**8. Conclusion**

Probiotics in general are widely available and advertised for numerous health benefits ranging from infectious and inflammatory disorders - including allergy -, gut health to cognitive performance and skin health. However, the level of available or supporting scientific evidence varies widely depending on the studied probiotic strain and its proposed health benefit. Since numerous pre-clinical studies and clinical trials have examined the efficacy of candidate strains in different models and target populations, it is not possible to make the general conclusion that "probiotics" work at large for this or that purpose. As discussed in the chapter, health benefits or immune effects are strikingly strain specific, which means that observations made on one strain cannot be extrapolated, unless proven, to any other strain. As reviewed recently by Kalliomäki *et al*. (Kalliomaki et al., 2010), particularly for AD, taking into account the pre-clinical studies and clinical trials done, it is too early for the scientific community to recommend a general use of probiotics in routine clinical practice, even though specific strains have been developed with success. The metaanalyses that have been performed on probiotics and health benefits often include results of clinical trials conducted with different strains in different formats (probiotic powders or strains included in a fermented food), in different settings (prevention or treatment) targeting different populations (at risk or diseased people, varying age populations) and relying on different administration regimes (dose, timing, length of the treatment). Yet, a beneficial effect has been reported typically in the case of necrotizing enterocolitis or antibiotic-associated diarrheas. For allergy, the situation is complicated by the fact that this disease corresponds to a syndrome covering multiple manifestations that are influenced by several factors -including environmental ones- that may impact on the onset or the perpetuation of the disease (Prescott and Bjorksten, 2007). The meta-analyses conducted so far diverge somewhat in their conclusions even if they agree on the fact that the evidence is better for allergy prevention than for treatment (Doege et al., 2011; Kalliomaki et al., 2010). In 2008, ILSI Europe organized an expert meeting to establish guidance for assessing the probiotic beneficial effects and to propose how to fill the gap in the areas of digestive system metabolism, chronic intestinal disorders, infections and

infants with AD manifestations linked to cow's milk allergy and are largely effective in reducing the severity of AD. To demonstrate an improvement with probiotic supplementation is by itself a challenging primary outcome. Different strains have been evaluated in pilot clinical trials (Table 3) with mixed results. Isolauri *et al.* showed that both *L. rhamnosus* LGG and *B. lactis* Bb12 were effective in reducing the severity of AD (Isolauri et al., 2000). Interestingly, in a recent publication LGG was however shown to have no effect

The selection of the target population also plays a major role in the success of these trials. Weston *et al.* demonstrated the efficacy of *L. fermentum* PCC in a cohort of subjects with moderate to severe AD while other studies have typically selected mild to moderate AD subjects and have not succeeded in showing the efficacy of the probiotic strains (Weston et al., 2005). Combinations, with other strains or with prebiotics have been attempted with a variable success. For example, van der Aa *et al.* evaluated a combination of *B. breve* M-16V with a prebiotic mixture. After 12 weeks, the severity of atopic dermatitis (AD) did not differ between the two groups, indicating no superiority of the synbiotic combination of (pro- and

Probiotics in general are widely available and advertised for numerous health benefits ranging from infectious and inflammatory disorders - including allergy -, gut health to cognitive performance and skin health. However, the level of available or supporting scientific evidence varies widely depending on the studied probiotic strain and its proposed health benefit. Since numerous pre-clinical studies and clinical trials have examined the efficacy of candidate strains in different models and target populations, it is not possible to make the general conclusion that "probiotics" work at large for this or that purpose. As discussed in the chapter, health benefits or immune effects are strikingly strain specific, which means that observations made on one strain cannot be extrapolated, unless proven, to any other strain. As reviewed recently by Kalliomäki *et al*. (Kalliomaki et al., 2010), particularly for AD, taking into account the pre-clinical studies and clinical trials done, it is too early for the scientific community to recommend a general use of probiotics in routine clinical practice, even though specific strains have been developed with success. The metaanalyses that have been performed on probiotics and health benefits often include results of clinical trials conducted with different strains in different formats (probiotic powders or strains included in a fermented food), in different settings (prevention or treatment) targeting different populations (at risk or diseased people, varying age populations) and relying on different administration regimes (dose, timing, length of the treatment). Yet, a beneficial effect has been reported typically in the case of necrotizing enterocolitis or antibiotic-associated diarrheas. For allergy, the situation is complicated by the fact that this disease corresponds to a syndrome covering multiple manifestations that are influenced by several factors -including environmental ones- that may impact on the onset or the perpetuation of the disease (Prescott and Bjorksten, 2007). The meta-analyses conducted so far diverge somewhat in their conclusions even if they agree on the fact that the evidence is better for allergy prevention than for treatment (Doege et al., 2011; Kalliomaki et al., 2010). In 2008, ILSI Europe organized an expert meeting to establish guidance for assessing the probiotic beneficial effects and to propose how to fill the gap in the areas of digestive system metabolism, chronic intestinal disorders, infections and

on AD severity (Nermes et al., 2011).

**8. Conclusion** 

pre-biotic) over placebo (van der Aa et al., 2010).

allergic diseases and the conclusions of this work have been published (The journal of Nutrition, 140, Number 3S-I, supplement). Potential avenues for optimizing clinical trials in the field of probiotics and allergy, and caveats that may lead to misinterpretation of overall results were outlined (Kalliomaki et al., 2010).

A few studies point to the fact that probiotics may work only on IgE-mediated AD. These results although are based on (often retrospective) sub-grouping of the target population into IgE vs. non-IgE groups. Clinical trials are needed in the future specifically in large enough cohorts of IgE-mediated AD to substantiate this hypothesis.

Even though several probiotic candidate strains have been tested *in vitro* and in preclinical models of AD, it remains difficult to discuss the predictive value of these preclinical studies. Indeed there has not been sufficient alignment between the strains used for clinical trials and the ones used for preclinical studies. However, the preclinical models can certainly serve the purpose of (i) further understanding the mechanisms of action of specific strains that have been found to be beneficial in AD clinical trials, (ii) evaluating the best intervention window(s) (prenatal, perinatal, weaning, later in life), (iii) performing doseresponse curves and (iv) analyzing the impact of probiotic preparation/formulation or inclusion in a final product, to assess combinations of anti-allergy ingredients, and (v) supporting the dossier to submit for approval by ethical committees for human trials.

In conclusion, when analyzing the results of past and ongoing clinical trials performed with probiotics and allergy, it should be kept in mind that AD is a complex multifactorial disease whose onset or outcome may strongly depend on the complex interplay between the host, in particular its genetic background, the status of the immune system and intestinal microbiota, and environmental factors. Nevertheless, additional efforts in the area deserve to be pursued as nutritional interventions remain by themselves an interesting approach to manage allergic manifestations.
