Gut Permeability and Microbiome in Preterm Infants

NCT07667049 | Not Yet Recruiting Phase 1 DMC FDA Drug

• 2 other identifiers: HP-00110340125-10212000-M33003-TPPRGGRT-2
• Study Type: interventional
• Target: 150
• Locations: 0 countries
• Sites: N/A

Brief Summary

NEC, a life-threatening, GI emergency characterized by increased IP, affects approximately 7 to 10% of preterm neonates, and typically occurs within 7 to 14 days of birth with mortality as high as 30-50%. NEC symptoms mainly involve GI dysfunction, such as abdominal distension and feeding intolerance, but the presentation can be non-specific with few warning signs. Current therapies may be invasive, including surgical interventions that are often ineffective due to the rapid progression of the disease. Prematurity is the greatest risk factor for development of NEC due to physiological immaturity of the GI tract and altered levels of the normal GI microbiota. Several studies suggest that the initiation of an intense systemic and local inflammatory cascade leads to intestinal necrosis . Antenatal exposure to infection/inflammation may predispose the developing intestinal mucosa to subsequent injury or dysregulated inflammatory responses. Previous studies have linked presence of amniotic fluid infection/elevated cytokines, cord blood cytokines, and umbilical cord inflammation with risk for NEC in preterm neonates. In a rat model of NEC, maternal prenatal exposure to microbial LPS led to increased frequency and severity of intestinal injury. Taken together, these observations suggest that intestinal injury may be initiated in utero and contributes to increased IP at birth in the preterm neonate. Many of the defense mechanisms present in the mature intestine, such as peristalsis and tight junctions between intestinal epithelial cells are decreased in an immature intestine, and thus bacteria normally confined to the intestinal lumen are able to reach systemic organs and tissues. Bacterial translocation triggers the activation of an exaggerated inflammatory response, which leads to further epithelial damage. Our analysis of the initial cohort of 43 preterm infants, and others' previous studies have shown that IP is high at birth in preterms (\<33wk gestation) with a rapid maturation of the intestinal barrier over the first 2 weeks. However, in some infants, high IP persisted and/or recurred in association with altered levels of the normal microbiota (bacteria community composition). Specifically, the investigators observed that (1) rapid maturation of intestinal barrier function, characterized by decreased IP, correlates with increased microbial community diversity (Figure 1), and most outstandingly, the increased abundance of beneficial bacteria Clostridiales (Figure 2); (2) Clostridiales is highly transcriptionally active and co-active with the probiotic bacterium Bifidobacterium; (3) neonatal factors, including early introduction of breast milk, shorter period of antibiotic exposure, and later gestational age, favor the early colonization of the gut microbiota by members of Clostridiales and Bifidobacterium, which altogether are associated with improved intestinal barrier in preterm infants; (4) low Clostridiales spp. abundance (\<5%) and early gestational age (\<31.7wk) were identified to be the most discriminatory features for elevated IP by supervised learning scheme, reaching an accuracy of 86.1%. (5) Clostridiales and Bifidobacteriales are the most abundant bacteria groups in later stages (phase II/III at 6-18 months of age) as shown in Figure 2, suggesting a process of gaining prosperity of these two bacterial groups during intestine development after birth. Altogether our preliminary results suggest the early colonization of the natural occurring probiotics strains Clostridiales and Bifidobacterium strongly associate with rapid maturation of intestinal barrier function, and their measurement are highly promising for early detection and as potential nutritional supplement to prevent NEC in the high-risk preterm population. Investigators propose in this study to recruit additional 150 mother-infant dyads (justified in study size analysis in research design), to address our hypothesis that the two naturally occurring beneficial bacteria Clostridiales and Bifidobacterium are rapidly gaining prosperity during normal intestine development in association with improved barrier function measured by La/Rh ratio. This continuation of the initial study builds on the previous findings that identified commensal bacteria Clostridiales and Bifidobacterium species as a strong indicator to the lowered IP and rapid maturation of intestinal barrier, to substantiate measurement of these probiotic strains combined with associated neonatal factors to form an accurate, rapid detection of intestinal permeability abnormality. The investigators propose in this study to recruit additional 150 mother-infant dyads (justified in study size analysis in research design), to address our hypothesis that the two naturally occurring beneficial bacteria Clostridiales and Bifidobacterium are rapidly gaining prosperity during normal intestine development in association with improved barrier function measured by La/Rh ratio.

Conditions

Prematurity Complications

Keywords

Intestinal permeability; necrotizing enterocolitis; preterm infants; dual sugar probe test

Outcome Measures

Primary Outcomes (1)

• Measurement of intestinal permeability

  The study outcome measures will be intestinal permeability (quantitative) and leaky gut (binary). Increased levels of urine Lactulose/Rhamnose \[La/Rh\] ratio \>0.05 will identify infants with increased intestinal permeability (IP).

  1 year

Study Arms (1)

Lactulose-Rhamnose solution

OTHER

Drug: measurement of intestinal permeability

Interventions

measurement of intestinal permeability DRUG

Measure intestinal permeability by use of non-digestable sugars known to not cross the intestinal barrier in normal healthy intestinal tissue.

Lactulose-Rhamnose solution

Eligibility Criteria

• Age: Up to 4 Days
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• \<5 days Gestational age 24-32 weeks

You may not qualify if:

• Nonviable or planned withdrawal of care
• Significant GI dysfunction (e.g. heme-positive stools, abdominal distension (girth \>2 cm baseline), or bilious emesis/ aspirates.
• Triplet or higher order multiple
• Severe asphyxia
• Lethal chromosome abnormalities
• Cyanotic congenital heart disease
• Intestinal atresia or perforation
• Abdominal wall defects
• Known galactosemia or other galactose intolerance

Sponsors & Collaborators

• University of Maryland, Baltimore: lead

Related Publications (12)

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  PMID: 9473094 BACKGROUND

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  PMID: 22892368 BACKGROUND

• van Wijck K, Bessems BA, van Eijk HM, Buurman WA, Dejong CH, Lenaerts K. Polyethylene glycol versus dual sugar assay for gastrointestinal permeability analysis: is it time to choose? Clin Exp Gastroenterol. 2012;5:139-50. doi: 10.2147/CEG.S31799. Epub 2012 Jul 19.

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  PMID: 8125384 BACKGROUND

• Fasano A. Physiological, pathological, and therapeutic implications of zonulin-mediated intestinal barrier modulation: living life on the edge of the wall. Am J Pathol. 2008 Nov;173(5):1243-52. doi: 10.2353/ajpath.2008.080192. Epub 2008 Oct 2.

  PMID: 18832585 BACKGROUND

MeSH Terms

Conditions

Enterocolitis, Necrotizing

Condition Hierarchy (Ancestors)

Enterocolitis; Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Intestinal Diseases

Study Officials

• Marcela Pasetti, PhD

  University of Maryland

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Sripriya Sundararajan, MD

CONTACT

4103286003; ssundararajan@som.umaryland.edu

Bing Ma, PhD

CONTACT

608-334-4877; ssundararajan@som.umaryland.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: SCREENING
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: June 18, 2026
• First Posted: June 24, 2026
• Study Start: July 15, 2026
• Primary Completion (Estimated): June 30, 2027
• Study Completion (Estimated): June 30, 2027
• Last Updated: July 6, 2026

Record last verified: 2026-06

Data Sharing

• IPD Sharing: Will not share