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Editorial

Int Arch Allergy Immunol 2014;163:165167

DOI: 10.1159/000357946

Bugs versus Bugs: Probiotics,Microbiome and Allergy

M. Cecilia Berin

Pediatric Allergy and Immunology, Immunology Institute and Tisch Cancer Institute, Icahn School of

Medicine at Mount Sinai, New York, N.Y., USA

exposure to infections. Although exposure to infectionsmay be one source of immune education, the most exten-sive interaction of the human body with microbes occurswithin our own gut, which, in addition to being the siteof greatest bacterial colonization, is also the largest lym-phoid organ in the body. Over 40 years ago, it was report-ed that germ-free status resulted in spontaneous allergyand anaphylaxis to dietary milk in rabbits [8], suggestingthat the microbiota is important for actively suppressingallergic sensitization and supporting the concept of goodbugs that could be used therapeutically. It has been pro-posed that a change in the constituents of the intestinalmicrobiota promotes allergic disease, a concept support-ed by recent preclinical data [9]. Using culture-based ap-proaches to studying the human microbiome, there hasbeen a lack of consistent findings comparing healthy toatopic infants [10, 11]. However, the vast majority ofcommensal bacteria cannot be cultured and are not rep-resented in such approaches. The development of high-throughput genomic approaches for quantifying taxo-

nomic units has been used to study stool samples fromatopic infants compared to healthy controls, with a find-ing of reduced diversity and dysbiosis in allergic disease[12, 13]. Readers are referred to Garn et al. [14] for a com-prehensive review of the current state of microbiome re-search in allergic disease. Studies on larger birth cohortsare needed to definitively answer the question of howchanges in the microbiome precede the development ofatopic disease. Advances in sequencing techniques now

Probiotics, defined as live organisms which, when ad-ministered in adequate amounts, confer a health benefitto the host [1] have a long history of human use, such asthe ingestion of fermented milk products for health pur-poses. Commonly used probiotics include Lactobacillusor Bifidobacteriumspecies, which have effects on the im-mune system and intestinal barrier function that supporttheir use in the prevention or treatment of immune-me-diated disorders [24]. It remains poorly understood,however, how probiotics actually interact with our com-mensal bacteria. The intestine, particularly the large in-testine, is heavily colonized and commensal bacteria out-number human cells by a factor of 10 to 1. The intestinalmicrobiota plays a key role in the maintenance of mucosalhealth: it helps to metabolize nutrients, produce short-chain fatty acids required for epithelial metabolism andhas broad-ranging effects on the mucosal barrier, im-mune function and metabolism [5]. Manipulation ofhealth by altering the microbiome was first systematical-ly applied to livestock, where both antibiotics and probi-

otics have been used to promote weight gain [6].

Microbiome and Allergy

The growing prevalence of atopic disease in the devel-oped world led to the proposition of the hygiene hypoth-esis by Strachan [7] in 1989, in which he posited that therise in atopic disease was due to a decreased childhood

Published online: January 25, 2014

Correspondence to: Dr. M. Cecilia BerinIcahn School of Medicine at Mount Sinai1470 Madison Ave, 5-119New York, NY 10029 (USA)E-Mail cecilia.berin @ mssm.edu

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allow for accurate identification to the species level overtime [15], which will allow for the determination ofwhether there are species that prevent or promote the de-velopment of allergic disease. This good bug/bad bugconcept is fundamental to the theory of probiotic treat-ment (fig. 1).

Probiotics and Allergic Disease

Probiotics tested in human trials for the prevention ofallergic disease include Lactobacillusor Bifidobacteriumspecies or probiotic cocktails, given either postnatally orprenatally and postnatally. Preclinical studies on micehave supported an immunomodulatory effect of thesemicrobes, either in suppressing Th2 responses or pro-moting Th1 or Treg responses. Human trials have beenassociated with variable outcomes in the prevention ofeczema and allergic sensitization. In this issue of Interna-tional Archives of Allergy and Immunology, Loo et al. [16]provide 5-year follow-up data on a cohort of 253 Asianinfants at a high risk of allergic disease. Infants were ran-domized to receive a commercially available milk formu-

la supplemented with Bifidobacterium longumand Lacto-bacillus rhamnosus, or not supplemented, for the first 6months of life. In a previous report, after following theseinfants up to the age of 12 months, the investigators re-ported that there was no significant effect of probiotictreatment on outcomes of eczema or allergic sensitization[17]. In their current report, based on follow-up of thecohort yearly up to the age of 5 years, they found thatthere was no significant effect of early probiotic use on

eczema, asthma, allergic rhinitis, food allergy or sensitiza-tion to dust-mite allergens. An interesting aspect of thereport was that 92% of subjects used probiotics for a pe-riod of at least 1 year after the age of 2 years, making thegroup that had no regular exposure to probiotics up to the5th year of life very small. This postintervention probi-otic use was significantly associated with a reduced inci-dence of asthma and allergic rhinitis. These data suggestthat prolonged use of probiotics may contribute to theireffectiveness.

A recent meta-analysis [18] reported a significant ef-fect of probiotic use on total IgE and allergic sensitization,but no effect on asthma or wheeze. However, this was afinding only in studies that started supplementation pre-natally. Since the infant microbiome is derived primarilyfrom the mother, it may be necessary to alter the maternalmicrobiome in order to secure significant changes in theinfant microbiome. Alternatively, alterations in the ma-ternal microbiome could potentially alter factors in breastmilk that could promote immune tolerance. However, inthe absence of information on how probiotic treatmentinfluences either the maternal or the infant microbiome,the mechanism of action remains speculative.

Future Directions in Probiotic Research

The concept of the prevention of allergic diseasethrough manipulation of the gut microbiota is highly ap-pealing. As emphasized in a recent position paper fromthe World Allergy Organization [19], research on probi-otics is still in its infancy and there is more work that

Healthy

microbiota

Allergic

microbiota+ Probiotics

Outcome?

Colorversiona

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online

Fig. 1.It is not yet known how the micro-biota is altered in those with allergic diseasebeyond a reduction in diversity. More re-search is needed in order to identify, at the

species level, what prevents or promotes al-lergic disease and to determine how thebalance is altered in allergy. Furthermore,an understanding of how probiotic treat-ment influences microbial colonization iscurrently missing from probiotics research;this could shed light on how probioticscould be most effectively used for the pre-

vention or treatment of allergy.

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needs to be done to evaluate potential efficacy. Futurestudies need to consider the impact of probiotic treat-ment on the microbiome (both maternal and infant).There are data that feeding Lactobacillus caseican havesignificant impact on the infant microbiome [20], butthese changes have not yet been linked to health out-

comes. Diet clearly shapes the microbiome [21] and,therefore, it may be that probiotic strategies must also beaccompanied by dietary changes. Finally, emerging evi-dence for the potent regulatory activity of other bacterialstrains such as Clostridia [22, 23] indicates the need formore testing of novel probiotics.

References

1 Guarner F, Schaafsma GJ: Probiotics. Int JFood Microbiol 1998; 39: 237238.

2 Madsen KL, Doyle JS, Jewell LD, TaverniniMM, Fedorak RN: Lactobacillusspecies pre-vents colitis in interleukin 10 gene-deficientmice. Gastroenterology 1999; 116: 11071114.

3 Madsen K, Cornish A, Soper P, McKaigney C,Jijon H, Yachimec C, Doyle J, Jewell L, DeSimone C: Probiotic bacteria enhance murineand human intestinal epithelial barrier func-

tion. Gastroenterology 2001; 121: 580591.4 Pessi T, Sutas Y, Hurme M, Isolauri E: Inter-

leukin-10 generation in atopic children fol-lowing oral Lactobacillus rhamnosusgg. ClinExp Allergy 2000; 30: 18041808.

5 Blumberg R, Powrie F: Microbiota, disease,and back to health: a metastable journey. SciTransl Med 2012; 4: 137rv137.

6 Parker DS: Manipulation of the functional ac-tivity of the gut by dietary and other means(antibiotics/probiotics) in ruminants. J Nutr1990; 120: 639648.

7 Strachan DP: Hay fever, hygiene, and house-hold size. BMJ 1989; 299: 12591260.

8 Coates ME, ODonoghue PN: Milk allergy ininfant germ-free rabbits. Nature 1967; 213:307308.

9 Noval Rivas M, Burton OT, Wise P, ZhangYQ, Hobson SA, Garcia Lloret M, Chehoud C,Kuczynski J, Desantis T, Warrington J, HydeER, Petrosino JF, Gerber GK, Bry L, OettgenHC, Mazmanian SK, Chatila TA: A microbi-ota signature associated with experimentalfood allergy promotes allergic sensitizationand anaphylaxis. J Allergy Clin Immunol2013; 131: 201212.

10 Sepp E, Julge K, Mikelsaar M, Bjorksten B: In-testinal microbiota and immunoglobulin Eresponses in 5-year-old Estonian children.Clin Exp Allergy 2005; 35: 11411146.

11 Adlerberth I, Strachan DP, Matricardi PM,Ahrne S, Orfei L, Aberg N, Perkin MR, Tri-podi S, Hesselmar B, Saalman R, Coates AR,Bonanno CL, Panetta V, Wold AE: Gut mi-crobiota and development of atopic eczema in3 European birth cohorts. J Allergy Clin Im-munol 2007; 120: 343350.

12 Abrahamsson TR, Jakobsson HE, AnderssonAF, Bjorksten B, Engstrand L, Jenmalm MC:Low diversity of the gut microbiota in infants

with atopic eczema. J Allergy Clin Immunol2012; 129: 434440.

13 Wang M, Karlsson C, Olsson C, Adlerberth I,Wold AE, Strachan DP, Martricardi PM,Aberg N, Perkin MR, Tripodi S, Coates AR,Hesselmar B, Saalman R, Molin G, Ahrne S:Reduced diversity in the early fecal microbio-ta of infants with atopic eczema. J Allergy ClinImmunol 2008; 121: 129134.

14 Garn H, Neves JF, Blumberg RS, Renz H: Ef-fect of barrier microbes on organ-based in-flammation. J Allergy Clin Immunol 2013;131: 14651478.

15 Faith JJ, Guruge JL, Charbonneau M, Subra-manian S, Seedorf H, Goodman AL, Cle-mente JC, Knight R, Heath AC, Leibel RL,Rosenbaum M, Gordon JI: The long-term sta-bility of the human gut microbiota. Science2013; 341: 1237439.

16 Loo EX, Llanora GV, Lu Q, Aw MM, Lee BW,Shek LP: Supplementation with probiotics inthe first 6 months of life did not protectagainst eczema and allergy in at-risk Asian in-fants: a 5-year follow-up. Int Arch Allergy Im-munol 2013; 163: 2528.

17 Soh SE, Aw M, Gerez I, Chong YS, Rauff M,Ng YP, Wong HB, Pai N, Lee BW, Shek LP:Probiotic supplementation in the first 6months of life in at-risk Asian infants effectson eczema and atopic sensitization at the ageof 1 year. Clin Exp Allergy 2009; 39: 571578.

18 Elazab N, Mendy A, Gasana J, Vieira ER,Quizon A, Forno E: Probiotic administrationin early life, atopy, and asthma: a meta-analy-sis of clinical trials. Pediatrics 2013; 132:e666e676.

19 Fiocchi A, Burks W, Bahna SL, Bielory L,Boyle RJ, Cocco R, Dreborg S, Goodman R,Kuitunen M, Haahtela T, Heine RG, Lack G,Osborn DA, Sampson H, Tannock GW, LeeBW: Clinical use of probiotics in pediatric al-

lergy (CUPPA): a world allergy organizationposition paper. World Allergy Organ J 2012;5: 148167.

20 Cox MJ, Huang YJ, Fujimura KE, Liu JT,McKean M, Boushey HA, Segal MR, BrodieEL, Cabana MD, Lynch SV: Lactobacillus ca-sei abundance is associated with profoundshifts in the infant gut microbiome. PLoS One2010; 5:e8745.

21 Faith JJ, McNulty NP, Rey FE, Gordon JI: Pre-dicting a human gut microbiotas response todiet in gnotobiotic mice. Science 2011; 333:101104.

22 Atarashi K, Tanoue T, Shima T, Imaoka A,Kuwahara T, Momose Y, Cheng G, YamasakiS, Saito T, Ohba Y, Taniguchi T, Takeda K,Hori S, Ivanov, II, Umesaki Y, Itoh K, HondaK: Induction of colonic regulatory T cells byindigenous Clostridiumspecies. Science 2011;331: 337341.

23 Atarashi K, Tanoue T, Oshima K, Suda W,Nagano Y, Nishikawa H, Fukuda S, Saito T,Narushima S, Hase K, Kim S, Fritz JV, WilmesP, Ueha S, Matsushima K, Ohno H, Olle B,Sakaguchi S, Taniguchi T, Morita H, HattoriM, Honda K: Treg induction by a rationallyselected mixture of Clostridia strains from thehuman microbiota. Nature 2013; 500: 232236.