Dietary supplementation with Bifidobacterium longum subsp. infantis (B. infantis) in healthy breastfed infants: study protocol for a randomised controlled trial

Smita Awasthi, Reason Wilken, Forum Patel, J Bruce German, David A Mills, Carlito B Lebrilla, Kyoungmi Kim, Samara L Freeman, Jennifer T Smilowitz, April W Armstrong, Emanual Maverakis, Smita Awasthi, Reason Wilken, Forum Patel, J Bruce German, David A Mills, Carlito B Lebrilla, Kyoungmi Kim, Samara L Freeman, Jennifer T Smilowitz, April W Armstrong, Emanual Maverakis

Abstract

Background: The development of probiotics as therapies to cure or prevent disease lags far behind that of other investigational medications. Rigorously designed phase I clinical trials are nearly non-existent in the field of probiotic research, which is a contributing factor to this disparity. As a consequence, how to appropriately dose probiotics to study their efficacy is unknown. Herein we propose a novel phase I ascending dose trial of Bifidobacterium longum subsp. infantis (B. infantis) to identify the dose required to produce predominant gut colonisation in healthy breastfed infants at 6 weeks of age.

Methods/design: This is a parallel-group, placebo-controlled, randomised, double-blind ascending dose phase I clinical trial of dietary supplementation with B. infantis in healthy breastfed infants. The objective is to determine the pharmacologically effective dose (ED) of B. infantis required to produce predominant (>50 %) gut colonisation in breastfed infants at 6 weeks of age. Successively enrolled infant groups will be randomised to receive two doses of either B. infantis or placebo on days 7 and 14 of life. Stool samples will be used to characterise the gut microbiota at increasing doses of B. infantis.

Discussion: Probiotic supplementation has shown promising results for the treatment of a variety of ailments, but evidence-based dosing regimes are currently lacking. The ultimate goal of this trial is to establish a recommended starting dose of B. infantis for further efficacy-testing phase II trials designed to evaluate B. infantis for the prevention of atopic dermatitis and food allergies in at-risk children.

Trial registration: Clinicaltrials.gov # NCT02286999 , date of trial registration 23 October 2014.

Keywords: Atopic dermatitis; Atopy; Bifidobacterium infantis; Dose-escalation; Food allergy; Phase I clinical trial; Probiotic.

Figures

Fig. 1
Fig. 1
A parallel-group, placebo-controlled, randomised, double-blind ascending dose phase I study of dietary supplementation with B. infantis. Groups of healthy infants will receive increasing doses of B. infantis until it comprises 50 % of their gut microbiota, defined as the pharmacologically effective dose (ED). This figure arbitrarily designates Group 6 as receiving the ED of B. infantis. After the ED has been reached, two additional dose escalations will occur to determine the impact that additional B. infantis has on the gut microbiota. To satisfy Hanley’s Rule of Three, 30 infants will receive the highest dose of B. infantis. “X” represents the maximum recommended starting dose (MRSD). A modified Fibonacci Series (X, 2X, 3X, …) is used to guide the dose escalations. CFU colony-forming units

References

    1. Mackowiak PA. Recycling Metchnikoff: probiotics, the intestinal microbiome and the quest for long life. Front Public Health. 2013;1:52. doi: 10.3389/fpubh.2013.00052.
    1. Reid G, et al. The importance of guidelines in the development and application of probiotics. Curr Pharm Des. 2005;11(1):11–6. doi: 10.2174/1381612053382395.
    1. Viljanen M, et al. Probiotics in the treatment of atopic eczema/dermatitis syndrome in infants: a double-blind placebo-controlled trial. Allergy. 2005;60(4):494–500. doi: 10.1111/j.1398-9995.2004.00514.x.
    1. Rautava S, Kalliomaki M, Isolauri E. Probiotics during pregnancy and breast-feeding might confer immunomodulatory protection against atopic disease in the infant. J Allergy Clin Immunol. 2002;109(1):119–21. doi: 10.1067/mai.2002.120273.
    1. Weston S, et al. Effects of probiotics on atopic dermatitis: a randomised controlled trial. Arch Dis Child. 2005;90(9):892–7. doi: 10.1136/adc.2004.060673.
    1. Abrahamsson TR, et al. Probiotics in prevention of IgE-associated eczema: a double-blind, randomised, placebo-controlled trial. J Allergy Clin Immunol. 2007;119(5):1174–80. doi: 10.1016/j.jaci.2007.01.007.
    1. Rautava S, Arvilommi H, Isolauri E. Specific probiotics in enhancing maturation of IgA responses in formula-fed infants. Pediatr Res. 2006;60(2):221–4. doi: 10.1203/01.pdr.0000228317.72933.db.
    1. Kalliomaki M, et al. Probiotics in primary prevention of atopic disease: a randomised placebo-controlled trial. Lancet. 2001;357(9262):1076–9. doi: 10.1016/S0140-6736(00)04259-8.
    1. Hooper LV, et al. Molecular analysis of commensal host-microbial relationships in the intestine. Science. 2001;291(5505):881–4. doi: 10.1126/science.291.5505.881.
    1. Hooper LV, Gordon JI. Commensal host-bacterial relationships in the gut. Science. 2001;292(5519):1115–8. doi: 10.1126/science.1058709.
    1. Mazmanian SK, et al. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell. 2005;122(1):107–18. doi: 10.1016/j.cell.2005.05.007.
    1. Rakoff-Nahoum S, et al. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell. 2004;118(2):229–41. doi: 10.1016/j.cell.2004.07.002.
    1. Mazmanian SK. Capsular polysaccharides of symbiotic bacteria modulate immune responses during experimental colitis. J Pediatr Gastroenterol Nutr. 2008;46(Suppl 1):E11–2. doi: 10.1097/01.mpg.0000313824.70971.a7.
    1. Yu LC. Intestinal epithelial barrier dysfunction in food hypersensitivity. J Allergy (Cairo) 2012;2012:596081.
    1. Cao S, Feehley TJ, Nagler CR. The role of commensal bacteria in the regulation of sensitization to food allergens. FEBS Lett. 2014;588(22):4258–66. doi: 10.1016/j.febslet.2014.04.026.
    1. German JB, et al. Human milk oligosaccharides: evolution, structures and bioselectivity as substrates for intestinal bacteria. Nestle Nutr Workshop Ser Pediatr Program. 2008;62:205–18. doi: 10.1159/000146322.
    1. Barboza M, et al. Glycoprofiling bifidobacterial consumption of galacto-oligosaccharides by mass spectrometry reveals strain-specific, preferential consumption of glycans. Appl Environ Microbiol. 2009;75(23):7319–25. doi: 10.1128/AEM.00842-09.
    1. LoCascio RG, et al. Glycoprofiling of bifidobacterial consumption of human milk oligosaccharides demonstrates strain specific, preferential consumption of small chain glycans secreted in early human lactation. J Agric Food Chem. 2007;55(22):8914–9. doi: 10.1021/jf0710480.
    1. Huda MN, et al. Stool microbiota and vaccine responses of infants. Pediatrics. 2014;134(2):e362–72. doi: 10.1542/peds.2013-3937.
    1. Spergel JM. Epidemiology of atopic dermatitis and atopic march in children. Immunol Allergy Clin North Am. 2010;30(3):269–80. doi: 10.1016/j.iac.2010.06.003.
    1. Hanley JA, Lippman-Hand A. If nothing goes wrong, is everything all right? Interpreting zero numerators. JAMA. 1983;249(13):1743–5. doi: 10.1001/jama.1983.03330370053031.
    1. Underwood MA, et al. A comparison of two probiotic strains of bifidobacteria in premature infants. J Pediatr. 2013;163(6):1585–91. doi: 10.1016/j.jpeds.2013.07.017.
    1. Le Tourneau C, Lee JJ, Siu LL. Dose escalation methods in phase I cancer clinical trials. J Natl Cancer Inst. 2009;101(10):708–20. doi: 10.1093/jnci/djp079.
    1. LoRusso PM, Boerner SA, Seymour L. An overview of the optimal planning, design, and conduct of phase I studies of new therapeutics. Clin Cancer Res. 2010;16(6):1710–8. doi: 10.1158/1078-0432.CCR-09-1993.
    1. Korn EL, et al. Clinical trial designs for cytostatic agents: are new approaches needed? J Clin Oncol. 2001;19(1):265–72.
    1. Parulekar WR, Eisenhauer EA. Phase I trial design for solid tumor studies of targeted, non-cytotoxic agents: theory and practice. J Natl Cancer Inst. 2004;96(13):990–7. doi: 10.1093/jnci/djh182.
    1. Sleijfer S, Wiemer E. Dose selection in phase I studies: why we should always go for the top. J Clin Oncol. 2008;26(10):1576–8. doi: 10.1200/JCO.2007.15.5192.
    1. Cannistra SA. Challenges and pitfalls of combining targeted agents in phase I studies. J Clin Oncol. 2008;26(22):3665–7. doi: 10.1200/JCO.2008.17.2676.
    1. Enomoto T, 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(4):575–85. doi: 10.2332/allergolint.13-OA-0683.
    1. Garaiova I, et al. Probiotics and vitamin C for the prevention of respiratory tract infections in children attending preschool: a randomised controlled pilot study. Eur J Clin Nutr. 2014;69(3):373–9. doi: 10.1038/ejcn.2014.174.
    1. Forsberg A, et al. Pre- and postnatal administration of Lactobacillus reuteri decreases TLR2 responses in infants. Clin Transl Allergy. 2014;4:21. doi: 10.1186/2045-7022-4-21.
    1. Zampieri N, et al. Lactobacillus paracasei subsp. paracasei F19 in Bell's stage 2 of necrotizing enterocolitis. Minerva Pediatr. 2013;65(4):353–60.
    1. Allen SJ, et al. Probiotics in the prevention of eczema: a randomised controlled trial. Arch Dis Child. 2014;99(11):1014–9. doi: 10.1136/archdischild-2013-305799.
    1. Saraoui T, et al. A unique in vivo experimental approach reveals metabolic adaptation of the probiotic Propionibacterium freudenreichii to the colon environment. BMC Genomics. 2013;14:911. doi: 10.1186/1471-2164-14-911.
    1. Sela DA, et al. The genome sequence of Bifidobacterium longum subsp. infantis reveals adaptations for milk utilization within the infant microbiome. Proc Natl Acad Sci U S A. 2008;105(48):18964–9. doi: 10.1073/pnas.0809584105.
    1. Marcobal A, et al. Consumption of human milk oligosaccharides by gut-related microbes. J Agric Food Chem. 2010;58(9):5334–40. doi: 10.1021/jf9044205.
    1. Wu KG, Li TH, Peng HJ. Lactobacillus salivarius plus fructo-oligosaccharide is superior to fructo-oligosaccharide alone for treating children with moderate to severe atopic dermatitis: a double-blind, randomised, clinical trial of efficacy and safety. Br J Dermatol. 2012;166(1):129–36. doi: 10.1111/j.1365-2133.2011.10596.x.
    1. Kukkonen K, et al. Probiotics and prebiotic galacto-oligosaccharides in the prevention of allergic diseases: a randomised, double-blind, placebo-controlled trial. J Allergy Clin Immunol. 2007;119(1):192–8. doi: 10.1016/j.jaci.2006.09.009.
    1. Zivkovic AM, Barile D. Bovine milk as a source of functional oligosaccharides for improving human health. Adv Nutr. 2011;2(3):284–9. doi: 10.3945/an.111.000455.
    1. Bernardeau M, et al. Safety assessment of dairy microorganisms: the Lactobacillus genus. Int J Food Microbiol. 2008;126(3):278–85. doi: 10.1016/j.ijfoodmicro.2007.08.015.
    1. Snydman DR. The safety of probiotics. Clin Infect Dis. 2008;46(Suppl 2):S104–11. doi: 10.1086/523331.
    1. Saxelin M, et al. Lactobacilli and bacteremia in southern Finland, 1989–1992. Clin Infect Dis. 1996;22(3):564–6. doi: 10.1093/clinids/22.3.564.
    1. Salminen MK, et al. Lactobacillus bacteremia during a rapid increase in probiotic use of Lactobacillus rhamnosus GG in Finland. Clin Infect Dis. 2002;35(10):1155–60. doi: 10.1086/342912.
    1. Allen SJ, et al. Dietary supplementation with lactobacilli and bifidobacteria is well tolerated and not associated with adverse events during late pregnancy and early infancy. J Nutr. 2010;140(3):483–8. doi: 10.3945/jn.109.117093.
    1. Mackay AD, et al. Lactobacillus endocarditis caused by a probiotic organism. Clin Microbiol Infect. 1999;5(5):290–2. doi: 10.1111/j.1469-0691.1999.tb00144.x.
    1. Land MH, et al. Lactobacillus sepsis associated with probiotic therapy. Pediatrics. 2005;115(1):178–81.
    1. Rautio M, et al. Liver abscess due to a Lactobacillus rhamnosus strain indistinguishable from L. rhamnosus strain GG. Clin Infect Dis. 1999;28(5):1159–60. doi: 10.1086/514766.
    1. Borriello SP, et al. Safety of probiotics that contain lactobacilli or bifidobacteria. Clin Infect Dis. 2003;36(6):775–80. doi: 10.1086/368080.
    1. Ha GY, et al. Case of sepsis caused by Bifidobacterium longum. J Clin Microbiol. 1999;37(4):1227–8.
    1. Ohishi A, et al. Bifidobacterium septicemia associated with postoperative probiotic therapy in a neonate with omphalocele. J Pediatr. 2010;156(4):679–81. doi: 10.1016/j.jpeds.2009.11.041.
    1. Jenke A, et al. Bifidobacterium septicaemia in an extremely low-birthweight infant under probiotic therapy. Arch Dis Child Fetal Neonatal Ed. 2012;97(3):F217–8. doi: 10.1136/archdischild-2011-300838.
    1. Tsangalis D, et al. Bioavailability of isoflavone phytoestrogens in postmenopausal women consuming soya milk fermented with probiotic bifidobacteria. Br J Nutr. 2005;93(6):867–77. doi: 10.1079/BJN20041299.
    1. Lammers KM, et al. Effect of probiotic strains on interleukin 8 production by HT29/19A cells. Am J Gastroenterol. 2002;97(5):1182–6. doi: 10.1111/j.1572-0241.2002.05693.x.
    1. Gao XW, et al. Dose-response efficacy of a proprietary probiotic formula of Lactobacillus acidophilus CL1285 and Lactobacillus casei LBC80R for antibiotic-associated diarrhea and Clostridium difficile-associated diarrhea prophylaxis in adult patients. Am J Gastroenterol. 2010;105(7):1636–41. doi: 10.1038/ajg.2010.11.

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