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  • Clinical Research Article
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Assessment trial of the effect of enteral insulin on the preterm infant intestinal microbiota

Pediatric Research volume 95, pages 1117–1123 (2024)Cite this article

Abstract

Background

Insulin might be associated with changes in infant gastrointestinal microbiota. The objective of this randomized controlled trial was to assess the efficacy of two doses of recombinant human(rh) enteral insulin administration compared to placebo in intestinal microbiota.

Methods

19 preterm patients were recruited at the NICU of La Paz University Hospital (Madrid, Spain). Subjects received 2000 µIU of rh enteral insulin/ml(n = 8), 400 µIU of rh enteral insulin/ml(n = 6) or placebo(n = 5) for 28 days administered once per day. Extracted DNA from fecal samples collected at the beginning and end of treatment were analyzed. The 16S rRNA V4 region was amplified and sequenced in a Miseq(Illumina®) sequencer using 2 × 250 bp paired end. Resulting reads were filtered and analyzed using Qiime2 software. Metabolic activity was assessed by GC.

Results

Gestational age and birth weight did not differ between groups. At the phylum level, both insulin treated groups increased the relative abundance of Bacillota, while Pseudomonadota decreased. No change was observed in infants receiving placebo. At the genus level, insulin at both doses showed enriching effects on Clostridium. We found a significant increase in concentrations of fecal propionate in both rh insulin treated groups.

Conclusion

Rh insulin may modify neonatal intestinal microbiota and SCFAs in preterm infants.

Impact statement

  • Decrease of Pseudomonadota (former Proteobacteria phylum) and increase of Bacillota (former Firmicutes phylum) obtained in this study are the changes observed previously in low-risk infants for NEC.

  • The administration of recombinant enteral insulin may modify the microbiota of preterm new-borns and SCFAs.

  • Modulation of the microbiota may be a mechanism whereby insulin contributes to neonatal intestinal maturation and/or protection.

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Fig. 1: Microbial diversity.
Fig. 2: Species richness.
Fig. 3: Microbiome analyses at the phylum level.
Fig. 4: Microbiome analyses at the genus level.
Fig. 5: Determination of short-chain and branched-chain fatty acids in feces.
Fig. 6: Heatmap of the Pearson correlation coefficients among various short-chain fatty acids (SCFA) and between SCFA and the predominant bacterial Phyla and Families (generated using GraphPad Prism).

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Data availability

All data generated or analyzed during this study are included in this published article [and its supplementary information files].

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Acknowledgements

We wish to particularly acknowledge and thank the study participants and their families for their contribution to the study and the Biobank IdiPAZ (PT20/00004) integrated in the Spanish National Biobanks Network for their collaboration. The trial was previously funded by Nutrinia Ltd. (Ramat Gan, Israel), which acted as sponsor of the study at that time (currently, Elgan Pharma (Nazareth, Israel) acts as the sponsor). The authors had final responsibility for the design and conduct of this study. The sponsor had no role in the collection, management, analysis, and interpretation of the data. The sponsor was allowed to review and comment on the manuscript. The final version and decision to publish was made by the authors without contractual limits.

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Authors and Affiliations

  1. Department of Neonatology, La Paz University Hospital Health Research Institute, Madrid, Spain

    Bárbara Moreno-Sanz, Esperanza Escribano, Marta Cabrera Lafuente, María Teresa Montes, Rocío Amorós & Miguel Saenz de Pipaon

  2. Department of Microbiology, La Paz University Hospital Health Research Institute, Madrid, Spain

    Fernando Lázaro-Perona & Jesús Mingorance

  3. Department of Microbiology and Biochemistry of Dairy Products, IPLA-CSIC, Villaviciosa, Spain

    Silvia Arboleya & Miguel Gueimonde

  4. Diet, Microbiota and Health Group, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain

    Silvia Arboleya

  5. Universidad Autonoma de Madrid Madrid, Madrid, Spain

    Miguel Saenz de Pipaon

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  1. Bárbara Moreno-Sanz
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Contributions

B.M.-S.: Methodology, Validation, Formal Analysis, Investigation, Resources, Data Curation, Writing and Original Draft, Project Administration. F.L.P: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Resources, Data Curation, Writing, and Original Draft. E.E.: Methodology, Investigation, Data curation, Writing and Review and Editing, Supervision. M.C.L.: Conceptualization, Methodology, Investigation, Data curation, Writing and Review and Editing, Supervision. M.T.M..: Methodology, Investigation. R.A.: Methodology, Investigation. S.A.: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Resources, Writing, and Original Draft. M.G.: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Resources, Writing, and Original Draft. J.M.: Methodology, Validation, Formal analysis, Investigation, Resources, Writing, and Review and Editing. M.S.d.P.: Conceptualization, Methodology, Writing, and Review and Editing, Supervision, Funding Acquisition.

Corresponding author

Correspondence to Miguel Saenz de Pipaon.

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Competing interests

E.E.P., M.C.L., and M.S.d.P. reported receiving grants from Nutrinia Ltd during the conduct of the study. M.S.d.P. reported receiving lecture fees and travel reimbursements from Nutrinia Ltd during the conduct of the study. No other disclosures were reported.

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Moreno-Sanz, B., Lázaro-Perona, F., Escribano, E. et al. Assessment trial of the effect of enteral insulin on the preterm infant intestinal microbiota. Pediatr Res 95, 1117–1123 (2024). https://doi.org/10.1038/s41390-023-02917-3

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