Like its name, necrotizing enterocolitis (NEC) is nasty: death of tissue in the bowel. Primarily affecting preterm infants born before 32 weeks’ gestation, NEC—though fairly rare— is a serious and sometimes fatal disorder.
Though the causes of NEC are not completely understood, an abnormal gut microbiome is one important factor. Another one is the type of feeding, with pasteurized donor human milk linked with decreased risk.
Importantly, altering the immature gut with probiotics is a notable target for prevention of NEC.
Role of the microbiome in NEC
Abnormal gut bacteria (dysbiosis) is a significant risk factor in susceptibility to NEC, as deduced from observations, which include:
Premature infants have a markedly different intestinal microbiota than term infants. Fecal microbiome from preterm infants with NEC had increased relative abundances of Proteobacteria and decreased relative abundances of Firmicutes and Bacteroidetes prior to onset.
Beneficial bacteria, such as bifidobacteria, were less abundant in preterm infants who go on to develop NEC compared to matched unaffected peer preterm infants.
This dysbiosis is thought to be due to environmental factors inherent in neonatal intensive care, hygiene, antibiotic use, as well as genetics and immaturity of the intestinal immune responses.
In the latter instance, inflammation in NEC is driven by activation of the Toll-like receptor 4 in intestinal mucosa. Commensal bacteria play a role—albeit unclear—in this complex balance between tolerance and immunity in the immature gut.
Mechanisms of probiotic action
- Upregulation of cytoprotective genes
- Immune cell regulation
- Tightening of gut barrier
- Decreasing inflammation
- Competing against pathogens
- Producing metabolites involved in signaling
Probiotics in action against NEC
Probiotics have been extensively studied in preterm infants, with trials enrolling well over 10,000 infants in total. Once again, many variables (e.g. strains, dosages, ages of infant and treatment span) obfuscate the data. Nevertheless, the preponderance of evidence points to a role for probiotics in prevention of NEC.
The authors of one review concluded:
“Administration of probiotics to premature infants in most of the clinical trials performed to date is associated with a decreased incidence of NEC. Routine administration of probiotics to all premature infants has been proposed and is common practice in many countries.”
Which probiotics prevent NEC?
While many probiotics have been tested in trials to prevent NEC, not all probiotics are equally effective. Once again, comparing them is difficult given the variability and lack of standardization. A number of commercial probiotic preparations for NEC are available, as seen in this table.
Also complicating the choice for pediatric clinicians or formulary creators at hospitals are these concerns:
Products with demonstrated purity and stable numbers of live organisms are a must for this vulnerable group of infants. Regulatory bodies and stakeholders in many countries are addressing appropriate oversight for probiotic products. Meanwhile, clinical trials with rigorous design may yield products to prevent NEC that pass muster with agencies such as the Food and Drug Administration (FDA).
First do no harm. Risk of sepsis or blood infection from giving live microbes to such an at-risk population is a valid concern. However, the aggregated data from such large numbers appears to show the absolute risk of sepsis from probiotic supplementation is likely to be low.
According to Dr Arthur Ouwehand PhD of DuPont Nutrition & Health, “Most probiotics are produced as dietary supplements and not as drugs for use in extremely sensitive patients. Thus while the strain may be safe and the product is safe for the general population, the product may not be safe for these patients as they are not the intended target populations in most cases.” Stringent quality standards with third party verification of compliance with manufacturing and labeling accuracy are recommended by Dr Ouwehand and colleagues in “Probiotic use in at-risk populations.”
Optimal dose, initiation and duration of treatment
Though wide variability in study protocols exists, a few patterns emerged according to one review. The majority of trials used:
- Dosage of 1 to 6 × 109 CFU/d
- Initiation of treatment within the first several days of birth
- Duration for at least 28 days
In May of 2020, the European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) published a position paper using a network meta-analysis approach to identify strains with greatest potential efficacy for preventing major neonatal morbidities in preterm infants. This comprehensive guide addresses safety issues in addition to providing clinicians with valuable recommendations on dosages, duration, and the use of single-strain vs. multi-strain probiotics.
Probiotics are effective against NEC: numerous studies have confirmed a decrease in the incidence with delivery of probiotic microbes.
Yet the search for optimum probiotic preparations is clouded by large variability in studies and precautions about quality and safety. Further research should explore next generation probiotics based on newer genetic techniques.
Rest assured though that these are standard final steps in the long scientific process, with this particular journey aiming to save babies so they can take their first steps.
Mantziari A, Tölkkö S, Ouwehand AC, et al. The Effect of Donor Human Milk Fortification on The Adhesion of Probiotics In Vitro. Nutrients. 2020;12(1):182. Published 2020 Jan 9. doi:10.3390/nu12010182
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Pammi, Mohan et al. “Intestinal dysbiosis in preterm infants preceding necrotizing enterocolitis: a systematic review and meta-analysis.”Microbiome vol. 5,1 31. 9 Mar. 2017, doi:10.1186/s40168-017-0248-8
Sanders ME, Merenstein DJ, Ouwehand AC, et al. Probiotic use in at-risk populations. J Am Pharm Assoc (2003). 2016;56(6):680‐686. doi:10.1016/j.japh.2016.07.001
Underwood, Mark A. “Impact of probiotics on necrotizing enterocolitis.” Seminars in perinatology vol. 41,1 (2017): 41-51. doi:10.1053/j.semperi.2016.09.017
van den Akker, Chris H.P.et al. Probiotics and Preterm Infants, Journal of Pediatric Gastroenterology and Nutrition: May 2020 – Volume 70 – Issue 5 – p 664-680 doi: 10.1097/MPG.0000000000002655