The preterm gut microbiome is a complex dynamic community influenced by genetic and environmental factors and is implicated in the pathogenesis of necrotising enterocolitis (NEC) and sepsis. We aimed ...to explore the longitudinal development of the gut microbiome in preterm twins to determine how shared environmental and genetic factors may influence temporal changes and compared this to the expressed breast milk (EBM) microbiome. Stool samples (n = 173) from 27 infants (12 twin pairs and 1 triplet set) and EBM (n = 18) from 4 mothers were collected longitudinally. All samples underwent PCR-DGGE (denaturing gradient gel electrophoresis) analysis and a selected subset underwent 454 pyrosequencing. Stool and EBM shared a core microbiome dominated by Enterobacteriaceae, Enterococcaceae, and Staphylococcaceae. The gut microbiome showed greater similarity between siblings compared to unrelated individuals. Pyrosequencing revealed a reduction in diversity and increasing dominance of Escherichia sp. preceding NEC that was not observed in the healthy twin. Antibiotic treatment had a substantial effect on the gut microbiome, reducing Escherichia sp. and increasing other Enterobacteriaceae. This study demonstrates related preterm twins share similar gut microbiome development, even within the complex environment of neonatal intensive care. This is likely a result of shared genetic and immunomodulatory factors as well as exposure to the same maternal microbiome during birth, skin contact and exposure to EBM. Environmental factors including antibiotic exposure and feeding are additional significant determinants of community structure, regardless of host genetics.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Necrotising enterocolitis (NEC) is a devastating intestinal disease primarily affecting preterm infants. The underlying mechanisms are poorly understood: mother's own breast milk (MOM) is protective, ...possibly relating to human milk oligosaccharide (HMO) and infant gut microbiome interplay. We investigated the interaction between HMO profiles and infant gut microbiome development and its association with NEC.
We performed HMO profiling of MOM in a large cohort of infants with NEC (n=33) with matched controls (n=37). In a subset of 48 infants (14 with NEC), we also performed longitudinal metagenomic sequencing of infant stool (n=644).
Concentration of a single HMO, disialyllacto-N-tetraose (DSLNT), was significantly lower in MOM received by infants with NEC compared with controls. A MOM threshold level of 241 nmol/mL had a sensitivity and specificity of 0.9 for NEC. Metagenomic sequencing before NEC onset showed significantly lower relative abundance of
and higher relative abundance of
in infants with NEC. Longitudinal development of the microbiome was also impacted by low MOM DSLNT associated with reduced transition into preterm gut community types dominated by
spp and typically observed in older infants. Random forest analysis combining HMO and metagenome data before disease accurately classified 87.5% of infants as healthy or having NEC.
These results demonstrate the importance of HMOs and gut microbiome in preterm infant health and disease. The findings offer potential targets for biomarker development, disease risk stratification and novel avenues for supplements that may prevent life-threatening disease.
Aim
This narrative review summarises the benefits of maternal breastmilk to both the infant and the mother, specifically the benefits that relate to modification of the infant microbiome, and how ...this might vary in the preterm infant.
Methods
We used PubMed to primarily identify papers, reviews, case series and editorials published in English until May 2020. Based on this, we report on the components of breastmilk, their associated hypothesised benefits and the implications for clinical practice.
Results
Breastmilk is recommended as the exclusive diet for newborn infants because it has numerous nutritional and immunological benefits. Additionally, exposure to the maternal breastmilk microbiome may confer a lasting effect on gut health. In the preterm infant, breastmilk is associated with a significant reduction in necrotising enterocolitis, an inflammatory gastrointestinal disease and reduction in other key morbidities, together with improved neurodevelopmental outcomes.
Conclusion
These impacts have long‐term benefits for the child (and the mother) even after weaning. This benefit is likely due, in part, to modification of the infant gut microbiome by breastmilk microbes and bioactive components, and provide potential areas for research and novel therapies in preterm and other high‐risk infants.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Bionutrients (or immunonutrients) are dietary components present in milk, or supplements that could be added to milk diets, that impact health and disease. With few exceptions, most of these are ...present in human breastmilk and the majority are also present in amniotic fluid.
Bionutrients can be proteins and peptides including enzymes, hormones, immunoglobulins, and growth factors and can also be molecules such as human milk oligosaccharides, amino acids, or lipids such as docosahexaenoic acid. Many of these have ancient origins, are found in other species, and existed before mammalian lactation evolved. Bionutrients may act in diverse ways when administered enterally: they may impact gut bacterial communities or epithelial cell metabolism, or they may pass into the lamina propria where they interact with the gut and systemic immune systems. Clinical trials have often used bovine analogs such as lactoferrin or may use artificially synthesized or recombinant compounds including insulin, bile salt stimulated lipase, or oligosaccharides.
Challenges arise because the bioactivity of proteins, such as lactoferrin, may be affected by processing and pasteurization meaning that the impacts of commercial products may differ. The challenge of determining the optimal bioactivity of any single preparation may be even greater in complex compounds such as milk fat globule membrane. It is also possible that bioactivity is affected by the milk matrix, that is, may differ between formula and human milk.
Finally, it is important to appreciate that nutrients do not function in isolation, and most will not act like drugs, that is, they may take several days or longer to exert an affect.
· Breastmilk contains high concentrations of bionutrients and provides more than macro- and micronutrients.. · Bionutrients can be proteins (e.g. enzymes, hormones, or immunoglobulins) or molecules (e.g. human milk oligosaccharides or amino acids).. · Bionutrients can be added to milk feeds but high quality trials are needed..
The thick mucus layer of the gut provides a barrier to infiltration of the underlying epithelia by both the normal microbiota and enteric pathogens. Some members of the microbiota utilise mucin ...glycoproteins as a nutrient source, but a detailed understanding of the mechanisms used to breakdown these complex macromolecules is lacking. Here we describe the discovery and characterisation of endo-acting enzymes from prominent mucin-degrading bacteria that target the polyLacNAc structures within oligosaccharide side chains of both animal and human mucins. These O-glycanases are part of the large and diverse glycoside hydrolase 16 (GH16) family and are often lipoproteins, indicating that they are surface located and thus likely involved in the initial step in mucin breakdown. These data provide a significant advance in our knowledge of the mechanism of mucin breakdown by the normal microbiota. Furthermore, we also demonstrate the potential use of these enzymes as tools to explore changes in O-glycan structure in a number of intestinal disease states.
Late onset sepsis (LOS) in preterm infants is associated with considerable morbidity and mortality. While studies have implicated gut bacteria in the aetiology of the disease, functional analysis and ...mechanistic insights are generally lacking. We performed temporal bacterial (n = 613) and metabolomic (n = 63) profiling on extensively sampled stool from 7 infants with LOS and 28 matched healthy (no LOS or NEC) controls.
The bacteria isolated in diagnostic blood culture usually corresponded to the dominant bacterial genera in the gut microbiome. Longitudinal changes were monitored based on preterm gut community types (PGCTs), where control infants had an increased number of PGCTs compared to LOS infants (P = 0.011). PGCT 6, characterised by Bifidobacteria dominance, was only present in control infants. Metabolite profiles differed between LOS and control infants at diagnosis and 7 days later, but not 7 days prior to diagnosis. Bifidobacteria was positively correlated with control metabolites, including raffinose, sucrose, and acetic acid.
Using multi-omic analysis, we show that the gut microbiome is involved in the pathogenesis of LOS. While the causative agent of LOS varies, it is usually abundant in the gut. Bifidobacteria dominance was associated with control infants, and the presence of this organism may directly protect, or act as a marker for protection, against gut epithelial translocation. While the metabolomic data is preliminary, the findings support that gut development and protection in preterm infants is associated with increased in prebiotic oligosaccharides (e.g. raffinose) and the growth of beneficial bacteria (e.g. Bifidobacterium).
Development of the gut microbiome in early life Ahearn‐Ford, Sinead; Berrington, Janet E.; Stewart, Christopher J.
Experimental physiology,
1 May 2022, Volume:
107, Issue:
5
Journal Article
Peer reviewed
Open access
New Findings
What is the topic of this review?
The importance of the early life gut microbiome, with a focus on preterm infants and microbially related diseases. Current techniques to study the ...preterm gut microbiome are appraised, and the potential of recent methodological advancements is discussed.
What advances does it highlight?
Recent findings in the field achieved by the application of advanced technologies, the applicability of intestinally derived organoid models to study host–microbiome interactions in the preterm gut, and recent developments in enhancing the physiological relevance of such models. Preterm intestinally derived organoids may provide novel insights into the mechanisms underlying preterm disease, as well as diagnosis and treatment opportunities. These models have huge translational potential, offering a step towards precision medicine.
Accumulating evidence affirms the importance of the gut microbiome in both health and disease. In early life, there exists a critical period in which the composition of gut microbes is particularly malleable and subject to a wide range of influencing factors. Disturbances to microbial communities during this time may be beneficial or detrimental to short and long‐term health outcomes. For infants born prematurely, naïve immune systems, immature gastrointestinal tracts and additional clinical needs put this population at high risk of abnormal microbial colonisation, resulting in increased susceptibility to diseases including necrotising enterocolitis (NEC) and late‐onset sepsis (LOS). Traditional cell culture methods, gnotobiotic animals, molecular sequencing techniques (16S rRNA gene sequencing and metagenomics) and advanced ‘omics’ technologies (transcriptomics, proteomics and metabolomics) have been fundamental in exploring the associations between diet, gut microbes, microbial functions and disease. Despite significant investment and ongoing research efforts, prevention and treatment strategies in NEC and LOS remain limited. Recent endeavours have focused on searching for new, more physiologically relevant models to simulate the preterm intestine. Preterm intestinally derived organoids represent a promising in vitro approach in the study of host–microbiome interactions in the preterm infant gut, offering new and exciting possibilities in this field.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
To compare outcomes after surgically managed necrotising enterocolitis (NEC) and focal intestinal perforation (FIP) in infants <32 weeks requiring transfer to or presenting in a single surgical ...centre.
Retrospective review of transferred and inborn NEC or FIP, from January 2013 to December 2020.
107 transfers with possible NEC or FIP contributed 92 cases (final diagnoses NEC (75) and FIP (17)); 113 inborn cases: NEC (84) and FIP (29).
In infants with a final diagnosis of NEC, medical management after transfer was as common as when inborn (41% TC vs 54% p = 0.12). Unadjusted all-cause mortality was lower in inborn NEC (19% vs 27%) and FIP (10% vs 29%). In infants undergoing surgery unadjusted mortality attributable to NEC or FIP was lower if inborn (21% vs 41% NEC, 7% vs 24% FIP). In regression analysis of surgically treated infants, being transferred was associated with increased all-cause mortality (OR 2.55 (1.03–6.79)) and mortality attributable to NEC or FIP (OR 4.89 (1.80–14.97)).
These data require replication, but if confirmed, suggest that focusing care for infants at highest risk of developing NEC or FIP in a NICU with on-site surgical expertise may improve outcomes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
9.
Deaths in Preterm Infants: Changing Pathology Over 2 Decades Berrington, Janet Elizabeth, MD; Hearn, Richard Iain, MBChB; Bythell, Mary, MSc ...
The Journal of pediatrics,
2012, January 2012, 2012-Jan, 2012-01-00, 20120101, Volume:
160, Issue:
1
Journal Article
Peer reviewed
Open access
Objective To establish how cause of death for live-born preterm infants (24-31 weeks gestation) has changed in a single large UK population over 2 decades. Study design This was an interrogation of a ...population-based survey of >680 000 live births (between 1988 and 2008) for deaths in the first postnatal year. We collected cause of death grouped into major etiologies: respiratory, infection, malformation, necrotizing enterocolitis (NEC), and other. Data were analyzed in three 7-year epochs and 2 gestational groups (<27 and 28-31 weeks). Numbers, rates per 1000 live births, and proportional contributions to each epoch were analyzed. Results A total of 1504 deaths occurred. The infants who died had a median gestational age of 26 weeks (IQR, 25-28 weeks) and a median birth weight of 880 g (IQR, 700-1170 g). The number of deaths decreased with each later epoch (from 671 to 473 and then to 360), as did the proportion of deaths from respiratory causes (64% to 62% and then to 49%). The proportion of deaths occurring after 40 weeks postmenstrual age remained stable across the 3 epochs (8.8%, 8%, and 8%). Deaths from infection and NEC increased with time (from 11% to 13% and then to 21%), as did median time to death (from 2.7 to 3.8 days). Conclusion Infection and NEC are increasingly prevalent causes of death in preterm infants.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Review of age of onset of necrotising enterocolitis (NEC) and focal intestinal perforation (FIP) in very preterm (≤32 weeks) and/or very low birthweight (VLBW, ≤1500 g) infants.
Preregistered review ...undertaken according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses in July 2021 and updated October 2021.
MEDLINE/ PubMed, Embase, CINAHL and Cochrane Central Register of Controlled Trials.
Eligible studies reported age of onset of NEC and/or FIP in randomised controlled trials of >200 or observational studies of >500 infants.
Titles/abstracts were screened; eligible articles underwent data extraction. Age of onset as day of life (DOL) and/or corrected gestational age (CGA) were extracted alongside study information, such as NEC definition, included population, intervention, location and dates studied. Weighted means were used to compare onset by birth gestation, study type, NEC definition, trial intervention, location and dates studied. Comparison was done by Mann-Whitney U test or one-way analysis of variance.
Of the 747 screened studies 188 were eligible. Removal of duplicates, studies without onset data and ineligible populations left 10 RCTs and 14 observational studies contributing 51 NEC cohorts; 49 reported onset DOL and 14 CGA. 2984 cases of NEC had average DOL onset of 16.7 (15.5 in RCTs, 16.9 in observational studies), and CGA onset of 30.1 weeks. Gestation did not impact DOL onset. No other demographic feature impacted NEC onset. Few studies included data on FIP.
Average onset of NEC in exclusively very preterm/very low birthweight infants is in the third week of life and unlike in cohorts including more mature or heavier infants is not impacted by birth gestation.
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