REVIEW

Probiotics, Prebiotics, and Synbiotics for the Prevention of Necrotizing Enterocolitis1,2 Kathene C Johnson-Henry,3 Thomas R Abrahamsson,4 Richard You Wu,3,5 and Philip M Sherman3,5–7* 3

Cell Biology Program, Research Institute, Division of Gastroenterology, Hepatology, and Nutrition, Hospital for Sick Children; 5Department of Laboratory Medicine and Pathobiology, Faculty of Medicine; 6Department of Nutritional Sciences; and 7Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada; and 4Department of Clinical and Experimental Medicine, Division of Pediatrics, Linköping University, Linköping, Sweden

ABSTRACT

Necrotizing enterocolitis (NEC) is a devastating intestinal disease in preterm infants characterized by barrier disruption, intestinal microbial dysbiosis, and persistent inflammation of the colon, which results in high mortality rates. Current strategies used to manage this disease are not sufficient, although the use of human breast milk reduces the risk of NEC. Mother’s milk is regarded as a fundamental nutritional source for neonates, but pasteurization of donor breast milk affects the composition of bioactive compounds. Current research is evaluating the benefits and potential pitfalls of adding probiotics and prebiotics to pasteurized milk so as to improve the functionality of the milk and thereby reduce the burden of illness caused by NEC. Probiotics (live micro-organisms that confer health to the host) and prebiotics (nondigestible oligosaccharides that stimulate the growth of healthy bacteria) are functional foods known to mediate immune responses and modulate microbial populations in the gut. Clinical research shows strain- and compoundspecific responses when probiotics or prebiotics are administered in conjunction with donor breast milk for the prevention of NEC. Despite ongoing controversy surrounding optimal treatment strategies, randomized controlled studies are now investigating the use of synbiotics to reduce the incidence and severity of NEC. Synbiotics, a combination of probiotics and prebiotics, have been proposed to enhance beneficial health effects in the intestinal tract more than either agent administered alone. This review considers the implications of using probiotic-, prebiotic-, and synbioticsupplemented breast milk as a strategy to prevent NEC and issues that could be encountered with the preparations. Adv Nutr 2016;7:928–37. Keywords: synbiotics, probiotics, prebiotics, functional foods, necrotizing enterocolitis, inflammation, breast milk, human milk oligosaccharides, neonatology, premature

Introduction

Research efforts of the authors are supported by Lallemand Health Solutions (Montreal, Canada) and the Canadian Institutes of Health Research (MOP-89894 and IOP-92890). TRA received funding for a clinical trial from Biogaia AB, Sweden. PMS is the recipient of a Canada Research Chair in Gastrointestinal Disease. 2 Author disclosures: KC Johnson-Henry, TR Abrahamsson, R You Wu, and PM Sherman, no conflicts of interest. 8 Abbreviations used: EGF, epidermal growth factor; FOS, fructo-oligosaccharide; GOS, galacto-oligosaccharide; HMO, human-milk oligosaccharide; IBD, inflammatory bowel disease; NEC, necrotizing enterocolitis; sIgA, secretory IgA; TLR, toll-like receptor; VLBW, very low birth weight; ZO-1, zona occludins 1. *To whom correspondence should be addressed. E-mail: [email protected].

cancer (5), diabetes and obesity (6), and necrotizing enterocolitis (NEC) (7) are all considered to be associated with gut dysbiosis and perturbations in the composition and function of the intestinal microflora. More recently, investigators have searched for ways to modulate the human bacterial flora so as to either prevent or treat human disease. Some studies have shown that the use of functional foods can modulate the composition and function of the gut microbiome as a way to alleviate symptoms and signs of IBD, irritable bowel syndrome (8), and colic in infants (9) and to prevent NEC in premature newborns (10). NEC is a leading cause of morbidity and mortality in very-low-birth-weight (VLBW) premature infants (11). The estimated cost of health care for these infants is between $500 million and $1 billion/y in the United States (12). Common symptoms include gastric retention of enteral feedings, abdominal distension, and blood per rectum (12). This devastating and debilitating disease causes mucosal inflammation, intestinal epithelial cell death, sepsis, transmural

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ã2016 American Society for Nutrition. Adv Nutr 2016;7:928–37; doi:10.3945/an.116.012237.

The human body contains a complex and still far from completely understood array of tens of trillions of microbes, including bacteria, viruses, phages, Archeae, and fungi (1). A healthy microbiome consists predominantly of commensal bacteria, which play an important role in providing the balance between health and disease (2). Alterations in this microbial homeostasis can lead to the onset of specific disorders. For instance, the development of diseases such as inflammatory bowel diseases (IBDs 8 ) (3), allergy (4), 1

perforations resulting in the contents of the intestine leaking out into the peritoneal cavity, and eventually multiple organ failure (13). The American Society for Parenteral and Enteral Nutrition clinical practice guidelines outline many questions surrounding preventive and treatment strategies for NEC (14). Randomized controlled studies showed that the mother’s own breast milk markedly improved health and survival in this vulnerable population of premature infants (15, 16). Although enteral administration of human breast milk, either as the mother’s own or by the use of donor milk banks, is a widely used prevention strategy in many parts of the world (17), probiotics, prebiotics, and more recently, synbiotics are also being evaluated for their potential use as supplements in either donor breast milk or formula to reduce the incidence of NEC (18). The purpose of this review is to consider critically the implications of using a synbiotic preparation as a supplement to enhance gut function and promote health in infants at risk of developing NEC.

Current Status of Knowledge NEC NEC is a life-threatening disease of unknown etiology in premature infants, which is characterized by excessive intestinal mucosal inflammation and epithelial cell death (12). The incidence of definitive NEC (defined as Bell stages II and III) (19) is ;7% among VLBW premature infants (20) but varies in prevalence over time and in various parts of the world. Regional differences in the occurrence of disease within countries have raised the consideration of environmental and infectious triggers as potential etiologic or exacerbating factors in the pathobiology of NEC (12). The mortality rate is high and has not decreased in the past decade despite remarkable advances in most other aspects of perinatal care (11). Surgical intervention rates remain as high as 50% (21). The higher risk of developing NEC in premature newborns is considered to be associated with the immaturity of the developing host immune system (22), defects in intestinal epithelial barrier function, gut dysmotility, and impaired regulation of the microvascular circulation (12, 13). Because gut microbes can potentially affect each of these functions (23, 24), there is now increasing interest in considering both the composition and the function of the developing gut microbiota as another factor potentially related to the risk of premature neonates developing NEC. Interestingly, antibiotic treatment has been associated with decreased microbial diversity and an increased risk of infants developing NEC (25). Prospective studies that analyzed stool samples before the onset of NEC suggest that the disease is associated with reduced microbial diversity that could accentuate the impact of single dominant species of microbes. Such dysbiosis is promoted by the widespread use of antibiotics in the neonatal intensive care unit setting (26, 27). The results of meta-analyses of prospective randomized clinical trials related to the role of probiotics in preventing NEC also support the importance of the gut microbiota in the pathogenesis of disease (28). Recent studies

support the importance of the gut microbiome and suggest that maintaining environmental homeostasis (microbial, immune balance) could prove beneficial for preventing NEC in preterm infants (29). Management strategies To date, the medical management of NEC consists primarily of supportive care, bowel rest, withdrawal of enteral feedings, administration of broad-spectrum antibiotics, and surgery to remove severely affected areas of intestine (12).

Breast milk. Randomized controlled trials have shown that the enteral administration of breast milk markedly improves the health and survival of premature infants (30), although the specific mechanisms by which breast milk elicits such beneficial effects remain largely unknown. Human breast milk contains Bifidobacteria and lactic-acid producing Lactobacillus species (31), bacteria that can dampen host proinflammatory immune responses, enhance gut epithelial barrier integrity, and promote the fermentation of dietary carbohydrates. In addition, human breast milk is rich with nutrients such as carbohydrates, proteins, and fats that are considered the optimal source of nutrition for newborns #6 mo of age (32). In addition to fulfilling nutritional demands, breast milk also provides immunologic factors that compensate for the immature immune system of the newborn. This is especially important to the preterm infant (33, 34). For example, at birth, preterm infants do not have fully mature antibodyproducing plasma cells, which results in a temporary deficiency in secretory IgA (sIgA) required to protect intestinal mucosa from luminal microorganisms. Breast milk also stimulates beneficial microbes (Bifidobacteria and Lactobacilli) in the gut lumen to trigger sIgA production (35). Mother’s own milk contains an abundance of bioactive growth factors, such as lactoferrin, epidermal growth factor (EGF), and TGF-a and TGF-b. These growth factors promote the functional maturation of the intestinal epithelium, regulate inflammatory responses, and enhance tissue healing in damaged cells (32). It is currently thought that intestinal barrier disruption, a cardinal feature triggering NEC, is a toll-like receptor (TLR) 4–dependent phenomenon (36, 37). Humans with NEC and rodent models of NEC both show elevated TLR4 expression that triggers enterocyte apoptosis and mucosal inflammation (38). EGF is highly abundant in both amniotic fluid as well as in breast milk; it inhibits TLR-4 signaling and prevents the development of NEC in animal models (39–41). In addition to promoting the developing mucosal immune system in newborns, breast milk has an important role in establishing the newborn gut microbiota (42). Full-term breastfed neonates are colonized with a number of bacterial species, including Bifidobacteria, Lactobacilli, Bacteroidetes, Proteobacteria, and Streptococci (43), all of which contribute to gut function. VLBW preterm infants possess a greater number of pathogenic microbes, such as Escherichia coli and Clostridium difficile, despite being fed breast milk (27). Functional foods and NEC 929

There are many sugars present in human milk, the most abundant components being lactose and oligosaccharides (44). The gut microbial composition is influenced by humanmilk oligosaccharides (HMOs), which are an abundant and diverse family of glycans. Unlike lactose, HMOs traverse the gastrointestinal tract unaffected by stomach acidity, intestinal absorption, and enzymatic hydrolysis (45). Once reaching the distal ileum and colon, specific Bifidobacteria species such as Bifidobacterium longum subsp. infantis, utilize HMOs as a main carbon source in exclusively breastfed infants (46). To degrade HMOs, specific HMO-utilization genes, such as those expressing cleavage enzymes or transporters, are transcriptionally activated in bacteria to confer a growth advantage in the mixed microbial community present in the distal small bowel and large intestine (47). These effects are essential for microbiome development at birth because HMOs are the first prebiotic substrates ingested by neonates. Differences in exposure during early life likely contribute to distinct “pioneer” microbial communities, which may have long-term consequences on promoting health and affecting the development of chronic noncommunicable diseases later in life (48). For instance, the growth of Bifidobacteria can compete with harmful pathogens and generate metabolites such as SCFAs (butyrate, acetate, propionate), which promote intestinal epithelial barrier function (49). Moreover, HMOs structurally mimic the carbohydrate-binding motifs of certain enteric pathogens, such as enteropathogenic E. coli and Candida albicans, to prevent microbial adhesion to the luminal surface of enterocytes (50). The effects of HMOs are multifactorial, including direct effects on epithelial cells and indirect effects on the immune system and microbial composition (45), which could prove beneficial in alleviating NEC. It is interesting to note that, although HMOs are intrinsic to mother’s milk, the composition is not universal. One study that investigated the constituents of milk samples from 52 mothers at 34–38 wk of gestation showed that, although there were a number of conserved metabolites between subjects, there was great variability in the types of oligosaccharides present (44). The consumption of breast milk by preterm infants reduces the occurrence of NEC, as shown in both prospective randomized controlled trials and in observational studies (15, 51). In VLBW infants (those with a birth weight 1000 g administered a synbiotic preparation containing 8 probiotic strains (mixture of various strains of Lactobacillus and Bifidobacterium), in combination with FOSs, did not show significant improvements in the severity of NEC, sepsis, or mortality compared with the untreated cohort (18). None of the studies that evaluated the efficacy of synbiotics in premature infants as a strategy to prevent NEC have investigated potential underlying mechanisms of action. Despite the complexity and cost of clinical trials, to add to our current knowledge base and to direct future dietary interventions the study of underlying potential mechanisms of

FIGURE 3 Schematic representation of proposed direct and indirect effects of probiotics (A), prebiotics (B), and synbiotics (C) that promote beneficial effects on the host, which include bacterial colonization, epithelial barrier integrity, intracellular signaling, innate and adaptive immunity, and metabolic processes in the intestinal tract. 934 Johnson-Henry et al.

action should be included as an integral part of all future clinical trials in this field.

Conclusions The complexity of defining the most appropriate probiotic, prebiotic, or synbiotic combination for use in various clinical settings is becoming increasingly evident. Probiotics exert strain-specific mechanisms of action (100). Prebiotics also exert effects on the host in a structure-specific manner (79). Varying doses of probiotics and prebiotics, and the complementary or synergistic effects of compounds contained in a synbiotic preparation (96), are each important considerations to take into account when formulating an intervention strategy. Potentiation of individual responses is frequently considered when justifying the use of synbiotic preparations (Figure 2). Although it is presumed that a combination of 2 individual bioactive agents may prove better that either one alone, antagonistic effects should also be considered (Figure 3). Although it is often thought that there is little or no interaction between the prebiotic and the probiotic contained in a synbiotic preparation, a recent study showed, with the use of epithelial cells grown in tissue culture, that prebiotics have a direct effect on the adherence ability of certain probiotic strains while having no impact on other strains (101). An in-depth analysis of potential prebioticprobiotic interactions should be conducted by using relevant and replicable in vitro model systems and in animal models of human disease. To date, there appears to be insufficient evidence to warrant recommending the use of synbiotics in conjunction with pasteurized breast milk for the prevention of NEC outside of the setting of a registered randomized clinical trial. Advances in the field are likely to be driven by studies that include hypothesis-driven research focused on unraveling the underlying mechanisms of action of the ingredients contained in the synbiotic preparation under evaluation. Probiotics and prebiotics on their own each have complex and diverse mechanisms of action. Trying to formulate a synthetic compound with the biological and structural complexities of human breast milk has proven to be challenging. Combining both prebiotics and probiotics into a synbiotic preparation is a first rough approximation to mimic the composition of HMOs and probiotics contained in human breast milk. Factors that must be taken into account when investigating synbiotics include the potential for synergistic responses, antagonistic reactions, additive effects, and either the enhancement or masking of adverse effects. In addition to future studies that assess the efficacy of synbiotics and potential mechanisms of action of individual components, documenting the safety of the combined preparations will be essential before considering the more widespread use of such formulations in premature infants as a management strategy to prevent NEC.

Acknowledgments All authors read and approved the final manuscript.

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Functional foods and NEC 937

Probiotics, Prebiotics, and Synbiotics for the Prevention of Necrotizing Enterocolitis.

Necrotizing enterocolitis (NEC) is a devastating intestinal disease in preterm infants characterized by barrier disruption, intestinal microbial dysbi...
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