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COMMENTARY |
Department of Pediatrics,
Medical College of Wisconsin,
Milwaukee, WI 53226
Children’s Research Institute,
Children’s Hospital of Wisconsin,
Milwaukee, WI 53226
Department of Pediatrics,
Section of Infectious Diseases,
Medical College of Wisconsin,
Milwaukee, WI 53226
Necrotizing enterocolitis (NEC) is a serious gastrointestinal disease seen predominantly in very low birth weight (VLBW) infants during their hospitalization in a neonatal intensive care unit (NICU). NEC is probably a complex, multifactorial disease associated with immaturity of intestinal function as well as immature systemic and mucosal immune responses, enteric feeding, and microbiologic influences such as abnormal bacterial gas production that produces the pathognomonic radiographic finding of pneumatosis intestinalis.1,2
Currently, the precise contribution of each of these factors is unknown. Without this understanding, preventive measures have been theoretical and not consistently effective. In this issue of Pediatrics, Lin et al3 demonstrate that prophylactic administration of a probiotic mixture of Lactobacillus acidophilus and Bifidobacterium infantis given to VLBW infants reduces the incidence of all cases of NEC as well as severe stage III NEC.3
An important rationale for the use of probiotics in neonates at risk for NEC is the observation that the VLBW infant has aberrant fecal colonization when compared with term infants.1,4–6 VLBW infants often have a paucity (oligocolonization) of normal enteric bacterial species and a delayed onset of colonization compared with term infants. The aseptic NICU environment, which paradoxically has many resistant enteric organisms, may predispose VLBW infants to the development of an aberrant fecal flora. In addition, most VLBW infants receive prophylactic parenteral broad-spectrum antibiotics after birth, which contributes to delayed, aberrant, and antimicrobial-resistant bacterial or fungal colonization. Furthermore, many VLBW infants often receive no enteric feedings immediately after birth; when they are fed, they may receive formula rather than human milk. Human milk helps to establish a normal fecal flora in term infants and probably does so in VLBW infants.4
The establishment of a normal intestinal bacterial flora has important implications for health or disease. In animals, early bacterial colonizers "imprint" and become the dominant intrinsic intestinal flora for the host.7 A normal flora may resist colonization by highly pathogenic bacteria.8 Probiotics may assist in establishing a normal nonpathogenic flora by preventing the binding of pathogenic bacteria to the enterocyte, by the local production of antimicrobial products, or by altering the intestinal lumen pH by producing potentially microbicidal short-chain volatile fatty acids, which may inhibit the proliferation of pathogenic microorganisms.4,9–11 In addition, a normal flora may enhance mucosal IgA production and stimulate the local production of antiinflammatory cytokines.12 The intestinal commensal flora also interacts with intestinal toll-like receptors, which are part of an innate immune system that triggers toll-like receptor signaling, which helps regulate the local microenvironment.13 Given the association of the development of a "monoflora" with impending NEC,14–16 probiotic administration may be a means to protect VLBW neonates by artificially enforcing diversity of flora or by preventing colonization with potential pathogens.
Prior experience in VLBW infants treated with different probiotic preparations has sometimes suggested benefit while universally demonstrating safety. Kitajima et al17 administered Bifidobacterium breve to >150 VLBW infants and demonstrated high colonization rates, no adverse events attributed to the organism, and enhanced weight gain. The effect on the occurrence or severity of NEC was not reported. In a double-blind trial, Dani et al18 randomized 585 VLBW infants in 12 NICUs in Italy to receive Lactobacillus GG once a day until discharge. There were no statistically significant effects for their main outcome variables of urinary tract infection, sepsis, or NEC.
In all of the most recent trials of probiotics, no adverse effects have been reported. Nonetheless, one must be cautious in the introduction of any new and potentially infectious agent as therapy for immunologically immature VLBW infants. Bacillus sp. and Saccharomyces, administered as probiotics, were associated with invasive disease in target populations.12,19 There have been multiple reports of Lactobacillus species causing serious infections in adults, children, and infants who did not receive probiotics.20–24 These infections include bacteremia, sepsis, meningitis, and endocarditis. Although predisposing risk factors may have been present (central venous catheters, congenital heart disease), some of these patients seemed to be otherwise normal hosts. In contrast to these case reports, population-based studies indicate that the rates of invasive disease by lactobacilli are extremely low.20 It can also be argued that for bacteremias originating from endogenous flora (such as those occurring with NEC), infection with lactobacilli are preferable over potential pathogens such as Klebsiella, Enterobacter, or yeast. A more important safety issue follows from the observation that early bacterial colonizers "imprint" the host and are hard to replace once established.24 The manipulation may persist for decades. Although studies of probiotics in neonates should contend with the long-term consequences of iatrogenic colonization, pragmatists can again argue that lactobacilli are preferred colonizers over many endemic NICU pathogens.
The experience of the group from the China Medical Children’s Hospital in Taichung, Taiwan, is very encouraging.3 The authors caution that probiotic use in neonates must be better understood and their results confirmed before it becomes general practice. Limitations of the published studies in neonates include interstrain differences in benefit and the absence of a defined effective dose or duration of therapy.25–27 There is uncertainty whether multiple probiotic strains are necessary for colonization resistance. Most stably healthy colonic and vaginal flora include 2 species of lactobacilli.28,29 The current study would have benefited from demonstration of a microbiologic "take" of the 2 probiotic organisms. Given that Lin et al conducted their study in an institution with a relatively high rate of background NEC, occurring primarily in the first 2 weeks of life (the first week was excluded by study design), it remains to be determined whether the benefit can be extrapolated to centers with lower rates of NEC or NEC of more subacute onset. Given that NEC clusters in place and time, randomized trials across institutions are indicated.1,2
The ability to manipulate the enteric microbial flora in VLBW infants toward a normal nonpathogenic microenvironment addresses one of the fundamental issues in the pathogenesis of NEC (abnormal bacterial intestinal gas production and bacterial translocation).1,2,4 The current study is clearly of great importance and should be duplicated with a greater sample size and enhanced scientific methods to identify the protective mechanism(s) involved. This is an ideal example of a valuable protocol that could be adopted by the neonatal network of the National Institute of Child Health and Human Development.
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FOOTNOTES |
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Address correspondence to Robert M. Kliegman, MD, Department of Pediatrics, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226. E-mail: rkliegma{at}mail.mcw.edu
No conflict of interest declared.
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REFERENCES |
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 TOP REFERENCES |
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This article has been cited by other articles:
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  J. Neu, M. Douglas-Escobar, and M. Lopez Microbes and the Developing Gastrointestinal Tract Nutr Clin Pract, April 1, 2007; 22(2): 174 - 182. [Abstract] [Full Text] [PDF]
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 J. Neu Gastrointestinal development and meeting the nutritional needs of premature infants Am. J. Clinical Nutrition, February 1, 2007; 85(2): 629S - 634S. [Abstract] [Full Text] [PDF]
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 N. Jesse and J. Neu Necrotizing Enterocolitis: Relationship to Innate Immunity, Clinical Features, and Strategies for Prevention NeoReviews, March 1, 2006; 7(3): e143 - e150. [Full Text] [PDF]
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 A. Marini, G. Boehm, F. Negretti, and M. Agosti Probiotics, Prebiotics, or Both in a Very Low Birth Weight Infant Pediatrics, August 1, 2005; 116(2): 522 - 523. [Full Text] [PDF]
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 Journal Watch Arch. Dis. Child., May 1, 2005; 90(5): 544 - 545. [Full Text] [PDF]
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 Probiotics for Infants: Two Studies, Two Successes Journal Watch (General), February 11, 2005; 2005(211): 3 - 3. [Full Text]
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 Probiotics in Infants: Two Studies, Two Successes Journal Watch Pediatrics and Adolescent Medicine, February 1, 2005; 2005(201): 2 - 2. [Full Text]
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