Gut Permeability and Microbiome in Preterm Infants

Официальное название

Gut Permeability and Microbiome in Very Low Birth Weight Preterm Neonates.

Обзор

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.

Вмешательства

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

Первичные конечные точки

• Measurement of intestinal permeability [Срок оценки: 1 year]

Критерии участия

Критерии включения

<5 days Gestational age 24-32 weeks

Критерии исключения

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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Скрининг

Центры проведения

Список центров уточняется — проверьте первичный протокол.

Публикации

• van Elburg RM, Fetter WP, Bunkers CM, Heymans HS. Intestinal permeability in relation to birth weight and gestational and postnatal age. Arch Dis Child Fetal Neonatal Ed. 2003 Jan;88(1):F52-5. doi: 10.1136/fn.88.1.f52. PMID 12496227
• Noone C, Menzies IS, Banatvala JE, Scopes JW. Intestinal permeability and lactose hydrolysis in human rotaviral gastroenteritis assessed simultaneously by non-invasive differential sugar permeation. Eur J Clin Invest. 1986 Jun;16(3):217-25. doi: 10.1111/j.1365-2362.1986.tb01332.x. PMID 3089818
• Malagon I, Onkenhout W, Klok M, van der Poel PF, Bovill JG, Hazekamp MG. Gut permeability in neonates after a stage 1 Norwood procedure. Pediatr Crit Care Med. 2005 Sep;6(5):547-9. doi: 10.1097/01.pcc.0000175990.72753.97. PMID 16148815
• Piena M, Albers MJ, Van Haard PM, Gischler S, Tibboel D. Introduction of enteral feeding in neonates on extracorporeal membrane oxygenation after evaluation of intestinal permeability changes. J Pediatr Surg. 1998 Jan;33(1):30-4. doi: 10.1016/s0022-3468(98)90355-4. PMID 9473094
• Albers MJ, Steyerberg EW, Hazebroek FW, Mourik M, Borsboom GJ, Rietveld T, Huijmans JG, Tibboel D. Glutamine supplementation of parenteral nutrition does not improve intestinal permeability, nitrogen balance, or outcome in newborns and infants undergoing digestive-tract surgery: results from a double-blind, randomized, controlled trial. Ann Surg. 2005 Apr;241(4):599-606. doi: 10.1097/01.sla.000015 PMID 15798461
• Rouwet EV, Heineman E, Buurman WA, ter Riet G, Ramsay G, Blanco CE. Intestinal permeability and carrier-mediated monosaccharide absorption in preterm neonates during the early postnatal period. Pediatr Res. 2002 Jan;51(1):64-70. doi: 10.1203/00006450-200201000-00012. PMID 11756641
• Piena-Spoel M, Albers MJ, ten Kate J, Tibboel D. Intestinal permeability in newborns with necrotizing enterocolitis and controls: Does the sugar absorption test provide guidelines for the time to (re-)introduce enteral nutrition? J Pediatr Surg. 2001 Apr;36(4):587-92. doi: 10.1053/jpsu.2001.22288. PMID 11283883
• Beach RC, Menzies IS, Clayden GS, Scopes JW. Gastrointestinal permeability changes in the preterm neonate. Arch Dis Child. 1982 Feb;57(2):141-5. doi: 10.1136/adc.57.2.141. PMID 7065710

Идентификаторы

NCT: NCT07667049 · HP-00110340 · 125-10212000-M33003-TPPRGGRT-2

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗