Oral delivery of a probiotic induced changes at the nasal mucosa of seasonal allergic rhinitis subjects after local allergen challenge: a randomised clinical trial

Kamal Ivory, Andrew M Wilson, Prasanna Sankaran, Marta Westwood, Justin McCarville, Claire Brockwell, Allan Clark, Jack R Dainty, Laurian Zuidmeer-Jongejan, Claudio Nicoletti, Kamal Ivory, Andrew M Wilson, Prasanna Sankaran, Marta Westwood, Justin McCarville, Claire Brockwell, Allan Clark, Jack R Dainty, Laurian Zuidmeer-Jongejan, Claudio Nicoletti

Abstract

Objective: To determine effects of probiotic consumption on clinical and immunological parameters of seasonal allergic rhinitis (SAR) in an out-of-season single nasal allergen challenge.

Methods: In a study registered at ClinicalTrials.Gov (NCT01123252), a 16-week dietary intervention was undertaken in 60 patients with allergic rhinitis (>16 years old). Using a double-blinded, placebo-controlled anonymised design, the patients were divided equally into two groups. One group was given a dairy drink containing Lactobacillus casei Shirota to ingest daily while the other consumed a similar drink without bacteria. Participants attended the clinic on two consecutive days before the intervention and then again at the end of the study period. On the first day of each 2-day visit, following clinical examination, assessments were made of total nasal symptoms scores and peak nasal inspiratory flow. Nasal scrapings, nasal lavage and blood were collected for laboratory analyses of cellular phenotypes, soluble mediator release and in vitro responses to pollen allergen. These procedures were repeated 24 hours following nasal allergen challenge.

Results: Prior to and following intervention there were no detectable differences between study groups in measured clinical outcome. After intervention, there were differences between groups in their percentages of CD86+ epithelial cells (p = 0.0148), CD86+CD252+ non-epithelial cells (p = 0.0347), sIL-1RII release (p = 0.0289) and IL-1β (p = 0.0224) levels at the nasal mucosa. Delivery of probiotic also suppressed production of sCD23 (p = 0.0081), TGF-β (p = 0.0283) and induced increased production of IFN-γ (p = 0.0351) in supernatants of cultured peripheral blood.

Conclusions & clinical relevance: This study did not show significant probiotic-associated changes with respect to the primary clinical endpoint. An absence of overt clinical benefit may be due to an inability of single nasal challenges to accurately represent natural allergen exposure. Nevertheless, oral delivery of probiotics produced changes of the immunological microenvironment at the nasal mucosa in individuals affected by SAR.

Trial registration: ClinicalTrials.Gov NCT01123252.

Conflict of interest statement

Competing Interests: The study was funded by Yakult Honsha Ltd. and it was conducted as a doubleblinded, placebo-controlled clinical trial. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Figure 1. Patient recruitment and retention.
Figure 1. Patient recruitment and retention.
Patient recruitment and retention is described.
Figure 2. Base-line and follow-up measurements.
Figure 2. Base-line and follow-up measurements.
TNSS (A,B) and PNIF (C,D) were recorded at baseline and then at 5, 10 and 30 minutes then hourly for 12 hours following nasal allergen challenge at pre-intervention (A,C) and post-intervention (B,D) periods.
Figure 3. Changes in IL-1β and sIL-1RII…
Figure 3. Changes in IL-1β and sIL-1RII at the nasal mucosa.
Changes from base-line (24 hr–0 hr) in IL-1β levels in nasal lavage (y1 axis) or sIL-1RII release from nasal epithelial cells (y2 axis) are compared before (pre) and after (post) intervention for control (A) and treatment (B) group; (*p≤0.05). Data are presented as scatter plots showing mean pg/ml with 95% CI.
Figure 4. CD86 expression at the nasal…
Figure 4. CD86 expression at the nasal mucosa.
After intervention, the percentages of CD86+ Cytokeratin+ epithelial (A) and CD86+ CD252+ non-epithelial (B) cells are compared at baseline between control (C0) and treatment (T0) groups and then again 24 hours after nasal allergen challenge (C24, T24); (*p≤0.05). Data are presented as scatter plots showing mean values with 95% CI.
Figure 5. Systemic effects on IFN-γ production.
Figure 5. Systemic effects on IFN-γ production.
Systemic effects of intervention are noted in change from baseline (24 hr–0 hr) in IFN-γ production by PBMNC cultured for 6 days in the absence (nasal allergen) or presence (nasal+in vitro allergen) of added pollen; (*p≤0.05). Data are presented as scatter plots showing mean pg/ml with 95% CI.
Figure 6. Systemic effects on TGF-β production.
Figure 6. Systemic effects on TGF-β production.
Systemic effects of intervention are noted in change from baseline (24 hr–0 hr) in TGF-β secretion by 6-day cultures of PBMNC in the absence (nasal allergen) or presence (nasal+in vitro allergen) of added pollen; (*p≤0.05). Data are presented as scatter plots showing mean pg/ml with 95% CI.
Figure 7. Systemic effects on sCD23 release.
Figure 7. Systemic effects on sCD23 release.
Systemic effects of intervention on sCD23 release from the cell surface are compared between control (C) and treatment (T) groups when PBMNC were cultured for 6 days without any challenge (no Ag), after nasal challenge (nasal Ag), in vitro stimulation with pollen (in vitro Ag) or both nasal and in vitro challenge (nasal+in vitro Ag); (*p≤0.05). Data are presented as scatter plots showing mean pg/ml with 95% CI.

References

    1. Penders J, Stobberingh EE, van den Brandt PA, Thijs C (2007) The role of the intestinal microbiota in the development of atopic disorders. Allergy 62: 1223–1236.
    1. Blaiss MS (2010) Allergic rhinitis: Direct and indirect costs. Allergy Asthma Proc 31: 375–380.
    1. Snel J, Vissers YM, Smit BA, Jongen JM, van der Meulen ET, et al. (2011) Strain-specific immunomodulatory effects of Lactobacillus plantarum strains on birch-pollen-allergic subjects out of season. Clin Exp Allergy 41: 232–242.
    1. Ivory K, Chambers SJ, Pin C, Prieto E, Arques JL, et al. (2008) Oral delivery of Lactobacillus casei Shirota modifies allergen-induced immune responses in allergic rhinitis. Clin Exp Allergy 38: 1282–1289.
    1. Vliagoftis H, Kouranos VD, Betsi GI, Falagas ME (2008) Probiotics for the treatment of allergic rhinitis and asthma: systematic review of randomized controlled trials. Ann Allergy Asthma Immunol 101: 70–79.
    1. Ishida Y, Nakamura F, Kanzato H, Sawada D, Hirata H, et al. (2005) Clinical effects of Lactobacillus acidophilus strain L-92 on perennial allergic rhinitis: A double-blind, placebo-controlled study. J Dairy Sci 88: 527–533.
    1. Wang MF, Lin HC, Wang YY, Hsu CH (2004) Treatment of perennial allergic rhinitis with lactic acid bacteria. Pediatric allergy and immunology: official publication of the European Soc Pediatr Allergy Immunol 15: 152–158.
    1. Aldinucci C, Bellussi L, Monciatti G, Passali GC, Salerni L, et al. (2002) Effects of dietary yoghurt on immunological and clinical parameters of rhinopathic patients. Eur J Clin Nutr 56: 1155–1161.
    1. Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, et al. (2005) Standardization of Spirometry. Eur Respir J 26: 319–338.
    1. Dreskin SC, Dale SN, Foster SM, Martin D, Buchmeier A, et al. (2002) Measurement of changes in mRNA for IL-5 in noninvasive scrapings of nasal epithelium taken from patients undergoing nasal allergen challenge. J Immunol Methods 268: 189–195.
    1. Grunberg K, Timmers MC, Smits HH, de Klerk EP, Dick EC, et al. (1997) Spaan WJ, Hiemstra PS, Sterk PJ, Effect of experimental rhinovirus 16 colds on airway hyperresponsiveness to histamine and interleukin-8 in nasal lavage in asthmatic subjects in vivo. Clin Exp Allergy 27: 36–45.
    1. Jensen LE (2010) Targeting the IL-1 family members in skin inflammation. Curr Opin Investig Drugs 11: 1211–1220.
    1. Sim TC, Grant JA, Hilsmeier KA, Fukuda Y, Alam R (1994) Proinflammatory cytokines in nasal secretions of allergic subjects after antigen challenge. Am J Respir Crit Care Med 149: 339–344.
    1. Nambu A, Nakae S (2010) IL-1 and Allergy. Allergol Int 59: 125–135.
    1. Gupta K, Bewtra A (1999) IL-1 receptor-type expression in relation to atopy. J Allergy Clin Immunol 103: 1100–1107.
    1. Wang DL, Zhang SY, Li LA, Liu X, Mei KR, et al. (2010) Structural insights into the assembly and activation of IL-1 beta with its receptors. Nat Immunol 11: 905–911.
    1. Wesche H, Resch K, Martin MU (1998) Effects of IL-1 receptor accessory protein on IL-1 binding. Febs Lett 429: 303–306.
    1. Takizawa R, Pawankar R, Yamagishi S, Takenaka H, Yagi T (2007) Increased expression of HLA-DR and CD86 in nasal epithelial cells in allergic rhinitics: antigen presentation to T cells and up-regulation by diesel exhaust particles. Clin Exp Allergy 37: 420–433.
    1. Hartmann E, Graefe H, Hopert A, Pries R, Rothenfusser S, Poeck H, et al. (2006) Analysis of plasmacytoid and myeloid dendritic cells in nasal epithelium. Clin Vaccine Immunol 13: 1278–1286.
    1. Chieppa M, Rescigno M, Huang AYC, Germain RN (2006) Dynamic imaging of dendritic cell extension into the small bowel lumen in response to epithelial cell TLR engagement. J Exp Med 203: 2841–2852.
    1. Qureshi OS, Zheng Y, Nakamura K, Attridge K, Manzotti C, et al. (2011) Trans-Endocytosis of CD80 and CD86: A Molecular Basis for the Cell-Extrinsic Function of CTLA-4. Science 332: 600–603.
    1. Rasche C, Wolfram C, Wahls M, Worm M (2007) Differential immunomodulating effects of inactivated probiotic bacteria on the allergic immune response. Acta Derm Venereol 87: 305–311.
    1. Rogala B, Rymarczyk B (1999) Soluble CD23 in allergic diseases. Arch Immunol Ther Exp 147: 251–255.
    1. Cooper AM, Hobson PS, Jutton MR, Kao MW, Drung B, et al. (2012) Soluble CD23 controls IgE synthesis and homeostasis in human B cells. J Immunol 188: 3199–3207.
    1. Roever AC, Heine G, Zuberbier T, Worm M (2003) Allergen-mediated modulation of CD23 expression is interferon-gamma and interleukin-10 dependent in allergic and non-allergic individuals. Clin Exp Allergy 33: 1568–1575.
    1. Ciprandi G, Fenoglio D, Di Gioacchino M, Ferrera A, Ferrera F, et al. (2008) Sublingual Immunotherapy Provides an Early Increase of Interferon-Gamma Production. J Biol Reg Homeos Ag 22: 169–173.
    1. Fonseca DM, Paula MO, Wowk PF, Campos LW, Gembre AF, et al. (2011) IFN-gamma-mediated efficacy of allergen-free immunotherapy using mycobacterial antigens and CpG-ODN. Immunol Cell Biol 89: 777–785.
    1. Hamid QA, Schotman E, Jacobson MR, Walker SM, Durham SR (1997) Increases in IL-12 messenger RNA+ cells accompany inhibition of allergen-induced late skin responses after successful grass pollen immunotherapy. J Allergy Clin Immunol 99: 254–260.
    1. Strober W, Kelsall B, Fuss I, Marth T, Ludviksson B, et al. (1997) Ehrhardt R, Neurath M, Reciprocal IFN-gamma and TGF-beta responses regulate the occurrence of mucosal inflammation. Immunol Today 18: 61–64.
    1. Trotta R, Dal Col J, Yu J, Ciarlariello D, Thomas B, et al. (2008) TGF-beta utilizes SMAD3 to inhibit CD16-mediated IFN-gamma production and antibody-dependent cellular cytotoxicity in human NK cells. J Immunol 181: 3784–3792.
    1. Wen FQ, Liu X, Kobayashi T, Abe S, Fang Q, et al. (2004) Interferon-gamma inhibits transforming growth factor-beta production in human airway epithelial cells by targeting Smads. Am J Respir Cell Mol Biol 30: 816–822.
    1. Shen ZJ, Esnault S, Rosenthal LA, Szakaly RJ, Sorkness RL, et al. (2008) Pin1 regulates TGF-beta1 production by activated human and murine eosinophils and contributes to allergic lung fibrosis. J Clin Invest 118: 479–490.
    1. Salib RJ (2007) Transforming growth factor-beta gene expression studies in nasal mucosal biopsies in naturally occurring allergic rhinitis. Ann R Coll Surg Engl 89: 563–573.
    1. Olsson N, Piek E, ten Dijke P, Nilsson G (2000) Human mast cell migration in response to members of the transforming growth factor-beta family. J Leukoc Biol 67: 350–356.
    1. Gruber BL, Marchese MJ, Kew RR (1994) Transforming growth factor-beta 1 mediates mast cell chemotaxis. J Immunol 152: 5860–5867.
    1. Ciprandi G, De Amici M, Tosca MA, Pistorio A, Marseglia GL (2009) Sublingual immunotherapy affects specific antibody and TGF-beta serum levels in patients with allergic rhinitis. Int J Immunopathol Pharmacol 22: 1089–1096.
    1. Wachholz PA, Nouri-Aria KT, Wilson DR, Walker SM, Verhoef A, et al. (2002) Grass pollen immunotherapy for hayfever is associated with increases in local nasal but not peripheral Th1 ∶ Th2 cytokine ratios. Immunology 105: 56–62.
    1. Wilson DR, Irani AM, Walker SM, Jacobson MR, Mackay IS, et al. (2001) Grass pollen immunotherapy inhibits seasonal increases in basophils and eosinophils in the nasal epithelium. Clin Exp Allergy 31: 1705–1713.
    1. van de Pol MA, Lutter R, van Ree R, van der Zee JS (2012) Increase in allergen-specific IgE and ex vivo Th2 responses after a single bronchial challenge with house dust mite in allergic asthmatics. Allergy 67: 67–73.
    1. Wheeler JG, Shema SJ, Bogle ML, Shirrell MA, Burks AW, et al. (1997) Pittler A, Helm RM, Immune and clinical impact of Lactobacillus acidophilus on asthma. Ann Allergy Asthma Immunol 79: 229–233.
    1. Demoly P, Campbell A, Lebel B, Bousquet J (1999) Experimental models in rhinitis. Clin Exp Allergy 29 Suppl 3: 72–76.
    1. Rousseau MC, Boulay ME, Goronfolah L, Denburg J, Keith P, et al. (2011) Comparative responses to nasal allergen challenge in allergic rhinitic subjects with or without asthma. Allergy, Asthma, Clin Immunol Available: . Accessed 2013 October 10.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe