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Effects of early-life gut microbiota on the neurodevelopmental outcomes of preterm infants: a multi-center, longitudinal observational study in China

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Abstract

To prospectively investigate associations between the features of gut microbiota at the fourth week after birth in preterm infants and neurodevelopment from 1 month of corrected age to 6 months of corrected age (MCA). Seventy-seven preterm infants were recruited from three NICUs of three tertiary hospitals between Apr 2021 to Sep 2022. Stool samples were collected during the fourth week after birth. Illumina MiSeq high-throughput sequencing technology was used to detect the composition and diversity of gut microbiota. Neurodevelopment assessments of preterm infants were conducted at 1, 3, and 6 MCA using the Ages and Stages Questionnaire, the third edition (ASQ-3). Spearman correlation, a generalized linear mixed model (GLMM), and permutational multivariate analysis of variance (PERMANOVA) analysis were used to horizontally and prospectively explore the associations between gut microbial and ASQ-3 dimension scores at each time point. The GLMM showed no significant associations between the alpha diversity and neurodevelopmental trajectory from 1 to 6 MCA. The beta diversity was significantly associated with gross motor scores at 1, 3, and 6 MCA (R2 = 0.067, p = 0.001; R2 = 0.039, p = 0.020; R2 = 0.031, p = 0.047); communication scores at 3 MCA (R2 = 0.030, p = 0.040); and fine motor scores at 6 MCA (R2 = 0.035, p = 0.022). After adjusting for covariates, the GLMM showed that the relative abundance of Klebsiella was negatively associated with gross motor score trajectory from 1 to 6 MCA (β =  − 1.449; 95% CI, − 2.275 to − 0.572; p = 0.001), while the relative abundance of Lactobacillus displayed a positive association (β = 1.421; 95% CI, 0.139 to 2.702; p = 0.030). Moreover, the relative abundance of Streptococcus was negatively associated with fine motor trajectory from 1 to 6 MCA (β =  − 1.669; 95% CI, − 3.305 to − 0.033; p = 0.046).

Conclusion: Our results suggest a possible association between the neonatal gut microbial diversity; the relative abundance of Klebsiella, Streptococcus, and Lactobacillus; and neurodevelopment from 1 to 6 MCA. In the future, clinical staff can focus on the window period of gut microbiota colonization, and implement probiotics targeted at the dominant genera to improve the neurodevelopment of preterm infants.

What is Known:

• In the fields of biology and medicine, current studies suggest that gut microbiota may play an important role in the critical window period of neurodevelopment through the gut-brain axis pathway.

• Extensive preclinical research has implied the vital role of the initial gut colonization in the long-term neurodevelopment of children.

What is New:

• The early-life gut microbiota was associated with neurodevelopment in preterm infants within 6 months of corrected age (MCA).

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Data availability

The raw sequence data of gut microbiota from this study were uploaded to the NCBI database to generate SRA numbers, which are processed, processing ID “SUB13569272”. Once the SRA number is obtained, the data will be released on 2024–01-30 with a Doi link.

Abbreviations

ASQ:

The Ages and Stages Questionnaire

DD:

Developmental delay

GLMM:

Generalized linear mixed model

MCA:

Months of corrected age

NICU:

Neonatal intensive care unit

PERMANOVA:

Permutational multivariate analysis of variance

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Acknowledgements

The authors sincerely appreciate the support from the staff of Renmin Hospital of Wuhan University, Zhongnan Hospital of Wuhan University, and Xiaogan Central Hospital and the participation of preterm families.

Funding

This work was supported by the National College Student Innovation and Entrepreneurship Project in China (Grant numbers: 202110486089).

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Author notes

  1. Dan Zhang and Yancong Lan contributed equally to this work and were considered co-first authors.

Authors and Affiliations

  1. School of Nursing, Wuhan University, No. 115, Donghu Road, Wuchang District, Wuhan, 430071, People’s Republic of China

    Dan Zhang, Yancong Lan, Jun Zhang, Mi Cao & Xinyi Yang

  2. Department of Pediatrics, Women and Children’s Hospital, Zhongnan Hospital, Wuhan University, Wuhan, People’s Republic of China

    Xia Wang

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  1. Dan Zhang
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Contributions

All authors contributed to the study conceptualization and design. Methodology, investigation, formal analysis, and writing—original draft preparation were mainly performed by DZ. Writing—reviewing, editing and article revisions were performed by YC L. Methodology, supervision, and project administration were performed by JZ. Investigation and data curation were also performed by MC, XY Y, and XW. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Jun Zhang.

Ethics declarations

Ethics approval

This is an observational study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of University of the Medical Department of University (Approval ID: WHU-LFMD-IRB2022011).

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Written informed consent was obtained from the parents.

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The authors affirm that human research participants provided informed consent for publication.

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The authors declare no competing interests.

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Communicated by Daniele De Luca

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Zhang, D., Lan, Y., Zhang, J. et al. Effects of early-life gut microbiota on the neurodevelopmental outcomes of preterm infants: a multi-center, longitudinal observational study in China. Eur J Pediatr 183, 1733–1740 (2024). https://doi.org/10.1007/s00431-024-05423-8

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