Ghisolfi, Jacques*; Roberfroid, Marcel†; Rigo, Jacques‡; Moro, Guido§; Polanco, Isabel¶
Section Editor(s): Baker, Robert D. Jr. M.D., Ph.D.; Rosenthal, Philip M.D.; Sherman, Philip M. M.D., F.R.C.P.C.; Finkel, Yigael M.D., Ph.D.
*Department of Gastroenterology and Nutrition
Hôpital des Enfants, Toulouse, France
†Université Catholique de Louvain,
‡Service Universitaire de Néonatologie—CHR,
§UO di Neonatologia, Presidio Ospedaliera Macedonio
Melloni, Milano, Italy
¶Servicio de Gastroenterologia y Nutrition, Hopital Infantil
Universitario La Paz, Madrid, Spain
Infant and follow-up formula supplemented with probiotics and prebiotics are currently marketed supposedly to mimic some of the beneficial aspects of human milk or to improve a poorly defined state of “well-being.” But today the benefits or the potential risks of using such formula are not fully known and some important questions remain unanswered or only partly answered (1,2).
The composition of the intestinal commensal microflora varies all along the digestive tract as well as in different microhabitats like the epithelial mucus layer, the deep mucus layer of the crypts, and the surface of mucosal epithelial cells. These specific colonizations depend on external and internal factors including luminally available molecules, mucus quality, and host-microbial and microbial-microbial interactions (3). These factors contribute to establishing and maintaining a site specific but diversified gut microflora which plays important physiological roles conditioning the functions of the intestinal epithelium and of the mucosa, as well as local and systemic immune responses. These physiological roles are not just functions of the common probiotic organisms bifidobacteria and lactobacilli, but rather are due to the whole commensal bacterial population. As a consequence of the host's genetic identity, each individual has his own specific bacterial community but we have no idea how orally introduced foreign bacteria strains might influence the microbial-microbial and/ or host-microbial interactions. Moreover, the composition of an intestinal microflora remains difficult to evaluate due to methodological limitations. Fecal samples probably represent the flora of the distal colon, but certainly not of the ileum, the proximal colon, or the microhabitats. Traditional bacteriologic culture methods have significant limitations in identifying the commensal organisms of the human GI tract, and previously reported results are open to serious question. New molecular tools that allow a better investigation of the colonization of the gut by autochthonous or foreign specific bacterial species have recently been validated. Such new investigations will allow a better understanding of the complex microbial interactions and their functions.
In newborns, more than in adults, the micro-organisms entering the digestive tract are likely to colonize the intestine because they become established in permanent niches by inducing changes in mucus composition and epithelial gene expressions. Consequently they influence the characteristics and the stability of the infant gut microflora (3). This ecosystem acts as a specific stimulus for regulatory mediators that control the neonatal expression of microbial receptors, gene expression of mucins, innate epithelial defenses, and development of the native immune system (4). The entire commensal gut flora acquired during the early post-natal period plays an important role on these acquisitions and what really happens when its composition is artificially modified at this age is unknown.
Notwithstanding this uncertainty, the addition of bifidobacteria or lactobacilli cultures to infant formula with the aim of modifying the fecal flora of bottle-fed infants is more and more used today. The probiotic strains used to supplement infant formulas do not always belong to the specific ecosystem of the recipient and probably do not have the same impact on the ecosystem as the autochthonous bacteria. Some probiotic strains certainly have some specific effects on the intestine by targeting gut mucus glycoproteins, by reducing gut permeability, or by enhancing local intestinal and systemic immunity. However, since it is still unknown how these specific actions work and how they are controlled by the host, the selection of probiotics on criteria related to specific bacterial competitiveness and performances remain controversial. Although bifidobacteria and lactobacilli can usually be detected in the feces of infants given supplemented formula, great differences have been reported in the fecal recovery of the organisms in different subjects consuming the same product, at an identical daily dose. This emphasizes the importance of host factors in the colonization process.
Another approach to modifying infant intestinal microflora has been recently proposed which makes use of prebiotics, essentially inulin, oligofructose, and transoligosaccharides. This approach aims at modifying the composition of the commensal gut microflora by selectively stimulating the growth of supposedly health promoting indigenous micro-organisms. Such an effect has essentially been demonstrated for bifidobacteria and lactobacilli and more recently for the eubacteria in infants as well as in adults. Prebiotics also significantly decrease the number of E Coli and clostridia in faeces. They act as selective fermentation substrates and influence microbial activities and mineral intestinal absorption, as well as immune processes. The understanding of the clinical consequences to infants receiving prebiotic supplementation is preliminary and needs further investigation.
When using probiotic or prebiotic supplemented formula to feed infants, health benefits are observed, but it is not always clear that they are directly linked to the observed changes in the colonic microflora. Probiotics have been used with some success to treat diaper rash and constipation, to decrease the incidence and severity of infant acute diarrheal diseases and respiratory infections, and to prevent atopic disease in high-risk infants. Prebiotics have been shown to be effective in treating constipation and other intestinal discomforts, in enhancing immune response and in reducing the severity of acute diarrheal diseases, febrile events, antibiotic use, and day care absenteeism. However, further experimental and clinical studies are still needed to provide conclusive evidence that a specific probiotic strain, or a particular prebiotic or a mixture of prebiotics, is effective in preventing or treating common diseases or improving infant well-being.
Regarding risks, probiotics or prebiotics have been extensively studied in adult humans with no observed adverse effects in normal use conditions. Neither probiotics nor prebiotics have a negative influence on infant growth, nitrogen balance, mineral bioavailability, or hydration. A unique case of anaphylactic reaction to inuline and oligofructose has been reported in one adult, but a risk of allergenic sensitization thus far is not supported by any pediatric observations nor has it been confirmed in adults. In infants, the main questions concerning potential risks are the immediate or long-term toxicity of promoting a particular bacteria in the intestine, and the early or long-time modulation of the complex microbial system. Up to now, no adverse microbial or immunological effects have been reported in infants or in adults. However, a better understanding of the short- and long-term consequences of artificially modifying the composition of a healthy intestinal infant microflora, by introducing a foreign bacteria strain (probiotics), on long-term control of autochthonous flora and on activation of the mucosal immune system certainly remains an important challenge for the future of pediatric nutrition research. In this context, we must consider that the prebiotic approach is possibly a more natural way to influence the gut microflora than most probiotics.
In today's attempt to improve infant and follow-up formulas, probiotics or prebiotics supplementation represents a fascinating concept and the presently available scientific knowledge justifies from now on the consumption of some of these products by infants. However, despite recent important advances, the data available actually remain, in many cases, preliminary. Ongoing and upcoming research will certainly bring, in the near future, new and convincing data to answer the main questions. In any case, there is a need for a rigorous scientific evaluation of all products marketed to insure their safety and efficacy. For this reason, intervention studies are absolutely necessary to evaluate the immediate and long-term benefits and the absence of harmful consequences of any new formula. This evaluation must be part of a program of public health policy and not only performed by industry.
1. Scientific Committee on Food. European Commission. Additional statement on the use of resistant short chain carbohydrates (oligofructosyl-saccharose and oligogalactosyl-lactose) in infant formulae and in follow-on formulae. December 13th, 2001.
2. Murch SH. Toll of allergy reduced by probiotics. Lancet 2001; 357:1057–9.
3. Hooper LV, Gosdon JI. Commensal host-bacterial relationships in the gut. Science 2001; 292:1115–8.
4. Gröenlund MM, Arvilommi H, Kero P, et al. Importance of intestinal colonisation in the maturation of humoral immunity in early infancy: a prospective follow up study of healthy infants aged 0–6 months. Arch Dis Child Fetal Neonatal 2000; 83:F186–F92.
© 2002 Lippincott Williams & Wilkins, Inc.