SEARCHSYSTEMATIC_REVIEWneonatology, pediatrics

systematic_review·neonatology, pediatrics, gastroenterology, nutrition, microbiology·PMC10026866

A systematic review of associations between gut microbiota composition and growth failure in preterm neonates

Gut Microbes · 3 authors, 2 centres

AI SUMMARY

FIDELITY 100%

POPULATIONPreterm neonates (gestational age < 37 weeks, including extremely preterm < 28 weeks and very low birth weight < 1500 g)

INTERVENTIONNot applicable (systematic review of observational and interventional studies; two RCTs tested enhanced parenteral nutrition or probiotic Limosilactobacillus reuteri DSM 17938)

COMPARISONInfants with appropriate postnatal growth versus those with growth failure (variably defined across studies)

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TL;DR

This systematic review of 14 studies found that while each study reported significant associations between gut microbiota composition and growth in preterm neonates, there was striking inconsistency across studies regarding which microbial taxa were linked to growth or growth failure. The most commonly reported association was an increased abundance of Staphylococcus in infants with growth failure, but overall, no single microbial feature was consistently associated with growth across studies. The authors highlight that variability in growth definitions, sample timing, and statistical methods undermines reproducibility and call for standardized protocols and preregistration in future research.

Full summary

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**Background** More than 50,000 premature very low birth weight infants are born annually in the US, and half develop postnatal growth failure of largely unknown etiology. Preclinical models have established causal links between gut microbiota and growth: germ-free mice colonized with microbiota from malnourished children show poor growth, and microbial metabolites such as short-chain fatty acids (SCFAs) promote bone growth and weight gain via mechanisms involving IGF-1, Wnt10b, and regulatory T cells. Human milk oligosaccharides (HMOs) are fermented by gut bacteria into absorbable energy and growth-promoting metabolites, and HMO-deficient breast milk from mothers of malnourished infants fails to support weight gain in gnotobiotic animals unless bacteria are present. Despite these mechanistic insights, no microbiota-based biomarkers or therapies have been translated to the neonatal intensive care unit. This systematic review aimed to identify consistent associations between gut microbiota composition and postnatal growth in human preterm neonates.

**Methods** The review was registered in PROSPERO (CRD42022361402) and followed PRISMA guidelines. Four databases (PubMed, Web of Science, Cochrane Library, Medline/Ovid) were searched in September 2022. Inclusion criteria: prospective, retrospective, longitudinal, cross-sectional, case-control, or RCT designs studying preterm infants during their newborn hospitalization, evaluating gut microbiome composition and postnatal growth, and assessing microbiota-growth associations. Exclusion criteria: reviews, meta-analyses, animal/in vitro studies, non-preterm infants, protocols, conference abstracts, non-English studies, and studies lacking microbiota-growth analyses. Of 860 records identified, 14 met inclusion criteria. Data extracted included author, year, location, study type, sample size, gestational age, birth weight, diet, sample collection methods, sequencing strategy, and all reported microbiota-growth associations. Because of methodological heterogeneity, a quantitative meta-analysis was precluded; instead, qualitative synthesis was performed using Venn diagrams. Additionally, an exploratory secondary analysis was conducted on a previously published dataset of 245 longitudinally collected fecal samples from 125 preterm infants (<32 weeks GA, <1500 g) to test how 16 different definitions of growth failure (combining 8 growth metrics × 2 age metrics [PMA vs. postnatal week]) influenced taxonomic associations.

**Key Results** The 14 studies included 2 RCTs (one testing enhanced parenteral nutrition, one testing L. reuteri DSM 17938) and 12 observational studies (10 prospective cohorts, 1 nested case-control, 1 retrospective cohort). Geographic distribution: 5 in China, 4 in Europe, 4 in the US, 1 in Brazil. Gestational ages ranged from <28 weeks to <37 weeks; birth weights from <1000 g to <2500 g. Thirteen studies used 16S rRNA gene sequencing (various V regions); one used qPCR. None used whole metagenomic sequencing.

Across studies, Shannon diversity was positively correlated with growth in three studies and negatively correlated in three studies. Microbiota maturity was positively associated with growth in one study and negatively in another. At the taxon level, 58 distinct taxa were reported as significantly associated with growth. The most consistent finding was a negative association between Staphylococcus abundance and growth (4 studies). Streptococcus was positively associated with growth in 5 studies but negatively associated in others. For the 32 taxa positively associated with growth, 26 (81%) were reported in only a single study; for the 34 taxa negatively associated with growth, 30 (88%) were reported in only a single study. Taxa with conflicting directionality across studies included Enterobacteriaceae, Streptococcaceae, Acinetobacter, Bacteroides, Enterobacter, Enterococcus, Serratia, and Streptococcus.

The secondary analysis of 245 samples demonstrated that changing the definition of growth failure dramatically altered which taxa were significantly associated with growth. For example, defining growth failure as head circumference velocity <1 cm/week classified 87% of samples as growth failure, whereas change in head circumference z-score > −1.2 classified only 11% as growth failure. No single taxonomic feature was consistently associated with growth across all 16 definitions. At the phylum level, Proteobacteria positively associated with growth in 4/16 definitions, and Bacteroidetes negatively associated with growth in 7/16 definitions. Genera negatively associated across multiple definitions included Staphylococcus, Prevotella, and Streptococcus. Genera positively associated across multiple definitions included Veillonella, Enterococcus, Clostridium sensu stricto, Negativicoccus, Acinetobacter, and Clostridium cluster XI.

**Clinical Implications** The lack of consistent microbiota-growth associations across studies precludes the identification of clinically actionable microbial biomarkers or therapeutic targets for growth failure in preterm neonates. The authors identify five key recommendations: (1) preregister all study protocols including statistical plans; (2) capture comprehensive metadata on confounders (mode of delivery, gestational age, sex, antibiotics, diet, comorbidities); (3) report all tested associations across multiple growth definitions in supplemental materials; (4) consider alternatives to 16S sequencing such as whole metagenomic sequencing with metabolomics; and (5) use standardized reporting guidelines such as the STORMS checklist. The authors emphasize that the wide variability in growth failure definitions—ranging from weight <3rd or <10th percentile at 36 weeks PMA, to negative change in weight z-score, to weekly weight gain rate <6th percentile—is a major barrier to cross-study comparability. They note that the Fenton growth chart-based definition of weight <10th percentile at 36 weeks PMA has not been validated to predict adverse outcomes and does not account for proportional growth or genetic potential. Until standardized definitions and methodologies are adopted, the translation of microbiome discoveries into clinical interventions for neonatal growth failure will remain elusive.

PICO

PPOPULATION

Preterm neonates (gestational age < 37 weeks, including extremely preterm < 28 weeks and very low birth weight < 1500 g)

IINTERVENTION

Not applicable (systematic review of observational and interventional studies; two RCTs tested enhanced parenteral nutrition or probiotic Limosilactobacillus reuteri DSM 17938)

OOUTCOME

Associations between gut microbiota composition (alpha diversity, beta diversity, relative abundance of taxa) and postnatal growth metrics (weight, length, head circumference z-scores, percentiles, velocities)

STUDY TYPE

systematic_review

SPECIALTY

neonatology

SUMMARISED BY

AI pipeline

FIDELITY CHECK

100% · A

ORIGINAL PAPER

PMC10026866

A systematic review of associations between gut microbiota composition and growth failure in preterm neonates

Gut Microbes

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ABSTRACT

ABSTRACT Growth failure is among the most prevalent and devastating consequences of prematurity. Up to half of all extremely preterm neonates struggle to grow despite modern nutrition practices. Although elegant preclinical models suggest causal roles for the gut microbiome, these insights have not yet translated into biomarkers that identify at-risk neonates or therapies that prevent or treat growth failure. This systematic review aims to identify features of the neonatal gut microbiota that are positively or negatively associated with early postnatal growth. We identified 860 articles, of which 14 were eligible for inclusion. No two studies used the same definitions of growth, ages at stool collection, and statistical methods linking microbiota to metadata. In all, 58 different taxa were associated with growth, with little consensus among studies. Two or more studies reported positive associations with Enterobacteriaceae, Bacteroides , Bifidobacterium , Enterococcus , and Veillonella , and negative associations with Citrobacter, Klebsiella , and Staphylococcus . Streptococcus was positively associated with growth in five studies and negatively associated with growth in three studies. To gain insight into how the various definitions of growth could impact results, we performed an exploratory secondary analysis of 245 longitudinally sampled preterm infant stools, linking microbiota composition to multiple clinically relevant definitions of neonatal growth. Within this cohort, every definition of growth was associated with a different combination of microbiota features. Together, these results suggest that the lack of consensus in defining neonatal growth may limit our capacity to detect consistent, meaningful clinical associations that could be leveraged into improved care for preterm neonates. KEYWORDS: Growth failure, gut microbiome, malnutrition, neonate, postnatal growth, preterm infant, underweight

CITATION EXPORT

Larissa L Neves, Amy B Hair, Geoffrey A Preidis. A systematic review of associations between gut microbiota composition and growth failure in preterm neonates. Gut Microbes. (2023). https://doi.org/10.1080/19490976.2023.2190301

AUTHORS

3 · 2 CENTRES

Larissa L Neves, Amy B Hair, Geoffrey A Preidis

aDivision of Gastroenterology, Hepatology, & Nutrition, Department of Pediatrics, Baylor College of Medicine and Texas Children’s Hospital, Houston, TX, USA
bDivision of Neonatology, Department of Pediatrics, Baylor College of Medicine and Texas Children’s Hospital, Houston, TX, USA