Necrotizing enterocolitis and the microbiome: Current status and future directions

Abstract Decades of research have failed to define the pathophysiology of necrotizing enterocolitis (NEC), a devastating pediatric gastrointestinal disorder of preterm infants. However, recent evidence suggests that host-microbiota interactions, in which microbial dysbiosis is followed by loss of barrier integrity, inflammation, and necrosis, are central to NEC development. Thus, greater knowledge of the preterm infant microbiome could accelerate attempts to diagnose, treat, and prevent NEC. Here, we summarize clinical characteristics of and risk factors for NEC, the structure of the pre-event NEC microbiome, how this community interfaces with host immunology, and microbiome-based approaches that might prevent or lessen the severity of NEC in this very vulnerable population.

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Recent advances in understanding necrotizing enterocolitis

F1000Research ◽

10.12688/f1000research.17228.1 ◽

2019 ◽

Vol 8 ◽

pp. 107 ◽

Cited By ~ 8

Author(s):

Mashriq Alganabi ◽

Carol Lee ◽

Edoardo Bindi ◽

Bo Li ◽

Agostino Pierro

Keyword(s):

Risk Factors ◽

Preterm Infants ◽

Necrotizing Enterocolitis ◽

Advanced Disease ◽

Current Understanding ◽

Disease Development ◽

Current Management ◽

Future Directions ◽

Ongoing Research ◽

Factors Associated

Necrotizing enterocolitis is a devastating intestinal disease affecting preterm infants. In spite of ongoing research and advancement in neonatal care, mortality remains high, especially in infants with advanced disease. The mechanism of disease development, the progression of intestinal injury, and management remain areas of ongoing research and controversy. In this review, we examine our current understanding of the disease, its epidemiology, the risk factors associated with the development of the disease, and its pathophysiology. We also describe current management and new emerging research highlighting potential future directions.

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Nutritional strategies and gut microbiota composition as risk factors for necrotizing enterocolitis in very-preterm infants

American Journal of Clinical Nutrition ◽

10.3945/ajcn.117.152967 ◽

2017 ◽

Vol 106 (3) ◽

pp. 821-830 ◽

Cited By ~ 25

Author(s):

Jean-Christophe Rozé ◽

Pierre-Yves Ancel ◽

Patricia Lepage ◽

Laetitia Martin-Marchand ◽

Ziad Al Nabhani ◽

...

Keyword(s):

Risk Factors ◽

Gut Microbiota ◽

Preterm Infants ◽

Necrotizing Enterocolitis ◽

Microbiota Composition ◽

Very Preterm Infants ◽

Very Preterm ◽

Nutritional Strategies ◽

Gut Microbiota Composition

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Risk factors for necrotizing enterocolitis in very preterm infants: a case–control study in southwest China

The Journal of Maternal-Fetal & Neonatal Medicine ◽

10.1080/14767058.2017.1395011 ◽

2017 ◽

Vol 32 (6) ◽

pp. 896-901 ◽

Cited By ~ 2

Author(s):

Ling-ping Zhang ◽

Xiao-ping Lei ◽

Li-juan Luo ◽

Wen-bin Dong

Keyword(s):

Risk Factors ◽

Preterm Infants ◽

Necrotizing Enterocolitis ◽

Southwest China ◽

Case Control Study ◽

Case Control ◽

Very Preterm Infants ◽

Very Preterm ◽

Control Study

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Risk Factors for Necrotizing Enterocolitis in Preterm Infants

Advances in Neonatal Care ◽

10.1097/01.anc.0000338019.56405.29 ◽

2008 ◽

Vol 8 (5) ◽

pp. 285-290 ◽

Cited By ~ 32

Author(s):

Brigit M. Carter ◽

Diane Holditch-Davis

Keyword(s):

Risk Factors ◽

Preterm Infants ◽

Necrotizing Enterocolitis

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Fecal filtrate transplantation protects against necrotizing enterocolitis

The ISME Journal ◽

10.1038/s41396-021-01107-5 ◽

2021 ◽

Author(s):

Anders Brunse ◽

Ling Deng ◽

Xiaoyu Pan ◽

Yan Hui ◽

Josué L. Castro-Mejía ◽

...

Keyword(s):

Preterm Infants ◽

Necrotizing Enterocolitis ◽

Fecal Microbiota Transplantation ◽

Gastrointestinal Disorder ◽

Preventive Therapy ◽

Fecal Microbiota ◽

Rrna Gene ◽

Ileal Mucosa ◽

Relevant Animal Model ◽

Life Threatening

AbstractNecrotizing enterocolitis (NEC) is a life-threatening gastrointestinal disorder afflicting preterm infants, which is currently unpreventable. Fecal microbiota transplantation (FMT) is a promising preventive therapy, but the transfer of pathogenic microbes or toxic compounds raise concern. Removal of bacteria from donor feces by micropore filtering may reduce this risk of bacterial infection, while residual bacteriophages could maintain the NEC-preventive effects. We aimed to assess preclinical efficacy and safety of fecal filtrate transplantation (FFT). Using fecal material from healthy suckling piglets, we compared rectal FMT administration (FMT, n = 16) with cognate FFT by either rectal (FFTr, n = 14) or oro-gastric administration (FFTo, n = 13) and saline (CON, n = 16) in preterm, cesarean-delivered piglets as models for preterm infants. We assessed gut pathology and analyzed mucosal and luminal bacterial and viral composition using 16S rRNA gene amplicon and meta-virome sequencing. Finally, we used isolated ileal mucosa, coupled with RNA-Seq, to gauge the host response to the different treatments. Oro-gastric FFT completely prevented NEC, which was confirmed by microscopy, whereas FMT did not perform better than control. Oro-gastric FFT increased viral diversity and reduced Proteobacteria relative abundance in the ileal mucosa relative to control. An induction of mucosal immunity was observed in response to FMT but not FFT. As preterm infants are extremely vulnerable to infections, rational NEC-preventive strategies need incontestable safety profiles. We show in a clinically relevant animal model that FFT, as opposed to FMT, efficiently prevents NEC without any recognizable side effects.

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Brachial-Ankle PWV: Current Status and Future Directions as a Useful Marker in the Management of Cardiovascular Disease and/or Cardiovascular Risk Factors

Journal of Atherosclerosis and Thrombosis ◽

10.5551/jat.32979 ◽

2016 ◽

Vol 23 (2) ◽

pp. 128-146 ◽

Cited By ~ 39

Author(s):

Hirofumi Tomiyama ◽

Chisa Matsumoto ◽

Kazuki Shiina ◽

Akira Yamashina

Keyword(s):

Risk Factors ◽

Cardiovascular Disease ◽

Cardiovascular Risk ◽

Cardiovascular Risk Factors ◽

Current Status ◽

Future Directions

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The Microbiome and Metabolome of Preterm Infant Stool Are Personalized and Not Driven by Health Outcomes, Including Necrotizing Enterocolitis and Late-Onset Sepsis

mSphere ◽

10.1128/msphere.00104-18 ◽

2018 ◽

Vol 3 (3) ◽

Cited By ~ 33

Author(s):

Stephen Wandro ◽

Stephanie Osborne ◽

Claudia Enriquez ◽

Christine Bixby ◽

Antonio Arrieta ◽

...

Keyword(s):

Health Outcomes ◽

Preterm Infant ◽

Preterm Infants ◽

Necrotizing Enterocolitis ◽

Gut Microbiome ◽

Infant Health ◽

Late Onset ◽

Bacterial Composition ◽

Fecal Samples ◽

Late Onset Sepsis

ABSTRACTThe assembly and development of the gut microbiome in infants have important consequences for immediate and long-term health. Preterm infants represent an abnormal case for bacterial colonization because of early exposure to bacteria and frequent use of antibiotics. To better understand the assembly of the gut microbiota in preterm infants, fecal samples were collected from 32 very low birth weight preterm infants over the first 6 weeks of life. Infant health outcomes included health, late-onset sepsis, and necrotizing enterocolitis (NEC). We characterized bacterial compositions by 16S rRNA gene sequencing and metabolomes by untargeted gas chromatography-mass spectrometry. Preterm infant fecal samples lacked beneficialBifidobacteriumspp. and were dominated byEnterobacteriaceae,Enterococcus, andStaphylococcusorganisms due to nearly uniform antibiotic administration. Most of the variance between the microbial community compositions could be attributed to the baby from which the sample derived (permutational multivariate analysis of variance [PERMANOVA]R2= 0.48,P< 0.001), while clinical status (health, NEC, or late-onset sepsis) and overlapping times in the neonatal intensive care unit (NICU) did not explain a significant amount of variation in bacterial composition. Fecal metabolomes were also found to be unique to the individual (PERMANOVAR2= 0.43,P< 0.001) and weakly associated with bacterial composition (Mantel statisticr= 0.23 ± 0.05,P< 0.05). No measured metabolites were found to be associated with necrotizing enterocolitis, late-onset sepsis, or a healthy outcome. Overall, preterm infant gut microbial communities were personalized and reflected antibiotic usage.IMPORTANCEPreterm infants face health problems likely related to microbial exposures, including sepsis and necrotizing enterocolitis. However, the role of the gut microbiome in preterm infant health is poorly understood. Microbial colonization differs from that of healthy term babies because it occurs in the NICU and is often perturbed by antibiotics. We measured bacterial compositions and metabolomic profiles of 77 fecal samples from 32 preterm infants to investigate the differences between microbiomes in health and disease. Rather than finding microbial signatures of disease, we found that both the preterm infant microbiome and the metabolome were personalized and that the preterm infant gut microbiome is enriched in microbes that commonly dominate in the presence of antibiotics. These results contribute to the growing knowledge of the preterm infant microbiome and emphasize that a personalized view will be important to disentangle the health consequences of the preterm infant microbiome.

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The microbiome and metabolome of pre-term infant stool is personalized, and not driven by health outcomes including necrotizing enterocolitis and late-onset sepsis

10.1101/125922 ◽

2017 ◽

Author(s):

Stephen Wandro ◽

Stephanie Osborne ◽

Claudia Enriquez ◽

Christine Bixby ◽

Antonio Arrieta ◽

...

Keyword(s):

Health Outcomes ◽

Preterm Infant ◽

Preterm Infants ◽

Necrotizing Enterocolitis ◽

Gut Microbiome ◽

Infant Health ◽

Late Onset ◽

Bacterial Composition ◽

Fecal Samples ◽

Late Onset Sepsis

AbstractThe assembly and development of the gut microbiome in infants has important consequences for immediate and long-term health. Preterm infants represent an abnormal case for bacterial colonization because of early exposure to bacteria and frequent use of antibiotics. To better understand the assembly of the gut microbiota in preterm infants, fecal samples were collected from 32 very low birthweight preterm infants over the first six weeks of life. Infant health outcomes included healthy, late-onset sepsis, and necrotizing enterocolitis (NEC). We characterized the bacterial composition by 16S rRNA gene sequencing and metabolome by untargeted gas chromatography mass spectrometry. Preterm infant fecal samples lacked beneficial Bifidobacterium and were dominated by Enterobacteriaceae, Enterococcus, and Staphylococcus due to the near uniform antibiotic administration. Most of the variance between the microbial community compositions could be attributed to which baby the sample came from (Permanova R2=0.48, p<0.001), while clinical status (healthy, NEC, or late-onset sepsis), and overlapping time in the NICU did not explain a significant amount of variation in bacterial composition. Fecal metabolomes were also found to be unique to the individual (Permanova R2=0.43, p<0.001) and weakly associated with bacterial composition (Mantel statistic r = 0.23 ± 0.05 (p = 0.03 ± 0.03). No measured metabolites were found to be associated with necrotizing enterocolitis, late-onset sepsis or a healthy outcome. Overall, preterm infants gut microbial communities were personalized and reflected antibiotic usage.ImportancePreterm infants face health problems likely related to microbial exposures including sepsis and necrotizing enterocolitis. However, the role of the gut microbiome in preterm infant health is poorly understood. Microbial colonization differs from healthy term babies because it occurs in the NICU and is often perturbed by antibiotics. We measured bacterial compositions and metabolomic profiles of 77 fecal samples from thirty-two preterm infants to investigate the differences between microbiomes in health and disease. Rather than finding microbial signatures of disease, we found the preterm infant microbiome and metabolome were both personalized, and that the preterm infant gut microbiome is enriched in microbes that commonly dominate in the presence of antibiotics. These results contribute to the growing knowledge of the preterm infant microbiome and emphasize that a personalized view will be important to disentangling the health consequences of the preterm infant microbiome.

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Combination of CRP, PCT, N%, Bell stage and add milk the day before onset of NEC for predicting surgical necrotizing enterocolitis and their clinical significance

10.21203/rs.2.17689/v1 ◽

2019 ◽

Author(s):

Li Wang ◽

Jingwei Huang ◽

Lili Wang

Keyword(s):

Risk Factors ◽

Necrotizing Enterocolitis ◽

Gestational Age ◽

Clinical Characteristics ◽

Stage I ◽

Conservative Group ◽

Significant Difference ◽

Independent Risk Factors ◽

Surgical Group ◽

The Ideal

Abstract Objects Necrotizing enterocolitis (NEC) is a severe neonatal disease. The present study aimed to identify risk factors of NEC and predict surgical NEC.Methods According to the modified Bell’s staging criteria, 235 neonates with NEC admitted between Jan 1, 2015 and Sep 30, 2019 were divided into surgical group (n=47) and conservative group (n=188). Data concerning clinical characteristics and therapeutic management were collected. Infection values of WBC, N%, PLT, CRP, PCT were measured before treatment (T0), on the next day after treatment (T1).Results 1. Surgical group were associated with gestational age, small for gestational age, add milk before onset of NEC, hospitalization expense compared to conservative group (p=0.040, 0.048, 0.045, 0.011), in addition to N%0, N%1, PLT1, CRP1 and PCT1 (p=0.049, 0.003, 0.018, <0.001, 0.003). There was significant difference in NEC among Bell stage I, II and III between surgical group and conservative group (χ2=49.358, p<0.001). 2. Regression analysis showed that Bell stage I, II and III NEC (OR 12.331, 6.315, p=0.038, 0.025), N%1 (OR 0.959, p=0.032), CRP1 (OR 0.978, p=0.039) and PCT1 (OR 0.983, p=0.036), add milk before onset of NEC (OR 7.117, p=0.021) were all independent risk factors to predict surgical NEC. 3. The AUC of combined Bell stage I, II and III NEC, N%1, CRP1, PCT1, add milk the day before onset of NEC (P) in predicting surgical NEC was 0.924 (95%CI 0.865~0.983, p<0.001). The ideal cutoff value of P was 0.729, with a sensitivity of 85.7% and specificity of 87.5%.Conclusion Increased Levels of CRP1, PCT1, N%1, Bell stage I, II and III, and add milk the day before onset of NEC are all independent risk factors of NEC, and combined of them can be used to predict the development of surgical NEC.

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