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Editorial

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2 pages, 168 KiB

Open AccessEditorial

Neonatal Microbiome, Intestinal Inflammation, and Necrotizing Enterocolitis

by Kathryn Y. Burge and Troy A. Markel

Microorganisms 2022, 10(7), 1382; https://doi.org/10.3390/microorganisms10071382 - 9 Jul 2022

Cited by 2 | Viewed by 1399

Abstract

Necrotizing enterocolitis (NEC), the most common gastrointestinal emergency in the neonatal intensive care unit (NICU), is a leading cause of preterm infant morbidity and mortality [...] Full article

(This article belongs to the Special Issue Neonatal Microbiome, Intestinal Inflammation, and Necrotizing Enterocolitis (NEC))

Research

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14 pages, 1765 KiB

Open AccessArticle

Occurrence of Neonatal Necrotizing Enterocolitis in Premature Neonates and Gut Microbiota: A Case–Control Prospective Multicenter Study

by Julio Aires, Zehra Esra Ilhan, Lancelot Nicolas, Laurent Ferraris, Johanne Delannoy, Maxime Bredel, Anne Chauvire-Drouard, Frédéric Barbut, Jean-Christophe Rozé, Patricia Lepage, Marie-José Butel and ClosNEC Study Group

Microorganisms 2023, 11(10), 2457; https://doi.org/10.3390/microorganisms11102457 - 29 Sep 2023

Cited by 3 | Viewed by 1652

Abstract

Background: Necrotizing enterocolitis (NEC) is still one of the leading causes of neonatal death. The present study reports the data from a French case–control prospective multicenter study. Methods: A total of 146 preterm neonates (PNs) with or without NEC were included. Bacterial 16S [...] Read more.

Background: Necrotizing enterocolitis (NEC) is still one of the leading causes of neonatal death. The present study reports the data from a French case–control prospective multicenter study. Methods: A total of 146 preterm neonates (PNs) with or without NEC were included. Bacterial 16S rRNA gene sequencing was performed on stool samples (n = 103). Specific culture media were used to isolate Escherichia coli, Clostridium butyricum, and Clostridium neonatale, and strains were phenotypically characterized. Results: The gut microbiota of PNs was dominated by Firmicutes and Proteobacteria, and five enterotypes were identified. The microbiota composition was similar between NEC cases and PN controls. However, differences were observed in the relative abundance of Lactobacillus genus, which was significantly lower in the NEC group, whereas that of the Clostridium cluster III was significantly higher (p < 0.05). Within enterotypes, several phylotypes were significantly more abundant in NEC cases (p < 0.05). Regarding perinatal factors, a statistical association was found between the gut microbiota and cesarean delivery and antifungal therapy. In NEC cases and PN controls, the carriage rates and virulence genes of uropathogenic E. coli were equivalent based on culture. No correlation was found between E. coli, C. butyricum, and C. neonatale carriages, beta-lactam resistance, and antibiotic treatment. Conclusions: At disease onset, our data support a microbiota dysbiosis between NEC and control infants at the genus level. In addition, it provides valuable information on bacterial antimicrobial susceptibility. Full article

(This article belongs to the Special Issue Neonatal Microbiome, Intestinal Inflammation, and Necrotizing Enterocolitis (NEC))

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17 pages, 3769 KiB

Open AccessArticle

The Detrimental Effects of Peripartum Antibiotics on Gut Proliferation and Formula Feeding Injury in Neonatal Mice Are Alleviated with Lactobacillus rhamnosus GG

by Alain Cuna, Marianne Nsumu, Heather L. Menden, Susana Chavez-Bueno and Venkatesh Sampath

Microorganisms 2023, 11(6), 1482; https://doi.org/10.3390/microorganisms11061482 - 1 Jun 2023

Cited by 2 | Viewed by 1880

Abstract

Peripartum antibiotics can negatively impact the developing gut microbiome and are associated with necrotizing enterocolitis (NEC). The mechanisms by which peripartum antibiotics increase the risk of NEC and strategies that can help mitigate this risk remain poorly understood. In this study, we determined [...] Read more.

Peripartum antibiotics can negatively impact the developing gut microbiome and are associated with necrotizing enterocolitis (NEC). The mechanisms by which peripartum antibiotics increase the risk of NEC and strategies that can help mitigate this risk remain poorly understood. In this study, we determined mechanisms by which peripartum antibiotics increase neonatal gut injury and evaluated whether probiotics protect against gut injury potentiated by peripartum antibiotics. To accomplish this objective, we administered broad-spectrum antibiotics or sterile water to pregnant C57BL6 mice and induced neonatal gut injury to their pups with formula feeding. We found that pups exposed to antibiotics had reduced villus height, crypt depth, and intestinal olfactomedin 4 and proliferating cell nuclear antigen compared to the controls, indicating that peripartum antibiotics impaired intestinal proliferation. When formula feeding was used to induce NEC-like injury, more severe intestinal injury and apoptosis were observed in the pups exposed to antibiotics compared to the controls. Supplementation with the probiotic Lactobacillus rhamnosus GG (LGG) reduced the severity of formula-induced gut injury potentiated by antibiotics. Increased intestinal proliferating cell nuclear antigen and activation of the Gpr81-Wnt pathway were noted in the pups supplemented with LGG, suggesting partial restoration of intestinal proliferation by probiotics. We conclude that peripartum antibiotics potentiate neonatal gut injury by inhibiting intestinal proliferation. LGG supplementation decreases gut injury by activating the Gpr81-Wnt pathway and restoring intestinal proliferation impaired by peripartum antibiotics. Our results suggest that postnatal probiotics may be effective in mitigating the increased risk of NEC associated with peripartum antibiotic exposure in preterm infants. Full article

(This article belongs to the Special Issue Neonatal Microbiome, Intestinal Inflammation, and Necrotizing Enterocolitis (NEC))

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24 pages, 12858 KiB

Open AccessArticle

Microbiota from Preterm Infants Who Develop Necrotizing Enterocolitis Drives the Neurodevelopment Impairment in a Humanized Mouse Model

by Jing Lu, Alexander Drobyshevsky, Lei Lu, Yueyue Yu, Michael S. Caplan and Erika C. Claud

Microorganisms 2023, 11(5), 1131; https://doi.org/10.3390/microorganisms11051131 - 26 Apr 2023

Cited by 6 | Viewed by 2617

Abstract

Necrotizing enterocolitis (NEC) is the leading basis for gastrointestinal morbidity and poses a significant risk for neurodevelopmental impairment (NDI) in preterm infants. Aberrant bacterial colonization preceding NEC contributes to the pathogenesis of NEC, and we have demonstrated that immature microbiota in preterm infants [...] Read more.

Necrotizing enterocolitis (NEC) is the leading basis for gastrointestinal morbidity and poses a significant risk for neurodevelopmental impairment (NDI) in preterm infants. Aberrant bacterial colonization preceding NEC contributes to the pathogenesis of NEC, and we have demonstrated that immature microbiota in preterm infants negatively impacts neurodevelopment and neurological outcomes. In this study, we tested the hypothesis that microbial communities before the onset of NEC drive NDI. Using our humanized gnotobiotic model in which human infant microbial samples were gavaged to pregnant germ-free C57BL/6J dams, we compared the effects of the microbiota from preterm infants who went on to develop NEC (MNEC) to the microbiota from healthy term infants (MTERM) on brain development and neurological outcomes in offspring mice. Immunohistochemical studies demonstrated that MNEC mice had significantly decreased occludin and ZO-1 expression compared to MTERM mice and increased ileal inflammation marked by the increased nuclear phospho-p65 of NFκB expression, revealing that microbial communities from patients who developed NEC had a negative effect on ileal barrier development and homeostasis. In open field and elevated plus maze tests, MNEC mice had worse mobility and were more anxious than MTERM mice. In cued fear conditioning tests, MNEC mice had worse contextual memory than MTERM mice. MRI revealed that MNEC mice had decreased myelination in major white and grey matter structures and lower fractional anisotropy values in white matter areas, demonstrating delayed brain maturation and organization. MNEC also altered the metabolic profiles, especially carnitine, phosphocholine, and bile acid analogs in the brain. Our data demonstrated numerous significant differences in gut maturity, brain metabolic profiles, brain maturation and organization, and behaviors between MTERM and MNEC mice. Our study suggests that the microbiome before the onset of NEC has negative impacts on brain development and neurological outcomes and can be a prospective target to improve long-term developmental outcomes. Full article

(This article belongs to the Special Issue Neonatal Microbiome, Intestinal Inflammation, and Necrotizing Enterocolitis (NEC))

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Review

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12 pages, 311 KiB

Open AccessReview

The Impact of Stress, Microbial Dysbiosis, and Inflammation on Necrotizing Enterocolitis

by Venkata Yeramilli, Riadh Cheddadi, Heather Benjamin and Colin Martin

Microorganisms 2023, 11(9), 2206; https://doi.org/10.3390/microorganisms11092206 - 31 Aug 2023

Cited by 5 | Viewed by 1567

Abstract

Necrotizing enterocolitis (NEC) is the leading cause of intestinal morbidity and mortality in neonates. A large body of work exists; however, the pathogenesis of NEC remains poorly understood. Numerous predictors have been implicated in the development of NEC, with relatively less emphasis on [...] Read more.

Necrotizing enterocolitis (NEC) is the leading cause of intestinal morbidity and mortality in neonates. A large body of work exists; however, the pathogenesis of NEC remains poorly understood. Numerous predictors have been implicated in the development of NEC, with relatively less emphasis on maternal factors. Utilizing human tissue plays a crucial role in enhancing our comprehension of the underlying mechanisms accountable for this devastating disease. In this review, we will discuss how maternal stress affects the pathogenesis of NEC and how changes in the intestinal microbiome can influence the development of NEC. We will also discuss the results of transcriptomics-based studies and analyze the gene expression changes in NEC tissues and other molecular targets associated with the pathogenesis of NEC. Full article

(This article belongs to the Special Issue Neonatal Microbiome, Intestinal Inflammation, and Necrotizing Enterocolitis (NEC))

25 pages, 1144 KiB

Open AccessReview

Volatile Organic Compound Assessment as a Screening Tool for Early Detection of Gastrointestinal Diseases

by Costa Dalis, Fikir M. Mesfin, Krishna Manohar, Jianyun Liu, W. Christopher Shelley, John P. Brokaw and Troy A. Markel

Microorganisms 2023, 11(7), 1822; https://doi.org/10.3390/microorganisms11071822 - 17 Jul 2023

Cited by 6 | Viewed by 2615

Abstract

Gastrointestinal (GI) diseases have a high prevalence throughout the United States. Screening and diagnostic modalities are often expensive and invasive, and therefore, people do not utilize them effectively. Lack of proper screening and diagnostic assessment may lead to delays in diagnosis, more advanced [...] Read more.

Gastrointestinal (GI) diseases have a high prevalence throughout the United States. Screening and diagnostic modalities are often expensive and invasive, and therefore, people do not utilize them effectively. Lack of proper screening and diagnostic assessment may lead to delays in diagnosis, more advanced disease at the time of diagnosis, and higher morbidity and mortality rates. Research on the intestinal microbiome has demonstrated that dysbiosis, or unfavorable alteration of organismal composition, precedes the onset of clinical symptoms for various GI diseases. GI disease diagnostic research has led to a shift towards non-invasive methods for GI screening, including chemical-detection tests that measure changes in volatile organic compounds (VOCs), which are the byproducts of bacterial metabolism that result in the distinct smell of stool. Many of these tools are expensive, immobile benchtop instruments that require highly trained individuals to interpret the results. These attributes make them difficult to implement in clinical settings. Alternatively, electronic noses (E-noses) are relatively cheaper, handheld devices that utilize multi-sensor arrays and pattern recognition technology to analyze VOCs. The purpose of this review is to (1) highlight how dysbiosis impacts intestinal diseases and how VOC metabolites can be utilized to detect alterations in the microbiome, (2) summarize the available VOC analytical platforms that can be used to detect aberrancies in intestinal health, (3) define the current technological advancements and limitations of E-nose technology, and finally, (4) review the literature surrounding several intestinal diseases in which headspace VOCs can be used to detect or predict disease. Full article

(This article belongs to the Special Issue Neonatal Microbiome, Intestinal Inflammation, and Necrotizing Enterocolitis (NEC))

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15 pages, 1119 KiB

Open AccessReview

Development of the Neonatal Intestinal Barrier, Microbiome, and Susceptibility to NEC

by Alena Golubkova and Catherine J. Hunter

Microorganisms 2023, 11(5), 1247; https://doi.org/10.3390/microorganisms11051247 - 9 May 2023

Cited by 9 | Viewed by 2811

Abstract

The function of the intestinal barrier is partially dependent on host maturity and the colonization patterns of the microbiome to which it is exposed. Premature birth and stressors of neonatal intensive care unit (NICU)-related support (e.g., antibiotics, steroids, etc.) can alter the host [...] Read more.

The function of the intestinal barrier is partially dependent on host maturity and the colonization patterns of the microbiome to which it is exposed. Premature birth and stressors of neonatal intensive care unit (NICU)-related support (e.g., antibiotics, steroids, etc.) can alter the host internal environment resulting in changes in the intestinal barrier. Pathogenic microbial proliferation and breach of the immature intestinal barrier are proposed to be crucial steps in the development of neonatal diseases such as necrotizing enterocolitis. This article will review the current literature on the intestinal barrier in the neonatal gut, the consequences of microbiome development for this defense system, and how prematurity can influence neonatal susceptibility to gastrointestinal infection. Full article

(This article belongs to the Special Issue Neonatal Microbiome, Intestinal Inflammation, and Necrotizing Enterocolitis (NEC))

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21 pages, 458 KiB

Open AccessReview

The Nonbacterial Microbiome: Fungal and Viral Contributions to the Preterm Infant Gut in Health and Disease

by Adam Wilson, Brett Bogie, Hala Chaaban and Kathryn Burge

Microorganisms 2023, 11(4), 909; https://doi.org/10.3390/microorganisms11040909 - 31 Mar 2023

Cited by 4 | Viewed by 2892

Abstract

The intestinal microbiome is frequently implicated in necrotizing enterocolitis (NEC) pathogenesis. While no particular organism has been associated with NEC development, a general reduction in bacterial diversity and increase in pathobiont abundance has been noted preceding disease onset. However, nearly all evaluations of [...] Read more.

The intestinal microbiome is frequently implicated in necrotizing enterocolitis (NEC) pathogenesis. While no particular organism has been associated with NEC development, a general reduction in bacterial diversity and increase in pathobiont abundance has been noted preceding disease onset. However, nearly all evaluations of the preterm infant microbiome focus exclusively on the bacterial constituents, completely ignoring any fungi, protozoa, archaea, and viruses present. The abundance, diversity, and function of these nonbacterial microbes within the preterm intestinal ecosystem are largely unknown. Here, we review findings on the role of fungi and viruses, including bacteriophages, in preterm intestinal development and neonatal intestinal inflammation, with potential roles in NEC pathogenesis yet to be determined. In addition, we highlight the importance of host and environmental influences, interkingdom interactions, and the role of human milk in shaping fungal and viral abundance, diversity, and function within the preterm intestinal ecosystem. Full article

(This article belongs to the Special Issue Neonatal Microbiome, Intestinal Inflammation, and Necrotizing Enterocolitis (NEC))

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