Targeting Gut Microbiota and Metabolites for Very Preterm Infants Through Oropharyngeal Administration of Colostrum

Targeting Gut Microbiota and Metabolites for Very Preterm Infants Through Oropharyngeal Administration of Colostrum: Protocol for a Multicenter Randomized Controlled Trial

Background: Oropharyngeal administration of colostrum (OAC) has an immune stimulating effect on oropharyngeal-associated lymphoid tissue, and can also promote the maturation of the gastrointestinal tract. However, how OAC promotes intestinal maturation in preterm infants by altering the gut microbiota remains unclear. We aim to assess the changes of gut microbiota and metabolites after OAC in very preterm infants.

Methods: A multicenter, double-blind, randomized controlled trial will be conducted in 3 large NICUs in Shenzhen, China, for preterm infants with gestational age less than 32 weeks and birth weight less than 1500g. The intervention group will be given 0.2ml colostrum for oropharyngeal administration every 3 hours, which will start between the first 48 to 72 hours and continue for 5 consecutive days; The control group will be given sterile water for oropharyngeal administration, and the administration scheme will be the same as above. Stool samples will be collected at the first defecation and the 7th day after birth. It is estimated that 320 preterm infants will participate in the study within 1 year. 16sRNA gene sequencing and liquid chromatography-mass spectrometry will be used to analyze the effect of OAC on gut microbiota and metabolites.

Discussion: The proposal advocates for the promotion of OAC as a safe and relatively beneficial initiative among neonatal intensive care units, and this initiative may contribute to the establishment of a dominant intestinal flora. Findings of this study may help to improve the health outcomes of preterm infants by constructing targeted gut microbiota in future studies.

Study Overview

• Status: Not yet recruiting
• Conditions: Gut Microbiota; Metabolites
• Intervention / Treatment: Other: Oropharyngeal administration of colostrum; Other: Oropharyngeal administration of sterile water

Detailed Description

Preterm infants with gestational age < 32 weeks and weight < 1500g will be evaluated. Infants who met the inclusion criteria will be randomly divided into two groups according to the ratio of 1:1. The intervention group will be given oropharyngeal colostrum every 3 hours for 5 days; the control group will be given sterile water with the same dosage and administration scheme. Stool samples will be collected at the first defecation and the 7th day to detect the gut microbiota and metabolites.

• Study Type: Interventional
• Enrollment (Anticipated): 320
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Zhangbin Yu, PhD; Phone Number: 13913994149; Email: yuzhangbin@126.com

Study Locations

• China
  • Guangdong
    • Shenzhen, Guangdong, China
      • Shenzhen People's Hospital
      • Contact: Zhangbin Yu, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 7 months (CHILD)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion criteria:

• gestational age less than 32 weeks and birth weight less than 1500g;
• admission to NICU ≤ 24 hours;
• be able to start the agreement within 72 hours of birth.

Exclusion criteria:

• birth asphyxia (defined as umbilical artery / first hour arterial PH < 7.0 or cardiopulmonary resuscitation in the delivery room);
• birth complicated with severe gastrointestinal malformations (such as intestinal atresia, esophago-tracheal fistula, intestinal rotation abnormalities, congenital megacolon);
• prenatal diagnosis of congenital chromosomal abnormalities or suspected congenital genetic metabolic diseases;
• maternal drug abuse or contraindications to breastfeeding (HIV and cytomegalovirus infection).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: The intervention group will be given colostrum for oropharyngeal administration; The intervention group will be given 0.2ml colostrum for oropharyngeal administration every 3 hours, which will start between the first 48 to 72 hours and continue for 5 consecutive days.	Other: Oropharyngeal administration of colostrum; The intervention group will be given 0.2ml colostrum for oropharyngeal administration every 3 hours.
PLACEBO_COMPARATOR: The control group will be given sterile water for oropharyngeal administration; The control group will be given sterile water for oropharyngeal administration, and the administration scheme will be the same as above.	Other: Oropharyngeal administration of sterile water; The control group will be given 0.2ml sterile water for oropharyngeal administration every 3 hours.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
A between-group difference in gut microbial alpha diversity will be measured by Shannon diversity index at the 7th day.	Shannon diversity Index explains species richness and evenness, which is one of the alpha diversity indexes and less affected by rare species.	1 year
Between-group differences in the concentration of fecal metabolites (short chain fatty acids) will be quantitatively measured by non targeted liquid chromatography-mass spectrometry (LC-MS) at the 7th day.	Non-targeted LC-MS will be used to evaluate short chain fatty acids and other organic acids and alcohols. The relative and absolute quantitative results of metabolites will be calculated by fold change (FC) value, and the difference of metabolite expression between the two groups will be explored.	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
A between-group difference in the Simpson diversity index at the 7th day	Simpson diversity index explains species richness, which is one of the alpha diversity indexes and susceptible to rare species.	1 year
A between-group difference in the Chao1 diversity index at the 7th day.	Chao1 diversity index explains species richness, which is one of the alpha diversity indexes.	1 year
Proportion of gut microbiota (phylum and genus level）at the 7th day.	After preprocessing to remove low-quality sequences, the original data will be analyzed according to the steps of 16S rRNA discovery, clustering and identification. Calculate the number of operational taxonomic units (OTUs) of each sample at a 97% sequence similarity level. A specific taxonomic units represents a specific species.	1 year
Gut microbial beta diversity explaining between-sample dissimilarity will be calculated using the Vegan package.	Adonis permutational multivariate analysis of variance of Bray-Curtis distances with 9999 permutations will be used to compare the microbial community structure between each of the two groups at the 7th day.	1 year
Correlation between dominant microbiota and metabolites	The correlation between the relative abundance of dominant bacterial taxa from 16S rRNA gene sequencing and the intensity of metabolites of interest will be determined by sparse partial least squares regression (SPLs) at the first defecation at the 7th day.	1 year

Collaborators and Investigators

• Sponsor: Shenzhen People's Hospital
• Collaborators: Shenzhen Bao'an Maternal and Child Health Hospital; Longgang Maternal and Child Health Hospital, Shenzhen, Guangdong
• Investigators: Principal Investigator: Zhangbin Yu, PhD, Shenzhen People's Hospital

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): October 1, 2022
• Primary Completion (ANTICIPATED): October 1, 2023
• Study Completion (ANTICIPATED): October 1, 2023

Study Registration Dates

• First Submitted: July 20, 2022
• First Submitted That Met QC Criteria: July 27, 2022
• First Posted (ACTUAL): August 1, 2022

Study Record Updates

• Last Update Posted (ACTUAL): August 2, 2022
• Last Update Submitted That Met QC Criteria: July 30, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Other Study ID Numbers: SZPH-2022-52

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No