A Nutritional Approach to Feeding a Targeted Bacterial Strain in the NICU

Michael J Fitzgerald, MD

Michael J Fitzgerald, MD is an Attending Neonatologist, Medical Director, Elmhurst NICU at the Edward Elmhurst Health System. Dr Fitzgerald is also a Co-Founder of DuPage Neonatology Associates.

Probiotic use in the NICU has been considered as a promising tool for the prevention of necrotizing enterocolitis (NEC) with a focus on the very low birth weight (VLBW) population of infants <32 weeks or <1500 grams, and the data appear to show a lower risk of NEC in preterm infants fed a probiotic.1   From a pharmaceutical perspective, however,  the evidence and precision on which strains, or how much of each strain, to use for NEC prevention is inconclusive, primarily due to a lack of understanding or focus on the mechanism of action. As a result, expert groups have conflicting viewpoints.

This dichotomy is clear from two recently published articles regarding the use of probiotics in the NICU. The first was a meta-analysis of 56 RCTs and 30 observational studies (including over 80,000 patients total) on the use of probiotics to prevent NEC,2 published in the Journal of the American Medical Association (JAMA) Pediatrics. After evaluating the results, Razak et al. suggested that the evidence supports the routine use of probiotics for preterm infants. The authors further referenced support for this recommendation by citing the Canadian Pediatric Society guidelines,3 the American Gastroenterology Association,4 and the European Society for Paediatric Gastroenterology Hepatology and Nutrition.5

A contrary viewpoint was written by the American Academy of Pediatrics (AAP) Committee on Fetus and Newborn.6 The Committee took the position that, due to the lack of FDA-regulated pharmaceutical products and the heterogeneity of the clinical data between different probiotics, the current evidence does not support routine administration of probiotics to preterm infants.

Given that preterm infants are a particularly vulnerable population, the cautionary tone from the AAP committee regarding safety is well warranted; however, the specific and narrow pharmaceutical perspective on probiotic use to treat NEC does not represent the whole story of patient care in the NICU. Proposed here is a new lens through which to view NICU probiotic use, focusing on a nutritional, rather than a pharmaceutical, intervention to provide comprehensive management of the preterm infant gut microbiome. While improved NEC outcomes may result, the use of probiotics in the NICU is intended to improve overall health outcomes.

Differentiating between a pharmaceutical vs nutritional approach when utilizing probiotics as standard of care:

It is well established in the literature that preterm infants acquire high levels of nosocomial pathogenic bacteria in their gut microbiome that may disrupt evolutionarily appropriate gut assembly, resulting in microbiome instability and a loss of function.7 This imbalance of pathogenic and beneficial bacteria causes enteric inflammation and puts preterm infants at risk for a number of adverse outcomes.8 Managing this microbial imbalance in the preterm gut should be a clear patient care goal in the NICU. Said another way, if a Bifidobacterium dominant microbiome in a breast-fed infant is natural and developmentally appropriate in early infancy, it stands to reason that achieving this should be a milestone in the care of premature infants.

Research published by Nguyen et al. in 2021 showed that modulation of the gut microbiome is achievable in preterm infants without the use of antibiotics through the nutritional approach of feeding a targeted bacterial strain, activated B. infantis EVC001 (EVC001) in addition to human milk.9  Contrary to most probiotic strains on the market, which have been selected based on availability and production characteristics rather than function, the EVC001 bacterial strain was determined as an infant gut symbiont that works synergistically with human milk to provide benefits to the infant, including colonization resistance to opportunistic pathogens.10 EVC001 was selected specifically for its growth characteristics on human milk oligosaccharides (HMO), the third most abundant class of nutrients in human milk, as evidenced in the EVC001 genome. Compared to other B. infantis strains, EVC001 has a functional H5 gene cluster important in the ability to use HMO,11 which highlights the importance of selecting specific strains for their ability to modulate the microbiome in an age- and diet-appropriate manner. The EVC001 strain is commercially available in the product Evivo® with MCT Oil which is designated as a Food for Special Dietary Use (FSDU) specifically to meet dietary needs that exist due to age of infancy and lactation. Evivo with MCT Oil is regulated as a food under the FDA Food Safety Modernization Act, not under dietary supplement regulations.

Feeding EVC001 along with human milk is a nutritional solution with an established mechanism of action, unique in providing a comprehensive approach to improving newborn gut health.9,12,13 This nutritional approach provides a broad spectrum of biological benefits to the infant through its ability to completely break down HMO. As a result of these biological changes in the gut, observational studies from NICUs using EVC001 as standard of care have reported significant improvements in intrinsic factors related to the onset of NEC, including reduction in enteric inflammation and reduced abundance of Enterobacteriacae, such as E. coli and Klebsiella oxytoca.9 In addition to NEC-related benefits, clear indicators of improved gut health, such as significant reduction in diaper dermatitis and antibiotic usage, have been seen in preterm infants receiving EVC001.9

Given the above clinical outcomes and the known mechanisms of action, numerous prominent healthcare institutions have successfully introduced the routine use of B. infantis EVC001 in their NICUs, including use in extremely low birth weight (ELBW) infants.

In conclusion, comprehensive management of the preterm infant gut through nutritional intervention aimed at modulating the microbiome can yield health benefits to the infant, including, but not limited to, the reduction or elimination of known causative factors related to NEC. As demonstrated in clinical studies using EVC001, this is possible due to the unique capacity of the EVC001 strain to utilize specific components of human milk (i.e., HMOs), colonize the infant gut, displace hospital acquired microorganisms,10 and produce specific metabolites that lower enteric inflammation and modulate the immune system.14

Addressing the safety of activated B. infantis EVC001 as a high-quality nutritional product:   

Routine use of high-quality food-grade nutritional products is commonly practiced in NICUs across the United States. The targeted EVC001 bacterial strain in Evivo with MCT Oil was selected for use in the NICU at Edward-Elmhurst because of the high-quality standards, rigorous testing throughout the end-to-end product life cycle, and transparent labeling with 8 billion CFU of the designated EVC001 strain guaranteed through the ‘best if used by’ date.

Selecting a NICU-appropriate form was also important when adopting Evivo as part of the feeding protocol at Edward- Elmhurst. Contrary to other products, Evivo with MCT Oil is designed with the neonate in mind, manufactured in a single-use, ready-to-feed liquid which facilitates adherence to the Infant and Pediatric Feeding 3rd Edition recommendation.15 Finally, but most importantly, B. infantis is an infant gut symbiont and the EVC001 strain is a non-pathogenic species that lacks virulence factors.16 It has been fed under the care and direction of health professionals as a microbiome management product many thousands of times to preterm infants, including ELBW infants, as a nutritional product.

Pointing to recent and future research of EVC001 in preterm infants:

A series of strong and consistent data on the unique benefits of activated B. infantis EVC001 has been presented in recent published clinical trials,9,14,17 and recently presented at neonatology conferences such as Cool Topics in Neonatology, Hot Topics in Neonatology and the NEC society.9,14,17

Furthermore, a clinical trial was recently completed at Winnie Palmer Hospital in Orlando, FL, which systematically assessed safety and tolerability of the product among preterm infants <1500 grams or gestational age at birth <33 weeks.18 This study adds to a growing body of data that demonstrates how feeding EVC001 to preterm infants in the NICU provides care givers with a new tool to address comprehensive management of the infant gut microbiome, leading to improved global gut health and overall healthier infants. Additionally, the beneficial impact of actively managing the preterm infant gut microbiome was clearly demonstrated in a recent study at Oregon Health and Science University13 which showed significant reductions in NEC and NEC-related mortality among VLBW and especially ELBW infants fed Evivo with MCT Oil.

Concluding remarks

While the AAP Committee Report wisely raises awareness over the need for high-quality probiotics for the preterm population, their view on probiotics solely as a drug for the prevention of NEC is very narrow. A drug implies a certain amount of accepted risk to solve the indication; however, if missing symbionts and overabundance of hospital-acquired bacteria are a root cause and key to the overall health of the preterm infant, a more global approach must be considered.

Over the past few years, it has become clear that the gut microbiome is an important “microbiological organ” that, if managed properly, has been implicated in many beneficial aspects of neonatal health, including the reduction of opportunistic pathogens, antimicrobial resistance, enteric inflammation, diaper dermatitis and feeding intolerance, all issues that greatly affect preterm outcomes in the NICU. Given that the AAP’s Committee on Fetus and Newborn may not issue another report for several years and gut microbiome science and clinical usage is rapidly developing, hospital leaders are encouraged to follow new research carefully to make the best evidence-based, informed decisions for their patients. Finally, we should consider nutritional-based approaches to comprehensively manage the infant gut microbiome for the improvement of all health outcomes in addition to the pharmaceutical approach as suggested by the recent AAP Committee Report. infant gut microbiome for the improvement of all health outcomes in addition to the pharmaceutical approach as suggested by the recent AAP Committee Report.

References

  1. Sharif, S., Meader, N., Oddie, S. J., Rojas-Reyes, M. X. & McGuire, W. Probiotics to prevent necrotising enterocolitis in very preterm or very low birth weight infants. Cochrane Db Syst Rev 10, CD005496 (2020).
  2. Razak, A., Patel, R. M. & Gautham, K. S. Use of Probiotics to Prevent Necrotizing Enterocolitis. Jama Pediatr 175, (2021).
  3. Using probiotics in the paediatric population | Canadian Paediatric Society. https://www.cps.ca/en/documents/position/probiotics-in-the-paediatric-population.
  4. Su, G. L. et al. AGA Clinical Practice Guidelines on the Role of Probiotics in the Management of Gastrointestinal Disorders. Gastroenterology 159, 697–705 (2020).
  5. Akker, C. H. P. van den et al. Probiotics and Preterm Infants: A Position Paper by the European Society for Paediatric Gastroenterology Hepatology and Nutrition Committee on Nutrition and the European Society for Paediatric Gastroenterology Hepatology and Nutrition Working Group for Probiotics and Prebiotics. J Pediatric Gastroenterology Nutrition 70, 664–680 (2020).
  6. Poindexter, B. & NEWBORN, C. O. F. A. Use of Probiotics in Preterm Infants. Pediatrics e2021051485 (2021) doi:10.1542/peds.2021-051485.
  7. Grier, A. et al. Impact of prematurity and nutrition on the developing gut microbiome and preterm infant growth. Microbiome 5, 158 (2017).
  8. Pammi, M. et al. Intestinal dysbiosis in preterm infants preceding necrotizing enterocolitis: a systematic review and meta-analysis. Microbiome 5, 31 (2017).
  9. Nguyen, M. et al. Impact of Probiotic B. infantis EVC001 Feeding in Premature Infants on the Gut Microbiome, Nosocomially Acquired Antibiotic Resistance, and Enteric Inflammation. Frontiers Pediatrics 9, 618009 (2021).
  10. Duar, R. M., Kyle, D. & Casaburi, G. Colonization Resistance in the Infant Gut: The Role of B. infantis in Reducing pH and Preventing Pathogen Growth. High-throughput 9, 7 (2020).
  11. Duar, R. M. et al. Comparative Genome Analysis of Bifidobacterium longum subsp. infantis Strains Reveals Variation in Human Milk Oligosaccharide Utilization Genes among Commercial Probiotics. Nutrients 12, 3247 (2020).
  12. Duar, R. M., Henrick, B. M., Casaburi, G. & Frese, S. A. Integrating the Ecosystem Services Framework to Define Dysbiosis of the Breastfed Infant Gut: The Role of B. infantis and Human Milk Oligosaccharides. Frontiers Nutrition 7, 33 (2020).
  13. Frese, S. A. et al. Persistence of Supplemented Bifidobacterium longum subsp. infantis EVC001 in Breastfed Infants. Msphere 2, e00501-17 (2017).
  14. Henrick, B. M. et al. Bifidobacteria-mediated immune system imprinting early in life. Cell (2021) doi:10.1016/j.cell.2021.05.030.
  15. Robbins, S. T. & Meyers, R. Infant Feedings: Guidelines for Preparation of Human Milk and Formula in Health Care Facilities. (American Dietetic Association, 2011).
  16. Casaburi, G. & Frese, S. A. Colonization of breastfed infants by Bifidobacterium longum subsp. infantis EVC001 reduces virulence gene abundance. Hum Microbiome J 9, 7–10 (2018).
  17. Tobias, J. et al. Feeding Activated Bifidobacterium infantis EVC001 to Very Low Birth Weight Infants is Associated with Significant Reduction in Rates of Necrotizing Enterocolitis.pdf. MedRxiv (2021) doi:https://doi.org/10.1101/2021.06.29.21259737.
  18. The FOUNDATION Study – Full Text View – ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03939546.

Learn more about Evivo (activated B. infantis EVC001)

The first and only infant probiotic clinically demonstrated to functionally metabolize human milk oligosaccharides to improve the biochemistry of the infant gut.