the possible biological relevance of gMOS in human health and development. Based on the existing literature, seven biological functions of gMOS were identified, namely, MOS action as prebiotics, immune modulators, and pathogen traps; their modulation of intestinal cells; protective effect against necrotizing enterocolitis; improved brain development; and positive effects on stressor exposure. Overall, goat milk is a viable alternate supply of functional MOS that could be employed in a newborn formula.
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Affiliation(s)
| | - Anastasia Chrysovalantou Chatziioannou
- CarbExplore
Research BV, Groningen, 9747 AN The Netherlands
- Department
of Chemistry, Laboratory of Analytical Biochemistry, University of Crete, Heraklion, 70013, Greece
| | | | | | | | - Lubbert Dijkhuizen
- CarbExplore
Research BV, Groningen, 9747 AN The Netherlands
- Microbial
Physiology, Groningen Biomolecular Sciences and Biotechnology Institute
(GBB), University of Groningen, Groningen, 9747 AG, The Netherlands
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Singh SV, Ganguly R, Jaiswal K, Yadav AK, Kumar R, Pandey AK. Molecular signalling during cross talk between gut brain axis regulation and progression of irritable bowel syndrome: A comprehensive review. World J Clin Cases 2023; 11:4458-4476. [PMID: 37469740 PMCID: PMC10353503 DOI: 10.12998/wjcc.v11.i19.4458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Revised: 05/09/2023] [Accepted: 06/06/2023] [Indexed: 06/30/2023] Open
Abstract
Irritable bowel syndrome (IBS) is a chronic functional disorder which alters gastrointestinal (GI) functions, thus leading to compromised health status. Pathophysiology of IBS is not fully understood, whereas abnormal gut brain axis (GBA) has been identified as a major etiological factor. Recent studies are suggestive for visceral hyper-sensitivity, altered gut motility and dysfunctional autonomous nervous system as the main clinical abnormalities in IBS patients. Bidirectional signalling interactions among these abnormalities are derived through various exogenous and endogenous factors, such as microbiota population and diversity, microbial metabolites, dietary uptake, and psychological abnormalities. Strategic efforts focused to study these interactions including probiotics, antibiotics and fecal transplantations in normal and germ-free animals are clearly suggestive for the pivotal role of gut microbiota in IBS etiology. Additionally, neurotransmitters act as communication tools between enteric microbiota and brain functions, where serotonin (5-hydroxytryptamine) plays a key role in pathophysiology of IBS. It regulates GI motility, pain sense and inflammatory responses particular to mucosal and brain activity. In the absence of a better understanding of various interconnected crosstalks in GBA, more scientific efforts are required in the search of novel and targeted therapies for the management of IBS. In this review, we have summarized the gut microbial composition, interconnected signalling pathways and their regulators, available therapeutics, and the gaps needed to fill for a better management of IBS.
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Affiliation(s)
- Shiv Vardan Singh
- Department of Biochemistry, University of Allahabad, Allahabad (Prayagraj) 211002, Uttar Pradesh, India
| | - Risha Ganguly
- Department of Biochemistry, University of Allahabad, Allahabad (Prayagraj) 211002, Uttar Pradesh, India
| | - Kritika Jaiswal
- Department of Biochemistry, University of Allahabad, Allahabad (Prayagraj) 211002, Uttar Pradesh, India
| | - Aditya Kumar Yadav
- Department of Biochemistry, University of Allahabad, Allahabad (Prayagraj) 211002, Uttar Pradesh, India
| | - Ramesh Kumar
- Department of Biochemistry, University of Allahabad, Allahabad (Prayagraj) 211002, Uttar Pradesh, India
| | - Abhay K Pandey
- Department of Biochemistry, University of Allahabad, Allahabad (Prayagraj) 211002, Uttar Pradesh, India
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7
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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.
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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.
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Magner C, Jenkins D, Koc F, Tan MH, O'Toole M, Boyle J, Maguire N, Duignan S, Murphy K, Ross P, Stanton C, McMahon CJ. Protocol for a prospective cohort study exploring the gut microbiota of infants with congenital heart disease undergoing cardiopulmonary bypass (the GuMiBear study). BMJ Open 2023; 13:e067016. [PMID: 37001916 PMCID: PMC10069492 DOI: 10.1136/bmjopen-2022-067016] [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: 04/04/2023] Open
Abstract
INTRODUCTION The gut microbiota develops from birth and matures significantly during the first 24 months of life, playing a major role in infant health and development. The composition of the gut microbiota is influenced by several factors including mode of delivery, gestational age, feed type and treatment with antibiotics. Alterations in the pattern of gut microbiota development and composition can be associated with illness and compromised health outcomes.Infants diagnosed with 'congenital heart disease' (CHD) often require surgery involving cardiopulmonary bypass (CPB) early in life. The impact of this type of surgery on the integrity of the gut microbiome is poorly understood. In addition, these infants are at significant risk of developing the potentially devastating intestinal condition necrotising enterocolitis. METHODS AND ANALYSIS This study will employ a prospective cohort study methodology to investigate the gut microbiota and urine metabolome of infants with CHD undergoing surgery involving CPB. Stool and urine samples, demographic and clinical data will be collected from eligible infants based at the National Centre for Paediatric Cardiac Surgery in Ireland. Shotgun metagenome sequencing will be performed on stool samples and urine metabolomic analysis will identify metabolic biomarkers. The impact of the underlying diagnosis, surgery involving CPB, and the influence of environmental factors will be explored. Data from healthy age-matched infants from the INFANTMET study will serve as a control for this study. ETHICS AND DISSEMINATION This study has received full ethical approval from the Clinical Research Ethics Committee of Children's Health Ireland, GEN/826/20.
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Affiliation(s)
- Claire Magner
- School of Nursing, Midwifery and Health Systems, University College Dublin, Dublin, Ireland
| | - Dominic Jenkins
- Laboratory, Children's Health Ireland at Crumlin, Crumlin, Ireland
| | - Fatma Koc
- School of Microbiology, University College Cork, Cork, Ireland
- Food Biosciences, Teagasc Food Research Centre, Cork, Ireland
| | - Mong Hoi Tan
- Department Paediatric Cardiology, Children's Health Ireland at Crumlin, Dublin, Ireland
| | - Molly O'Toole
- Department Paediatric Cardiology, Children's Health Ireland at Crumlin, Dublin, Ireland
| | - Jordan Boyle
- Department Paediatric Cardiology, Children's Health Ireland at Crumlin, Dublin, Ireland
| | - Niamh Maguire
- Department Paediatric Cardiology, Children's Health Ireland at Crumlin, Dublin, Ireland
| | - Sophie Duignan
- Department Paediatric Cardiology, Children's Health Ireland at Crumlin, Dublin, Ireland
| | - Kiera Murphy
- University College Cork APC Microbiome Institute, Cork, Ireland
- Food Biosciences, Teagasc Food Research Centre, Moorepark, Ireland
| | - Paul Ross
- University College Cork College of Science Engineering and Food Science, Cork, Ireland
| | - Catherine Stanton
- University College Cork APC Microbiome Institute, Cork, Ireland
- Teagasc Food Research Centre, Moorepark, Ireland
| | - Colin J McMahon
- Department Paediatric Cardiology, Children's Health Ireland at Crumlin, Dublin, Ireland
- University College Dublin School of Medicine, Dublin, Ireland
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9
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Abstract
Necrotizing enterocolitis (NEC) is the leading cause of death and disability from gastrointestinal disease in premature infants. The mortality of patients with NEC is approximately 30%, a figure that has not changed in many decades, reflecting the need for a greater understanding of its pathogenesis. Progress towards understanding the cellular and molecular mechanisms underlying NEC requires the study of highly translational animal models. Such animal models must mimic the biology and physiology of premature infants, while still allowing for safe experimental manipulation of environmental and microbial factors thought to be associated with the risk and severity of NEC. Findings from animal models have yielded insights into the interactions between the host, the colonizing microbes, and the innate immune receptor Toll-like Receptor 4 (TLR4) in driving disease development. This review discusses the relative strengths and weaknesses of available in vivo, in vitro, and NEC-in-a-dish models of this disease. We also highlight the unique contributions that each model has made to our understanding of the complex interactions between enterocytes, microbiota, and immune cells in the pathogenesis of NEC. The overall purpose of this review is to provide a menu of options regarding currently available animal models of NEC, while in parallel hopefully reducing the potential uncertainty and confusion regarding NEC models to assist those who wish to enter this field from other disciplines.
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Affiliation(s)
- Carla M Lopez
- Division of Pediatric Surgery and the Department of Surgery at the Johns Hopkins University, Bloomberg Children's Center, The Johns Hopkins Hospital, Room 7323, 1800 Orleans Street, Baltimore, MD 21287, USA
| | - Maame Efua S Sampah
- Division of Pediatric Surgery and the Department of Surgery at the Johns Hopkins University, Bloomberg Children's Center, The Johns Hopkins Hospital, Room 7323, 1800 Orleans Street, Baltimore, MD 21287, USA
| | - Johannes W Duess
- Division of Pediatric Surgery and the Department of Surgery at the Johns Hopkins University, Bloomberg Children's Center, The Johns Hopkins Hospital, Room 7323, 1800 Orleans Street, Baltimore, MD 21287, USA
| | - Asuka Ishiyama
- Division of Pediatric Surgery and the Department of Surgery at the Johns Hopkins University, Bloomberg Children's Center, The Johns Hopkins Hospital, Room 7323, 1800 Orleans Street, Baltimore, MD 21287, USA
| | - Raheel Ahmad
- Division of Pediatric Surgery and the Department of Surgery at the Johns Hopkins University, Bloomberg Children's Center, The Johns Hopkins Hospital, Room 7323, 1800 Orleans Street, Baltimore, MD 21287, USA
| | - Chhinder P Sodhi
- Division of Pediatric Surgery and the Department of Surgery at the Johns Hopkins University, Bloomberg Children's Center, The Johns Hopkins Hospital, Room 7323, 1800 Orleans Street, Baltimore, MD 21287, USA
| | - David J Hackam
- Division of Pediatric Surgery and the Department of Surgery at the Johns Hopkins University, Bloomberg Children's Center, The Johns Hopkins Hospital, Room 7323, 1800 Orleans Street, Baltimore, MD 21287, USA.
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10
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Subramanian S, Geng H, Du C, Chou PM, Bu HF, Wang X, Swaminathan S, Tan SC, Ridlon JM, De Plaen IG, Tan XD. Feeding mode influences dynamic gut microbiota signatures and affects susceptibility to anti-CD3 mAb-induced intestinal injury in neonatal mice. Am J Physiol Gastrointest Liver Physiol 2022; 323:G205-G218. [PMID: 35819158 PMCID: PMC9394775 DOI: 10.1152/ajpgi.00337.2021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 07/01/2022] [Accepted: 07/02/2022] [Indexed: 01/31/2023]
Abstract
Feeding modes influence the gut microbiome, immune system, and intestinal barrier homeostasis in neonates; how feeding modes impact susceptibility to neonatal gastrointestinal (GI) diseases is still uncertain. Here, we investigated the impact of dam feeding (DF) and formula feeding (FF) on features of the gut microbiome and physiological inflammation during the first 2 days of postnatal development and on the susceptibility to intestinal injury related to the inflammatory state in neonatal mouse pups. 16S rRNA sequencing data revealed microbiome changes, lower α-diversity, and a distinct pattern of β-diversity including expansion of f_Enterobacteriaceae and f_Enterococcaceae in the ileum of FF pups compared with DF pups by postnatal day (P)2. Together with gut dysbiosis, the FF cohort also had greater ileal mucosa physiological inflammatory activity compared with DF pups by P2 but maintained normal histological features. Interestingly, FF but not DF mouse pups developed necrotizing enterocolitis (NEC)-like intestinal injury within 24 h after anti-CD3 mAb treatment, suggesting that FF influences the susceptibility to intestinal injury in neonates. We further found that NEC-like incidence in anti-CD3 mAb-treated FF neonatal pups was attenuated by antibiotic treatment. Collectively, our data suggest that FF predisposes mouse pups to anti-CD3 mAb-induced intestinal injury due to abnormal f_Enterobacteriaceae and f_Enterococcaceae colonization. These findings advance our understanding of FF-associated microbial colonization and intestinal inflammation, which may help inform the development of new therapeutic approaches to GI diseases like NEC in infants.NEW & NOTEWORTHY This report shows that a feeding mode profoundly affects gut colonization in neonatal mice. Furthermore, our results demonstrate that formula feeding predisposes mouse pups to anti-CD3 mAb-induced necrotizing enterocolitis (NEC)-like intestinal injury upon inadequate microbial colonization. The study suggests the role of the combined presence of formula feeding-associated dysbiosis and mucosal inflammation in the pathogenesis of NEC and provides a new mouse model to study this disease.
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Affiliation(s)
- Saravanan Subramanian
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Center for Intestinal and Liver Inflammation Research, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois
- Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Hua Geng
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Center for Intestinal and Liver Inflammation Research, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois
- Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Chao Du
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Center for Intestinal and Liver Inflammation Research, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois
- Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Pauline M Chou
- Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Heng-Fu Bu
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Center for Intestinal and Liver Inflammation Research, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois
- Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Xiao Wang
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Center for Intestinal and Liver Inflammation Research, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois
- Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Suchitra Swaminathan
- Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Stephanie C Tan
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Center for Intestinal and Liver Inflammation Research, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois
- Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Jason M Ridlon
- Department of Animal Sciences, University of Illinois Urbana-Champaign, Urbana, Illinois
| | - Isabelle G De Plaen
- Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
- Division of Neonatology, Department of Pediatrics, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois
| | - Xiao-Di Tan
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Center for Intestinal and Liver Inflammation Research, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois
- Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
- Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
- Department of Research and Development, Jesse Brown Department of Veterans Affairs Medical Center, Chicago, Illinois
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11
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Chen W, Ma J, Jiang Y, Deng L, Lv N, Gao J, Cheng J, Liang JB, Wang Y, Lan T, Liao X, Mi J. Selective Maternal Seeding and Rearing Environment From Birth to Weaning Shape the Developing Piglet Gut Microbiome. Front Microbiol 2022; 13:795101. [PMID: 35547153 PMCID: PMC9083071 DOI: 10.3389/fmicb.2022.795101] [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: 10/14/2021] [Accepted: 03/28/2022] [Indexed: 01/04/2023] Open
Abstract
The acquisition and development of the mammalian microbiome early in life are critical to establish a healthy host-microbiome symbiosis. Despite recent advances in understanding microbial sources in infants, the relative contribution of various microbial sources to the colonization of the gut microbiota in pigs remains unclear. Here, we longitudinally sampled the microbiota of 20 sow-piglet pairs (three piglets per sow) reared under identical conditions from multiple body sites and the surrounding weaning environment from birth to 28 days postpartum (1,119 samples in total). Source-tracking analysis revealed that the contribution of various microbial sources to the piglet gut microbiome gradually changed over time. The neonatal microbiota was initially sparsely populated, and the predominant contribution was from the maternal vaginal microbiota that increased gradually from 69.0% at day 0 to 89.3% at day 3 and dropped to 0.28% at day 28. As the piglets aged, the major microbial community patterns were most strongly associated with the sow feces and slatted floor, with contributions increasing from 0.52 and 9.6% at day 0 to 62.1 and 33.8% at day 28, respectively. The intestinal microbial diversity, composition, and function significantly changed as the piglets aged, and 30 age-discriminatory bacterial taxa were identified with distinctive time-dependent shifts in their relative abundance, which likely reflected the effect of the maternal and environmental microbial sources on the selection and adaptation of the piglet gut microbiota. Overall, these data demonstrate that the vaginal microbiota is the primary source of the gut microbiota in piglets within 3 days after birth and are gradually replaced by the sow fecal and slatted floor microbiota over time. These findings may offer novel strategies to promote the establishment of exogenous symbiotic microbes to improve piglet gut health.
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Affiliation(s)
- Wei Chen
- College of Animal Science, National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou, China.,Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, Guangzhou, Chain
| | - Jingyun Ma
- College of Animal Science, National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou, China.,Ministry of Agriculture Key Laboratory of Tropical Agricultural Environment, South China Agricultural University, Guangzhou, China
| | - Yiming Jiang
- Institute of Virology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.,Institute of Virology, Technical University of Munich, Munich, Germany
| | - Li Deng
- Institute of Virology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.,Institute of Virology, Technical University of Munich, Munich, Germany
| | - Ning Lv
- College of Animal Science, National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou, China.,Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, Guangzhou, Chain
| | - Jinming Gao
- College of Animal Science, National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou, China.,Ministry of Agriculture Key Laboratory of Tropical Agricultural Environment, South China Agricultural University, Guangzhou, China
| | - Jian Cheng
- College of Animal Science, National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou, China.,Ministry of Agriculture Key Laboratory of Tropical Agricultural Environment, South China Agricultural University, Guangzhou, China
| | - Juan Boo Liang
- Laboratory of Sustainable Animal Production and Biodiversity, Institute of Tropical Agriculture and Food Security, University Putra Malaysia, Serdang, Malaysia
| | - Yan Wang
- College of Animal Science, National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou, China.,Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, Guangzhou, Chain
| | - Tian Lan
- College of Animal Science, National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou, China.,Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, Guangzhou, Chain
| | - Xindi Liao
- College of Animal Science, National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou, China.,Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, Guangzhou, Chain.,Key Laboratory of Animal Health Aquaculture and Environmental Control, Guangzhou, China
| | - Jiandui Mi
- College of Animal Science, National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou, China.,Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, Guangzhou, Chain
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12
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Bozzi Cionci N, Lucaccioni L, Pietrella E, Ficara M, Spada C, Torelli P, Bedetti L, Lugli L, Di Gioia D, Berardi A. Antibiotic Exposure, Common Morbidities and Main Intestinal Microbial Groups in Very Preterm Neonates: A Pilot Study. Antibiotics (Basel) 2022; 11:237. [PMID: 35203839 PMCID: PMC8868158 DOI: 10.3390/antibiotics11020237] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 02/07/2022] [Accepted: 02/08/2022] [Indexed: 01/27/2023] Open
Abstract
Prematurity exposes newborns to increased risks of infections and it is associated with critical morbidities. Preterm infants often require antibiotic therapies that can affect the correct establishment of gut microbiota. The aim of this study was to investigate targeted intestinal bacteria in preterm neonates with common morbidities and receiving antibiotic treatments of variable duration. Stool samples were collected after birth, at 15, 30 and 90 days of life. qPCR quantification of selected microbial groups (Bifidobacterium spp., Bacteroides fragilis group, Enterobacteriaceae, Clostridium cluster I and total bacteria) was performed and correlation between their levels, the duration of antibiotic treatment and different clinical conditions was studied. An increasing trend over time was observed for all microbial groups, especially for Bifdobacterium spp. Prolonged exposure to antibiotics in the first weeks of life affected Clostridium and B. fragilis levels, but these changes no longer persisted at 90 days of life. Variations of bacterial counts were associated with the length of hospital stay, feeding and mechanical ventilation. Late-onset sepsis and patent ductus arteriosus reduced the counts of Bifidobacterium, whereas B. fragilis was influenced by compromised respiratory conditions. This study can be a start point for the identification of microbial biomarkers associated with some common morbidities and tailored strategies for a healthy microbial development.
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Affiliation(s)
- Nicole Bozzi Cionci
- Department of Agricultural and Food Sciences, University of Bologna, 40127 Bologna, Italy; (N.B.C.); (D.D.G.)
| | - Laura Lucaccioni
- Pediatric Unit, Department of Medical and Surgical Sciences for Mothers, Children and Adults, University of Modena and Reggio Emilia, 41124 Modena, Italy
| | - Elisa Pietrella
- Pediatric Unit, Department of Medical for Mothers and Children, Ramazzini Hospital, 41012 Carpi, Italy;
| | - Monica Ficara
- Pediatric Unit, Department of Medical for Mothers and Children, Bufalini Hospital, 47521 Cesena, Italy;
| | - Caterina Spada
- Neonatal Intensive Care Unit, Department of Medical for Mothers and Children, Bufalini Hospital, 47521 Cesena, Italy;
| | - Paola Torelli
- Neonatal Intensive Care Unit, Department of Medical and Surgical Sciences for Mothers, Children and Adults, University of Modena and Reggio Emilia, 41124 Modena, Italy; (P.T.); (L.B.); (L.L.); (A.B.)
| | - Luca Bedetti
- Neonatal Intensive Care Unit, Department of Medical and Surgical Sciences for Mothers, Children and Adults, University of Modena and Reggio Emilia, 41124 Modena, Italy; (P.T.); (L.B.); (L.L.); (A.B.)
- PhD Program in Clinical and Experimental Medicine, University of Modena and Reggio Emilia, 41124 Modena, Italy
| | - Licia Lugli
- Neonatal Intensive Care Unit, Department of Medical and Surgical Sciences for Mothers, Children and Adults, University of Modena and Reggio Emilia, 41124 Modena, Italy; (P.T.); (L.B.); (L.L.); (A.B.)
| | - Diana Di Gioia
- Department of Agricultural and Food Sciences, University of Bologna, 40127 Bologna, Italy; (N.B.C.); (D.D.G.)
| | - Alberto Berardi
- Neonatal Intensive Care Unit, Department of Medical and Surgical Sciences for Mothers, Children and Adults, University of Modena and Reggio Emilia, 41124 Modena, Italy; (P.T.); (L.B.); (L.L.); (A.B.)
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13
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Plummer EL, Danielewski JA, Garland SM, Su J, Jacobs SE, Murray GL. The effect of probiotic supplementation on the gut microbiota of preterm infants. J Med Microbiol 2021; 70. [PMID: 34431764 PMCID: PMC8513625 DOI: 10.1099/jmm.0.001403] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Introduction. Probiotic supplementation of preterm infants may prevent serious morbidities associated with prematurity.Aim. To investigate the impact of probiotic supplementation on the gut microbiota and determine factors associated with detection of probiotic species in the infant gut.Hypothesis/Gap Statement. Probiotic supplementation increases the long-term colonization of probiotic species in the gut of preterm infants.Methodology. Longitudinal stool samples were collected from a cohort of very preterm infants participating in a blinded randomized controlled trial investigating the impact of probiotic supplementation (containing Bifidobacterium longum subsp. infantis BB-02, Bifidobacterium animalis subsp. lactis BB-12 and Streptococcus thermophilus TH-4) for prevention of late-onset sepsis. The presence of B. longum subsp. infantis, B. animalis subsp. lactis and S. thermophilus was determined for up to 23 months after supplementation ended using real-time PCR. Logistic regression was used to investigate the impact of probiotic supplementation on the presence of each species.Results. Detection of B. longum subsp. infantis [odds ratio (OR): 53.1; 95 % confidence interval (CI): 35.6-79.1; P < 0.001], B. animalis subsp. lactis (OR: 89.1; 95 % CI: 59.0-134.5; P < 0.001) and S. thermophilus (OR: 5.66; 95 % CI: 4.35-7.37; P < 0.001) was increased during the supplementation period in infants receiving probiotic supplementation. Post-supplementation, probiotic-supplemented infants had increased detection of B. longum subsp. infantis (OR: 2.53; 95 % CI: 1.64-3.90; P < 0.001) and B. animalis subsp. lactis (OR: 1.59; 95 % CI: 1.05-2.41; P=0.030). Commencing probiotic supplementation before 5 days from birth was associated with increased detection of the probiotic species over the study period (B. longum subsp. infantis, OR: 1.20; B. animalis subsp. lactis, OR: 1.28; S. thermophilus, OR: 1.45).Conclusion. Probiotic supplementation with B. longum subsp. infantis BB-02, B. animalis subsp. lactis BB-12 and S. thermophilus TH-4 enhances the presence of probiotic species in the gut microbiota of very preterm infants during and after supplementation. Commencing probiotic supplementation shortly after birth may be important for improving the long-term colonization of probiotic species.
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Affiliation(s)
- Erica L Plummer
- Centre for Women's Infectious Diseases Research, The Royal Women's Hospital, Parkville, Victoria, Australia.,Infection & Immunity Theme, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.,Central Clinical School, Monash University, Melbourne, VIC, Australia
| | - Jennifer A Danielewski
- Centre for Women's Infectious Diseases Research, The Royal Women's Hospital, Parkville, Victoria, Australia.,Infection & Immunity Theme, Murdoch Children's Research Institute, Melbourne, Victoria, Australia
| | - Suzanne M Garland
- Centre for Women's Infectious Diseases Research, The Royal Women's Hospital, Parkville, Victoria, Australia.,Infection & Immunity Theme, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.,Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, Victoria, Australia
| | - Jenny Su
- Centre for Women's Infectious Diseases Research, The Royal Women's Hospital, Parkville, Victoria, Australia.,Infection & Immunity Theme, Murdoch Children's Research Institute, Melbourne, Victoria, Australia
| | - Susan E Jacobs
- Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, Victoria, Australia.,Neonatal Services, The Royal Women's Hospital, Parkville, Victoria, Australia.,Clinical Sciences, Murdoch Children's Research Institute, Melbourne, Victoria, Australia
| | - Gerald L Murray
- Centre for Women's Infectious Diseases Research, The Royal Women's Hospital, Parkville, Victoria, Australia.,Infection & Immunity Theme, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.,Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, Victoria, Australia
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14
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Major histocompatibility complex class II genetic diversity and the genetic influence on gut microbiota in Guizhou minipigs. Folia Microbiol (Praha) 2021; 66:997-1008. [PMID: 34309822 DOI: 10.1007/s12223-021-00903-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 07/20/2021] [Indexed: 10/20/2022]
Abstract
Major histocompatibility complex (MHC) is an important complex that presents antigen to T cells. The second exon of swine MHC (SLA) class II genes has antigen binding sites that bind with extracellular antigen. Populations with high MHC gene diversity result in low gut microbiota, and individuals with MHC gene heterozygote have lower gut microbiota diversity than that of homozygote. The pig is an animal with organs physiologically and anatomically similar to humans than any other mammal, and the pig is also suitably developed as a laboratory animal to establish the animal models of human disease. However, the relationship between SLA genetic diversity and the gut microbes of the pig is ambiguous. We studied the characterization of SLA class II genes and calculated the genetic diversity, and then we selected experimental animal groups divided by different SLA genotypes to investigate the gut microbiota composition by sequencing V3 to V4 hypervariable regions of bacterial 16 s rRNA from fecal samples. Our results showed that Guizhou minipigs had a low SLA genetic diversity, which may be due to the small founder population. The Guizhou minipig population deviated from neutral selection and balancing selection, which shows that Guizhou minipigs experience a strong artificial selection in recent years. We observed that the sex differences influenced gut microbiota much more deeply than that of genetics. Our results also showed that the individual with heterozygote of genes at the SLA class II region had much higher abundant gut microbiota than that of the homozygote.
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15
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Sangild PT, Vonderohe C, Melendez Hebib V, Burrin DG. Potential Benefits of Bovine Colostrum in Pediatric Nutrition and Health. Nutrients 2021; 13:nu13082551. [PMID: 34444709 PMCID: PMC8402036 DOI: 10.3390/nu13082551] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 07/02/2021] [Accepted: 07/13/2021] [Indexed: 12/12/2022] Open
Abstract
Bovine colostrum (BC), the first milk produced from cows after parturition, is increasingly used as a nutritional supplement to promote gut function and health in other species, including humans. The high levels of whey and casein proteins, immunoglobulins (Igs), and other milk bioactives in BC are adapted to meet the needs of newborn calves. However, BC supplementation may improve health outcomes across other species, especially when immune and gut functions are immature in early life. We provide a review of BC composition and its effects in infants and children in health and selected diseases (diarrhea, infection, growth-failure, preterm birth, necrotizing enterocolitis (NEC), short-bowel syndrome, and mucositis). Human trials and animal studies (mainly in piglets) are reviewed to assess the scientific evidence of whether BC is a safe and effective antimicrobial and immunomodulatory nutritional supplement that reduces clinical complications related to preterm birth, infections, and gut disorders. Studies in infants and animals suggest that BC should be supplemented at an optimal age, time, and level to be both safe and effective. Exclusive BC feeding is not recommended for infants because of nutritional imbalances relative to human milk. On the other hand, adverse effects, including allergies and intolerance, appear unlikely when BC is provided as a supplement within normal nutrition guidelines for infants and children. Larger clinical trials in infant populations are needed to provide more evidence of health benefits when patients are supplemented with BC in addition to human milk or formula. Igs and other bioactive factors in BC may work in synergy, making it critical to preserve bioactivity with gentle processing and pasteurization methods. BC has the potential to become a safe and effective nutritional supplement for several pediatric subpopulations.
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Affiliation(s)
- Per Torp Sangild
- Comparative Pediatrics & Nutrition, University of Copenhagen, DK-1870 Copenhagen, Denmark;
- Department of Neonatology, Rigshospitalet, DK-1870 Copenhagen, Denmark
- Department of Pediatrics, Odense University Hospital, DK-5000 Odense, Denmark
| | - Caitlin Vonderohe
- USDA-ARS Children’s Nutrition Research Center, Pediatrics, Gastroenterology & Nutrition, Baylor College of Medicine, Houston, TX 77030, USA; (C.V.); (V.M.H.)
| | - Valeria Melendez Hebib
- USDA-ARS Children’s Nutrition Research Center, Pediatrics, Gastroenterology & Nutrition, Baylor College of Medicine, Houston, TX 77030, USA; (C.V.); (V.M.H.)
| | - Douglas G. Burrin
- USDA-ARS Children’s Nutrition Research Center, Pediatrics, Gastroenterology & Nutrition, Baylor College of Medicine, Houston, TX 77030, USA; (C.V.); (V.M.H.)
- Correspondence: ; Tel.: +1-713-798-7049
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16
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Fournier E, Roussel C, Dominicis A, Ley D, Peyron MA, Collado V, Mercier-Bonin M, Lacroix C, Alric M, Van de Wiele T, Chassard C, Etienne-Mesmin L, Blanquet-Diot S. In vitro models of gut digestion across childhood: current developments, challenges and future trends. Biotechnol Adv 2021; 54:107796. [PMID: 34252564 DOI: 10.1016/j.biotechadv.2021.107796] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 07/05/2021] [Accepted: 07/06/2021] [Indexed: 02/08/2023]
Abstract
The human digestion is a multi-step and multi-compartment process essential for human health, at the heart of many issues raised by academics, the medical world and industrials from the food, nutrition and pharma fields. In the first years of life, major dietary changes occur and are concomitant with an evolution of the whole child digestive tract anatomy and physiology, including colonization of gut microbiota. All these phenomena are influenced by child exposure to environmental compounds, such as drugs (especially antibiotics) and food pollutants, but also childhood infections. Due to obvious ethical, regulatory and technical limitations, in vivo approaches in animal and human are more and more restricted to favor complementary in vitro approaches. This review summarizes current knowledge on the evolution of child gut physiology from birth to 3 years old regarding physicochemical, mechanical and microbial parameters. Then, all the available in vitro models of the child digestive tract are described, ranging from the simplest static mono-compartmental systems to the most sophisticated dynamic and multi-compartmental models, and mimicking from the oral phase to the colon compartment. Lastly, we detail the main applications of child gut models in nutritional, pharmaceutical and microbiological studies and discuss the limitations and challenges facing this field of research.
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Affiliation(s)
- Elora Fournier
- Université Clermont Auvergne, INRAE, UMR 454 MEDIS, Microbiologie Environnement Digestif et Santé, CRNH Auvergne, 63000 Clermont-Ferrand, France; Toxalim, Research Centre in Food Toxicology, INRAE, ENVT, INP-Purpan, UPS, Université de Toulouse, 31000 Toulouse, France
| | - Charlène Roussel
- Laval University, INAF Institute of Nutrition and Functional Foods, G1V 0A6 Quebec, Canada
| | - Alessandra Dominicis
- European Reference Laboratory for E. coli, Istituto Superiore di Sanità, Rome, Italy
| | - Delphine Ley
- Université Lille 2, Faculté de Médecine, Inserm U995 Nutritional Modulation of Infection and Inflammation, 59045 Lille, France
| | - Marie-Agnès Peyron
- Université Clermont Auvergne, INRAE, UNH, Unité de Nutrition Humaine, CRNH Auvergne, 63000 Clermont-Ferrand, France
| | - Valérie Collado
- Université Clermont Auvergne, EA 4847, CROC, Centre de Recherche en Odontologie Clinique, 63000 Clermont-Ferrand, France
| | - Muriel Mercier-Bonin
- Toxalim, Research Centre in Food Toxicology, INRAE, ENVT, INP-Purpan, UPS, Université de Toulouse, 31000 Toulouse, France
| | - Christophe Lacroix
- Laboratory of Food Biotechnology, Institute of Food, Nutrition and Health, ETH Zurich, 8092 Zürich, Switzerland
| | - Monique Alric
- Université Clermont Auvergne, INRAE, UMR 454 MEDIS, Microbiologie Environnement Digestif et Santé, CRNH Auvergne, 63000 Clermont-Ferrand, France
| | - Tom Van de Wiele
- Ghent University, Center for Microbial Ecology and Technology (CMET), Coupure Links 653, 9000 Ghent, Belgium
| | - Christophe Chassard
- Université Clermont Auvergne, INRAE, VetAgro Sup, UMRF, 15000 Aurillac, France
| | - Lucie Etienne-Mesmin
- Université Clermont Auvergne, INRAE, UMR 454 MEDIS, Microbiologie Environnement Digestif et Santé, CRNH Auvergne, 63000 Clermont-Ferrand, France
| | - Stéphanie Blanquet-Diot
- Université Clermont Auvergne, INRAE, UMR 454 MEDIS, Microbiologie Environnement Digestif et Santé, CRNH Auvergne, 63000 Clermont-Ferrand, France.
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17
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Frau A, Lett L, Slater R, Young GR, Stewart CJ, Berrington J, Hughes DM, Embleton N, Probert C. The Stool Volatile Metabolome of Pre-Term Babies. Molecules 2021; 26:3341. [PMID: 34199338 PMCID: PMC8199543 DOI: 10.3390/molecules26113341] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 05/13/2021] [Accepted: 05/27/2021] [Indexed: 11/16/2022] Open
Abstract
The fecal metabolome in early life has seldom been studied. We investigated its evolution in pre-term babies during their first weeks of life. Multiple (n = 152) stool samples were studied from 51 babies, all <32 weeks gestation. Volatile organic compounds (VOCs) were analyzed by headspace solid phase microextraction gas chromatography mass spectrometry. Data were interpreted using Automated Mass Spectral Deconvolution System (AMDIS) with the National Institute of Standards and Technology (NIST) reference library. Statistical analysis was based on linear mixed modelling, the number of VOCs increased over time; a rise was mainly observed between day 5 and day 10. The shift at day 5 was associated with products of branched-chain fatty acids. Prior to this, the metabolome was dominated by aldehydes and acetic acid. Caesarean delivery showed a modest association with molecules of fungal origin. This study shows how the metabolome changes in early life in pre-term babies. The shift in the metabolome 5 days after delivery coincides with the establishment of enteral feeding and the transition from meconium to feces. Great diversity of metabolites was associated with being fed greater volumes of milk.
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Affiliation(s)
- Alessandra Frau
- Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Crown Street, Liverpool L69 3GE, UK; (L.L.); (R.S.); (C.P.)
| | - Lauren Lett
- Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Crown Street, Liverpool L69 3GE, UK; (L.L.); (R.S.); (C.P.)
| | - Rachael Slater
- Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Crown Street, Liverpool L69 3GE, UK; (L.L.); (R.S.); (C.P.)
| | - Gregory R. Young
- Hub for Biotechnology in the Built Environment, Northumbria University, Newcastle upon Tyne NE1 8ST, UK;
| | - Christopher J. Stewart
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE1 8ST, UK; (C.J.S.); (J.B.)
| | - Janet Berrington
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE1 8ST, UK; (C.J.S.); (J.B.)
- Department of Neonatology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 8ST, UK;
| | - David M. Hughes
- Department of Health Data Science, University of Liverpool, Liverpool, Merseyside L69 3GA, UK;
| | - Nicholas Embleton
- Department of Neonatology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 8ST, UK;
- Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne NE1 8ST, UK
| | - Chris Probert
- Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Crown Street, Liverpool L69 3GE, UK; (L.L.); (R.S.); (C.P.)
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18
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Haq SU, Bhat UA, Kumar A. Prenatal stress effects on offspring brain and behavior: Mediators, alterations and dysregulated epigenetic mechanisms. J Biosci 2021. [DOI: 10.1007/s12038-021-00153-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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19
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Yang M, Du J, Yang Q, Dou W, Jiang M, Hei M. Influence of Family Integrated Care on the Intestinal Microbiome of Preterm Infants With Necrotizing Enterocolitis and Enterostomy: A Preliminary Study. Front Pediatr 2021; 9:678254. [PMID: 34900854 PMCID: PMC8662560 DOI: 10.3389/fped.2021.678254] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 10/28/2021] [Indexed: 11/13/2022] Open
Abstract
The aim of this study was to investigate the influence of family integrated care (FICare) on the intestinal microbiome of preterm infants with necrotizing enterocolitis and enterostomy. This was a prospective pilot study at Beijing Children's Hospital. Premature infants with an enterostomy who met the enrollment criteria were divided into the 2-week FICare and non-FICare groups (non-randomly). We collected their fecal samples and subjected the intestinal microbiomes to 16S rRNA gene sequencing. Operational taxonomic units (OTU) were analyzed to assess the intestinal microbiome richness, and we then carried out α-diversity, β-diversity, and species clustering analyses and a linear discriminant analysis (LDA) effect size (LEfSe) analysis to identify the differences in the microbial communities between the two groups. There were 12 patients enrolled in the study (FICare, n = 7; non-FICare, n = 5). There were no significant between-group differences in demographic characteristics, or in the relative abundances of phyla and genera. The major bacterial phyla were Proteobacteria, Firmicutes, and Actinobacteria, and Serratia, Enterococcus, Cronobacter, and Bifidobacterium dominated at the genus level. The α-diversity analysis indicated that the intestinal flora was more diverse in the non-FICare group than the FICare group (p < 0.05). However, most of the other indicators did not suggest a difference between the two groups. There was a high proportion of shared OTUs between the two groups, and the PCoA and clustering analyses indicated that the two groups were difficult to distinguish, indicating that the intestinal microbiomes were relatively similar between the groups. In summary, short-term FICare had no significant positive effect on the establishment of intestinal flora diversity in premature infants with necrotizing enterocolitis and enterostomy. The trial was registered in the Chinese Clinical Trial Registry (ChiCTR-OPN-17011801).
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Affiliation(s)
- Mengyang Yang
- Department of Neonatology, Neonatal Center, Beijing Children's Hospital, Capital Medical University, National Center of Children's Health, Beijing, China
| | - Juan Du
- Department of Neonatology, Neonatal Center, Beijing Children's Hospital, Capital Medical University, National Center of Children's Health, Beijing, China
| | - Qin Yang
- Department of Neonatology, Neonatal Center, Beijing Children's Hospital, Capital Medical University, National Center of Children's Health, Beijing, China
| | - Wenyan Dou
- Department of Neonatology, Neonatal Center, Beijing Children's Hospital, Capital Medical University, National Center of Children's Health, Beijing, China
| | - Min Jiang
- Department of Neonatology, Neonatal Center, Beijing Children's Hospital, Capital Medical University, National Center of Children's Health, Beijing, China
| | - Mingyan Hei
- Department of Neonatology, Neonatal Center, Beijing Children's Hospital, Capital Medical University, National Center of Children's Health, Beijing, China
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20
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Elmentaite R, Ross ADB, Roberts K, James KR, Ortmann D, Gomes T, Nayak K, Tuck L, Pritchard S, Bayraktar OA, Heuschkel R, Vallier L, Teichmann SA, Zilbauer M. Single-Cell Sequencing of Developing Human Gut Reveals Transcriptional Links to Childhood Crohn's Disease. Dev Cell 2020; 55:771-783.e5. [PMID: 33290721 PMCID: PMC7762816 DOI: 10.1016/j.devcel.2020.11.010] [Citation(s) in RCA: 187] [Impact Index Per Article: 37.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 09/04/2020] [Accepted: 11/06/2020] [Indexed: 02/07/2023]
Abstract
Human gut development requires the orchestrated interaction of differentiating cell types. Here, we generate an in-depth single-cell map of the developing human intestine at 6–10 weeks post-conception. Our analysis reveals the transcriptional profile of cycling epithelial precursor cells; distinct from LGR5-expressing cells. We propose that these cells may contribute to differentiated cell subsets via the generation of LGR5-expressing stem cells and receive signals from surrounding mesenchymal cells. Furthermore, we draw parallels between the transcriptomes of ex vivo tissues and in vitro fetal organoids, revealing the maturation of organoid cultures in a dish. Lastly, we compare scRNA-seq profiles from pediatric Crohn’s disease epithelium alongside matched healthy controls to reveal disease-associated changes in the epithelial composition. Contrasting these with the fetal profiles reveals the re-activation of fetal transcription factors in Crohn’s disease. Our study provides a resource available at www.gutcellatlas.org, and underscores the importance of unraveling fetal development in understanding disease.
Single-cell RNA-seq map of the developing and pediatric human intestine Cycling BEX5+ epithelial precursors are distinct from adult LGR5+ stem cells Human fetal intestinal organoids mature in culture Fetal transcription factors are reactivated in the Crohn’s disease epithelium
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Affiliation(s)
- Rasa Elmentaite
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK
| | - Alexander D B Ross
- Wellcome Trust, MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0SZ, UK; Department of Surgery, University of Cambridge, Cambridge CB2 0QQ, UK; Department of Paediatrics, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Kenny Roberts
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK
| | - Kylie R James
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK
| | - Daniel Ortmann
- Wellcome Trust, MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0SZ, UK; Department of Surgery, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Tomás Gomes
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK
| | - Komal Nayak
- Department of Paediatrics, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Liz Tuck
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK
| | - Sophie Pritchard
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK
| | | | - Robert Heuschkel
- Department of Paediatric Gastroenterology, Hepatology and Nutrition, Cambridge University Hospitals Trust, Cambridge CB2 0QQ, UK
| | - Ludovic Vallier
- Wellcome Trust, MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0SZ, UK; Department of Surgery, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Sarah A Teichmann
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK; Theory of Condensed Matter, Cavendish Laboratory, Department of Physics, University of Cambridge, Cambridge CB3 0HE, UK; European Molecular Biology Laboratory, European Bioinformatics Institute (EBI), Wellcome Genome Campus, Hinxton CB10 1SA, UK.
| | - Matthias Zilbauer
- Wellcome Trust, MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0SZ, UK; Department of Paediatrics, University of Cambridge, Cambridge CB2 0QQ, UK; Department of Paediatric Gastroenterology, Hepatology and Nutrition, Cambridge University Hospitals Trust, Cambridge CB2 0QQ, UK.
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21
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Ali F, Lui K, Wang A, Day AS, Leach ST. The perinatal period, the developing intestinal microbiome and inflammatory bowel diseases: What links early life events with later life disease? J R Soc N Z 2020; 50:371-383. [DOI: 10.1080/03036758.2019.1706586] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Accepted: 12/17/2019] [Indexed: 12/13/2022]
Affiliation(s)
- Fathalla Ali
- School of Women’s and Children’s Health, University of New South Wales, Sydney, Australia
| | - Kei Lui
- School of Women’s and Children’s Health, University of New South Wales, Sydney, Australia
- Department of Newborn Care, Royal Hospital for Women, Sydney, Australia
| | - Alex Wang
- Faculty of Health, University of Technology Sydney, Sydney, Australia
| | - Andrew S. Day
- Department of Paediatrics, University of Otago, Christchurch, New Zealand
| | - Steven T. Leach
- School of Women’s and Children’s Health, University of New South Wales, Sydney, Australia
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22
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Jayasinghe TN, Vatanen T, Chiavaroli V, Jayan S, McKenzie EJ, Adriaenssens E, Derraik JGB, Ekblad C, Schierding W, Battin MR, Thorstensen EB, Cameron-Smith D, Forbes-Blom E, Hofman PL, Roy NC, Tannock GW, Vickers MH, Cutfield WS, O'Sullivan JM. Differences in Compositions of Gut Bacterial Populations and Bacteriophages in 5-11 Year-Olds Born Preterm Compared to Full Term. Front Cell Infect Microbiol 2020; 10:276. [PMID: 32612960 PMCID: PMC7309444 DOI: 10.3389/fcimb.2020.00276] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Accepted: 05/11/2020] [Indexed: 12/17/2022] Open
Abstract
Preterm infants are exposed to major perinatal, post-natal, and early infancy events that could impact on the gut microbiome. These events include infection, steroid and antibiotic exposure, parenteral nutrition, necrotizing enterocolitis, and stress. Studies have shown that there are differences in the gut microbiome during the early months of life in preterm infants. We hypothesized that differences in the gut microbial composition and metabolites in children born very preterm persist into mid-childhood. Participants were healthy prepubertal children aged 5-11 years who were born very preterm (≤32 weeks of gestation; n = 51) or at term (37-41 weeks; n = 50). We recorded the gestational age, birth weight, mode of feeding, mode of birth, age, sex, and the current height and weight of our cohort. We performed a multi'omics [i.e., 16S rRNA amplicon and shotgun metagenomic sequencing, SPME-GCMS (solid-phase microextraction followed by gas chromatography-mass spectrometry)] analysis to investigate the structure and function of the fecal microbiome (as a proxy of the gut microbiota) in our cross-sectional cohort. Children born very preterm were younger (7.8 vs. 8.3 years; p = 0.034), shorter [height-standard deviation score (SDS) 0.31 vs. 0.92; p = 0.0006) and leaner [BMI (body mass index) SDS -0.20 vs. 0.29; p < 0.0001] than the term group. Children born very preterm had higher fecal calprotectin levels, decreased fecal phage richness, lower plasma arginine, lower fecal branched-chain amino acids and higher fecal volatile (i.e., 3-methyl-butanoic acid, butyrolactone, butanoic acid and pentanoic acid) profiles. The bacterial microbiomes did not differ between preterm and term groups. We speculate that the observed very preterm-specific changes were established in early infancy and may impact on the capacity of the very preterm children to respond to environmental changes.
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Affiliation(s)
| | - Tommi Vatanen
- Liggins Institute, University of Auckland, Auckland, New Zealand
- The Broad Institute of MIT and Harvard, Cambridge, MA, United States
| | | | - Sachin Jayan
- Liggins Institute, University of Auckland, Auckland, New Zealand
| | | | | | - José G. B. Derraik
- Liggins Institute, University of Auckland, Auckland, New Zealand
- A Better Start—National Science Challenge, University of Auckland, Auckland, New Zealand
| | - Cameron Ekblad
- Liggins Institute, University of Auckland, Auckland, New Zealand
| | | | | | | | | | | | - Paul L. Hofman
- Liggins Institute, University of Auckland, Auckland, New Zealand
| | - Nicole C. Roy
- AgResearch, Palmerston North, New Zealand
- The Riddet Institute, Massey University, Palmerston North, New Zealand
- The High-Value Nutrition Challenge, Auckland, New Zealand
| | - Gerald W. Tannock
- The Riddet Institute, Massey University, Palmerston North, New Zealand
- Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand
| | - Mark H. Vickers
- Liggins Institute, University of Auckland, Auckland, New Zealand
| | - Wayne S. Cutfield
- Liggins Institute, University of Auckland, Auckland, New Zealand
- Quadram Institute Bioscience, Norwich, United Kingdom
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23
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Bæk O, Brunse A, Nguyen DN, Moodley A, Thymann T, Sangild PT. Diet Modulates the High Sensitivity to Systemic Infection in Newborn Preterm Pigs. Front Immunol 2020; 11:1019. [PMID: 32536925 PMCID: PMC7267211 DOI: 10.3389/fimmu.2020.01019] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Accepted: 04/28/2020] [Indexed: 12/11/2022] Open
Abstract
Background: Preterm infants are born with an immature immune system, limited passive immunity, and are at risk of developing bacteremia and sepsis in the postnatal period. We hypothesized that enteral feeding, with or without added immunoglobulins, improves the clinical response to systemic infection by coagulase negative staphylococci. Methods: Using preterm cesarean delivered pigs as models for preterm infants, we infused live Staphylococcus epidermidis (SE, 5 × 109 colony forming units per kg) systemically 0–3 days after birth across five different experiments. SE infection responses were assessed following different gestational age at birth (preterm vs. term), enteral milk diets (bovine colostrum, infant formula with or without added porcine plasma) and with/without systemic immunoglobulins. Pigs infected with SE were assessed 12–48 h for clinical variables, blood bacteriology, chemistry, hematology, and gut dysfunction (intestinal permeability, necrotizing enterocolitis lesions). Results: Adverse clinical responses and increased mortality were observed in preterm vs. term pigs, when infected with SE just after birth. Feeding bovine colostrum just after birth improved blood SE clearance and clinical status (improved physical activity and intestinal structure, fewer bone marrow bacteria), relative to pigs fed infant formula. A few days later, clinical responses to SE bacteremia (hematology, neutrophil phagocytic capacity, T cell subsets) were less severe, and less affected by different milk diets, with or without added immunoglobulins. Conclusion: Prematurity increases the sensitivity of newborn pigs to SE bacteremia, potentially causing sepsis. Sensitivity to systemic SE infection decreases rapidly in the days after preterm birth. Both age and diet (parenteral nutrition, colostrum, milk, formula) may influence gut inflammation, bacterial translocation and systemic immune development in the days after birth in preterm newborns.
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Affiliation(s)
- Ole Bæk
- Comparative Pediatrics and Nutrition, Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Anders Brunse
- Comparative Pediatrics and Nutrition, Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Duc Ninh Nguyen
- Comparative Pediatrics and Nutrition, Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Arshnee Moodley
- Veterinary Clinical Microbiology, Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Thomas Thymann
- Comparative Pediatrics and Nutrition, Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Per Torp Sangild
- Comparative Pediatrics and Nutrition, Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Department of Neonatology, Rigshospitalet, Copenhagen, Denmark.,Department of Pediatrics, Odense University Hospital, Odense, Denmark
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24
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Early Effect of Supplemented Infant Formulae on Intestinal Biomarkers and Microbiota: A Randomized Clinical Trial. Nutrients 2020; 12:nu12051481. [PMID: 32443684 PMCID: PMC7284641 DOI: 10.3390/nu12051481] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 05/11/2020] [Accepted: 05/16/2020] [Indexed: 12/11/2022] Open
Abstract
Background: Post-natal gut maturation in infants interrelates maturation of the morphology, digestive, and immunological functions and gut microbiota development. Here, we explored both microbiota development and markers of gut barrier and maturation in healthy term infants during their early life to assess the interconnection of gut functions during different infant formulae regimes. Methods: A total of 203 infants were enrolled in this randomized double-blind controlled trial including a breastfed reference group. Infants were fed starter formulae for the first four weeks of life, supplemented with different combination of nutrients (lactoferrin, probiotics (Bifidobacterium animal subsp. Lactis) and prebiotics (Bovine Milk-derived Oligosaccharides—BMOS)) and subsequently fed the control formula up to eight weeks of life. Stool microbiota profiles and biomarkers of early gut maturation, calprotectin (primary outcome), elastase, α-1 antitrypsin (AAT) and neopterin were measured in feces at one, two, four, and eight weeks. Results: Infants fed formula containing BMOS had lower mean calprotectin levels over the first two to four weeks compared to the other formula groups. Elastase and AAT levels were closer to levels observed in breastfed infants. No differences were observed for neopterin. Global differences between the bacterial communities of all groups were assessed by constrained multivariate analysis with hypothesis testing. The canonical correspondence analysis (CCA) at genus level showed overlap between microbiota profiles at one and four weeks of age in the BMOS supplemented formula group with the breastfed reference, dominated by bifidobacteria. Microbiota profiles of all groups at four weeks were significantly associated with the calprotectin levels at 4 (CCA, p = 0.018) and eight weeks of age (CCA, p = 0.026). Conclusion: A meaningful correlation was observed between changes in microbiota composition and gut maturation marker calprotectin. The supplementation with BMOS seems to favor gut maturation closer to that of breastfed infants.
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25
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Ahnfeldt AM, Bæk O, Hui Y, Nielsen CH, Obelitz-Ryom K, Busk-Anderson T, Ruge A, Holst JJ, Rudloff S, Burrin D, Nguyen DN, Nielsen DS, Zachariassen G, Bering SB, Thymann T, Sangild PT. Nutrient Restriction has Limited Short-Term Effects on Gut, Immunity, and Brain Development in Preterm Pigs. J Nutr 2020; 150:1196-1207. [PMID: 32069355 DOI: 10.1093/jn/nxaa030] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2019] [Revised: 09/30/2019] [Accepted: 01/30/2020] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Extrauterine growth restriction (EUGR) in preterm infants is associated with higher morbidity and impaired neurodevelopment. Early nutrition support may prevent EUGR in preterm infants, but it is not known if this improves organ development and brain function in the short and long term. OBJECTIVE Using pigs as models for infants, we hypothesized that diet-induced EUGR impairs gut, immunity, and brain development in preterm neonates during the first weeks after birth. METHODS Forty-four preterm caesarean-delivered pigs (Danish Landrace × Large White × Duroc, birth weight 975 ± 235 g, male:female ratio 23:21) from 2 sows were fed increasing volumes [32-180 mL/(kg·d)] of dilute bovine milk (EUGR group) or the same diet fortified with powdered bovine colostrum for 19 d (CONT group, 50-100% higher protein and energy intake than the EUGR group). RESULTS The EUGR pigs showed reduced body growth (-39%, P < 0.01), lower plasma albumin, phosphate, and creatine kinase concentrations (-35 to 14%, P < 0.05), increased cortisol and free iron concentrations (+130 to 700%, P < 0.05), and reduced relative weights of the intestine, liver, and spleen (-38 to 19%, all P < 0.05). The effects of EUGR on gut structure, function, microbiota, and systemic immunity were marginal, although EUGR temporarily increased type 1 helper T cell (Th1) activity (e.g. more blood T cells and higher Th1-related cytokine concentrations on day 8) and reduced colon nutrient fermentation (lower SCFA concentration; -45%, P < 0.01). Further, EUGR pigs showed increased relative brain weights (+19%, P < 0.01), however, memory and learning, as tested in a spatial T-maze, were not affected. CONCLUSION Most of the measured organ growth, and digestive, immune, and brain functions showed limited effects of diet-induced EUGR in preterm pigs during the first weeks after birth. Likewise, preterm infants may show remarkable physiological adaptation to deficient nutrient supply during the first weeks of life although early life malnutrition may exert negative consequences later.
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Affiliation(s)
- Agnethe May Ahnfeldt
- Department of Veterinary and Animal Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Ole Bæk
- Department of Veterinary and Animal Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Yan Hui
- Department of Food Science, Food Microbiology, University of Copenhagen, Copenhagen, Denmark
| | | | - Karina Obelitz-Ryom
- Department of Veterinary and Animal Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Tilla Busk-Anderson
- Department of Veterinary and Animal Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Anne Ruge
- Department of Veterinary and Animal Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens Juul Holst
- Department of Biomedical Sciences, Faculty of Health, University of Copenhagen, Copenhagen, Denmark
| | - Silvia Rudloff
- Institute of Nutritional Science, Justus-Liebig-University Giessen, Giessen, Germany
| | - Douglas Burrin
- Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas, USA
| | - Duc Ninh Nguyen
- Department of Veterinary and Animal Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Dennis Sandris Nielsen
- Department of Food Science, Food Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Gitte Zachariassen
- Hans Christian Andersen Children's Hospital, Odense University Hospital, Odense, Denmark
| | - Stine Brandt Bering
- Department of Veterinary and Animal Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Thomas Thymann
- Department of Veterinary and Animal Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Per Torp Sangild
- Department of Veterinary and Animal Sciences, University of Copenhagen, Copenhagen, Denmark.,Hans Christian Andersen Children's Hospital, Odense University Hospital, Odense, Denmark
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26
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Van Belkum M, Mendoza Alvarez L, Neu J. Preterm neonatal immunology at the intestinal interface. Cell Mol Life Sci 2020; 77:1209-1227. [PMID: 31576423 PMCID: PMC11105006 DOI: 10.1007/s00018-019-03316-w] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Revised: 08/21/2019] [Accepted: 09/19/2019] [Indexed: 12/17/2022]
Abstract
Fetal and neonatal development represents a critical window for setting a path toward health throughout life. In this review, we focus on intestinal immunity, how it develops, and its implications for subsequent neonatal diseases. We discuss maternal nutritional and environmental exposures that dictate outcomes for the developing fetus. Although still controversial, there is evidence in support of an in utero microbiome. Specific well-intentioned and routine applications of antibiotics, steroids, and surgical interventions implemented before, during, and after birth skew the neonate towards pro-inflammatory dysbiosis. Shortly after birth, a consortium of maternal and environmentally derived bacteria, through cross-talk with the developing host immune system, takes center stage in developing or disrupting immune homeostasis at the intestinal interface. We also examine subsequent immunological cross-talks, which involve neonatal myeloid and lymphoid responses, and their potential impacts on health and disease such as necrotizing enterocolitis and sepsis, especially critical disease entities for the infant born preterm.
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Affiliation(s)
- Max Van Belkum
- Division of Neonatology, Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL, 32610, USA
| | - Lybil Mendoza Alvarez
- Division of Neonatology, Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL, 32610, USA
| | - Josef Neu
- Division of Neonatology, Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL, 32610, USA.
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27
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Tirone C, Pezza L, Paladini A, Tana M, Aurilia C, Lio A, D'Ippolito S, Tersigni C, Posteraro B, Sanguinetti M, Di Simone N, Vento G. Gut and Lung Microbiota in Preterm Infants: Immunological Modulation and Implication in Neonatal Outcomes. Front Immunol 2019; 10:2910. [PMID: 31921169 PMCID: PMC6920179 DOI: 10.3389/fimmu.2019.02910] [Citation(s) in RCA: 74] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Accepted: 11/27/2019] [Indexed: 12/23/2022] Open
Abstract
In recent years, an aberrant gastrointestinal colonization has been found to be associated with an higher risk for postnatal sepsis, necrotizing enterocolitis (NEC) and growth impairment in preterm infants. As a consequence, the reasons of intestinal dysbiosis in this population of newborns have increasingly become an object of interest. The presence of a link between the gut and lung microbiome's development (gut-lung axis) is emerging, and more data show as a gut-brain cross talking mediated by an inflammatory milieu, may affect the immunity system and influence neonatal outcomes. A revision of the studies which examined gut and lung microbiota in preterm infants and a qualitative analysis of data about characteristic patterns and related outcomes in terms of risk of growing impairment, Necrotizing Enterocolitis (NEC), Bronchopulmonary Dysplasia (BPD), and sepsis have been performed. Microbiota take part in the establishment of the gut barrier and many data suggest its immune-modulator role. Furthermore, the development of the gut and lung microbiome (gut-lung axis) appear to be connected and able to lead to abnormal inflammatory responses which have a key role in the pathogenesis of BPD. Dysbiosis and the gut predominance of facultative anaerobes appear to be crucial to the pathogenesis and subsequently to the prevention of such diseases.
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Affiliation(s)
- Chiara Tirone
- Fondazione Policlinico Universitario A. Gemelli IRCCS, U.O.C. di Neonatologia, Dipartimento di Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Rome, Italy.,Università Cattolica del Sacro Cuore, Istituto di Clinica Pediatrica, Rome, Italy
| | - Lucilla Pezza
- Fondazione Policlinico Universitario A. Gemelli IRCCS, U.O.C. di Neonatologia, Dipartimento di Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Rome, Italy.,Università Cattolica del Sacro Cuore, Istituto di Clinica Pediatrica, Rome, Italy
| | - Angela Paladini
- Fondazione Policlinico Universitario A. Gemelli IRCCS, U.O.C. di Neonatologia, Dipartimento di Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Rome, Italy.,Università Cattolica del Sacro Cuore, Istituto di Clinica Pediatrica, Rome, Italy
| | - Milena Tana
- Fondazione Policlinico Universitario A. Gemelli IRCCS, U.O.C. di Neonatologia, Dipartimento di Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Rome, Italy.,Università Cattolica del Sacro Cuore, Istituto di Clinica Pediatrica, Rome, Italy
| | - Claudia Aurilia
- Fondazione Policlinico Universitario A. Gemelli IRCCS, U.O.C. di Neonatologia, Dipartimento di Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Rome, Italy.,Università Cattolica del Sacro Cuore, Istituto di Clinica Pediatrica, Rome, Italy
| | - Alessandra Lio
- Fondazione Policlinico Universitario A. Gemelli IRCCS, U.O.C. di Neonatologia, Dipartimento di Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Rome, Italy.,Università Cattolica del Sacro Cuore, Istituto di Clinica Pediatrica, Rome, Italy
| | - Silvia D'Ippolito
- Fondazione Policlinico Universitario A. Gemelli IRCCS, U.O.C. di Ostetricia e Patologia Ostetrica, Dipartimento di Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Rome, Italy.,Università Cattolica del Sacro Cuore, Istituto di Clinica Ostetrica e Ginecologica, Rome, Italy
| | - Chiara Tersigni
- Fondazione Policlinico Universitario A. Gemelli IRCCS, U.O.C. di Ostetricia e Patologia Ostetrica, Dipartimento di Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Rome, Italy.,Università Cattolica del Sacro Cuore, Istituto di Clinica Ostetrica e Ginecologica, Rome, Italy
| | - Brunella Posteraro
- Fondazione Policlinico Universitario A. Gemelli IRCCS, Dipartimento di Scienze di Laboratorio e Infettivologiche, Rome, Italy.,Istituto di Microbiologia, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Maurizio Sanguinetti
- Fondazione Policlinico Universitario A. Gemelli IRCCS, Dipartimento di Scienze di Laboratorio e Infettivologiche, Rome, Italy.,Istituto di Microbiologia, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Nicoletta Di Simone
- Fondazione Policlinico Universitario A. Gemelli IRCCS, U.O.C. di Ostetricia e Patologia Ostetrica, Dipartimento di Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Rome, Italy.,Università Cattolica del Sacro Cuore, Istituto di Clinica Ostetrica e Ginecologica, Rome, Italy
| | - Giovanni Vento
- Fondazione Policlinico Universitario A. Gemelli IRCCS, U.O.C. di Neonatologia, Dipartimento di Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Rome, Italy.,Università Cattolica del Sacro Cuore, Istituto di Clinica Pediatrica, Rome, Italy
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Barreiros Mota I, Marques C, Faria A, Neto MT, Cordeiro-Ferreira G, Virella D, Pita A, Pereira-da-Silva L, Calhau C. Colonisation of the proximal intestinal remnant in newborn infants with enterostomy: a longitudinal study protocol. BMJ Open 2019; 9:e028916. [PMID: 31767579 PMCID: PMC6886948 DOI: 10.1136/bmjopen-2019-028916] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Revised: 09/17/2019] [Accepted: 10/15/2019] [Indexed: 12/23/2022] Open
Abstract
INTRODUCTION The gut microbiota plays a main role in the maintenance of host's health. Exposure to different conditions in early life contributes to distinct 'pioneer' bacterial communities in the intestine, which shape the newborn infant development. Newborn infants with congenital malformations of the gastrointestinal tract (CMGIT), necrotising enterocolitis (NEC) and spontaneous intestinal perforation (SIP) commonly require abdominal surgery and enterostomy. The knowledge about the colonisation of these newborns' intestine by microorganisms is scarce. This protocol is designed to explore the microbial colonisation over time of the proximal intestinal remnant in newborn infants who underwent surgery for CMGIT, NEC or SIP and require enterostomy. METHODS AND ANALYSIS The literature about microbiota colonisation in newborn infants with enterostomy was reviewed and an observational, longitudinal, prospective study was designed. The infants will be recruited at the Neonatal Intensive Care Unit of the Hospital Dona Estefânia, Centro Hospitalar Universitário de Lisboa Central. Samples of the enterostomy effluent will be collected every 3 days, through 21 days after the first collection. The microorganisms colonising the proximal intestinal remnant will be identified using the 16S rRNA sequence analysis and a subset of microorganisms will be quantified using real-time PCR. This protocol may serve as basis for future observational and interventional studies on the modulation of the intestinal microbiota (eg, probiotics) on short and long-term outcomes in this population. ETHICS AND DISSEMINATION This study protocol was approved by the Ethics Committee of Centro Hospitalar Universitário de Lisboa Central (441/2017) and by the Ethics Committee of NOVA Medical School, Universidade Nova de Lisboa (n°50/2018/CEFCM). The results will be spread through peer-reviewed publications and presentations at international scientific meetings. TRIAL REGISTRATION NUMBER NCT03340259.
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Affiliation(s)
- Inês Barreiros Mota
- Nutrition and Metabolism, NOVA Medical School | Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisbon, Portugal
- CINTESIS - Center for Health Technology and Services Research, Porto, Portugal
| | - Cláudia Marques
- Nutrition and Metabolism, NOVA Medical School | Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisbon, Portugal
- CINTESIS - Center for Health Technology and Services Research, Porto, Portugal
| | - Ana Faria
- Nutrition and Metabolism, NOVA Medical School | Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisbon, Portugal
- CINTESIS - Center for Health Technology and Services Research, Porto, Portugal
- Comprehensive Health Research Centre, Universidade NOVA de Lisboa, Lisbon, Portugal
| | - Maria Teresa Neto
- Neonatal Intensive Care Unit, Hospital Dona Estefânia, Centro Hospitalar Universitário de Lisboa Central, Lisbon, Portugal
- Medicine of Woman, Childhood and Adolescence, NOVA Medical School | Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisbon, Portugal
| | - Gonçalo Cordeiro-Ferreira
- Neonatal Intensive Care Unit, Hospital Dona Estefânia, Centro Hospitalar Universitário de Lisboa Central, Lisbon, Portugal
| | - Daniel Virella
- Neonatal Intensive Care Unit, Hospital Dona Estefânia, Centro Hospitalar Universitário de Lisboa Central, Lisbon, Portugal
- Research Unit, Centro Hospitalar Universitário de Lisboa Central, Lisbon, Portugal
| | - Ana Pita
- Neonatal Intensive Care Unit, Hospital Dona Estefânia, Centro Hospitalar Universitário de Lisboa Central, Lisbon, Portugal
| | - Luís Pereira-da-Silva
- Neonatal Intensive Care Unit, Hospital Dona Estefânia, Centro Hospitalar Universitário de Lisboa Central, Lisbon, Portugal
- Medicine of Woman, Childhood and Adolescence, NOVA Medical School | Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisbon, Portugal
- Research Unit, Centro Hospitalar Universitário de Lisboa Central, Lisbon, Portugal
| | - Conceição Calhau
- Nutrition and Metabolism, NOVA Medical School | Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisbon, Portugal
- CINTESIS - Center for Health Technology and Services Research, Porto, Portugal
- Unidade Universitária Lifestyle Medicine, José de Mello Saúde by NOVA Medical School, Lisbon, Portugal
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Cai C, Zhang Z, Morales M, Wang Y, Khafipour E, Friel J. Feeding practice influences gut microbiome composition in very low birth weight preterm infants and the association with oxidative stress: A prospective cohort study. Free Radic Biol Med 2019; 142:146-154. [PMID: 30851363 DOI: 10.1016/j.freeradbiomed.2019.02.032] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Revised: 02/23/2019] [Accepted: 02/28/2019] [Indexed: 12/12/2022]
Abstract
Knowledge about the development of the preterm infant gut microbiota is emerging and is critical to their health. Very-low-birth-weight (VLBW; birth weight, <1500 g) infants usually have special dietary needs while showing increased oxidative stress related to intensive care. This prospective cohort study assessed the effect of feeding practice on gut microbiome development and oxidative stress in preterm infants. Fecal samples were collected from each infant in the early (1-2 weeks of enteral feeding) and late (2-4 weeks of enteral feeding) feeding stages. We performed high-throughput sequencing of V3-V4 regions of the 16S rRNA gene to analyze the fecal microbiome composition of 20 VLBW preterm infants and to determine the association of gut bacterial composition with feeding practice using an oxidative stress marker (urinary F2-isoprostane). Our results showed that feeding practices in the late stage significantly influenced the gut microbiome composition and oxidative stress in preterm infants. Preterm infants fed human milk + human milk fortifier and only formula diets showed a significant increase in F2-isoprostane levels (P < 0.05) compared with those fed human milk + formula diet. The gut microbiome of the infants fed the human milk + Human milk fortifier diet showed the lower relative abundance of Veillonella (P < 0.05) compared with that of the infants fed the human milk + formula diet. The gut microbiome of the infants fed the only formula diet showed the lowest microbial diversity and the highest relative abundance of Terrisporobacter (P < 0.05) compared with the gut microbiome of the infants fed the other diets. Correlation network analysis showed that urinary F2-isoprostane level was positively correlated with Terrisporobacter and Enterobacteriaceae abundance (P < 0.05) in the preterm infants. In conclusion, these data suggest that feeding practice affects the bacterial diversity and composition in the gut microbiome and is associated with oxidative stress in VLBW preterm infants.
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Affiliation(s)
- Chenxi Cai
- Department of Food and Human Nutritional Sciences, Faculty of Agricultural and Food Sciences, 208A Human Ecology Building, University of Manitoba, Winnipeg, MB, R3T 2N2, Canada.
| | - Zhengxiao Zhang
- Department of Animal Science, Faculty of Agricultural and Food Sciences, 208A Human Ecology Building, University of Manitoba, Winnipeg, MB, R3T 2N2, Canada.
| | - Maria Morales
- Department of Food and Human Nutritional Sciences, Faculty of Agricultural and Food Sciences, 208A Human Ecology Building, University of Manitoba, Winnipeg, MB, R3T 2N2, Canada.
| | - Yanan Wang
- Department of Animal Science, Faculty of Agricultural and Food Sciences, 208A Human Ecology Building, University of Manitoba, Winnipeg, MB, R3T 2N2, Canada.
| | - Ehsan Khafipour
- Department of Animal Science, Faculty of Agricultural and Food Sciences, 208A Human Ecology Building, University of Manitoba, Winnipeg, MB, R3T 2N2, Canada
| | - James Friel
- Department of Food and Human Nutritional Sciences, Faculty of Agricultural and Food Sciences, 208A Human Ecology Building, University of Manitoba, Winnipeg, MB, R3T 2N2, Canada.
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Dierikx TH, Berkhout DJC, Visser L, Benninga MA, Roeselers G, de Boer NKH, de Vries JIP, de Meij TGJ. The influence of timing of Maternal administration of Antibiotics during cesarean section on the intestinal Microbial colonization in Infants (MAMI-trial): study protocol for a randomised controlled trial. Trials 2019; 20:479. [PMID: 31382981 PMCID: PMC6683546 DOI: 10.1186/s13063-019-3552-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Accepted: 07/02/2019] [Indexed: 02/08/2023] Open
Abstract
Background A disturbance in the early colonisation of the gut by microorganisms is associated with an aberrant innate immune system and a variety of clinical conditions later in life. Several factors are considered to influence this initial colonisation, including maternally administered antibiotics during pregnancy and delivery. Recent revisions to international obstetric guidelines have resulted in the exposure of all infants born by caesarean section (CS) to broad-spectrum antibiotics perinatally. To date, the consequences of these new guidelines on neonatal gut colonisation and the associated short- and long-term health implications have not yet been addressed. The aim of this study is to investigate the influence of the timing of antibiotic administration during CS to the mother on the course of neonatal intestinal colonisation up to 2 years of age. Methods/design This single-centre randomised controlled trial will recruit 40 women scheduled for an elective CS. The subjects will be randomised to receive 1500 mg of cefuroxime intravenously either prior to the skin incision (n = 20) or after clamping of the umbilical cord (n = 20). Levels of cefuroxime in cord blood will be determined for exposed neonates. Faecal samples from the children will be collected on days 1, 7 and 28 days and at 2 years old and analysed by 16S sequencing. Shannon-diversity indices, absolute and relative abundances, and unsupervised and supervised classification methods will be used to evaluate the effect of the timing of intrapartum cefuroxime administration on the composition of the microbiota. The outcomes for both study groups will be compared to the intestinal microbiota of vaginally born infants (n = 20). To detect possible effects on health state, a questionnaire on health-related issues will be taken at the age of 2 years. Discussion In the proposed study, changes in the intestinal microbiota of 40 children born by CS will be followed until the age of 2 years. Research on this topic is necessary since significant effects relating to the timing of antibiotic administration on microbial colonisation may conflict with the current guidelines, as this may have health consequences later in life. Trial registration Netherlands Clinical Trial Registry, NTR6000. Retrospectively registered on 25 July 2016. Electronic supplementary material The online version of this article (10.1186/s13063-019-3552-8) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Thomas H Dierikx
- Department of Paediatric Gastroenterology, Amsterdam UMC, location VUmc, 1081 HV, Amsterdam, The Netherlands.
| | - Daniel J C Berkhout
- Department of Paediatric Gastroenterology, Amsterdam UMC, location VUmc, 1081 HV, Amsterdam, The Netherlands
| | - Laura Visser
- Department of Gynaecology and Obstetrics, Amsterdam UMC, location VUmc, 1081 HV, Amsterdam, The Netherlands
| | - Marc A Benninga
- Department of Paediatric Gastroenterology, Amsterdam UMC, location AMC, 1105 AZ, Amsterdam, The Netherlands
| | | | - Nanne K H de Boer
- Department of Gastroenterology and Hepatology, Amsterdam UMC, location VUmc, AG&M Research Institute, 1081 HV, Amsterdam, The Netherlands
| | - Johanna I P de Vries
- Department of Gynaecology and Obstetrics, Amsterdam UMC, location VUmc, 1081 HV, Amsterdam, The Netherlands
| | - Tim G J de Meij
- Department of Paediatric Gastroenterology, Amsterdam UMC, location VUmc, 1081 HV, Amsterdam, The Netherlands
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Dahl C, Stigum H, Valeur J, Iszatt N, Lenters V, Peddada S, Bjørnholt JV, Midtvedt T, Mandal S, Eggesbø M. Preterm infants have distinct microbiomes not explained by mode of delivery, breastfeeding duration or antibiotic exposure. Int J Epidemiol 2019; 47:1658-1669. [PMID: 29688458 DOI: 10.1093/ije/dyy064] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/09/2018] [Indexed: 12/21/2022] Open
Abstract
Background Preterm infants have low gut microbial diversity and few anaerobes. It is unclear whether the low diversity pertains to prematurity itself or is due to differences in delivery mode, feeding mode or exposure to antibiotics. Methods The Norwegian Microbiota Study (NoMIC) was established to examine the colonization of the infant gut and health outcomes. 16S rRNA gene Illumina amplicon-sequenced samples from 519 children (160 preterms), collected at 10 days, 4 months and 1 year postnatally, were used to calculate alpha diversity. Short-chain fatty acids (SCFA) were analysed with gas chromatography and quantified using flame ionization detection. We regressed alpha diversity on gestational age, taking into account possible confounding and mediating factors, such as breastfeeding and antibiotics. Taxonomic differences were tested using Analysis of Composition of Microbiomes (ANCOM) and SCFA profile (as a functional indicator of the microbiota) was tested by Wilcoxon rank-sum. Results Preterm infants had 0.45 Shannon units lower bacterial diversity at 10 days postnatally compared with infants born at term (95% confidence interval: -0.60, -0.32). Breastfeeding status and antibiotic exposure were not significant mediators of the gestational age-diversity association, although time spent in the neonatal intensive care unit was. Vaginally born, exclusively breastfed preterm infantss not exposed to antibiotics at 10 days postnatally had fewer Firmicutes and more Proteobacteria than children born at term and an SCFA profile indicating lower saccharolytic fermentation. Conclusions Preterm infants had distinct gut microbiome composition and function in the early postnatal period, not explained by factors more common in preterms, such as shorter breastfeeding duration, more antibiotics or caesarean delivery.
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Affiliation(s)
- Cecilie Dahl
- Department of Environmental Exposure and Epidemiology, Norwegian Institute of Public Health, Oslo, Norway
| | - Hein Stigum
- Department of Non-Communicable Diseases, Norwegian Institute of Public Health, Oslo, Norway
| | - Jørgen Valeur
- Unger-Vetlesen Institute, Lovisenberg Diaconal Hospital, Oslo, Norway
| | - Nina Iszatt
- Department of Environmental Exposure and Epidemiology, Norwegian Institute of Public Health, Oslo, Norway
| | - Virissa Lenters
- Department of Environmental Exposure and Epidemiology, Norwegian Institute of Public Health, Oslo, Norway
| | - Shyamal Peddada
- Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA
| | - Jørgen V Bjørnholt
- Department of Microbiology, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Tore Midtvedt
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden
| | - Siddhartha Mandal
- Center for Environmental Health, Public Health Foundation of India, Gurgaon, India
| | - Merete Eggesbø
- Department of Environmental Exposure and Epidemiology, Norwegian Institute of Public Health, Oslo, Norway
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Monk C, Lugo-Candelas C, Trumpff C. Prenatal Developmental Origins of Future Psychopathology: Mechanisms and Pathways. Annu Rev Clin Psychol 2019; 15:317-344. [PMID: 30795695 PMCID: PMC7027196 DOI: 10.1146/annurev-clinpsy-050718-095539] [Citation(s) in RCA: 206] [Impact Index Per Article: 34.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The developmental origins of health and disease hypothesis applied to neurodevelopmental outcomes asserts that the fetal origins of future development are relevant to mental health. There is a third pathway for the familial inheritance of risk for psychiatric illness beyond shared genes and the quality of parental care: the impact of pregnant women's distress-defined broadly to include perceived stress, life events, depression, and anxiety-on fetal and infant brain-behavior development. We discuss epidemiological and observational clinical data demonstrating that maternal distress is associated with children's increased risk for psychopathology: For example, high maternal anxiety is associated with a twofold increase in the risk of probable mental disorder in children. We review several biological systems hypothesized to be mechanisms by which maternal distress affects fetal and child brain and behavior development, as well as the clinical implications of studies of the developmental origins of health and disease that focus on maternal distress. Development and parenting begin before birth.
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Affiliation(s)
- Catherine Monk
- Department of Psychiatry, Columbia University, New York, NY 10032, USA;
- Department of Obstetrics and Gynecology, Columbia University, New York, NY 10032, USA
- New York State Psychiatric Institute, New York, NY 10032, USA; ,
| | - Claudia Lugo-Candelas
- Department of Psychiatry, Columbia University, New York, NY 10032, USA;
- New York State Psychiatric Institute, New York, NY 10032, USA; ,
| | - Caroline Trumpff
- Department of Psychiatry, Columbia University, New York, NY 10032, USA;
- New York State Psychiatric Institute, New York, NY 10032, USA; ,
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Extended spectrum beta-lactamase-producing Klebsiella pneumoniae outbreak reveals incubators as pathogen reservoir in neonatal care center. Eur J Pediatr 2019; 178:505-513. [PMID: 30671695 DOI: 10.1007/s00431-019-03323-w] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2018] [Revised: 12/18/2018] [Accepted: 01/15/2019] [Indexed: 12/12/2022]
Abstract
In the context of a 3-month extended-spectrum beta-lactamase-producing Klebsiella pneumonia (ESBL-KP) outbreak in a neonatal care center (NCC), hygiene practices and hospital environment were investigated. ESBL-KP strains isolated from patients and environment were compared by molecular typing. The density of incidence of multi-drug-resistant bacteria (MDRB) was calculated from January 2014 to September 2016. The 3-month ESBL-KP outbreak involved 19 patients. Clinical strains from the 19 patients displayed the same molecular profile between them, and with a strain isolated from an incubator after cleaning. Furthermore, 52.4% of incubator mattresses were positive for diverse pathogens. Hygiene practices were acceptable except for external practitioners and parents. In addition to classical infection control (IC) measures, the replacement of mattresses and the improvement of incubators disinfection stopped the outbreak. The protocol of disinfection was revised and microbiological control was implemented. A significant decrease of MDRB incidence was concomitant (p value = 0.03219) but 3 months later, MDRB incidence increased again.Conclusion: This investigation highlighted incubators and mattresses as critical materials associated to infectious risk in NCC. NCC and IC teams should implement efficient protocol for incubators disinfection and monitoring. What is Known: • Environment in neonatal intensive care units is often suspected as reservoir for Enterobacteriaceae outbreaks but is scarcely investigated. • Incubators and mattresses offer wet and warm conditions suitable for pathogens multiplication, but microbiological survey is not performed routinely for assessing bacterial contamination. What is New: • Incubators and mattresses serve as reservoir for pathogens and relay in outbreak. • An infection control protocol associating efficient disinfection and microbiology analysis is proposed.
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Morais J, Marques C, Teixeira D, Durão C, Faria A, Brito S, Cardoso M, Macedo I, Tomé T, Calhau C. FEEDMI: A Study Protocol to Determine the Influence of Infant-Feeding on Very-Preterm-Infant's Gut Microbiota. Neonatology 2019; 116:179-184. [PMID: 31132782 DOI: 10.1159/000496547] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Accepted: 01/03/2019] [Indexed: 11/19/2022]
Abstract
BACKGROUND Preterm infants are especially vulnerable to gut microbiota disruption and dysbiosis since their early gut microbiota is less abundant and diverse. Several factors may influence infants' gut microbiota, such as the mother's diet, mode of delivery, antibiotic exposure, and type of feeding. OBJECTIVES This study aims to examine the factors associated with very-preterm neonate's intestinal microbiota, namely: (1) type of infant-feeding (breast milk, donor human milk with or without bovine protein-based fortifier, and preterm formula); (2) maternal diet; and (3) mode of delivery. METHODS This is an observational study conducted in a cohort of very preterm infants hospitalized in the neonatal intensive care unit of Maternidade Dr. Alfredo da Costa. After delivery, the mothers are asked to collect their own fecal samples and are invited to complete a semiquantitative food frequency questionnaire. The maternal diet will be classified in accordance to the Mediterranean Diet adherence score. Stool samples have been collected from very premature infants every 7 days for 21 days. DNA has been extracted from the fecal samples, and different bacterial genus and species will be quantified by real-time polymerase chain reaction. RESULTS AND CONCLUSIONS It is hypothesized that significant differences in the microbiota composition and clinical outcomes of very preterm infants will be observed depending on the type of infant feeding. In addition, this study will clarify how pasteurized donor's milk influences the intestinal microbiota colonization of preterm infants. This is a pioneer study developed in collaboration with the country's Human Milk Bank. We also expect to find microbiota alterations in infants according to the mode of delivery and to maternal diet. This study will contribute to increase the evidence on the effects of breast or donor human milk and its fortification with a bovine protein-based fortifier on infant microbiota.
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Affiliation(s)
- Juliana Morais
- Nutrition and Metabolism, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisbon, Portugal.,CINTESIS, Center for Health Technology Services Research, Porto, Portugal
| | - Cláudia Marques
- Nutrition and Metabolism, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisbon, Portugal.,CINTESIS, Center for Health Technology Services Research, Porto, Portugal
| | - Diana Teixeira
- Nutrition and Metabolism, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisbon, Portugal.,CINTESIS, Center for Health Technology Services Research, Porto, Portugal.,Unidade Universitária Lifestyle Medicine José de Mello Saúde by NOVA Medical School, Lisbon, Portugal
| | - Catarina Durão
- Nutrition and Metabolism, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisbon, Portugal.,EPIUnit - Institute of Public Health, Universidade do Porto, Porto, Portugal
| | - Ana Faria
- Nutrition and Metabolism, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisbon, Portugal.,CINTESIS, Center for Health Technology Services Research, Porto, Portugal.,Comprehensive Health Research Centre, Universidade NOVA de Lisboa, Lisbon, Portugal
| | - Sara Brito
- Neonatal Intensive Care Unit, Maternidade Dr. Alfredo da Costa, Centro Hospitar de Lisboa Central, Lisbon, Portugal
| | - Manuela Cardoso
- Nutrition and Dietetics Unit, Maternidade Dr. Alfredo da Costa, Centro Hospitalar de Lisboa Central, Lisbon, Portugal
| | - Israel Macedo
- Neonatal Intensive Care Unit, Maternidade Dr. Alfredo da Costa, Centro Hospitar de Lisboa Central, Lisbon, Portugal
| | - Teresa Tomé
- Neonatal Intensive Care Unit, Maternidade Dr. Alfredo da Costa, Centro Hospitar de Lisboa Central, Lisbon, Portugal
| | - Conceição Calhau
- Nutrition and Metabolism, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisbon, Portugal, .,CINTESIS, Center for Health Technology Services Research, Porto, Portugal, .,Unidade Universitária Lifestyle Medicine José de Mello Saúde by NOVA Medical School, Lisbon, Portugal,
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Grev J, Berg M, Soll R, Cochrane Neonatal Group. Maternal probiotic supplementation for prevention of morbidity and mortality in preterm infants. Cochrane Database Syst Rev 2018; 12:CD012519. [PMID: 30548483 PMCID: PMC6516999 DOI: 10.1002/14651858.cd012519.pub2] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
BACKGROUND Inflammation may contribute to preterm birth and to morbidity of preterm infants. Preterm infants are at risk for alterations in the normal protective microbiome. Oral probiotics administered directly to preterm infants have been shown to decrease the risk for severe necrotizing enterocolitis (NEC) as well as the risk of death, but there are safety concerns about administration of probiotics directly to preterm infants. Through decreasing maternal inflammation, probiotics may play a role in preventing preterm birth and/or decreasing the inflammatory milieu surrounding delivery of preterm infants, and may alter the microbiome of the preterm infant when given to mothers during pregnancy. Probiotics given to mothers after birth of preterm infants may effect infant bacterial colonization, which could potentially reduce the incidence of NEC. OBJECTIVES 1. To compare the efficacy of maternal probiotic administration versus placebo or no intervention in mothers during pregnancy for the prevention of preterm birth and the prevention of morbidity and mortality of infants born preterm.2. To compare the efficacy of maternal probiotic administration versus placebo, no intervention, or neonatal probiotic administration in mothers of preterm infants after birth on the prevention of mortality and preterm infant morbidities such as NEC. SEARCH METHODS We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2017, Issue 2), MEDLINE via PubMed (1966 to 21 March 2017), Embase (1980 to 21 March 2017), and CINAHL (1982 to 21 March 2017). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomized controlled trials and quasi-randomized trials. SELECTION CRITERIA We included randomized controlled trials in the review if they administered oral probiotics to pregnant mothers at risk for preterm birth, or to mothers of preterm infants after birth. Quasi-randomized trials were eligible for inclusion, but none were identified. Studies enrolling pregnant women needed to administer probiotics at < 36 weeks' gestation until the trimester of birth. Probiotics considered were of the genera Lactobacillus, Bifidobacterium or Saccharomyces. DATA COLLECTION AND ANALYSIS We used the standard methods of the Cochrane Collaboration and Cochrane Neonatal to determine the methodologic quality of studies, and for data collection and analysis. MAIN RESULTS We included 12 eligible trials with a total of 1450 mothers and 1204 known infants. Eleven trials administered probiotics to mothers during pregnancy and one trial administered probiotics to mothers after birth of their preterm infants. No studies compared maternal probiotic administration directly with neonatal administration. Included prenatal trials were highly variable in the indication for the trial, the gestational age and duration of administration of probiotics, as well as the dose and formulation of the probiotics. The pregnant women included in these trials were overall at low risk for preterm birth. In a meta-analysis of trial data, oral probiotic administration to pregnant women did not reduce the incidence of preterm birth < 37 weeks (typical risk ratio (RR) 0.92, 95% confidence interval (CI) 0.32 to 2.67; 4 studies, 518 mothers and 506 infants), < 34 weeks (typical risk difference (RD) 0.00, 95% CI -0.02 to 0.02; 2 studies, 287 mothers and infants), the incidence of infant mortality (typical RD 0.00, 95% CI -0.02 to 0.02; 2 studies, 309 mothers and 298 infants), or the gestational age at birth (mean difference (MD) 0.15, 95% CI -0.33 to 0.63; 2 studies, 209 mothers with 207 infants).One trial studied administration of probiotics to mothers after preterm birth and included 49 mothers and 58 infants. There were no significant differences in the risk of any NEC (RR 0.44, 95% CI 0.13 to 1.46; 1 study, 58 infants), surgery for NEC (RR 0.15, 95% CI 0.01 to 2.58; 1 study, 58 infants), death (RR 0.66, 95% CI 0.06 to 6.88; 1 study, 58 infants), and death or NEC (RR 0.53, 95% CI 0.19 to 1.49; 1 study, 58 infants). There was an improvement in time to reach 50% enteral feeds in infants whose mothers received probiotics, but the estimate is imprecise (MD -9.60 days, 95% CI -19.04 to -0.16 days; 58 infants). No other improvement in any neonatal outcomes were reported. The estimates were imprecise and do not exclude the possibility of meaningful harms or benefits from maternal probiotic administration. There were no cases of culture-proven sepsis with the probiotic organism. The GRADE quality of evidence was judged to be low to very low due to inconsistency and imprecision. AUTHORS' CONCLUSIONS There is insufficient evidence to conclude whether there is appreciable benefit or harm to neonates of either oral supplementation of probiotics administered to pregnant women at low risk for preterm birth or oral supplementation of probiotics to mothers of preterm infants after birth. Oral supplementation of probiotics to mothers of preterm infants after birth may decrease time to 50% enteral feeds, however, this estimate is extremely imprecise. More research is needed for post-natal administration of probiotics to mothers of preterm infants, as well as to pregnant mothers at high risk for preterm birth.
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Affiliation(s)
| | - Marie Berg
- Johns Hopkins All Children's HospitalPediatrics/Neonatology601 Fifth Street South, Suite 501St. PetersburgFloridaUSA33606
| | - Roger Soll
- Larner College of Medicine at the University of VermontDivision of Neonatal‐Perinatal Medicine, Department of Pediatrics111 Colchester AvenueBurlingtonVermontUSA05401
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Plummer EL, Bulach DM, Murray GL, Jacobs SE, Tabrizi SN, Garland SM. Gut microbiota of preterm infants supplemented with probiotics: sub-study of the ProPrems trial. BMC Microbiol 2018; 18:184. [PMID: 30424728 PMCID: PMC6234596 DOI: 10.1186/s12866-018-1326-1] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2017] [Accepted: 10/25/2018] [Indexed: 12/15/2022] Open
Abstract
Background The ProPrems trial, a multi-center, double-blind, placebo-controlled randomized trial, previously reported a 54% reduction in necrotizing enterocolitis (NEC) of Bell stage 2 or more from 4.4 to 2.0% in 1099 infants born before 32 completed weeks’ gestation and weighing < 1500 g, receiving probiotic supplementation (with Bifidobacterium longum subsp. infantis BB-02, Streptococcus thermophilus TH-4 and Bifidobacterium animalis subsp. lactis BB-12). This sub-study investigated the effect of probiotic supplementation on the gut microbiota in a cohort of very preterm infants in ProPrems. Results Bifidobacterium was found in higher abundance in infants who received the probiotics (AOR 17.22; 95% CI, 3.49–84.99, p < 0.001) as compared to the placebo group, and Enterococcus was reduced in infants receiving the probiotic during the supplementation period (AOR 0.27; 95% CI, 0.09–0.82, p = 0.02). Conclusion Probiotic supplementation with BB-02, TH-4 and BB-12 from soon after birth increased the abundance of Bifidobacterium in the gut microbiota of very preterm infants. Increased abundance of Bifidobacterium soon after birth may be associated with reducing the risk of NEC in very preterm infants. Electronic supplementary material The online version of this article (10.1186/s12866-018-1326-1) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Erica L Plummer
- The Royal Women's Hospital, Parkville, VIC, 3052, Australia. .,Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville, VIC, 3052, Australia.
| | - Dieter M Bulach
- Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, VIC, 3800, Australia.,The University of Melbourne, Parkville, VIC, 3050, Australia.,Victorian Life Sciences Computation Initiative, The University of Melbourne, Parkville Campus, LAB-14, 700 Swanston St, Carlton, VIC, 3053, Australia
| | - Gerald L Murray
- The Royal Women's Hospital, Parkville, VIC, 3052, Australia.,Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville, VIC, 3052, Australia.,Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, VIC, 3800, Australia
| | - Susan E Jacobs
- The Royal Women's Hospital, Parkville, VIC, 3052, Australia.,Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville, VIC, 3052, Australia.,The University of Melbourne, Parkville, VIC, 3050, Australia
| | - Sepehr N Tabrizi
- The Royal Women's Hospital, Parkville, VIC, 3052, Australia.,Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville, VIC, 3052, Australia.,The University of Melbourne, Parkville, VIC, 3050, Australia.,The Royal Children's Hospital, 50 Flemington Rd, Parkville, VIC, 3052, Australia
| | - Suzanne M Garland
- The Royal Women's Hospital, Parkville, VIC, 3052, Australia.,Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville, VIC, 3052, Australia.,The University of Melbourne, Parkville, VIC, 3050, Australia.,The Royal Children's Hospital, 50 Flemington Rd, Parkville, VIC, 3052, Australia
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Maternal psychological distress during pregnancy and childhood health outcomes: a narrative review. J Dev Orig Health Dis 2018; 10:274-285. [PMID: 30378522 DOI: 10.1017/s2040174418000557] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Maternal psychological distress is common in pregnancy and may influence the risk of adverse outcomes in children. Psychological distress may cause a suboptimal intrauterine environment leading to growth and developmental adaptations of the fetus and child. In this narrative review, we examined the influence of maternal psychological distress during pregnancy on fetal outcomes and child cardiometabolic, respiratory, atopic and neurodevelopment-related health outcomes. We discussed these findings from an epidemiological and life course perspective and provided recommendations for future studies. The literature in the field of maternal psychological distress and child health outcomes is extensive and shows that exposure to stress during pregnancy is associated with multiple adverse child health outcomes. Because maternal psychological distress is an important and potential modifiable factor during pregnancy, it should be a target for prevention strategies in order to optimize fetal and child health. Future studies should use innovative designs and strategies in order to address the issue of causality.
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Gobert G, Cotillard A, Fourmestraux C, Pruvost L, Miguet J, Boyer M. Droplet digital PCR improves absolute quantification of viable lactic acid bacteria in faecal samples. J Microbiol Methods 2018; 148:64-73. [DOI: 10.1016/j.mimet.2018.03.004] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Revised: 03/12/2018] [Accepted: 03/12/2018] [Indexed: 02/06/2023]
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Costeloe K, Bowler U, Brocklehurst P, Hardy P, Heal P, Juszczak E, King A, Panton N, Stacey F, Whiley A, Wilks M, Millar MR. A randomised controlled trial of the probiotic Bifidobacterium breve BBG-001 in preterm babies to prevent sepsis, necrotising enterocolitis and death: the Probiotics in Preterm infantS (PiPS) trial. Health Technol Assess 2018; 20:1-194. [PMID: 27594381 DOI: 10.3310/hta20660] [Citation(s) in RCA: 61] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Necrotising enterocolitis (NEC) and late-onset sepsis remain important causes of death and morbidity in preterm babies. Probiotic administration might strengthen intestinal barrier function and provide protection; this is supported by published meta-analyses, but there is a lack of large well-designed trials. OBJECTIVE To test the use of the probiotic Bifidobacterium breve strain BBG-001 to prevent NEC, late-onset sepsis and death in preterm babies while monitoring probiotic colonisation of participants. DESIGN Double-blind, randomised, placebo-controlled trial. SETTING Recruitment was carried out in 24 hospitals, and the randomisation programme used a minimisation algorithm. Parents, clinicians and outcome assessors were blinded to the allocation. PARTICIPANTS Babies born between 23 and 30 weeks' gestation and randomised within 48 hours of birth. Exclusions included life-threatening or any gastrointestinal malformation detected within 48 hours of birth and no realistic chance of survival. INTERVENTIONS Active intervention: 1 ml of B. breve BBG-001 in one-eighth-strength infant formula Neocate(®) (Nutricia Ltd, Trowbridge, UK), (6.7 × 10(7) to 6.7 × 10(9) colony-forming units) per dose administered enterally. Placebo: 1 ml of one-eighth-strength infant formula Neocate. Started as soon as practicable and continued daily until 36 weeks' postmenstrual age. MAIN OUTCOME MEASURES Primary outcomes were an episode of bloodstream infection, with any organism other than a skin commensal, in any baby between 72 hours and 46 weeks' postmenstrual age; an episode of NEC Bell stage ≥ 2 in any baby; and death before discharge from hospital. Secondary outcomes included stool colonisation with B. breve. RESULTS In total, 654 babies were allocated to receive probiotic and 661 to receive placebo over 37 months from July 2010. Five babies were withdrawn; 650 babies from the probiotic group and 660 from the placebo group were included in the primary analysis. Baseline characteristics were well balanced. There was no evidence of benefit for the primary outcomes {sepsis: 11.2% vs. 11.7% [adjusted relative risk (RR) 0.97, 95% confidence interval (CI) 0.73 to 1.29]; NEC Bell stage ≥ 2: 9.4% vs. 10.0% [adjusted RR 0.93, 95% CI 0.68 to 1.27]; and death: 8.3% vs. 8.5% [adjusted RR 0.93, 95% CI 0.67 to 1.30]}. B. breve colonisation status was available for 1186 (94%) survivors at 2 weeks' postnatal age, of whom 724 (61%) were positive: 85% of the probiotic group and 37% of the placebo group. There were no differences for subgroup analyses by minimisation criteria and by stool colonisation with B. breve at 2 weeks. No harms associated with the interventions were reported. LIMITATIONS Cross-colonisation of the placebo arm could have reduced statistical power and confounded results; analyses suggest that this did not happen. CONCLUSIONS This is the largest trial to date of a probiotic intervention. It shows no evidence of benefit and does not support routine use of probiotics for preterm infants. FUTURE WORK RECOMMENDATIONS The increasing understanding of the pathogenesis of NEC and sepsis will inform the choice of probiotics for testing and better define the target population. Future Phase III trials should incorporate monitoring of the quality and viability of the intervention and colonisation rates of participants; cluster design should be considered. TRIAL REGISTRATION Current Controlled Trials ISRCTN05511098 and EudraCT 2006-003445-17. FUNDING This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 66. See the NIHR Journals Library website for further project information.
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Affiliation(s)
- Kate Costeloe
- Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.,Homerton University Hospital NHS Foundation Trust, London, UK
| | - Ursula Bowler
- National Perinatal Epidemiology Unit, University of Oxford, Oxford, UK
| | - Peter Brocklehurst
- National Perinatal Epidemiology Unit, University of Oxford, Oxford, UK.,Institute for Women's Health, University College London, London, UK
| | - Pollyanna Hardy
- National Perinatal Epidemiology Unit, University of Oxford, Oxford, UK
| | - Paul Heal
- National Perinatal Epidemiology Unit, University of Oxford, Oxford, UK
| | - Edmund Juszczak
- National Perinatal Epidemiology Unit, University of Oxford, Oxford, UK
| | - Andy King
- National Perinatal Epidemiology Unit, University of Oxford, Oxford, UK
| | - Nicola Panton
- Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Fiona Stacey
- Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.,Homerton University Hospital NHS Foundation Trust, London, UK
| | - Angela Whiley
- Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Mark Wilks
- Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.,Barts Health NHS Trust, London, UK
| | - Michael R Millar
- Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.,Barts Health NHS Trust, London, UK
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Esaiassen E, Hjerde E, Cavanagh JP, Pedersen T, Andresen JH, Rettedal SI, Støen R, Nakstad B, Willassen NP, Klingenberg C. Effects of Probiotic Supplementation on the Gut Microbiota and Antibiotic Resistome Development in Preterm Infants. Front Pediatr 2018; 6:347. [PMID: 30505830 PMCID: PMC6250747 DOI: 10.3389/fped.2018.00347] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Accepted: 10/26/2018] [Indexed: 12/15/2022] Open
Abstract
Objectives: In 2014 probiotic supplementation (Lactobacillus acidophilus and Bifidobacterium longum subspecies infantis; InfloranⓇ) was introduced as standard of care to prevent necrotizing enterocolitis (NEC) in extremely preterm infants in Norway. We aimed to evaluate the influence of probiotics and antibiotic therapy on the developing gut microbiota and antibiotic resistome in extremely preterm infants, and to compare with very preterm infants and term infants not given probiotics. Study design: A prospective, observational multicenter study in six tertiary-care neonatal units. We enrolled 76 infants; 31 probiotic-supplemented extremely preterm infants <28 weeks gestation, 35 very preterm infants 28-31 weeks gestation not given probiotics and 10 healthy full-term control infants. Taxonomic composition and collection of antibiotic resistance genes (resistome) in fecal samples, collected at 7 and 28 days and 4 months age, were analyzed using shotgun-metagenome sequencing. Results: Median (IQR) birth weight was 835 (680-945) g and 1,290 (1,150-1,445) g in preterm infants exposed and not exposed to probiotics, respectively. Two extremely preterm infants receiving probiotic developed NEC requiring surgery. At 7 days of age we found higher median relative abundance of Bifidobacterium in probiotic supplemented infants (64.7%) compared to non-supplemented preterm infants (0.0%) and term control infants (43.9%). Lactobacillus was only detected in small amounts in all groups, but the relative abundance increased up to 4 months. Extremely preterm infants receiving probiotics had also much higher antibiotic exposure, still overall microbial diversity and resistome was not different than in more mature infants at 4 weeks and 4 months. Conclusion: Probiotic supplementation may induce colonization resistance and alleviate harmful effects of antibiotics on the gut microbiota and antibiotic resistome. Clinical Trial Registration: Clinicaltrials.gov: NCT02197468. https://clinicaltrials.gov/ct2/show/NCT02197468.
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Affiliation(s)
- Eirin Esaiassen
- Paediatric Research Group, Department of Clinical Medicine, UiT The Arctic University of Norway, Tromsø, Norway.,Department of Paediatrics, University Hospital of North Norway, Tromsø, Norway
| | - Erik Hjerde
- Department of Chemistry, Norstruct, UiT The Arctic University of Norway, Tromsø, Norway
| | - Jorunn Pauline Cavanagh
- Paediatric Research Group, Department of Clinical Medicine, UiT The Arctic University of Norway, Tromsø, Norway.,Department of Paediatrics, University Hospital of North Norway, Tromsø, Norway
| | - Tanja Pedersen
- Department of Paediatrics, Haukeland University Hospital, Bergen, Norway
| | - Jannicke H Andresen
- Department of Neonatal Intensive Care, Oslo University Hospital, Oslo, Norway
| | - Siren I Rettedal
- Department of Paediatrics, Stavanger University Hospital, Stavanger, Norway
| | - Ragnhild Støen
- Department of Paediatrics, St. Olavs University Hospital, Trondheim, Norway.,Department of Laboratory Medicine, Children's and Women's Health, University of Science and Technology, Trondheim, Norway
| | - Britt Nakstad
- Department of Paediatric and Adolescents Medicine, Akershus University Hospital, Nordbyhagen, Norway.,Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Nils P Willassen
- Department of Chemistry, Norstruct, UiT The Arctic University of Norway, Tromsø, Norway
| | - Claus Klingenberg
- Paediatric Research Group, Department of Clinical Medicine, UiT The Arctic University of Norway, Tromsø, Norway.,Department of Paediatrics, University Hospital of North Norway, Tromsø, Norway
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Grier A, Qiu X, Bandyopadhyay S, Holden-Wiltse J, Kessler HA, Gill AL, Hamilton B, Huyck H, Misra S, Mariani TJ, Ryan RM, Scholer L, Scheible KM, Lee YH, Caserta MT, Pryhuber GS, Gill SR. Impact of prematurity and nutrition on the developing gut microbiome and preterm infant growth. MICROBIOME 2017; 5:158. [PMID: 29228972 PMCID: PMC5725645 DOI: 10.1186/s40168-017-0377-0] [Citation(s) in RCA: 103] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/18/2017] [Accepted: 11/23/2017] [Indexed: 05/17/2023]
Abstract
BACKGROUND Identification of factors that influence the neonatal gut microbiome is urgently needed to guide clinical practices that support growth of healthy preterm infants. Here, we examined the influence of nutrition and common practices on the gut microbiota and growth in a cohort of preterm infants. RESULTS With weekly gut microbiota samples spanning postmenstrual age (PMA) 24 to 46 weeks, we developed two models to test associations between the microbiota, nutrition and growth: a categorical model with three successive microbiota phases (P1, P2, and P3) and a model with two periods (early and late PMA) defined by microbiota composition and PMA, respectively. The more significant associations with phase led us to use a phase-based framework for the majority of our analyses. Phase transitions were characterized by rapid shifts in the microbiota, with transition out of P1 occurring nearly simultaneously with the change from meconium to normal stool. The rate of phase progression was positively associated with gestational age at birth, and delayed transition to a P3 microbiota was associated with growth failure. We found distinct bacterial metabolic functions in P1-3 and significant associations between nutrition, microbiota phase, and infant growth. CONCLUSION The phase-dependent impact of nutrition on infant growth along with phase-specific metabolic functions suggests a pioneering potential for improving growth outcomes by tailoring nutrient intake to microbiota phase.
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MESH Headings
- Bacteria/classification
- Bacteria/genetics
- Bacteria/isolation & purification
- Breast Feeding
- Cohort Studies
- DNA, Bacterial
- Feces/microbiology
- Female
- Gastrointestinal Microbiome
- Gestational Age
- Humans
- Infant
- Infant Health
- Infant, Newborn
- Infant, Premature/growth & development
- Infant, Premature/physiology
- Infant, Premature, Diseases/diet therapy
- Infant, Premature, Diseases/prevention & control
- Male
- Meconium/microbiology
- Nutritional Status
- RNA, Ribosomal, 16S
- Sequence Analysis, DNA
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Affiliation(s)
- Alex Grier
- Genomics Research Center, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
| | - Xing Qiu
- Department of Biostatistics and Computational Biology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
| | - Sanjukta Bandyopadhyay
- Department of Biostatistics and Computational Biology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
| | - Jeanne Holden-Wiltse
- Department of Biostatistics and Computational Biology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
| | - Haeja A Kessler
- Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY, 14642, USA
| | - Ann L Gill
- Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY, 14642, USA
| | - Brooke Hamilton
- Department of Biological Sciences, Vanderbilt University, Nashville, TN, USA
| | - Heidie Huyck
- Division of Neonatology, Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
| | - Sara Misra
- Division of Neonatology, Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
| | - Thomas J Mariani
- Division of Neonatology, Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
- Pediatric Molecular and Personalized Medicine Program, Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
| | - Rita M Ryan
- Department of Pediatrics, Medical University of South Carolina, Charleston, SC, USA
| | - Lori Scholer
- Division of Neonatology, Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
| | - Kristin M Scheible
- Division of Neonatology, Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
| | - Yi-Horng Lee
- Division of Pediatric Surgery, Department of Surgery, Robert Wood Johnson University Hospital, New Brunswick, NJ, USA
| | - Mary T Caserta
- Division of Infectious Disease, Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
| | - Gloria S Pryhuber
- Division of Neonatology, Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
| | - Steven R Gill
- Genomics Research Center, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
- Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY, 14642, USA.
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Wiseman M, McBride B, Li J, Wey D, Zhu J, de Lange CFM. Effects of steeped or fermented distillers dried grains with solubles on growth performance in weanling pigs. J Anim Sci 2017; 95:3563-3578. [PMID: 28805885 DOI: 10.2527/jas.2017.1478] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Coproduct feeding value may be improved by enzyme and microbial inoculant treatment in liquid diets. Three experiments were conducted to assess growth performance in newly weaned 20-d-old pigs fed corn- and soybean meal-based diets with untreated, steeped, or partially fermented distillers dried grains with solubles (DDGS) from day of weaning. In Exp. 1, conventionally dry fed diets with untreated DDGS (DDGS) or without DDGS (Control) were fed. In Exp. 2, liquid diets (25% DM [75% moisture]) were fed with enzymes (β-glucanase and xylanase at 67.2 and 51.4 U/g DDGS, respectively) added to dry DDGS at the time of liquid feeding (UNSTP) or steeped with DDGS and added to liquid feed from d 5 to 12 of each batch prior to liquid feeding (STP). In Exp. 1 and 2 DDGS inclusion levels were 7.5% in phase 1 (d 0 to 7) and 25% in phase 2 (d 7 to 21) and phase 3 (d 21 to 35). In Exp. 3 liquid diets were fed with the Exp. 2 enzymes and silage inoculant (360,000 combined cfu and /g DDGS) added to dry DDGS at the time of liquid feeding (UNFER) or fermented with DDGS and added to liquid feed from d 1 to 7 of each batch before liquid feeding (FER). The inclusion levels of DDGS were 7.5% in phase 1 (d 0 to 7), 16.25% in phase 2 (d 7 to 21), and 25% in phase 3 (d 21 to 42 or 48). Experiment 3 diets were fed to light (LBW; 5.8 ± 0.6 kg) or heavy (HBW; 7.6 ± 0.8 kg) BW pigs at weaning, and results were analyzed separately. Pig BW and ADFI were measured weekly in each experiment. In Exp. 1, feeding diets with DDGS depressed ( < 0.05) ADFI on d 7 to 21 (491 vs. 375 ± 21 g DM/pig) and d 0 to 35 (456 vs. 405 ± 13 g DM/pig). In Exp. 2 growth performance was not affected. In Exp. 3 ADFI of HBW pigs was not affected. The HBW pigs fed FER had lower ( < 0.05) ADG and G:F on d 7 to 21 (323 vs. 264 ± 15 g/pig and 0.86 vs. 0.72 ± 0.02 g:g, respectively) and lower ( < 0.05) BW on d 21 (12.4 vs. 11.6 ± 0.2 kg) compared with HBW pigs fed UNFER. The LBW pigs fed FER had lower ( < 0.05) ADFI on d 0 to 7 and 7 to 21 (190 vs. 168 ± 3 and 318 vs. 273 ± 13 g DM/pig, respectively) and had greater ( < 0.05) ADG on d 42 to 48 (773 vs. 941 ± 60 g/pig) and BW on d 48 (24.5 vs. 25.8 ± 0.5 kg) compared with LBW pigs fed UNFER. Results show that up to 25% DDGS inclusion in weaning pig diets did not affect overall growth performance. Liquid-fed partially fermented DDGS had an influence on the growth performance of weanling pigs, particularly during the extended nursery period of pigs of light weaning weight in this study.
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Li Y, Nguyen DN, de Waard M, Christensen L, Zhou P, Jiang P, Sun J, Bojesen AM, Lauridsen C, Lykkesfeldt J, Dalsgaard TK, Bering SB, Sangild PT. Pasteurization Procedures for Donor Human Milk Affect Body Growth, Intestinal Structure, and Resistance against Bacterial Infections in Preterm Pigs. J Nutr 2017; 147:1121-1130. [PMID: 28298536 DOI: 10.3945/jn.116.244822] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2016] [Revised: 01/17/2017] [Accepted: 02/17/2017] [Indexed: 11/14/2022] Open
Abstract
Background: Holder pasteurization (HP) destroys multiple bioactive factors in donor human milk (DM), and UV-C irradiation (UVC) is potentially a gentler method for pasteurizing DM for preterm infants.Objective: We investigated whether UVC-treated DM improves gut maturation and resistance toward bacterial infections relative to HP-treated DM.Methods: Bacteria, selected bioactive components, and markers of antioxidant capacity were measured in unpasteurized donor milk (UP), HP-treated milk, and UVC-treated milk (all from the same DM pool). Fifty-seven cesarean-delivered preterm pigs (91% gestation; ratio of males to females, 30:27) received decreasing volumes of parental nutrition (average 69 mL · kg-1 · d-1) and increasing volumes of the 3 DM diets (n = 19 each, average 89 mL · kg-1 · d-1) for 8-9 d. Body growth, gut structure and function, and systemic bacterial infection were evaluated.Results: A high bacterial load in the UP (6×105 colony forming units/mL) was eliminated similarly by HP and UVC treatments. Relative to HP-treated milk, both UVC-treated milk and UP showed greater activities of lipase and alkaline phosphatase and concentrations of lactoferrin, secretory immunoglobulin A, xanthine dehydrogenase, and some antioxidant markers (all P < 0.05). The pigs fed UVC-treated milk and pigs fed UP showed higher relative weight gain than pigs fed HP-treated milk (5.4% and 3.5%), and fewer pigs fed UVC-treated milk had positive bacterial cultures in the bone marrow (28%) than pigs fed HP-treated milk (68%) (P < 0.05). Intestinal health was also improved in pigs fed UVC-treated milk compared with those fed HP-treated milk as indicated by a higher plasma citrulline concentration (36%) and villus height (38%) (P < 0.05) and a tendency for higher aminopeptidase N (48%) and claudin-4 (26%) concentrations in the distal intestine (P < 0.08). The gut microbiota composition was similar among groups except for greater proportions of Enterococcus in pigs fed UVC-treated milk than in pigs fed UP and those fed HP-treated milk in both cecum contents (20% and 10%) and distal intestinal mucosa (24% and 20%) (all P < 0.05).Conclusions: UVC is better than HP treatment in preserving bioactive factors in DM. UVC-treated milk may induce better weight gain, intestinal health, and resistance against bacterial infections as shown in preterm pigs as a model for DM-fed preterm infants.
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Affiliation(s)
- Yanqi Li
- Comparative Pediatrics and Nutrition and
| | | | - Marita de Waard
- Dutch Human Milk Bank, VU University Medical Center, Amsterdam, Netherlands
| | | | - Ping Zhou
- Department of Neonatology, Shenzhen Bao'an Maternal and Child Health Hospital, Shenzhen, China
| | | | - Jing Sun
- Comparative Pediatrics and Nutrition and
| | - Anders Miki Bojesen
- Department of Veterinary Disease Biology, University of Copenhagen, Copenhagen, Denmark
| | | | - Jens Lykkesfeldt
- Department of Veterinary Disease Biology, University of Copenhagen, Copenhagen, Denmark
| | | | | | - Per Torp Sangild
- Comparative Pediatrics and Nutrition and
- Department of Pediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen, Denmark
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Gabriel I, Olejek A, Stencel-Gabriel K, Wielgoś M. The influence of maternal vaginal flora on the intestinal colonization in newborns and 3-month-old infants. J Matern Fetal Neonatal Med 2017; 31:1448-1453. [PMID: 28420276 DOI: 10.1080/14767058.2017.1319352] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
AIM The role of maternal vaginal bacteria on the colonization of neonatal gut is still a matter of discussion. Our aim was to estimate the role of maternal vaginal flora on the development of intestinal flora in neonates and 3-month-old infants. METHODS Seventy-nine maternal-neonatal pairs were included in the study. Vaginal swabs were taken before the rupture of membranes after admission to the delivery ward. First neonatal stool (meconium) and stool at 3-month-old infants were collected and cultured. All samples were subjected to microbiological analysis for Streptococcus, Staphylococcus, Bifidobacterium, Clostridium (including C. difficile), Lactobacillus, Escherichia coli, Klebsiella pneumoniae, and Candida. RESULTS Maternal vagina was colonized mainly by streptococci (67%) followed by lactobacilli (58%) and Candida spp. (39%). Vaginal streptococci influenced the intestinal colonization in infants with staphylococci, C. difficile, and candida. CONCLUSION Vaginal lactobacilli influenced colonization with C. difficile, and Candida. Vaginal flora is a potent factor influencing the development of bacterial flora in the neonatal and infantile gut. The extension of the observation period until 3 months of life allow to discover the potential changes in the intestinal flora of children.
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Affiliation(s)
- Iwona Gabriel
- a Department of Gynecology, Obstetrics and Oncological Gynecology , Medical University of Silesia , Bytom , Poland.,b Division of Urogynecology, Department of Obstetrics and Gynecology , Brigham and Women's Hospital , Boston , MA , USA
| | - Anita Olejek
- b Division of Urogynecology, Department of Obstetrics and Gynecology , Brigham and Women's Hospital , Boston , MA , USA
| | | | - Miroslaw Wielgoś
- d 1st Department of Obstetrics and Gynecology , Medical University of Warsaw , Warsaw , Poland
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Probiotics to prevent necrotising enterocolitis and nosocomial infection in very low birth weight preterm infants. Br J Nutr 2017; 117:994-1000. [PMID: 28443531 DOI: 10.1017/s0007114517000769] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
The aim of the study was to determine whether routine probiotic supplementation (RPS) with Lactobacillus rhamnosus GG (LGG) or Lactobacillus acidophilus +Lactobacillus bifidum is associated with reduced risk of necrotising enterocolitis (NEC)≥Stage II in preterm neonates born at ≤32 weeks' gestation. We conducted a retrospective cohort study on the effect of probiotic supplementation in very low birth weight infants in our neonatal unit by comparing two periods: before and after supplementation. The incidence of NEC≥Stage II, late-onset sepsis and all-cause mortality was compared for an equal period 'before' (Period I) and 'after' (Period II) RPS with LGG or L. acidophillus+L. bifidum. Multivariate logistic regression analysis was conducted to adjust for relevant confounders. The study population was composed of 261 neonates (Period I v. II: 134 v. 127) with comparable gestation duration and birth weights. In <32 weeks, we observed a significant reduction in NEC≥Stage II (11·3 v. 4·8 %), late-onset sepsis (16 v. 10·5 %) and mortality (19·4 v. 2·3 %). The benefits in neonates aged ≤27 weeks did not reach statistical significance. RPS with LGG or L. acidophillus+L. bifidum is associated with a reduced risk of NEC≥Stage II, late-onset sepsis and mortality in preterm neonates born at ≤32 weeks' gestation.
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Pieper R, Vahjen W, Zentek J. Intestinal lactose and mineral concentration affect the microbial ecophysiology along the gastrointestinal tract of formula-fed neonatal piglets. J Anim Sci 2017; 94:3786-3795. [PMID: 27898903 DOI: 10.2527/jas.2016-0459] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Hyperprolificacy in modern pig breeds has led to increased use of artificial rearing and formula feeding of neonatal piglets, which may change their intestinal bacterial ecophysiology. Here, newborn piglets ( = 8 per group) were fed a bovine milk-based formula (FO) or allowed to suckle their mothers (sow milk [SM]) for 2 wk, and digesta samples from the stomach, jejunum, and colon were subsequently analyzed for enzyme activities, bacterial metabolites, and 16S rRNA transcripts of bacterial groups by quantitative real-time PCR. Jejunal lactase activity was lower and lactose concentration was greater in the jejunum and colon in the FO group compared with the SM group ( < 0.05). In the stomach, FO-fed pigs had a lower copy number of 16S rRNA transcripts for all analyzed bacterial groups ( < 0.05) except for the // group. In the jejunum, 16S rRNA transcripts of lactic acid bacteria and clostridial cluster I were lower ( < 0.05) in FO-fed pigs. In turn, transcript abundance of the group and clostridial cluster I was greater in FO-fed pigs in the colon ( < 0.05). In FO-fed piglets, concentrations of and lactate and total and individual short-chain fatty acids were higher in the colon ( < 0.05). Multivariate redundancy analysis revealed that the concentration of minerals (ash, Ca, Mg, K, Na, Mn, and Zn) were associated with reduced bacterial abundance and activity in the upper gastrointestinal tract, whereas lactose had the most pronounced effect on the colon microbiota. The present study revealed that, apart from lactose, the mineral concentration modifies the microbial communities in the gastrointestinal tract of FO-fed piglets.
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Rakers F, Rupprecht S, Dreiling M, Bergmeier C, Witte OW, Schwab M. Transfer of maternal psychosocial stress to the fetus. Neurosci Biobehav Rev 2017; 117:S0149-7634(16)30719-9. [PMID: 28237726 DOI: 10.1016/j.neubiorev.2017.02.019] [Citation(s) in RCA: 115] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2016] [Revised: 02/14/2017] [Accepted: 02/20/2017] [Indexed: 12/18/2022]
Abstract
Psychosocial maternal stress experienced during different vulnerable periods throughout gestation is thought to increase the individual's risk to develop neuropsychiatric, cardiovascular and metabolic disease in later life. Cortisol has generally been identified as the major mediator of maternal stress transfer to the fetus. Its lipophilic nature allows a trans-placental passage and thus excessive maternal cortisol could persistently impair the development of the fetal hypothalamic-pituitary-adrenal axis (HPAA). However, cortisol alone cannot fully explain all effects of maternal stress especially during early to mid pregnancy before maturation of the fetal HPAA has even begun and expression of fetal glucocorticoid receptors is limited. This review focuses on mediators of maternal fetal stress transfer that in addition to cortisol have been proposed as transmitters of maternal stress: catecholamines, cytokines, serotonin/tryptophan, reactive-oxygen-species and the maternal microbiota. We propose that the effects of psychosocial maternal stress on fetal development and health and disease in later life are not a consequence of a single pathway but are mediated by multiple stress-transfer mechanisms acting together in a synergistic manner.
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Affiliation(s)
- Florian Rakers
- Hans Berger Department of Neurology, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany.
| | - Sven Rupprecht
- Hans Berger Department of Neurology, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany.
| | - Michelle Dreiling
- Hans Berger Department of Neurology, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany.
| | - Christoph Bergmeier
- Hans Berger Department of Neurology, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany.
| | - Otto W Witte
- Hans Berger Department of Neurology, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany.
| | - Matthias Schwab
- Hans Berger Department of Neurology, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany.
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Grev J, Berg M, Soll R. Maternal probiotic supplementation for prevention of morbidity and mortality in preterm infants. Hippokratia 2017. [DOI: 10.1002/14651858.cd012519] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Affiliation(s)
| | - Marie Berg
- University of Vermont Medical Center; Division of Neonatal-Perinatal Medicine; Burlington Vermont USA 05401
| | - Roger Soll
- University of Vermont Medical Center; Division of Neonatal-Perinatal Medicine; Burlington Vermont USA 05401
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Hill CJ, Lynch DB, Murphy K, Ulaszewska M, Jeffery IB, O'Shea CA, Watkins C, Dempsey E, Mattivi F, Tuohy K, Ross RP, Ryan CA, O' Toole PW, Stanton C. Evolution of gut microbiota composition from birth to 24 weeks in the INFANTMET Cohort. MICROBIOME 2017; 5:4. [PMID: 28095889 PMCID: PMC5240274 DOI: 10.1186/s40168-016-0213-y] [Citation(s) in RCA: 359] [Impact Index Per Article: 44.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/16/2016] [Accepted: 11/24/2016] [Indexed: 05/22/2023]
Abstract
BACKGROUND The gut is the most extensively studied niche of the human microbiome. The aim of this study was to characterise the initial gut microbiota development of a cohort of breastfed infants (n = 192) from 1 to 24 weeks of age. METHODS V4-V5 region 16S rRNA amplicon Illumina sequencing and, in parallel, bacteriological culture. The metabolomic profile of infant urine at 4 weeks of age was also examined by LC-MS. RESULTS Full-term (FT), spontaneous vaginally delivered (SVD) infants' microbiota remained stable at both phylum and genus levels during the 24-week period examined. FT Caesarean section (CS) infants displayed an increased faecal abundance of Firmicutes (p < 0.01) and lower abundance of Actinobacteria (p < 0.001) after the first week of life compared to FT-SVD infants. FT-CS infants gradually progressed to harbouring a microbiota closely resembling FT-SVD (which remained stable) by week 8 of life, which was maintained at week 24. The gut microbiota of preterm (PT) infants displayed a significantly greater abundance of Proteobacteria compared to FT infants (p < 0.001) at week 1. Metabolomic analysis of urine at week 4 indicated PT-CS infants have a functionally different metabolite profile than FT (both CS and SVD) infants. Co-inertia analysis showed co-variation between the urine metabolome and the faecal microbiota of the infants. Tryptophan and tyrosine metabolic pathways, as well as fatty acid and bile acid metabolism, were found to be affected by delivery mode and gestational age. CONCLUSIONS These findings confirm that mode of delivery and gestational age both have significant effects on early neonatal microbiota composition. There is also a significant difference between the metabolite profile of FT and PT infants. Prolonged breastfeeding was shown to have a significant effect on the microbiota composition of FT-CS infants at 24 weeks of age, but interestingly not on that of FT-SVD infants. Twins had more similar microbiota to one another than between two random infants, reflecting the influence of similarities in both host genetics and the environment on the microbiota..
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Affiliation(s)
- Cian J Hill
- School of Microbiology, University College Cork, Cork, Ireland
- APC Microbiome Institute, University College Cork, Cork, Ireland
| | - Denise B Lynch
- School of Microbiology, University College Cork, Cork, Ireland
- APC Microbiome Institute, University College Cork, Cork, Ireland
| | - Kiera Murphy
- School of Microbiology, University College Cork, Cork, Ireland
- APC Microbiome Institute, University College Cork, Cork, Ireland
- Teagasc Moorepark Food Research Centre, Fermoy, Co. Cork, Ireland
| | - Marynka Ulaszewska
- Food Quality and Nutrition Department, Research and Innovation Centre, Fondazione Edmund Mach, San Michele All'adige, Italy
| | - Ian B Jeffery
- School of Microbiology, University College Cork, Cork, Ireland
| | - Carol Anne O'Shea
- Department of Neonatology, Cork University Maternity Hospital, Cork, Ireland
| | - Claire Watkins
- Teagasc Moorepark Food Research Centre, Fermoy, Co. Cork, Ireland
| | - Eugene Dempsey
- Department of Neonatology, Cork University Maternity Hospital, Cork, Ireland
| | - Fulvio Mattivi
- Food Quality and Nutrition Department, Research and Innovation Centre, Fondazione Edmund Mach, San Michele All'adige, Italy
| | - Kieran Tuohy
- Food Quality and Nutrition Department, Research and Innovation Centre, Fondazione Edmund Mach, San Michele All'adige, Italy
| | - R Paul Ross
- School of Microbiology, University College Cork, Cork, Ireland
- APC Microbiome Institute, University College Cork, Cork, Ireland
| | - C Anthony Ryan
- APC Microbiome Institute, University College Cork, Cork, Ireland
- Department of Neonatology, Cork University Maternity Hospital, Cork, Ireland
| | - Paul W O' Toole
- School of Microbiology, University College Cork, Cork, Ireland
- APC Microbiome Institute, University College Cork, Cork, Ireland
| | - Catherine Stanton
- APC Microbiome Institute, University College Cork, Cork, Ireland.
- Teagasc Moorepark Food Research Centre, Fermoy, Co. Cork, Ireland.
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Olm MR, Brown CT, Brooks B, Firek B, Baker R, Burstein D, Soenjoyo K, Thomas BC, Morowitz M, Banfield JF. Identical bacterial populations colonize premature infant gut, skin, and oral microbiomes and exhibit different in situ growth rates. Genome Res 2017; 27:601-612. [PMID: 28073918 PMCID: PMC5378178 DOI: 10.1101/gr.213256.116] [Citation(s) in RCA: 77] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2016] [Accepted: 01/09/2017] [Indexed: 12/22/2022]
Abstract
The initial microbiome impacts the health and future development of premature infants. Methodological limitations have led to gaps in our understanding of the habitat range and subpopulation complexity of founding strains, as well as how different body sites support microbial growth. Here, we used metagenomics to reconstruct genomes of strains that colonized the skin, mouth, and gut of two hospitalized premature infants during the first month of life. Seven bacterial populations, considered to be identical given whole-genome average nucleotide identity of >99.9%, colonized multiple body sites, yet none were shared between infants. Gut-associated Citrobacter koseri genomes harbored 47 polymorphic sites that we used to define 10 subpopulations, one of which appeared in the gut after 1 wk but did not spread to other body sites. Differential genome coverage was used to measure bacterial population replication rates in situ. In all cases where the same bacterial population was detected in multiple body sites, replication rates were faster in mouth and skin compared to the gut. The ability of identical strains to colonize multiple body sites underscores the habit flexibility of initial colonists, whereas differences in microbial replication rates between body sites suggest differences in host control and/or resource availability. Population genomic analyses revealed microdiversity within bacterial populations, implying initial inoculation by multiple individual cells with distinct genotypes. Overall, however, the overlap of strains across body sites implies that the premature infant microbiome can exhibit very low microbial diversity.
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Affiliation(s)
- Matthew R Olm
- Department of Plant and Microbial Biology, University of California, Berkeley, California 94720, USA
| | - Christopher T Brown
- Department of Plant and Microbial Biology, University of California, Berkeley, California 94720, USA
| | - Brandon Brooks
- Department of Plant and Microbial Biology, University of California, Berkeley, California 94720, USA
| | - Brian Firek
- Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA
| | - Robyn Baker
- Division of Newborn Medicine, Children's Hospital of Pittsburgh and Magee-Womens Hospital of UPMC, Pittsburgh, Pennsylvania 15213, USA
| | - David Burstein
- Department of Earth and Planetary Science, University of California, Berkeley, California 94709, USA
| | - Karina Soenjoyo
- Department of Plant and Microbial Biology, University of California, Berkeley, California 94720, USA
| | - Brian C Thomas
- Department of Earth and Planetary Science, University of California, Berkeley, California 94709, USA
| | - Michael Morowitz
- Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA
| | - Jillian F Banfield
- Department of Earth and Planetary Science, University of California, Berkeley, California 94709, USA.,Department of Environmental Science, Policy, and Management, University of California, Berkeley, California 94720, USA.,Earth Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA
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