Transplantation of maternal intestinal flora to the newborn after elective cesarean section (SECFLOR): study protocol for a double blinded randomized controlled trial

Noora Carpén, Petter Brodin, Willem M de Vos, Anne Salonen, Kaija-Leena Kolho, Sture Andersson, Otto Helve, Noora Carpén, Petter Brodin, Willem M de Vos, Anne Salonen, Kaija-Leena Kolho, Sture Andersson, Otto Helve

Abstract

Background: A complication of elective cesarean section (CS) delivery is its interference with the normal intestinal colonization of the infant, affecting the immune and metabolic signaling in early life- a process that has been associated with long-term morbidity, such as allergy and diabetes. We evaluate, in CS-delivered infants, whether the normal intestinal microbiome and its early life development can be restored by immediate postnatal transfer of maternal fecal microbiota (FMT) to the newborn, and how this procedure influences the maturation of the immune system.

Methods: Sixty healthy mothers with planned elective CS are recruited and screened thoroughly for infections. A maternal fecal sample is taken prior to delivery and processed according to a transplantation protocol. After double blinded randomization, half of the newborns will receive a diluted aliquot of their own mother's stool orally administered in breast milk during the first feeding while the other half will be similarly treated with a placebo. The infants are clinically followed, and fecal samples are gathered weekly until the age of 4 weeks, then at the ages of 8 weeks, 3, 6, 12 and 24 months. The parents fill in questionnaires until the age of 24 months. Blood samples are taken at the age of 2-3 days and 3, 6, 12 and 24 months to assess development of major immune cell populations and plasma proteins throughout the first years of life.

Discussion: This is the first study to assess long-time effects on the intestinal microbiome and the development of immune system of a maternal fecal transplant given to term infants born by CS.

Trial registration: ClinicalTrials.gov NCT04173208 , registration date 21.11.2019.

Keywords: Cesarean section; Development of immune system; Microbiome; Newborn; Oral fecal transplant.

Conflict of interest statement

No competing interest to be declare.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Flowchart of SECFLOR Main Study

References

    1. Olszak T, et al. Microbial exposure during early life has persistent effects on natural killer T cell function. Science. 2012;336(6080):489–493.
    1. Olin A, et al. Stereotypic immune system development in newborn children. Cell. 2018;174(5):1277–1292.e14.
    1. Collado MC, et al. Gut microbiota: a source of novel tools to reduce the risk of human disease? Pediatr Res. 2015;77(1–2):182–188.
    1. Kalliomäki M, et al. Distinct patterns of neonatal gut microflora in infants in whom atopy was and was not developing. J Allergy Clin Immunol. 2001;107(1):129–134.
    1. Abrahamsson TR, et al. Low diversity of the gut microbiota in infants with atopic eczema. J Allergy Clin Immunol. 2012;129(2):434-40–440.e1-2.
    1. Vatanen T, et al. Variation in microbiome LPS immunogenicity contributes to autoimmunity in humans. Cell. 2016;165(6):1551.
    1. Sevelsted A, et al. Cesarean section and chronic immune disorders. Pediatrics. 2015;135(1):e92–e98.
    1. Andersen V, et al. Caesarean delivery and risk of chronic inflammatory diseases (inflammatory bowel disease, rheumatoid arthritis, coeliac disease, and diabetes mellitus): a population based registry study of 2,699,479 births in denmark during 1973–2016. Clin Epidemiol. 2020;12:287–293.
    1. Miller JE, et al. Mode of birth and risk of infection-related hospitalisation in childhood: a population cohort study of 7.17 million births from 4 high-income countries. PLoS Med. 2020;17(11):e1003429.
    1. Reyman M, et al. Impact of delivery mode-associated gut microbiota dynamics on health in the first year of life. Nat Commun. 2019;10(1):4997.
    1. de Weerth C, et al. Intestinal microbiota of infants with colic: development and specific signatures. Pediatrics. 2013;131(2):e550–e558.
    1. Korpela K, de Vos WM. Early life colonization of the human gut: microbes matter everywhere. Curr Opin Microbiol. 2018;44:70–78.
    1. Bäckhed F, et al. Dynamics and stabilization of the human gut microbiome during the first year of life. Cell Host Microbe. 2015;17(5):690–703.
    1. Ferretti P, et al. Mother-to-infant microbial transmission from different body sites shapes the developing infant gut microbiome. Cell Host Microbe. 2018;24(1):133–145.e5.
    1. Korpela K, et al. Selective maternal seeding and environment shape the human gut microbiome. Genome Res. 2018;28(4):561–568.
    1. Shao Y, et al. Stunted microbiota and opportunistic pathogen colonization in caesarean-section birth. Nature. 2019;574(7776):117–121.
    1. Salminen S, et al. Influence of mode of delivery on gut microbiota composition in seven year old children. Gut. 2004;53(9):1388–1389.
    1. Jakobsson HE, et al. Decreased gut microbiota diversity, delayed Bacteroidetes colonisation and reduced Th1 responses in infants delivered by caesarean section. Gut. 2014;63(4):559–566.
    1. Zimmermann P, Curtis N. The influence of the intestinal microbiome on vaccine responses. Vaccine. 2018;36(30):4433–4439.
    1. Harris VC, et al. significant correlation between the infant gut microbiome and rotavirus vaccine response in Rural Ghana. J Infect Dis. 2017;215(1):34–41.
    1. Harris V, et al. Rotavirus vaccine response correlates with the infant gut microbiota composition in Pakistan. Gut Microbes. 2018;9(2):93–101.
    1. Korpela K, et al. Probiotic supplementation restores normal microbiota composition and function in antibiotic-treated and in caesarean-born infants. Microbiome. 2018;6(1):182–182.
    1. Korpela K, et al. Fucosylated oligosaccharides in mother's milk alleviate the effects of caesarean birth on infant gut microbiota. Sci Rep. 2018;8(1):13757.
    1. Hermansson H, et al. Breast milk microbiota is shaped by mode of delivery and intrapartum antibiotic exposure. Front Nutr. 2019;6:4.
    1. Pelucchi C, et al. Probiotics supplementation during pregnancy or infancy for the prevention of atopic dermatitis: a meta-analysis. Epidemiology. 2012;23(3):402–414.
    1. Kuitunen M, et al. Probiotics prevent IgE-associated allergy until age 5 years in cesarean-delivered children but not in the total cohort. J Allergy Clin Immunol. 2009;123(2):335–341.
    1. Kallio S, et al. Perinatal probiotic intervention prevented allergic disease in a Caesarean-delivered subgroup at 13-year follow-up. Clin Exp Allergy. 2019;49(4):506–515.
    1. Dominguez-Bello MG, et al. Partial restoration of the microbiota of cesarean-born infants via vaginal microbial transfer. Nat Med. 2016;22(3):250–253.
    1. Kervinen K, et al. Vaginal microbiota in pregnancy: Role in induction of labor and seeding the neonate''s microbiota? J Biosci. 2019;44(5):116.
    1. Korpela K, et al. Maternal fecal microbiota transplantation in cesarean-born infants rapidly restores normal gut microbial development: a proof-of-concept study. Cell. 2020;183(2):324–334.e5.
    1. Place K, et al. Vaginal streptococcus B colonization is not associated with increased infectious morbidity in labor induction. Acta Obstet Gynecol Scand. 2021;100(8):1501–1510.
    1. Helve O, et al. Protocol for oral transplantation of maternal fecal microbiota to newborn infants born by cesarean section. STAR Protoc. 2021;2(1):100271.
    1. Korpela K, et al. Gut microbiota develop towards an adult profile in a sex-specific manner during puberty. Sci Rep. 2021;11(1):23297.
    1. van Nood E, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013;368(5):407–415.
    1. Kozich JJ, et al. Development of a dual-index sequencing strategy and curation pipeline for analyzing amplicon sequence data on the MiSeq Illumina sequencing platform. Appl Environ Microbiol. 2013;79(17):5112–5120.
    1. Virtanen S, et al. Vaginal Microbiota Composition Correlates Between Pap Smear Microscopy and Next Generation Sequencing and Associates to Socioeconomic Status. Sci Rep. 2019;9(1):7750.
    1. Korpela K, et al. Intestinal microbiome is related to lifetime antibiotic use in Finnish pre-school children. Nat Commun. 2016;7:10410.
    1. Korpela K. mare: Microbiota Analysis in R Easily. R package version 1.0. 2016 [cited 2016]. .
    1. Edgar RC. Search and clustering orders of magnitude faster than BLAST. Bioinformatics. 2010;26(19):2460–2461.
    1. Ramiro-Garcia J, et al. NG-Tax, a highly accurate and validated pipeline for analysis of 16S rRNA amplicons from complex biomes. F1000Res. 2016;5:1791.
    1. Salonen A, et al. Comparative analysis of fecal DNA extraction methods with phylogenetic microarray: effective recovery of bacterial and archaeal DNA using mechanical cell lysis. J Microbiol Methods. 2010;81(2):127–134.
    1. Pärnänen K, et al. Maternal gut and breast milk microbiota affect infant gut antibiotic resistome and mobile genetic elements. Nat Commun. 2018;9(1):3891.
    1. Nurk S, et al. metaSPAdes: a new versatile metagenomic assembler. Genome Res. 2017;27(5):824–834.
    1. Rosendahl J, et al. High-dose vitamin D supplementation does not prevent allergic sensitization of infants. J Pediatr. 2019;209:139–145.e1.
    1. Korpela K, et al. Cohort profile: finnish Health and Early Life Microbiota (HELMi) longitudinal birth cohort. BMJ Open. 2019;9(6):e028500.
    1. Wilson BC, et al. Oral administration of maternal vaginal microbes at birth to restore gut microbiome development in infants born by caesarean section: A pilot randomised placebo-controlled trial. EBioMedicine. 2021;69:103443.

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever