Probiotics and prebiotics in atopic dermatitis: Pros and cons (Review)

Ionut Serban Fanfaret, Daniel Boda, Laura Mihaela Ion, Daniela Hosseyni, Poliana Leru, Selda Ali, Sabina Corcea, Roxana Bumbacea, Ionut Serban Fanfaret, Daniel Boda, Laura Mihaela Ion, Daniela Hosseyni, Poliana Leru, Selda Ali, Sabina Corcea, Roxana Bumbacea

Abstract

Atopic dermatitis (AD) represents a chronic inflammatory skin condition in which the skin barrier is impaired; thus, the permeability is increased. Hence, there is a greater risk of allergic sensitization, as well as a higher pH and lower protection against resident microbes. Since this condition is currently increasing among children, it requires further study, as little is known regarding the pathogenesis that makes the skin prone to chronic relapsing inflammation. Trying to standardize the data regarding the use of prebiotics and probiotics in AD, we encountered tremendous variability in the literature data. Literature abounds in conflicting data: studies regarding prophylactic and therapeutic applications, different types of strains and dosages, applications in young children up to 5 years of age and above, usage of probiotics alone, prebiotics alone or synbiotics combined. There are also conflicting data regarding the outcome of these studies; some confirming a positive effect of prebiotics, probiotics or synbiotics and some showing no efficacy at all. The articles were divided into those assessing probiotics or prebiotics alone and a combination of the two, with studies showing a positive effect and studies proving no efficacy at all. We tried to critically analyze those articles showing weak and strong points. In summary, the most studied probiotics were the strains of Lactobacilli and Bifidobacteria. The Severity Scoring of Atopic Dermatitis (SCORAD) index was used to measure the efficacy of the treatment. Most studies compared their results with a placebo group and the efficacy when seen in moderate to severe forms of AD in patients with other allergic diseases present. However, the results are difficult to interpret, as in many studies the authors suggest that the disease may have a tendency to improve in time in some groups of patients.

Keywords: atopic dermatitis; chronic ski inflammation; gut microbiome; prebiotics; probiotics; synbiotics.

Conflict of interest statement

The authors declare that they have no competing interests.

Copyright: © Fanfaret et al.

References

    1. Sansotta N, Peroni DG, Romano S, Rugiano A, Vuilleumier P, Baviera G. The good bugs: The use of probiotics in pediatrics. Curr Opin Pediatr. 2019;31:661–669. doi: 10.1097/MOP.0000000000000808. Italian Society of Pediatric Allergy, Immunology (SIAIP), Microbiota Committee, Italy.
    1. Bantz SK, Zhu Z, Zheng T. The atopic march: Progression from atopic dermatitis to allergic rhinitis and asthma. J Clin Cell Immunol. 2014;5(202) doi: 10.4172/2155-9899.1000202.
    1. Bumbăcea RS, Deaconu CG, Berghea EC. Management problems in severe chronic inducible urticaria: Two case reports. Exp Ther Med. 2019;18:960–963. doi: 10.3892/etm.2019.7651.
    1. Bumbacea R, Berghea E, Giurcaneanu C. Frequency of contact sensitisation in children with atopic dermatitis. Allergy. 2007;62 (Suppl 83)(S319)
    1. Eichenfield LF, Tom WL, Chamlin SL, Feldman SR, Hanifin JM, Simpson EL, Berger TG, Bergman JN, Cohen DE, Cooper KD, et al. Guidelines of care for the management of atopic dermatitis: Section 1. Diagnosis and assessment of atopic dermatitis. J Am Acad Dermatol. 2014;70:338–351. doi: 10.1016/j.jaad.2013.10.010.
    1. Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema: ISAAC The International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee. Lancet. 1998;351:1225–1232. No authors listed.
    1. Rather IA, Bajpai VK, Kumar S, Lim J, Paek WK, Park YH. Probiotics and atopic dermtitis: An overview. Front Microbiol. 2016;7(507) doi: 10.3389/fmicb.2016.00507.
    1. Monti F, Agostini F, Gobbi F, Neri E, Schianchi S, Arcangeli F. Quality of life measures in Italian children with atopic dermatitis and their families. Ital J Pediatr. 2011;37(59) doi: 10.1186/1824-7288-37-59.
    1. Chernyshov PV, Sampogna F, Pustišek N, Marinovic B, Manolache L, Suru A, Salavastru CM, Tiplica GS, Stoleriu G, Kakourou T, et al. Validation of the dermatology-specific proxy instrument the infants and toddlers dermatology quality of life. J Eur Acad Dermatol Venereol. 2019;33:1405–1411. doi: 10.1111/jdv.15496.
    1. Kim NY, Ji GE. Effects of probiotics on the prevention of atopic dermatitis. Korean J Pediatr. 2012;55:193–201. doi: 10.3345/kjp.2012.55.6.193.
    1. Solomon I, Ilie MA, Draghici C, Voiculescu VM, Caruntu C, Boda D, Zurac S. The impact of lifestyle factors on evolution of atopic dermatitis: An alternative approach. Exp Ther Med. 2019;17:1078–1084. doi: 10.3892/etm.2018.6980.
    1. Bumbacea RS, Corcea SL, Ali S, Dinica LC, Fanfaret IS, Boda D. Mite allergy and atopic dermatitis: Is there a clear link? (Review) Exp Ther Med. 2020;20:3554–3560. doi: 10.3892/etm.2020.9120.
    1. Meneghin F, Fabiano V, Mameli C, Zuccotti GV. Probiotics and atopic dermatitis in children. Pharmaceuticals (Basel) 2012;5:727–744. doi: 10.3390/ph5070727.
    1. Bjorksten B. The intrauterine and postnatal environments. J Allergy Clin Immunol. 1999;104:1119–1127. doi: 10.1016/s0091-6749(99)70002-3.
    1. Ro ADB, Simpson MR, Rø TB, Storrø O, Johnsen R, Videm V, Øien T. Reduced Th22 cell proportion and prevention of atopic dermatitis in infants following maternal probiotic supplementation. Clin Exp Allergy. 2017;47:1014–1021. doi: 10.1111/cea.12930.
    1. Strachan DP. Hay fever, hygiene, and household size. BMJ. 1989;299:1259–1260. doi: 10.1136/bmj.299.6710.1259.
    1. Strachan DP. Family size, infection and atopy: The first decade of the ‘hygiene hypothesis’. Thorax. 2000;55 (Suppl 1):S2–S10. doi: 10.1136/thorax.55.suppl_1.s2.
    1. Prescott SL, Macaubas C, Holt BJ, Snallacombe TB, Loh R, Sly PD, Holt PG. Transplacental priming of the human immune system to environmental allergens: Universal skewing of initial T cell responses toward the Th2 cytokine profile. J Immunol. 1998;160:4730–4737.
    1. Kopp MV, Zehle C, Pichler J, Szépfalusi Z, Moseler M, Deichmann K, Forster J, Kuehr J. Allergen-specific T cell reactivity in cord blood: The influence of maternal cytokine production. Clin Exp Allergy. 2001;31:1536–1543. doi: 10.1046/j.1365-2222.2001.01198.x.
    1. Prescott SL, Macaubas C, Smallacombe T, Holt BJ, Sly PD, Holt PG. Development of allergen-specific T-cell memory in atopic and normal children. Lancet. 1999;353:196–200. doi: 10.1016/S0140-6736(98)05104-6.
    1. Sudo N, Sawamura S, Tanaka K, Aiba Y, Kubo C, Koga Y. The requirement of intestinal bacterial flora for the development of an IgE production system fully susceptible to oral tolerance induction. J Immunol. 1997;159:1739–1745.
    1. Riedler J, Braun-Fahrlander C, Eder W, Schreuer M, Waser M, Maisch S, Carr D, Schierl R, Nowak D, von Mutius E. Exposure to farming in early life and development of asthma and allergy: A cross-sectional survey. Lancet. 2001;358:1129–1133. doi: 10.1016/S0140-6736(01)06252-3. ALEX Study Team.
    1. Taylor AL, Dunstan JA, Prescott SL. Probiotic supplementation for the first 6 months of life fails to reduce the risk of atopic dermatitis and increases the risk of allergen sensitization in high-risk children: A randomized controlled trial. J Allergy Clin Immunol. 2007;119:184–191. doi: 10.1016/j.jaci.2006.08.036.
    1. Williams H, Robertson C, Stewart A, Aït-Khaled N, Anabwani G, Anderson R, Asher I, Beasley R, Björkstén B, Burr M, et al. Worldwide variations in the prevalence of symptoms of atopic eczema in the International study of asthma and allergies in childhood. J Allergy Clin Immunol. 1999;103:125–138. doi: 10.1016/s0091-6749(99)70536-1.
    1. Brandt EB, Sivaprasad U. Th2 cytokines and atopic dermatitis. J Clin Cell Immunol. 2011;2(110) doi: 10.4172/2155-9899.1000110.
    1. Kubo A, Nagao K, Amagai M. Epidermal barrier dysfunction and cutaneous sensitization in atopic diseases. J Clin Invest. 2012;122:440–447. doi: 10.1172/JCI57416.
    1. Candela M, Rampelli S, Turroni S, Severgnini M, Consolandi C, De Bellis G, Masetti R, Ricci G, Pession A, Brigidi P. Unbalance of intestinal microbiota in atopic children. BMC Microbiol. 2012;12(95) doi: 10.1186/1471-2180-12-95.
    1. Penders J, Stobberingh EE, van den Brandt PA, Thijs C. The role of the intestinal microbiota in the development of atopic disorders. Allergy. 2007;62:1223–1236. doi: 10.1111/j.1398-9995.2007.01462.x.
    1. Baker BS. The role of microorganisms in atopic dermatitis. Clin Exp Immunol. 2006;144:1–9. doi: 10.1111/j.1365-2249.2005.02980.x.
    1. Kunz B, Oranje AP, Labrèze L, Stalder JF, Ring J, Taïeb A. Clinical validation and guidelines for the SCORAD index: Consensus report of the European task force on atopic dermatitis. Dermatology. 1997;195:10–19. doi: 10.1159/000245677.
    1. Guarner F, Schaafsma GJ. Probiotics. Int J Food Microbiol. 1998;39:237–238. doi: 10.1016/s0168-1605(97)00136-0.
    1. Van Santvoort HC, Besselink MG, Timmerman HM, van Minnen LP, Akkermans LM, Gooszen HG. Probiotics in surgery. Surgery. 2008;143:1–7. doi: 10.1016/j.surg.2007.06.009.
    1. Frei R, Akdis M, O'Mahony L. Prebiotics, probiotics, synbiotics, and the immune system: Experimental data and clinical evidence. Curr Opin Gastroenterol. 2015;31:153–158. doi: 10.1097/MOG.0000000000000151.
    1. Enomoto T, Sowa M, Nishimori K, Shimazu S, Yoshida A, Yamada K, Furukawa F, Nakagawa T, Yanagisawa N, Iwabuchi N, et al. Effects of bifidobacterial supplementation to pregnant women and infants in the prevention of allergy development in infants and on fecal microbiota. Allergol Int. 2014;63:575–585. doi: 10.2332/allergolint.13-OA-0683.
    1. Rusu E, Enache G, Cursaru R, Alexescu A, Radu R, Onila O, Cavallioti T, Rusu F, Posea M, Jinga M, Radulian G. Prebiotics and probiotics in atopic dermatitis. Exp Ther Med. 2019;18:926–931. doi: 10.3892/etm.2019.7678.
    1. Borchers AT, Selmi C, Meyers FJ, Keen CL, Gershwin ME. Probiotics and immunity. J Gastroenterol. 2009;44:26–46. doi: 10.1007/s00535-008-2296-0.
    1. Alvarez-Olmos MI, Oberhelman RA. Probiotic agents and infectious diseases: A modern perspective on a traditional therapy. Clin Infect Dis. 2001;32:1567–1576. doi: 10.1086/320518.
    1. Roberfroid M, Gibson GR, Hoyles L, McCartney AL, Rastall R, Rowland I, Wolvers D, Watzl B, Szajewska H, Stahl B, et al. Prebiotic effects: Metabolic and health benefits. Br J Nutr. 2010;104 (Suppl 2):S1–S63. doi: 10.1017/S0007114510003363.
    1. Passeron T, Lacour JP, Fontas E, Ortonne JP. Prebiotics and synbiotics: Two promising approaches for the treatment of atopic dermatitis in children above 2 years. Allergy. 2006;61:431–437. doi: 10.1111/j.1398-9995.2005.00956.x.
    1. Gibson GR, Roberfroid MB. Dietary modulation of the human colonic microbiota: Introducing the concept of prebiotics. J Nutr. 1995;125:1401–1412. doi: 10.1093/jn/125.6.1401.
    1. Maslowski KM, Vieira AT, Ng A, Kranich J, Sierro F, Yu D, Schilter HC, Rolph MS, Mackay F, Artis D, et al. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature. 2009;461:1282–1286. doi: 10.1038/nature08530.
    1. De Preter V, Geboes K, Verbrugghe K, De Vuyst L, Vanhoutte T, Huys G, Swings J, Pot B, Verbeke K. The in vivo use of the stable isotope-labelled biomarkers lactose-[15N]ureide and [2H4]tyrosine to assess the effects of pro- and prebiotics on the intestinal flora of healthy human volunteers. Br J Nutr. 2004;92:439–446. doi: 10.1079/bjn20041228.
    1. Schley PD, Field CJ. The immune-enhancing effects of dietary fibres and prebiotics. Br J Nutr. 2002;87 (Suppl 2):S221–S230. doi: 10.1079/BJNBJN/2002541.
    1. Moro G, Minoli I, Mosca M, Fanaro S, Jelinek J, Stahl B, Boehm G. Dosage-related bifidogenic effects of galactoand fructooligosaccharides in formula-fed term infants. J Pediatr Gastroenterol Nutr. 2002;34:291–295. doi: 10.1097/00005176-200203000-00014.
    1. Haarman M, Knol J. Quantitative real-time PCR assays to identify and quantify fecal Bifidobacterium species in infants receiving a prebiotic infant formula. Appl Environ Microbiol. 2005;71:2318–2324. doi: 10.1128/AEM.71.5.2318-2324.2005.
    1. Schmelzle H, Wirth S, Skopnik H, Radke M, Knol J, Böckler HM, Brönstrup A, Wells J, Fusch C. Randomized double-blind study of the nutritional efficacy and bifidogenicity of a new infant formula containing partially hydrolyzed protein, a high beta-palmitic acid level, and nondigestible oligosaccharides. J Pediatr Gastroenterol Nutr. 2003;36:343–351. doi: 10.1097/00005176-200303000-00008.
    1. Kovacs Z, Benjamins E, Grau K, Ur Rehman A, Ebrahimi M, Czermak P. Recent developments in manufacturing oligosaccharides with prebiotic functions. Adv Biochem Eng Biotechnol. 2014;143:257–295. doi: 10.1007/10_2013_237.
    1. Blaser MJ. The microbiome revolution. J Clin Invest. 2014;124:4162–4165. doi: 10.1172/JCI78366.
    1. Gerlich J, Benecke N, Peters-Weist AS, Heinrich S, Roller D, Genuneit J, Weinmayr G, Windstetter D, Dressel H, Range U, et al. Pregnancy and perinatal conditions and atopic disease prevalence in childhood and adulthood. Allergy. 2018;73:1064–1074. doi: 10.1111/all.13372.
    1. Huang YJ, Marsland BJ, Bunyavanich S, O'Mahony L, Leung DY, Muraro A, Fleisher TA. The microbiome in allergic disease: Current understanding and future opportunities-2017 PRACTALL document of the American academy of allergy, asthma & immunology and the European academy of allergy and clinical immunology. J Allergy Clin Immunol. 2017;139:1099–1110. doi: 10.1016/j.jaci.2017.02.007.
    1. Di Gangi A, Di Cicco ME, Comberiati P, Peroni DG. Go with your gut: The shaping of T-cell response by gut microbiota in allergic asthma. Front Immunol. 2020;11(1485) doi: 10.3389/fimmu.2020.01485.
    1. Maslowski KM, Mackay CR. Diet, gut microbiota and immune responses. Nat Immunol. 2011;12:5–9. doi: 10.1038/ni0111-5.
    1. Gray LE, O'Hely M, Ranganathan S, Sly PD, Vuillermin P. The maternal diet, gut bacteria, and bacterial metabolites during pregnancy influence offspring asthma. Front Immunol. 2017;8(365) doi: 10.3389/fimmu.2017.00365.
    1. Kong HH, Oh J, Deming C, Conlan S, Grice EA, Beatson MA, Nomicos E, Polley EC, Komarow HD. et al. Temporal shifts in the skin microbiome associated with disease flares and treatment in children with atopic dermatitis. Genome Res. 2012;22:850–859. doi: 10.1101/gr.131029.111. NISC Comparative Sequence Program.
    1. Lunjani N, Satitsuksanoa P, Lukasik Z, Sokolowska M, Eiwegger T, O'Mahony L. Recent developments and highlights in mechanisms of allergic diseases: Microbiome. Allergy. 2018;73:2314–2327. doi: 10.1111/all.13634.
    1. Swanson KS, Gibson GR, Hutkins R, Reimer RA, Reid G, Verbeke K, Scott KP, Holscher HD, Azad MB, Delzenne NM, Sanders ME. The International scientific association for probiotics and prebiotics (ISAPP) consensus statement on the definition and scope of synbiotics. Nat Rev Gastroenterol Hepatol. 2020;17:687–701. doi: 10.1038/s41575-020-0344-2.
    1. Sommacal HM, Bersch VP, Vitola SP, Osvaldt AB. Perioperative synbiotics decrease postoperative complications in periampullary neoplasms: A randomized, double-blind clinical trial. Nutr Cancer. 2015;67:457–462. doi: 10.1080/01635581.2015.1004734.
    1. Stenman LK, Lehtinen MJ, Meland N, Christensen JE, Yeung N, Saarinen MT, Courtney M, Burcelin R, Lähdeaho ML, Linros J, et al. Probiotic with or without fiber controls body fat mass, associated with serum zonulin, in overweight and obese adults-randomized controlled trial. EBioMedicine. 2016;13:190–200. doi: 10.1016/j.ebiom.2016.10.036.
    1. Aldaghi M, Tehrani H, Karrabi M, Abadi FS, Sahebkar M. The effect of multistrain synbiotic and vitamin D3 supplements on the severity of atopic dermatitis among infants under 1 year of age: A double-blind, randomized clinical trial study. J Dermatolog Treat 1-6, 2020 (Epub ahead of print).
    1. Dissanayake E, Tani Y, Nagai K, Sahara M, Mitsuishi C, Togawa Y, Suzuki Y, Nakano T, Yamaide F, Ohno H, Shimojo N. Skin care and synbiotics for prevention of atopic dermatitis or food allergy in newborn infants: A 2 x 2 factorial, randomized, non-treatment controlled trial. Int Arch Allergy Immunol. 2019;180:202–211. doi: 10.1159/000501636.
    1. Isolauri E, Arvola T, Sutas Y, Moilanen E, Salminen S. Probiotics in the management of atopic eczema. Clin Exp Allergy. 2000;30:1604–1610. doi: 10.1046/j.1365-2222.2000.00943.x.
    1. Weston S, Halbert A, Richmond P, Prescott SL. Effects of probiotics on atopic dermatitis: A randomised controlled trial. Arch Dis Child. 2005;90:892–897. doi: 10.1136/adc.2004.060673.
    1. Smits HH, Engering A, van der Kleij D, de Jong EC, Schipper K, van Capel TM, Zaat BA, Yazdanbakhsh M, Wierenga EA, van Kooyk Y, Kapsenberg ML. Selective probiotic bacteria induce IL-10-producing regulatory T cells in vitro by modulating dendritic cell function through dendritic cell-specific intercellular adhesion molecule 3-brabbing nonintegrin. J Allergy Clin Immunol. 2005;115:1260–1267. doi: 10.1016/j.jaci.2005.03.036.
    1. Lesiak A, Smolewski P, Sobolewska-Sztychny D, Sysa-Jedrzejowska A, Narbutt J. The role of T regulatory cells and Toll-like receptors 2 and 4 in atopic dermatitis. Scand J Immunol. 2012;76:405–410. doi: 10.1111/j.1365-3083.2012.02739.x.
    1. Marlow G, Han DY, Wickens K, Stanley T, Crane J, Mitchell EA, Dekker J, Barthow C, Fitzharris P, Ferguson LR, Morgan AR. Differential effects of two probiotics on the risks of eczema and atopy associated with single nucleotide polymorphisms to Toll-like receptors. Pediatr Allergy Immunol. 2015;26:262–271. doi: 10.1111/pai.12371.
    1. Bode L. The functional biology of human milk oligosaccharides. Early Hum Dev. 2015;91:619–622. doi: 10.1016/j.earlhumdev.2015.09.001.
    1. Ruiz-Palacios GM, Cervantes LE, Ramos P, Chavez-Munguia B, Newburg DS. Campylobacter Jejuni binds intestinal H (O) antigen (Fuc alpha1, 2Gal beta1, 4GlcNAc), and fucosyloligosaccharides of human milk inhibit its binding and infection. J Biol Chem. 2003;278:14112–14120. doi: 10.1074/jbc.M207744200.
    1. Manthey CF, Autran CA, Eckmann L, Bode L. Human milk oligosaccharides protect against enteropathogenic Escherichia. coli attachment in vitro and EPEC colonization in suckling mice. J Pediatr Gastroenterol Nutr. 2014;58:167–170. doi: 10.1097/MPG.0000000000000172.
    1. Jantscher-Krenn E, Lauwaet T, Bliss LA, Reed SL, Gillin FD, Bode L. Human milk oligosaccharides reduce Entamoeba histolytica attachment and cytotoxicity in vitro. Br J Nutr. 2012;108:1839–1846. doi: 10.1017/S0007114511007392.
    1. Angeloni S, Ridet JL, Kusy N, Gao H, Crevoisier F, Guinchard S, Kochhar S, Sigrist H, Sprenger N. Glycoprofiling with micro-arrays of glycoconjugates and lectins. Glycobiology. 2005;15:31–41. doi: 10.1093/glycob/cwh143.
    1. Eiwegger T, Stahl B, Haidl P, Schmitt J, Boehm G, Dehlink E, Urbanek R, Szépfalusi Z. Prebiotic oligosaccharides: In vitro evidence for gastrointestinal epithelial transfer and immunomodulatory properties. Pediatr Allergy Immunol. 2010;21:1179–1188. doi: 10.1111/j.1399-3038.2010.01062.x.
    1. Vos AP, Haarman M, van Ginkel JW, Knol J, Garssen J, Stahl B, Boehm G, M'Rabet L. Dietary supplementation of neutral and acidic oligosaccharides enhances Th1-dependent vaccination responses in mice. Pediatr Allergy Immunol. 2007;18:304–312. doi: 10.1111/j.1399-3038.2007.00515.x.
    1. Bode L, Kunz C, Muhly-Reinholz M, Mayer K, Seeger W, Rudloff S. Inhibition of monocyte, lymphocyte, and neutrophil adhesion to endothelial cells by human milk oligosaccharides. Thromb Haemost. 2004;92:1402–1410. doi: 10.1160/TH04-01-0055.
    1. Bode L, Rudloff S, Kunz C, Strobel S, Klein N. Human milk oligosaccharides reduce platelet-neutrophil complex formation leading to a decrease in neutrophil beta 2 integrin expression. J Leukoc Biol. 2004;76:820–826. doi: 10.1189/jlb.0304198.
    1. Zhao M, Shen C, Ma L. Treatment efficacy of probiotics on atopic dermatitis, zooming in on infants: A systematic review and meta-analysis. Int J Dermatol. 2018;57:635–641. doi: 10.1111/ijd.13873.
    1. Niccoli AA, Artesi AL, Candio F, Ceccarelli S, Cozzali R, Ferraro L, Fiumana D, Mencacci M, Morlupo M, Pazzelli P, et al. Preliminary results on clinical effects of probiotic Lactobacillus salivarius LSO1 in children affected by atopic dermatitis. J Clin Gastroenterol. 2014;48 (Suppl 1):S34–S36. doi: 10.1097/MCG.0000000000000233.
    1. Rosenfeldt V, Benfeldt E, Nielsen SD, Michaelsen KF, Jeppesen DL, Valerius NH, Paerregaard A. Effect of probiotic lactobacillus strains in children with atopic dermatitis. J Allergy Clin Immunol. 2003;111:389–395. doi: 10.1067/mai.2003.389.
    1. Shane AL, Cabana MD, Vidry S, Merenstein D, Hummelen R, Ellis CL, Heimbach JT, Hempel S, Lynch SV, Sanders ME, Tancredi DJ. Guide to designing, conducting, publishing and communicating results of clinical studies involving probiotic applications in human participants. Gut Microbes. 2010;1:243–253. doi: 10.4161/gmic.1.4.12707.

Source: PubMed

3
Se inscrever