The PandA study is the first study of perinatal administration of probiotic bacteria for the primary prevention of atopic diseases in which strains were selected based on in vitro cytokine production. The PandA study thereby crossed the gap between in vitro effects of probiotic bacteria and outcomes in clinical trials. Furthermore, the PandA study tried to identify the immune modulating activities of probiotics in vivo in the context of clinical outcomes. Certain immunomodulatory effects demonstrated in vitro, such as the reduction in the Th2-associated cytokines IL-5 and IL-13, were subsequently observed ex vivo in whole blood cells obtained from probiotic-supplemented infants. Subsequently, the PandA study provided evidence that probiotic bacteria may induce beneficial clinical effects by modulating the early composition of the intestinal microbiota such as enhancing richness and diversity. In future studies the window of opportunity may allow to switch to another (combination of) probiotic in the absence of modulation of the intestinal microbiota and thereby a sort of “second chance” primary prevention. Furthermore, future studies need to continue identifying the immune activities of probiotics in vivo in the context of clinical outcomes. Figure 3 summarizes the potential mechanisms of action and clinical effects of perinatal administration of probiotic bacteria. There is a high public enthusiasm for probiotic use although conclusive evidence for “health benefits” is still required, and “health claims” from commercially available products overstate our current knowledge. Probiotics may be used to prevent and to treat a number of different diseases. The efficacy of treatment is proven in randomized double-blind placebo-controlled studies for a number of diseases of the gastrointestinal tract, like pouchitis, antibiotics-
associated diarrhea, and Clostridium difficile-induced enterocolitis 52-54. Some studies suggest
that probiotics may have beneficial effects in patients with lactose intolerance, rotavirus diarrhea, and irritable bowel disease. For other claims, proper supporting evidence is lacking. Detrimental
55 and potentially negative effects 29;44 have been reported as well which emphasizes the issue
of safety of probiotic bacteria. This calls for a critical and cautious approach in developing future studies with probiotic bacteria. The Dutch Food and Consumer Product Safety Authority (VWA) recently conducted a literature survey concerning the safety of the consumption of probiotic
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bacteria (www.vwa.nl). They concluded that there is no evidence for adverse effects in healthy individuals. Long term, possibly negative, effects in children should however be investigated. Worth mentioning is that different probiotics (even within a species) may differ with respect to effect. Therefore, it seems logical to hypothesize that not all probiotics will be beneficial in all diseases. In addition, probiotic bacteria are clearly not beneficial in every individual in the population, but probably only to those with a particular genetic susceptibility, maybe even within certain environmental co-factors. This challenges future studies how to choose monostrain or multispecies probiotics. The concept of strain selection based on in vitro cytokine profiles and potential interactions with the immune system could be used in combination with qualities concerning safety, survival of the first part of the gastro-intestinal tract, i.e. resistance to acid and bile, the capacity to reach high prevalence and abundance in fecal microbiota, and the capacity to modulate the resident intestinal microbiota. However, thorough strain selection does not guarantee probiotic effectiveness in vivo due to the complexity of the host, necessitating randomized clinical intervention.
Future research should focus on the long-term effects of perinatal administration of probiotic bacteria regarding the development of sensitization, asthma and allergic rhinitis. Furthermore, the effects of prenatal administration of probiotic bacteria to pregnant women on their intestinal microbiota and immune system and subsequently on their offspring should be more thoroughly addressed. Mechanistic studies are needed to unravel which component(s) of probiotic bacteria are crucial in determining their effects, what is the gastrointestinal niche of probiotic bacteria and how do they interact with the commensal microbiota and the gastrointestinal immune system. This should include well defined animal models but preferably human studies including intestinal biopsies (to study the intestinal microbiota and the first lining of the mucosal immune system of the gut) as well. Perinatal supplementation with probiotics holds promise for the prevention of childhood eczema. However, the clinical effects of single probiotic strains or combinations on the development of eczema should be confirmed in similar trials. The large heterogeneity in clinical studies and used probiotic preparations currently undermines solid scientific evidence and hampers the general recommendation to use probiotic bacteria in primary prevention of atopic diseases in high-risk children.
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Figure 3: Summary of potential effects of probiotic bacteria. a) After surviving the digestive process of the stomach and first part of the small intestine, probiotic bacteria may influence the composition of the developing intestinal microbiota by inducing more richness and diversity and by stimulating or inhibiting the presence of commensal bacterial communities. b) Recognition of probiotic bacteria by intestinal epithelial cells (IECs) may influence the secretion of cytokines and other tissue factors by IEC that direct the expression of cytokines and polarizing capacity of underlying dendritic cells (DC). c) Pattern recognition receptors including Toll-like receptors and C-type lectins are expressed by IECs and underlying intestinal dendritic cells and may recognize probiotic bacteria. Dendritic cells may interact with probiotic bacteria by extending their dendrites between tight junctions to directly sample the luminal microbiota, or bacteria may pass the intestinal epithelial barrier via M cells. d) In mesenteric lymphnodes and Peyer’s patches, DC may promote the differentiation of regulatory T cells and IgA-secreting B cells (not shown) or polarize T helper cells into Th1 or Th2 cells. Probiotic bacteria may thereby modulate the intestinal as well as the systemic immune system. e) How probiotic bacteria eventually influence the development of atopic diseases is not fully understood. f) Prenatal administration of probiotic bacteria to the mother may influence the composition of the intestinal microbiota of her newborn and may modulate the neonatal immune system.
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