Probiotics in Preterm Infants: A Controversial Issue

Abstract

Current research is directed toward innovative dietary compositions that exert specific effects on health promotion and reducing the risk of diseases. For example, the demonstration that the gut microbiota is an important constituent in the intestine's mucosal barrier has led to new therapeutic strategies for infections as well as allergic and inflammatory conditions. Specific probiotic bacteria have been shown to stabilize the gut microbial environment and the intestine's permeability barrier, and to enhance systemic and mucosal IgA responses. These comprise important targets in the preterm infant, who is particularly susceptible to infection and inflammation and in whom the immature enterocyte responds to intraluminal antigens with proinflammatory cytokines. Recent data point to differences in immunomodulatory effects between candidate probiotic bacteria. Each probiotic strain is a unique component itself, and each strain has specific properties that cannot be extrapolated from other, even closely related, strains. Therefore, these properties of probiotic bacteria should be characterized during preclinical and clinical evaluations. Furthermore, because probiotics are a tool with which to modify the gut barrier and microbiota, the strains used must be obtained from acceptable sources with a proven safety record and efficacy to guarantee their future clinical applications. The approach of supplementation with single components, however, overlooks the role of dietary composition, with its range of nutrients and other potentially active components, and also the conceivable combined effects. Consequently, research now focuses both on characterizing specific probiotic strains and on how the food matrix and the dietary content interact with the most efficient probiotic strains.

Probiotics are live microbial food supplements or components of bacteria that have been demonstrated to have beneficial effects on human health ⁽¹⁾. Probiotic therapy is based on the concept of normal gut microbiota. Abundant evidence implies that specific strains selected from the healthy gut microbiota exhibit powerful antipathogenic and anti-inflammatory capabilities. Oral introduction of probiotics has been shown to reinforce various lines of gut defence, including immune exclusion, immune elimination, and immune regulation. Probiotics also stimulate nonspecific host resistance to microbial pathogens and thereby aid in their eradication.

Probiotics are used to reduce the risk of diseases associated with gut barrier dysfunction. The probiotic performance of strains differs; different bacteria or components thereof have defined adherence sites and immunological effects, and varied effects in the healthy versus inflamed mucosal milieu. These specific probiotic properties may be exploited in the development of disease-specific prophylactic and therapeutic interventions.

GUT BARRIER: TARGET OF PROBIOTIC THERAPY

The mucosal surface of the gastrointestinal tract is an important organ of host defence. In addition to its principal physiological function, digestion and absorption of nutrients, the intestinal mucosa provides a protective interface between the internal environment and the constant challenge from antigens such as food and microorganisms from the external environment. Protection against potentially harmful agents encountered by the enteric route is ensured by a number of nonimmunological factors, including saliva, gastric acid, peristalsis, mucus, intestinal proteolysis, and epithelial cell membranes with the intercellular junctional complexes. The unique mucosal immune system constitutes 2 arms of defence: immune exclusion performed by the secretory immunoglobulin system and immune regulation pertaining to the state of specific hyporesponsiveness induced by prior oral administration of antigens.

During a variable period after birth, the mucosal immune system is functionally immature ⁽¹⁾. In newborns, the capacity to generate IgA-producing cells is inadequate. Their number increases progressively in response to intestinal antigenic stimulation, particularly when oral food intake begins and the gut microbiota is established. Establishment of a normal microbiota provides the host with the most substantial antigen challenge, with a strong stimulatory effect for the maturation of the gut-associated lymphoid tissue. There are data to suggest that delayed maturation of humoral immune defence mechanisms, particularly of circulating IgA- and IgM-secreting cells, is a consequence of aberrant compositional development of the gut microbiota.

The immune exclusion functions are incompletely developed in early infancy, this manifesting itself in transiently increased intestinal permeability. The binding of antigens to immature gut microvillus membrane is increased compared with the mature mucosa, which circumstance has been shown to correlate with the increased uptake of intact macromolecules.

With an immature immune system, the premature infant has lower gastric acid production, lower concentrations of protective mucus, lower proteolytic enzyme activity, and decreased gut motility. Also burdened with immature glycosylation patterns, leading to heightened risk of adherence and translocation of pathogens, the premature infant is particularly susceptible to infection and inflammation ⁽²⁾. Furthermore, the immature enterocyte responds to these antigen challenges with proinflammatory cytokines.

Inflammation and infection are again frequently accompanied by an imbalance in the intestinal microbiota. A strong inflammatory response may then be mounted to microbiota bacteria, leading to perpetuation of the inflammation and gut barrier dysfunction.

Probiotic bacteria may counteract the inflammatory process by stabilizing the gut microbial environment and the intestine's permeability barrier, and by enhancing the degradation of enteral antigens and altering their immunogenicity. Another explanation for the gut-stabilizing effect could be improvement of the intestine's immunological barrier, particularly intestinal IgA responses. Probiotic effects also may be mediated via control of the balance between pro- and anti-inflammatory cytokines. Modification of intestinal microbiota to increase the predominance of specific nonpathogenic bacteria and promotion of the gut immunological and nonimmunological barrier functions and thereby to alter the intestinal milieu may thus be taken as an alternative to attain prophylactic or therapeutic effects in premature infants who may develop a colonic microbiota radically different from that of healthy term infants ⁽³⁾. Indeed, reducing the risk of necrotizing enterocolitis in preterm infants is seen as one of the most exciting probiotic applications ⁽³⁾.

SAFETY OF PROBIOTIC THERAPY

A number of probiotics have a long history of safe use and a demonstrated safety record in human consumption, and no health concerns have been observed. As more adhesive strains have been selected for probiotic use, the ability to survive in gastric conditions and to adhere to the intestinal epithelium may entail a risk of translocation. Translocation may be enhanced by gut barrier dysfunction caused by immaturity or inflammation. Effective probiotics possess, however, properties that counteract epithelial damage and consequently reduce the risk of translocation. Nevertheless, the concept of translocation implies specific safety requirements for microbes used in premature infants.

Long-term colonization by probiotics or impairment of the natural diversity of the gut microbiota has been addressed with probiotic intervention at an early age. Permanent colonization has not been reported in clinical intervention studies ^(4,5). Thus, the probiotic impact on gut microbiota succession is temporary, but it may guide subsequent colonization and immunological development, conferring a clinical benefit. Moreover, perinatal probiotic therapy has not been shown to impair growth in infancy or early childhood ⁽⁶⁾.