Multi-strain probiotic formulations for treatment of immunological and allergic conditions

Abstract

The present invention provides a novel multi-strain probiotic formulation and relates to the use of the multi-strain formulation in therapy, in particular for the treatment or prevention of immunological or allergic diseases / disorders, such as allergic rhinitis or allergic conjunctivitis. In addition, the present invention also provides a novel therapeutic regimen that is easy to follow using the probiotic formulations provided herein.

Description

TECHNICAL FIELD

[0001] The present application provides a novel multi-strain probiotic formulation and relates to the use of the multi-strain formulation in therapy, in particular for the treatment or prevention of an immunological disease / disorder or an allergic disease / disorder, such as allergic rhinitis or allergic conjunctivitis. BACKGROUND

[0002] Allergic rhinitis (AR) is one of the most common chronic conditions worldwide, affecting approximately 400 million people. Allergic rhinitis often coexists with asthma and conjunctivitis and is a global health problem that imposes a huge burden and obstacle worldwide (Pawankar et al., World Allergy Organ J, 2014, 7(1), 12, doi: 10.1186 / 1939-4551-7-12). It is characterized by allergic symptoms such as rhinorrhea, nasal itching, sneezing and nasal congestion, typically resulting from an IgE-mediated reaction to inhaled allergens (e.g. plant pollens). Depending on the time of onset, AR can be divided into two categories: seasonal allergic rhinitis (SAR) and perennial allergic rhinitis (PAR) (see, e.g., Galli SJ et al., Nature, 2008, 454(7203): 445-454, doi: 10.1038 / nature07204; or Mims JW, Facial Plast Surg Clin North Am, 2012, 20(1): 11-20, doi: 10.1016 / j.fsc.2011.10.002). AR is often accompanied by allergic conjunctivitis (AC) with typical allergic symptoms, causing ocular discomfort and inflammatory reactions (e.g. itching, burning, redness and tearing). Thus, allergic rhinoconjunctivitis (ARC) is used for the combined symptoms of allergic rhinitis and allergic conjunctivitis.

[0003] AR is not only considered to cause health and social burden to patients, but also substantial economic loss and steadily increasing expenditure to the health sector and causes school and work absenteeism. The European Academy of Allergy and Clinical Immunology (EAACI) estimates that the annual economic cost of inadequate allergy treatment in the EU is between 55 and 151 billion Euros (see: "The European Academy of Allergy and Clinical Immunology (EAACI) Advocacy Manifesto Tackling the Allergy Crisis in Europe - Concerted Policy Action Needed"; Sullivan AA et al., "In-Depth Review of Allergic Rhinitis", updated October 2020, https: / / www.worldallergy.org / education-and-programs / education / allergic-disease-resource-center / professionals / in-depth-review-of-allergic-rhinitis).

[0004] Pathophysiology of AR:

[0005] The nasal mucosa is the first air conditioner of the respiratory tract and the first line of defense against airborne infectious agents. For these roles, it is essential to maintain and repair epithelial integrity and to be able to initiate an immune response. The immune response usually confers protection against potential pathogens to the human body, while it is able to distinguish between harmless antigens (e.g. self-antigens, food antigens) and environmental allergens to maintain the balance (Martin-Orozco E et al., Front Pediatr, 2017, 5: 117, doi: 10.3389 / fped.2017.00117). Harmless environmental substances, such as grass pollen and house dust mites, usually do not have a significant impact on the human body. In patients with AR, this distinction between harmful and harmless antigens is disturbed. The exact mechanism that contributes to the manifestation of the disease is not yet fully elucidated.

[0006] Generally, an allergic reaction occurs after a prior exposure and sensitization, in which an allergen (e.g., grass pollen) is presented to antigen presenting cells (APCs). During this period, dendritic cells in the nasal mucosa take up the allergen, process it and transport it to draining lymph nodes, where the processed allergen is presented to naive CD4+T cells. After antigen presentation, the naive CD4+T cells are activated and differentiate into allergen-specific type 2 helper T cells (TH2 cells), which induce B cell activation and IgE class switching, leading to differentiation of B cells into plasma cells producing allergen-specific IgE. These IgE antibodies reactive to the allergen bind to the surface of granulocytes and mast cells. These processes lead to the formation of a pool of memory allergen-specific TH2 cells and B cells. When a patient previously sensitized by contact with an allergen is re-exposed to the sensitizing allergen, the allergen binds to the allergen-specific IgE on the mast cells of the nasal mucosa, leading to mast cell activation and degranulation. This results in the release of pre-stored and newly synthesized mediators, including histamine, leukotrienes (leukotriene C4 and leukotriene D4), prostaglandin D2, and other products. These mediators interact with sensory nerves, blood vessels, and glands of the nose, causing acute AR symptoms, including rhinorrhea, nasal itching, sneezing, nasal congestion, and ocular itching, tearing (Mims JW, Facial Plast Surg Clin North Am, 2012, 20(1): 11-20, doi: 10.1016 / j.fsc.2011.10.002; “The European Academy of Allergy and Clinical Immunology (EAACI) Advocacy Manifesto Tackling the Allergy Crisis in Europe - Concerted Policy Action Needed”; Sullivan AA et al., “In-Depth Review of Allergic Rhinitis”, updated October 2020, https: / / www.worldallergy.org / education-and-programs / education / allergic-disease-resource-center / professionals / in-depth-review-of-allergic-rhinitis ).

[0007] Current treatment options for AR:

[0008] Available treatment options for AR include avoidance of allergen exposure, pharmacotherapy with H1-antihistamines or intranasal corticosteroids, and specific immunotherapy (SIT), where SIT is the only curative treatment option due to immunological reasons targeting the allergic reaction (Guvenç IA et al., Am J Rhinol Allergy, 2016, 30(5): 157-175, doi: 10.2500 / ajra.2016.30.4354; Zajac AE et al., Int Forum Allergy Rhinol, 2015, 5(6): 524-532, doi: 10.1002 / alr.21492). Avoidance of exposure is considered rather difficult for airborne allergens, such as pollen or house dust, especially in the pollen season or in the case of long-time indoor activities common in modern societies.

[0009] For AR patients, the use of pharmacotherapy for symptomatic treatment is the most common AR management. However, there are several drawbacks, including the side effects common to these drugs. These side effects can range from drowsiness to severe headaches and fever, affecting general well-being and reducing learning and work abilities (Meltzer EO, J Allergy Clin Immunol, 2001, 108(1 Suppl): S45-53, doi: 10.1067 / mai.2001.115566). Furthermore, long-term use can lead to habituation, i.e. an increased dose or application frequency is needed to achieve comparable relief (Church MK et al., Chem Immunol Allergy, 2014, 100: 302-310, doi: 10.1159 / 000359963). Finally, untreated and inappropriately treated (i.e. only symptomatic treatment) allergic reactions can lead to multiple allergic diseases or the development of other allergic conditions, causing further deterioration of health (Wheatley LM et al., N Engl J Med, 2015, 372(5): 456-463, doi: 10.1056 / NEJMcp1412282).

[0010] To date, the only curative treatment for AR is SIT, which changes the allergic immune mechanism by inducing desensitization to allergens. This is achieved by administering specific allergens in increasing doses during immunotherapy. However, this process is quite cumbersome, requiring multiple visits to the doctor and several years of treatment to achieve optimal efficacy. Known side effects include local reactions (itching, swelling, redness, local inflammation), systemic side effects, and even the risk of anaphylactic shock (Aboshady OA et al., Clin Exp Otorhinolaryngol, 2014, 7(4): 241-249, doi: 10.3342 / ceo.2014.7.4.241; Okubo K et al., J Nippon Med Sch, 2010, 77(6): 285-289, doi:10.1272 / jnms.77.285). Moreover, the proportion of patients who discontinue SIT is high for various reasons, including experienced side effects, lack of perceived efficacy, and long duration of treatment. The dropout rate is 56% in the first year of treatment and increases further, so that by the third year only 15% of patients are still receiving immunotherapy (Savi E et al., Allergy, 2013, 68(9): 1193-1195, doi: 10.1111 / all.12198).

[0011] In summary, the current therapies available for AR are accompanied by a large number of side effects for many patients, so there is a significant unmet medical need.

[0012] Role of the gastrointestinal microbiome in AR:

[0013] In recent years, new links between the development of allergic reactions and an imbalance in the gastrointestinal microbiome, known as dysbiosis, have been discovered. Dysbiosis as a term refers to a pathogenic imbalance or reduction in bacterial numbers and diversity of the microbiome (Wilkins LJ et al., Sci Rep, 2019, 9: 12918, doi:10.1038 / s41598-019-49452-y). Researchers have sought to explore the reasons for this significant shift in biological diversity, with the main hypothesis being that modern Western lifestyles and their high standards of hygiene and cleanliness can steadily contribute to a general reduction in the human microbiome. Other contributing factors include the intake of highly processed foods, the increase in urbanization, the use of antibiotics, and the rise in the rate of caesarean sections. In urbanized populations in the West, individual gut microbiome diversity is often reduced, which is thought to contribute to the spread of “modern diseases”, such as obesity, inflammatory bowel disease, and asthma, food intolerance and allergies (Barone M et al., PLoS One, 2019, 14(8): e0220619, doi: 10.1371 / journal.pone.0220619; Blaser MJ, Nat Rev Immunol, 2017, 17(8): 461-463, doi: 10.1038 / nri.2017.77).

[0014] Using data from the American Gut Project, a global, researcher-open database that brings together microbiome analysis data from millions of stool samples from all over the world (McDonald D et al., mSystems, 2018, 3(3): e00031-18, doi: 10.1128 / mSystems.00031-18), Hua et al. investigated the association between the human gut microbiome and the development of allergic reactions (Hua X et al., EBioMedicine, 2016, 3: 172-179, doi: 10.1016 / j.ebiom.2015.11.038). In this context, Hua et al. analyzed stool samples from 1879 participants and found that patients with allergic rhinitis showed a significantly altered microbial community composition (e.g., reduced diversity, reduced numbers of Clostridiales bacteria, and increased numbers of Bacteroidales bacteria).

[0015] Therefore, in recent years, the use of probiotics has attracted extensive attention in the scientific community. However, the results of trials investigating the efficacy of probiotics in the treatment of allergy are not consistent. This is mainly related to the composition of different probiotics and the strain-specific properties and effects. In addition, due to some limiting factors, such as different treatment durations, heterogeneity of the study population, and diversity of scoring systems used to determine AR symptoms, the results are difficult to compare. In summary, while a few studies provide strong evidence that specific probiotics can have some effect on the treatment of allergic diseases, many studies have failed to confirm their effectiveness (Dolle S et al., Int Arch Allergy Immunol, 2014, 163(1): 29-35, doi: 10.1159 / 000356328; Ivory K et al., PLoS One, 2013, 8(11): e78650, doi: 10.1371 / journal.pone.0078650; Nembrini C et al., Clin Transl Allergy, 2015, 5: 41, doi:10.1186 / s13601-015-0085-4; Perrin Y et al., Clin Transl Allergy, 2014, 4(1): 1, doi: 10.1186 / 2045-7022-4-1; Koyama T et al., Can J Microbiol, 2010, 56(9): 730-738, doi: 10.1139 / w10-061; Dennis-Wall JC et al., Am J Clin Nutr, 2017, 105(3): 758-767, doi: 10.3945 / ajcn.116.140012; Ouwehand AC et al., World J Gastroenterol, 2009, 15(26): 3261-3268, doi: 10.3748 / wjg.15.3261). Therefore, the medical community agrees that only specific probiotic preparations that have been proven effective in the treatment of allergic rhinitis in placebo-controlled clinical trials can be recommended for use. Therefore, there is an urgent need for clear compositions and treatment regimens that have been proven effective in placebo-controlled clinical trials.

[0016] Bacterial strain specificity:

[0017] There is ample evidence that probiotic bacteria act in a strain-specific manner. Even within the same species, different strains can differ significantly in their properties and thus can not exhibit similar therapeutic effects (McFarland LV et al., Front Med (Lausanne), 2018, 5: 124, doi: 10.3389 / fmed.2018.00124). Thus, based on the properties of a particular strain and the pathophysiological mechanisms of the relevant disease, even closely related strains can differ greatly in their efficacy or can even produce mutually contradictory effects. So far, it has not been possible to predict the effectiveness of a probiotic strain or combination of strains based on certain properties or in vitro studies. Therefore, the effectiveness of a particular probiotic strain or combination of probiotic strains always needs to be demonstrated in a well-designed clinical trial.

[0018] As an example, strain-specific effects of probiotics of the same species can be illustrated by comparing the efficacy of Lactobacillus plantarum MF1928 and Lactobacillus plantarum 299V in the treatment of gastrointestinal disorders. While the ingestion of Lactobacillus plantarum 299V (Ducrotté P et al., World J Gastroenterol, 2012, 18(30):4012-4018, doi:10.3748 / wjg.v18.i30.4012) significantly improved symptoms in patients with irritable bowel syndrome (IBS), the closely related strain Lactobacillus plantarum MF1298 led to a significant worsening of IBS symptoms (Farup PG et al., Gastroenterol Res Pract, 2012, 214102, doi: 10.1155 / 2012 / 214102). Similar effects were observed with the use of closely related strains of Lactobacillus paracasei LP-33, Lactobacillus paracasei HF.A00232, and Lactobacillus paracasei NCC2461 in the treatment of allergic reactions. Lactobacillus paracasei LP-33 can exhibit efficacy in improving the frequency of AR symptoms (Ahmed M et al., Pak J Med Sci, 2019, 35(6):1538-1543, doi: 10.12669 / pjms.35.6.744), but in contrast, treatment with Lactobacillus paracasei HF.A00232 (Lin WY et al., Pediatr Neonatol, 2014, 55(3):181-188, doi: 10.1016 / j.pedneo.2013.10.001) or Lactobacillus paracasei NCC2461 (Nembrini C et al., Clin Transl Allergy, 2015, 5:41, doi: 10.1186 / s13601-015-0085-4) had no positive effect on AR symptoms. Thus, even with close biological relationships, probiotic strains can differ significantly in their effectiveness.

[0019] For multi-strain products, the possible interactions between specific strains must also be considered. Different probiotic strains can have additive effects, but can also have opposite effects. Thus, clinical trials applying multi-strain therapy as an AR / ARC therapy have presented quite heterogeneous results; some studies show positive results, while others show no effect on AR symptoms. In a recent systematic review, McFarland and colleagues compared the efficacy of single strains versus multi-strain mixtures and arrived at a similar conclusion: “In most cases, single strains were comparable to mixtures. The selection of appropriate probiotics should be based on evidence-based efficacy trials, not the number of strains in the product. In most cases, multi-strain mixtures were not significantly more effective than single-strain probiotics” (McFarland LV, Dig Dis Sci, 2020, doi:10.1007 / s10620-020-06244-z).

[0020] In summary, specific probiotics can offer a promising therapeutic option for AR patients. However, due to strain-specific effects, careful selection of probiotic strains or strain combinations is necessary; furthermore, clinical trials are always needed to assess the effectiveness of each specific strain or strain combination. Thus, there is a great need for new formulations with clinically proven effectiveness. SUMMARY

[0021] Multi-strain formulation according to the invention:

[0022] The present invention aims to solve these deficiencies in the prior art and provides a technical solution to solve the technical problem - to provide a clinically proven probiotic formulation for the treatment of allergic rhinitis and other immunological or allergic diseases / disorders.

[0023] Thus, the present invention relates to a new multi-strain formulation (in particular a probiotic formulation) comprising the following bacterial strains:

[0024] - Bifidobacterium bifidum BB02;

[0025] - Lacticaseibacillus rhamnosus SP1;

[0026] - Bifidobacterium animalis ssp. Lactis Bi1;

[0027] - Lacticaseibacillus paracasei subsp. Paracasei IMC 502; and

[0028] - Lacticaseibacillus casei LC11 ;

[0029] Preferably, all 53 bacterial strains listed in Table 1 below are comprised.

[0030] A multi-strain preparation comprising the above 53 bacterial strains listed in Table 1, also referred to herein as “SYN-AR”.

[0031] As shown in Table 1, the novel multi-strain preparation of the present application preferably comprises 53 unique bacterial strains of different species, including: Bifidobacterium adolescentis, Bifidobacterium animalis, Bifidobacterium bifidum, Bifidobacterium breve, Bifidobacterium longum, Lactobacillus casei, Lactobacillus paracasei, Lactobacillus rhamnosus, Lactiplantibacillus plantarum, Lactobacillus acidophilus, Lactobacillus crispatus, Lactobacillus delbrueckii, Lactobacillus helveticus, Lactococcus lactis, Latilactobacillus sakei, Lentilactobacillus buchneri, Levilactobacillus brevis, Ligilactobacillus salivarius, Limosilactobacillus fermentum, Limosilactobacillus reuteri, Pediococcus acidilactici, Pediococcus pentosaceus, and Streptococcus thermophilus. All strains belong to major bacterial genera that are widely present in the gastrointestinal tract, vagina, and oral cavity of mammals, including humans. The specific strains listed in Table 1 have been deposited at the Leibniz Institute DSMZ (Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH, Inhoffenstr. 7B, 38124 Braunschweig, Germany) on June 16, 2021 (16.06.2021), July 15, 2021 (15.07.2021), and January 17, 2023 (17.01.2023).The deposited bacterial strains and their corresponding deposit numbers (as assigned by the DSMZ as international deposit authority under the Budapest Treaty), reference numbers and dates of deposit are shown in Table 1.

[0032] Table 1: Deposited bacterial strains (these strains are preferably all comprised in the multi-strain preparation of the present application)

[0033]

[0034]

[0035] .

[0036] Table 2 lists alternative names for the strains shown in Table 1.

[0037] Table 2: Deposited bacterial strains and their alternative strain names

[0038]

[0039] .

[0040] Thus, the present application provides a multi-strain preparation comprising the first five bacterial strains listed in Table 1 (and likewise in claim 1), preferably comprising all 53 bacterial strains listed in Table 1. In addition to the 53 strains listed in Table 1, the multi-strain preparation of the present application can comprise one or more other microorganisms, in particular one or more (e.g., 1, 2, 3, 4, or 5) other bacterial strains. Preferably, however, the multi-strain preparation does not comprise any other bacterial strains than the 53 strains listed in Table 1. More preferably, the multi-strain preparation does not comprise any other microorganisms than the 53 strains listed in Table 1. Thus, the present application in particular provides a multi-strain preparation consisting of the 53 bacterial strains listed in Table 1 above.

[0041] In certain embodiments, the multi-strain preparation of the present application comprises the following bacterial strains:

[0042] - Bifidobacterium bifidum BB02;

[0043] - Lactobacillus rhamnosus SP1;

[0044] - Bifidobacterium animalis lactis subsp. lactis Bi1;

[0045] - Paracaseicobacter paracasei subsp. paracasei IMC 502; and

[0046] - Lactobacillus casei LC11;

[0047] and at least one of the following bacterial strains, more preferably at least two, more preferably at least three, more preferably at least four, more preferably at least five, even more preferably at least ten, more preferably at least fifteen, more preferably at least twenty, more preferably at least twenty five, more preferably at least thirty, more preferably at least thirty five, more preferably at least forty, even more preferably at least forty five, even more preferably at least forty seven, or most preferably all of the strains:

[0048] - Bifidobacterium bifidum SP9;

[0049] - Bifidobacterium adolescentis SP77;

[0050] - Lactobacillus casei BGP93;

[0051] - Lactobacillus rhamnosus LR92;

[0052] - Bifidobacterium breve Bbr8;

[0053] - Bifidobacterium breve BL10;

[0054] - Lactobacillus crispatus SP28;

[0055] - Lactobacillus rhamnosus LB21;

[0056] - Lactobacillus rhamnosus IMC 501;

[0057] - Lactobacillus rhamnosus LR1;

[0058] - Lactobacillus acidophilus LA3;

[0059] - Lactobacillus acidophilus LA1;

[0060] - Lactobacillus plantarum subsp. plantarum 14D;

[0061] - Lactobacillus plantarum subsp. plantarum LB931;

[0062] - Lactobacillus plantarum subsp. plantarum BG112;

[0063] - Lactobacillus plantarum subsp. plantarum LP48;

[0064] - Pediococcus acidilactici PA09;

[0065] - Pediococcus pentosaceus PP02;

[0066] - Lactobacillus brevis SP48;

[0067] - Lactobacillus delbrueckii subsp. lactis LL82;

[0068] - Bifidobacterium longum subsp. longum SP54;

[0069] - M. fermentans LF2;

[0070] - M. fermentans CS57;

[0071] - Lactobacillus salivarius SP2;

[0072] - Bifidobacterium animalis subsp. lactis BLC1;

[0073] - Lactococcus lactis subsp. lactis SP38;

[0074] - Lactococcus lactis subsp. lactis SP47;

[0075] - Lactococcus lactis subsp. lactis SD13;

[0076] - Lactobacillus helveticus SP27;

[0077] - Lactobacillus helveticus LH102;

[0078] - Streptococcus thermophilus SP4;

[0079] - Streptococcus thermophilus Z57;

[0080] - Streptococcus thermophilus ST628;

[0081] - Lactobacillus buchneri subsp. buchneri LBC01;

[0082] - Lactobacillus delbrueckii subsp. bulgaricus LB2;

[0083] - Lactobacillus delbrueckii subsp. bulgaricus LB284;

[0084] - Paracaseicola casei subsp. paracasei 101 / 37;

[0085] - Paracaseicola casei subsp. paracasei BGP1;

[0086] - Paracaseicola casei subsp. paracasei BGP2;

[0087] - Lactobacillus sake subsp. sake LSK04;

[0088] - Lactobacillus sake subsp. sake LSK14;

[0089] - Lactobacillus casei LC10;

[0090] - Lactobacillus rhamnosus LRH01;

[0091] - Lactobacillus rhamnosus LRH05;

[0092] - Lactobacillus rhamnosus LRH14;

[0093] - Lactobacillus rhamnosus LRH58;

[0094] - Lactobacillus paracasei subsp. paracasei LPC43; and / or

[0095] - Lactococcus lactis subsp. lactis SL97.

[0096] In certain embodiments, the multi-strain formulation of the application comprises the following bacterial strains:

[0097] - Bifidobacterium bifidum BB02;

[0098] - Lactobacillus rhamnosus SP1;

[0099] - Bifidobacterium animalis lactis Bi1;

[0100] - Lactobacillus paracasei subsp. paracasei IMC 502;

[0101] - Lactobacillus casei LC11;

[0102] - Lactococcus lactis subsp. lactis SL97;

[0103] - Lactobacillus helveticus SP27;

[0104] - Lactobacillus brevis SP48;

[0105] - Streptococcus thermophilus SP4;

[0106] - Bifidobacterium longum subsp. longum SP54; and

[0107] - Bifidobacterium adolescentis SP77.

[0108] In certain embodiments, the multi-strain formulation of the application comprises the following bacterial strains:

[0109] - Bifidobacterium bifidum BB02;

[0110] - Lactobacillus rhamnosus SP1;

[0111] - Bifidobacterium animalis lactis Bi1;

[0112] - Lactobacillus paracasei subsp. paracasei IMC 502;

[0113] - Lactobacillus casei LC11;

[0114] - Lactobacillus helveticus LH102;

[0115] - Lactobacillus brevis SP48;

[0116] - Streptococcus thermophilus SP4;

[0117] - Lactobacillus rhamnosus LRH14;

[0118] - Lactobacillus paracasei paracasei subsp. LPC43;

[0119] - Lactobacillus casei LC10;

[0120] - Lactobacillus fermentum CS57; and

[0121] - Lactobacillus rhamnosus IMC501.

[0122] In certain embodiments, the multi-strain formulation of the application comprises the following bacterial strains:

[0123] - Bifidobacterium bifidum BB02;

[0124] - Lactobacillus rhamnosus SP1;

[0125] - Bifidobacterium animalis lactis subsp. Bi1;

[0126] - Lactobacillus paracasei paracasei subsp. IMC502;

[0127] - Lactobacillus casei LC11;

[0128] - Lactococcus lactis lactis subsp. SL97;

[0129] - Lactobacillus helveticus SP27;

[0130] - Lactobacillus brevis SP48;

[0131] - Streptococcus thermophilus SP4;

[0132] - Bifidobacterium longum longum subsp. SP54;

[0133] - Bifidobacterium adolescentis SP77;

[0134] - Lactobacillus helveticus LH102;

[0135] - Lactobacillus rhamnosus LRH14;

[0136] - Lactobacillus paracasei paracasei subsp. LPC43;

[0137] - Lactobacillus casei LC10;

[0138] - Lactobacillus fermentum CS57; and

[0139] - Lactobacillus rhamnosus IMC501.

[0140] In certain embodiments, the multi-strain preparation of the application comprises the following bacterial strains:

[0141] - Bifidobacterium bifidum BB02;

[0142] - Lactobacillus rhamnosus SP1;

[0143] - Bifidobacterium animalis lactis subsp. lactis Bi1;

[0144] - Paracaseicobacter paracasei subsp. paracasei IMC502;

[0145] - Lactobacillus casei LC11;

[0146] - Bifidobacterium bifidum SP9;

[0147] - Bifidobacterium adolescentis SP77;

[0148] - Lactobacillus casei BGP93;

[0149] - Mucolactobacillus reuteri LR92;

[0150] - Bifidobacterium breve Bbr8;

[0151] - Bifidobacterium breve BL10;

[0152] - Lactobacillus crispatus SP28;

[0153] - Lactobacillus rhamnosus IMC501;

[0154] - Lactobacillus exigus SP48;

[0155] - Bifidobacterium longum subsp. longum SP54;

[0156] - Lactobacillus helveticus SP27;

[0157] - Lactobacillus helveticus LH102;

[0158] - Streptococcus thermophilus SP4;

[0159] - Lactobacillus casei LC10;

[0160] - Lactobacillus rhamnosus LRH14;

[0161] - Paracaseicobacter paracasei subsp. paracasei LPC43; and

[0162] - Lactococcus lactis subsp. lactis SL97.

[0163] In certain embodiments, the multi-strain preparation of the application comprises the following bacterial strains:

[0164] - Bifidobacterium bifidum BB02;

[0165] - Lactobacillus rhamnosus SP1 ;

[0166] - Bifidobacterium animalis lactis Bi1 ;

[0167] - Paracaseicobacter paracasei subsp. paracasei IMC 502;

[0168] - Lactobacillus casei LC11 ;

[0169] - Bifidobacterium adolescentis SP77;

[0170] - Lactobacillus rhamnosus LB21 ;

[0171] - Lactobacillus rhamnosus IMC 501 ;

[0172] - Lactobacillus rhamnosus LR1 ;

[0173] - Lactobacillus acidophilus LA3;

[0174] - Lactobacillus acidophilus LA1 ;

[0175] - Lactobacillus plantarum subsp. plantarum 14D;

[0176] - Lactobacillus plantarum subsp. plantarum LB931 ;

[0177] - Lactobacillus brevis SP48;

[0178] - Bifidobacterium longum subsp. longum SP54;

[0179] - Mucilaginibacter fer brevicus CS57;

[0180] - Lactobacillus helveticus SP27;

[0181] - Lactobacillus helveticus LH102;

[0182] - Streptococcus thermophilus SP4;

[0183] - Lactobacillus casei LC10;

[0184] - Lactobacillus rhamnosus LRH14;

[0185] - Paracaseicobacter paracasei subsp. paracasei LPC43; and

[0186] - Lactococcus lactis subsp. lactis SL97.

[0187] In certain embodiments, the multi-strain formulation of the application comprises the following bacterial strains:

[0188] - Bifidobacterium bifidum BB02;

[0189] - Lactobacillus rhamnosus SP1 ;

[0190] - Bifidobacterium animalis lactis Bi1 ;

[0191] - Paracaseicobacter paracasei subsp. paracasei IMC 502;

[0192] - Caseicobacter casei LC11 ;

[0193] - Bifidobacterium adolescentis SP77;

[0194] - Lactobacillus rhamnosus IMC 501 ;

[0195] - Lactobacillus plantarum subsp. plantarum BG112;

[0196] - Lactobacillus plantarum subsp. plantarum LP48;

[0197] - Pediococcus acidilactici PA09;

[0198] - Pediococcus pentosaceus PP02;

[0199] - Lactobacillus brevis SP48;

[0200] - Lactobacillus delbrueckii subsp. lactis LL82;

[0201] - Bifidobacterium longum subsp. longum SP54;

[0202] - Lactobacillus fermentum LF2;

[0203] - Lactobacillus fermentum CS57;

[0204] - Lactobacillus helveticus SP27;

[0205] - Lactobacillus helveticus LH102;

[0206] - Streptococcus thermophilus SP4;

[0207] - Caseicobacter casei LC10;

[0208] - Lactobacillus rhamnosus LRH14;

[0209] - Paracaseicobacter paracasei subsp. paracasei LPC43; and

[0210] - Lactococcus lactis subsp. lactis SL97.

[0211] In certain embodiments, the multi-strain formulation of the application comprises the following bacterial strains:

[0212] - Bifidobacterium bifidum BB02;

[0213] - Lactobacillus rhamnosus SP1;

[0214] - Bifidobacterium animalis lactis Bi1;

[0215] - Paracaseicobacter paracasei subsp. paracasei IMC 502;

[0216] - Caseicobacter casei LC11;

[0217] - Bifidobacterium adolescentis SP77;

[0218] - Lactobacillus rhamnosus IMC 501;

[0219] - Lactobacillus brevis SP48;

[0220] - Bifidobacterium longum subsp. longum SP54;

[0221] - Mucilaginibacter ferus CS57;

[0222] - Lactobacillus salivarius SP2;

[0223] - Bifidobacterium animalis lactis BLC1;

[0224] - Lactococcus lactis subsp. lactis SP38;

[0225] - Lactococcus lactis subsp. lactis SP47;

[0226] - Lactococcus lactis subsp. lactis SD13;

[0227] - Lactobacillus helveticus SP27;

[0228] - Lactobacillus helveticus LH102;

[0229] - Streptococcus thermophilus SP4;

[0230] - Streptococcus thermophilus Z57;

[0231] - Caseicobacter casei LC10;

[0232] - Lactobacillus rhamnosus LRH14;

[0233] - Paracaseicobacter paracasei subsp. paracasei LPC43; and

[0234] - Lactococcus lactis subsp. lactis SL97.

[0235] In certain embodiments, the multi-strain formulation of the application comprises the following bacterial strains:

[0236] - Bifidobacterium bifidum BB02;

[0237] - Lactobacillus rhamnosus SP1;

[0238] - Bifidobacterium animalis lactis Bi1;

[0239] - Paracaseicobacter paracasei subsp. paracasei IMC 502;

[0240] - Caseobacter casei LC11;

[0241] - Bifidobacterium adolescentis SP77;

[0242] - Lactobacillus rhamnosus IMC 501;

[0243] - Lactobacillus brevis SP48;

[0244] - Bifidobacterium longum subsp. longum SP54;

[0245] - Mucilaginibacter ferus CS57;

[0246] - Lactobacillus helveticus SP27;

[0247] - Lactobacillus helveticus LH102;

[0248] - Streptococcus thermophilus SP4;

[0249] - Streptococcus thermophilus ST628;

[0250] - Lactobacillus buchneri subsp. buchneri LBC01;

[0251] - Lactobacillus delbrueckii subsp. bulgaricus LB2;

[0252] - Lactobacillus delbrueckii subsp. bulgaricus LB284;

[0253] - Paracaseicobacter paracasei subsp. paracasei 101 / 37;

[0254] - Paracaseicobacter paracasei subsp. paracasei BGP1;

[0255] - Caseobacter casei LC10;

[0256] - Lactobacillus rhamnosus LRH14;

[0257] - Paracaseicobacter paracasei subsp. paracasei LPC43; and

[0258] - Lactococcus lactis subsp. lactis SL97.

[0259] In certain embodiments, the multi-strain preparation of the application comprises the following bacterial strains:

[0260] - Bifidobacterium bifidum BB02;

[0261] - Lactobacillus rhamnosus SP1 ;

[0262] - Bifidobacterium animalis lactis subsp. lactis Bi1 ;

[0263] - Paracaseicobacter paracasei subsp. paracasei IMC 502;

[0264] - Caseicobacter casei LC11 ;

[0265] - Bifidobacterium adolescentis SP77;

[0266] - Lactobacillus rhamnosus IMC 501 ;

[0267] - Lactobacillus brevis SP48;

[0268] - Bifidobacterium longum subsp. longum SP54;

[0269] - Lactobacillus fermentum CS57;

[0270] - Lactobacillus helveticus SP27;

[0271] - Lactobacillus helveticus LH102;

[0272] - Streptococcus thermophilus SP4;

[0273] - Paracaseicobacter paracasei subsp. paracasei BGP2;

[0274] - Lactobacillus sake Lactobacillus sake subsp. sake LSK04;

[0275] - Lactobacillus sake Lactobacillus sake subsp. sake LSK14;

[0276] - Caseicobacter casei LC10;

[0277] - Lactobacillus rhamnosus LRH01 ;

[0278] - Lactobacillus rhamnosus LRH05;

[0279] - Lactobacillus rhamnosus LRH14;

[0280] - Lactobacillus rhamnosus LRH58;

[0281] - Paracaseicobacter paracasei subsp. paracasei LPC43; and

[0282] - Lactococcus lactis subsp. lactis SL97.

[0283] In certain embodiments, the multi-strain preparation of the application comprises the following bacterial strains:

[0284] - Bifidobacterium bifidum BB02;

[0285] - Lactobacillus rhamnosus SP1 ;

[0286] - Bifidobacterium animalis lactis subspecies Bi1 ;

[0287] - Paracaseicobacter paracasei subspecies IMC 502;

[0288] - Caseicobacter casei LC11 ;

[0289] - Bifidobacterium bifidum SP9;

[0290] - Bifidobacterium adolescentis SP77;

[0291] - Caseicobacter casei BGP93;

[0292] - Mucilaginibacter royalei LR92;

[0293] - Bifidobacterium breve Bbr8;

[0294] - Bifidobacterium breve BL10;

[0295] - Lactobacillus crispatus SP28;

[0296] - Lactobacillus rhamnosus LB21 ;

[0297] - Lactobacillus rhamnosus IMC 501 ;

[0298] - Lactobacillus rhamnosus LR1 ;

[0299] - Lactobacillus acidophilus LA3;

[0300] - Lactobacillus acidophilus LA1 ;

[0301] - Lactobacillus plantarum subspecies 14D;

[0302] - Lactobacillus plantarum subspecies LB931 ;

[0303] - Lactobacillus brevis SP48;

[0304] - Bifidobacterium longum subspecies SP54;

[0305] - Mucilaginibacter ferments CS57;

[0306] - Lactobacillus helveticus SP27;

[0307] - Lactobacillus helveticus LH102;

[0308] - Streptococcus thermophilus SP4;

[0309] - Lactobacillus casei LC10;

[0310] - Lactobacillus rhamnosus LRH14;

[0311] - Paracaseicobacter paracasei subsp. paracasei LPC43; and

[0312] - Lactococcus lactis subsp. lactis SL97;

[0313] wherein the above formulation preferably further comprises at least 4 other bacterial strains from Table 1, more preferably at least 10 other bacterial strains from Table 1, more preferably at least 15 other bacterial strains from Table 1, even more preferably at least 20 other bacterial strains from Table 1, again more preferably at least 24 other bacterial strains from Table 1.

[0314] In certain embodiments, the multi-strain formulations of the application comprise the following bacterial strains:

[0315] - Bifidobacterium bifidum BB02;

[0316] - Lactobacillus rhamnosus SP1 ;

[0317] - Bifidobacterium animalis lactis subsp. lactis Bi1 ;

[0318] - Paracaseicobacter paracasei subsp. paracasei IMC 502;

[0319] - Lactobacillus casei LC1 1 ;

[0320] - Bifidobacterium adolescentis SP77;

[0321] - Lactobacillus rhamnosus IMC 501 ;

[0322] - Lactobacillus plantarum subsp. plantarum BG1 12;

[0323] - Lactobacillus plantarum subsp. plantarum LP48;

[0324] - Pediococcus acidilactici PA09;

[0325] - Pediococcus pentosaceus PP02;

[0326] - Lactobacillus brevis SP48;

[0327] - Lactobacillus delbrueckii subsp. lactis LL82;

[0328] - Bifidobacterium longum subsp. longum SP54;

[0329] - M. fermentans LF2;

[0330] - M. fermentans CS57;

[0331] - L. salivarius SP2;

[0332] - Bifidobacterium animalis subsp. lactis BLC1;

[0333] - Lactococcus lactis subsp. lactis SP38;

[0334] - Lactococcus lactis subsp. lactis SP47;

[0335] - Lactococcus lactis subsp. lactis SD13;

[0336] - Lactobacillus helveticus SP27;

[0337] - Lactobacillus helveticus LH102;

[0338] - Streptococcus thermophilus SP4;

[0339] - Streptococcus thermophilus Z57;

[0340] - Lactobacillus casei Shirota LC10;

[0341] - Lactobacillus rhamnosus LRH14;

[0342] - Paracasei subsp. paracasei LPC43; and

[0343] - Lactococcus lactis subsp. lactis SL97;

[0344] wherein the above formulation preferably further comprises at least 4 other bacterial strains from Table 1, more preferably at least 10 other bacterial strains from Table 1, more preferably at least 15 other bacterial strains from Table 1, even more preferably at least 20 other bacterial strains from Table 1, again more preferably at least 24 other bacterial strains from Table 1.

[0345] In certain embodiments, the multi-strain formulations of the application comprise the following bacterial strains:

[0346] - Bifidobacterium bifidum BB02;

[0347] - Lactobacillus rhamnosus SP1;

[0348] - Bifidobacterium animalis subsp. lactis Bi1;

[0349] - Paracaseicilus paracasei subsp. paracasei IMC 502;

[0350] - Caseicilus casei LC11 ;

[0351] - Bifidobacterium adolescentis SP77;

[0352] - Lactobacillus rhamnosus IMC 501 ;

[0353] - Lactobacillus brevis SP48;

[0354] - Bifidobacterium longum subsp. longum SP54;

[0355] - Lactobacillus fermentum CS57;

[0356] - Lactobacillus helveticus SP27;

[0357] - Lactobacillus helveticus LH102;

[0358] - Streptococcus thermophilus SP4;

[0359] - Streptococcus thermophilus ST628;

[0360] - Lactobacillus buchneri subsp. buchneri LBC01;

[0361] - Lactobacillus delbrueckii subsp. bulgaricus LB2;

[0362] - Lactobacillus delbrueckii subsp. bulgaricus LB284;

[0363] - Paracaseicilus paracasei subsp. paracasei 101 / 37;

[0364] - Paracaseicilus paracasei subsp. paracasei BGP1;

[0365] - Paracaseicilus paracasei subsp. paracasei BGP2;

[0366] - Lactobacillus sakes Lactobacillus sake subsp. sake LSK04;

[0367] - Lactobacillus sakes Lactobacillus sake subsp. sake LSK14;

[0368] - Caseicilus casei LC10;

[0369] - Lactobacillus rhamnosus LRH01;

[0370] - Lactobacillus rhamnosus LRH05;

[0371] - Lactobacillus rhamnosus LRH14;

[0372] - Lactobacillus rhamnosus LRH58;

[0373] - Lactobacillus paracasei subsp. paracasei LPC43; and

[0374] - Lactococcus lactis subsp. lactis SL97;

[0375] wherein the above formulation preferably further comprises at least 4 other bacterial strains from Table 1, more preferably at least 10 other bacterial strains from Table 1, more preferably at least 15 other bacterial strains from Table 1, even more preferably at least 20 other bacterial strains from Table 1, and again more preferably at least 24 other bacterial strains from Table 1.

[0376] The concentration and relative amounts of the different bacterial strains comprised in the multi-strain formulation of the application (or the composition comprising the same) are not particularly limited. Preferably, each of the first 5 bacterial strains listed in Table 1 (or, preferably, each of the 53 different bacterial strains listed in Table 1 ) is present in a concentration of at least 10 5 colony forming units (CFU) per dosage unit (e.g. per capsule), wherein the total number of viable cells of the multi-strain formulation is preferably at least 1 x 10 10 CFU per dosage unit (e.g. per capsule). More preferably, the concentration of each of the 5 bacterial strains (preferably each of the 53 strains) and the total number of viable cells in the multi-strain formulation (or the composition) are as defined for the "SYN-AR-A" formulation in Table 4 (see Example 1 below). It will be appreciated that the multi-strain formulation is preferably a probiotic multi-strain formulation, and thus each of the above bacterial strains is viable in the multi-strain formulation.

[0377] In certain embodiments, the bacterial strains are comprised in the multi-strain formulation of the application in equal amounts. However, it is preferred that certain bacterial strains are present in the multi-strain formulation of the application in higher amounts than others. It is particularly preferred that Bifidobacterium animalis lactis Bi1 and / or Lactobacillus paracasei subsp. paracasei IMC 502 are present in the multi-strain formulation of the application in higher amounts than the remaining strains in the formulation. In certain embodiments, Bifidobacterium animalis lactis Bi1 and / or Lactobacillus paracasei subsp. paracasei IMC 502 are present in the multi-strain formulation of the application in an amount that is at least one order of magnitude, preferably at least two orders of magnitude, and more preferably at least three orders of magnitude higher than the average amount of the remaining strains comprised in the multi-strain formulation.

[0378] In certain embodiments, at least 50%, preferably at least 60%, more preferably at least 70%, even more preferably at least 80%, or even more preferably at least 90% of the bacterial strains (in CFU / dose unit) comprised in the multi-strain preparation of the application are Bifidobacterium animalis lactis Bii and / or Paracaseicobacter paracasei subsp. paracasei IMC 502.

[0379] Composition of the invention

[0380] As mentioned above, the present application provides a novel multi-strain preparation comprising 5 specific bacterial strains (preferably the novel multi-strain preparation comprises the 53 specific bacterial strains listed in Table 1 above), and compositions comprising the multi-strain preparation. The present application relates in particular to a probiotic composition comprising the multi-strain preparation. The composition can be provided in the form of, for example, a pharmaceutical composition or a food composition.

[0381] That is, the present application also relates to a composition comprising the multi-strain preparation provided herein. In particular, the composition comprises the multi-strain preparation of the application as an active ingredient. The composition can optionally comprise other molecules. Said other molecules can be active ingredients themselves, or can be inert, and can be comprised to achieve a variety of functions, such as for stabilizing the multi-strain preparation of the application, or for delaying, modulating and / or activating its functions, or for providing additional benefits (e.g. additional health benefits) to the patient receiving said composition. Non-limiting examples of such other molecules include pharmaceutically acceptable and / or ingestible carriers, adjuvants, other bacterial ingredients, pharmacologically active agents, proteins and / or peptides (in particular glutamine and / or glutamic acid-rich proteins and / or peptides), lipids, carbohydrates, vitamins, minerals and / or trace elements.

[0382] In certain embodiments, the composition is a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" means a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Examples of such carriers include water, saline, Ringer's solutions, and dextrose solutions. Non-aqueous vehicles (such as fixed oils and fatty acid ethyl esters) are also suitable for use in the present application, as are liposomes. The carrier(s) can suitably comprise minor amounts of additives such as agents to aid isotonicity and chemical stability. Such materials are non-toxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, succinate, acetic acid, and other organic acids or their salts; antioxidants such as ascorbic acid; low molecular weight (less than about ten amino acid residues) (poly)peptides such as polyarginine or tripeptides; proteins such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamic acid, aspartic acid, or arginine; monosaccharides, disaccharides, and other carbohydrates including cellulose or its derivatives, starch (e.g., corn starch), glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; counterions such as sodium; and / or nonionic surfactants such as polysorbates, poloxamers, or PEG. Particularly preferred carriers according to the present application include phosphate buffered saline solutions, water, emulsions (such as oil / water emulsions), various types of wetting agents, sterile solutions, and organic solvents including DMSO.

[0383] The term "ingestible carrier" as used herein means a carrier suitable for oral administration of the composition, which aids in the ingestion of the components of the composition. Suitable carriers can be selected by one skilled in the art without undue effort depending on the form of administration of the composition. Some non-limiting examples are provided: cellulose can be used as a carrier material for tablets or capsules; maltodextrin can be used in powder form; or dairy products can be used for administration in food form, as described in detail below.

[0384] The term "adjuvant" as used herein refers to a compound that, when used alone, has little, if any, direct effect, but modifies the effects of other compounds (e.g., any of the bacterial strains included in the multi-strain preparation of the application). Adjuvants are typically added to promote a more rapid, strong, and / or long-lasting reaction to the active ingredient, thus allowing for the use of lower doses. Non-limiting examples of adjuvants include, for example, aluminum hydroxide and aluminum phosphate, the organic compound squalene, and compounds that are currently being tested or have been identified as adjuvants, such as QS21, aluminum hydroxide and its derivatives, oil immersions, lipid A and its derivatives (e.g., monophosphoryl lipid A, MPL), CpG motifs, muramyl dipeptide (MDP), Freund's complete adjuvant (FCA), Freund's incomplete adjuvant (FIA), or MF59C (see, e.g., Garçon N et al., Expert Rev Vaccines, 2011, 10(4): 471-486, doi: 10.1586 / erv.11.29; Alving CR, Immunobiology, 1993, 187(3-5): 430-446, doi: 10.1016 / S0171-2985(11)80355-4; Petrovsky N et al., Immunol Cell Biol, 2004, 82(5): 488-496, doi: 10.1111 / j.0818-9641.2004.01272.x; Weiner GJ et al., Proc Natl Acad Sci USA, 1997, 94(20): 10833-10837, doi: 10.1073 / pnas.94.20.10833; Yoo YC et al., Vaccine, 1998, 16(2-3): 216-224, doi: 10.1016 / s0264-410x(97)00188-6; Steiner JW et al., Arch Pathol, 1960, 70:424-434; US 6,299,884; or US 6,451,325).

[0385] The term "pharmacologically active agent" as used herein refers to a chemical or biological compound which has a pharmacological activity and is pharmaceutically tolerable for a patient. Non-limiting examples include bisacodyl, loperamide, aminosalicylate, sulfasalazine, 5-aminosalicylic acid, 4-aminosalicylic acid, benzalazine, olsalazine, balsalazide, or bismuth subsalicylate. In particular, the pharmacologically active agent can be selected from the group of drugs known to be useful in the treatment of gastrointestinal disorders. Examples of such pharmacologically active agents are known in the art and are recorded in pharmacopeia directories (e.g. the "Rote Liste" in Germany) and are constantly updated.

[0386] The term "peptide" as used herein refers to a molecule consisting of up to 30 amino acids, whereas the term "protein" refers to a molecule consisting of more than 30 amino acids. Peptides and proteins can further form dimers, trimers and higher oligomers, i.e. consist of more than one molecule which can be identical or different. The corresponding higher order structures are therefore referred to as homodimers or heterodimers, homotrimers or heterotrimers, etc. The terms "peptide" and "protein" (wherein "protein" is used interchangeably with "polypeptide") also refer to naturally modified peptides / proteins, wherein the modifications are achieved by, e.g., glycosylation, acetylation, phosphorylation, etc. Such modifications are well known in the art. Preferably, glutamine and / or glutamic acid rich proteins and / or peptides are used, since glutamine / glutamic acid helps in the construction of intestinal cells and the reconstruction of damaged intestinal mucosa. Glutamine / glutamic acid rich proteins and / or peptides include, e.g., milk proteins, soy proteins or wheat proteins.

[0387] The term "lipid" as used herein is defined in accordance with the pertinent art. Non-limiting examples of suitable lipids as additional compounds include, e.g., olive oil, soybean oil, rapeseed oil or fish oil.

[0388] A "carbohydrate" is an organic compound consisting only of carbon, hydrogen and oxygen. Non-limiting examples of suitable carbohydrates as additional compounds include cellulose, lactose, maltodextrin, inulin, glucose, mannitol, fructooligosaccharides, mannit, maltose, dextrin, sorbitol or fructose.

[0389] According to the present application, "vitamins" include water-soluble vitamins as well as water-insoluble vitamins. Non-limiting examples of vitamins suitable as additional compounds include vitamin A (e.g., retinol, retinal, and carotenoids, including beta-carotene), vitamin Bl (thiamine), vitamin B2 (riboflavin), vitamin B3 (e.g., niacin, nicotinamide), vitamin B5 (pantothenic acid), vitamin B6 (e.g., pyridoxine, pyridoxamine, pyridoxal), vitamin B7 (biotin), vitamin B9 (e.g., folic acid, folinic acid), vitamin B 12 (e.g., cyanocobalamin, hydroxocobalamin, methylcobalamin), vitamin C (ascorbic acid), vitamin D (e.g., ergocalciferol, cholecalciferol), vitamin E (e.g., tocopherol, tocotrienol), and vitamin K (e.g., phylloquinone, menadione). Particularly preferred vitamins are the B vitamins, such as vitamin Bl (thiamine), vitamin B2 (riboflavin), vitamin B3 (e.g., niacin, nicotinamide), vitamin B5 (pantothenic acid), vitamin B6 (e.g., pyridoxine, pyridoxamine, pyridoxal), vitamin B7 (biotin), vitamin B9 (e.g., folic acid, folinic acid), and vitamin B 12 (e.g., cyanocobalamin, hydroxocobalamin, methylcobalamin). In a preferred embodiment, the composition according to the present application comprises vitamin B7 (biotin).

[0390] Non-limiting examples of "minerals" suitable as additional compounds include magnesium, calcium, zinc, selenium, iron, copper, manganese, chromium, molybdenum, potassium, vanadium, boron, and titanium. Magnesium and calcium are particularly preferred minerals.

[0391] The term "trace element" as used herein refers to a chemical element that is required in very small amounts for the growth, development, and / or physiology of an organism, preferably a human. Non-limiting examples of trace elements suitable as additional compounds include iodine, copper, or iron.

[0392] The composition according to the present application can be provided in the form of a prebiotic composition. For a prebiotic composition, the composition according to the present application further comprises a "prebiotic compound". The term "prebiotic compound" as used herein refers to a non-digestible compound which, when ingested by a subject, can confer a benefit to the subject due to the selective stimulation and / or activation of the growth of one or more beneficial bacteria present in the intestinal tract of said subject. Thus, the prebiotic compound is capable of rebalancing the bacterial flora. Preferably, the prebiotic composition according to the present application comprises inulin and / or fructo-oligosaccharides as prebiotic compound. Inulin is a soluble compound which is chemically a fructan, i.e. a polysaccharide formed of linear chains of fructose molecules (up to 100 fructose molecules) with terminal glucose residues. It has been demonstrated in the art that the consumption of inulin leads to an increase in bifidobacteria and lactobacilli in the intestinal tract. Lactobacilli produce lactase which is essential for correct digestion and the health of the colon. At the same time, a decrease in the number of harmful bacteria in the intestinal tract is observed. Fructo-oligosaccharides are shorter oligosaccharides fructans (up to 10 fructose molecules) which are resistant to hydrolysis by salivary and intestinal digestive enzymes. In the colon, they are fermented by anaerobic bacteria, thus improving the overall health of the gastrointestinal tract.

[0393] If one or more prebiotic compounds are present in the multi-strain preparation (or the corresponding composition) according to the present application, preferably the amount of prebiotic compound is at least 0.3 g, more preferably at least 0.5 g, more preferably at least 0.7 g, even more preferably at least 1 g, and more preferably at least 1.5 g of prebiotic compound per 1 g of bacterial strains comprised in the multi-strain preparation (or the corresponding composition).

[0394] The composition of the present application can also be in the form of a food composition. The term "food composition" as used herein refers to any food suitable for consumption by a human or an animal. Thus, non-limiting examples of "food compositions" include, for example, animal food, e.g., extruded and pelleted animal food or raw mix, and food for human consumption, including solid and liquid foods, such as beverages, including drinking water and dairy products, as described in more detail below. Thus, the term includes, but is not limited to, a food product, a dietary supplement, a nutritional supplement, a medical food, or a food for special medical purposes (FSMP). The term "dietary supplement" as used herein refers to a manufactured product intended to supplement the diet of a human or an animal, typically provided in the form of a pill, capsule, tablet, or liquid, and packaged in single or multiple dose units. Dietary supplements typically do not provide a large quantity of calories, but can contain other micronutrients, such as vitamins or minerals. According to the present application, the term "nutritional supplement" refers to a composition comprising a dietary supplement and a source of calories. For example, a nutritional supplement can be a meal replacement or a supplement, such as a nutritional or energy bar, a nutritional beverage or a concentrate. The term "food for special medical purposes" (FSMP) refers in particular to the corresponding food product as defined in Article 2(2)(g) of Regulation (EU) No 609 / 2013 of 22 May 2014 on food intended for particular nutritional uses, as of the version dated 28 April 2021 (see also EFSA Journal, 2015, 13(11): 4300).

[0395] Preferably, the food composition is a milk product. Non-limiting examples of milk products include acidified milk, dairy-based desserts, humanized milk, milk powder, concentrated milk, dairy-based sauces, milk beverages, and fermented milk products, such as yogurt (including frozen yogurt), yogurt drinks, fermented cream, kefir, sour cream, crème fraiche, cheese, and cheese sauce. The term "milk product", as used herein, includes products derived from animal (i.e., dairy products) or plant sources (i.e., non-dairy products). Milk products of animal origin include products made from the milk of, for example, a cow, a sheep, a goat, or a water buffalo. Milk products of plant origin include fermented products derived from plant sources, such as products made from soy milk, rice milk, almond milk, coconut milk, or grain milk (e.g., oat milk).

[0396] According to the present application, the composition can be in solid or liquid form and can be formulated by conventional methods. For example, methods of formulating pharmaceutical compositions have been described in the art, for example, in "Remington: The Science and Practice of Pharmacy", Pharmaceutical Press, 22ndedition. Generally, the method of preparing a composition involves bringing into intimate contact the active ingredients with the additional compounds required. The product is then shaped or contoured in whatever manner is desired.

[0397] Depending on the type of composition, it can be formulated into a variety of forms. For example, pharmaceutical compositions as well as prebiotic compositions can be formulated into dosage forms for oral, parenteral (e.g. intramuscular, intravenous, subcutaneous, intradermal, intra-arterial, intra-cardiac), rectal, nasal, topical, aerosol or vaginal administration. Oral administration is particularly preferred. For oral administration, the composition is administered by oral ingestion, in particular by swallowing. Thus, the composition can be administered orally into the gastrointestinal tract. Non-limiting examples of preferred forms for oral administration include, coated and uncoated tablets, soft gelatin capsules, hard gelatin capsules, lozenges, troches, cachets, wafers, capsules, solutions, emulsions, suspensions, syrups, elixirs, powders for reconstitution and granules, dispersible powders and granules (e.g. sterile packaged powders or granules), medicinal chewing gum, chewable tablets and effervescent tablets, which can contain flavourings or colourings, for immediate release, delayed release, modified release, sustained release, pulsed release or controlled release applications. The composition can also be incorporated into a food product to provide a food composition.

[0398] Tablets can contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine; disintegrants such as starch (preferably corn, potato or tapioca starch), sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose and certain complex silicates; and granulating binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl monostearate and talc can be included. Solid compositions of a similar type can also be employed as fillers in gelatin capsules. Preferred excipients in this regard include lactose, starch (preferably corn, wheat, rice or potato starch), cellulose (preferably microcrystalline cellulose), and high molecular weight polyethylene glycols. For aqueous suspensions and / or elixirs, the multi-strain preparation of the application can be combined with various sweetening or flavouring agents, colouring or flavouring agents and perfuming agents, emulsifying and / or suspending agents, and diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.

[0399] In a particularly preferred embodiment, the multi-strain preparation of the application is comprised in a capsule. The term "capsule" as used herein refers to a pharmaceutically inactive envelope intended to contain at least one pharmaceutically active ingredient. The capsule shell is usually made from an aqueous solution of a gelatinizing agent, such as an animal protein (mainly gelatin) or a plant polysaccharide or a derivative thereof. In certain embodiments, the capsule shell is made from gelatin. In a preferred embodiment, the capsule shell is made from hydroxypropyl methylcellulose (HPMC).

[0400] In addition to the multi-strain preparation of the application, the capsule can further comprise a filler. In certain embodiments, the filler is a carbohydrate, such as corn starch.

[0401] The capsule can further comprise one or more anti-caking agents. As used herein, the term "anti-caking agent" refers to an additive added to a powdered or granular material to prevent caking. Some examples of anti-caking agents include, but are not limited to, tribasic calcium phosphate, powdered cellulose, magnesium stearate, sodium bicarbonate, sodium ferrocyanide, potassium ferrocyanide, calcium ferrocyanide, bone phosphate, sodium silicate, silicon dioxide, calcium silicate, magnesium trisilicate, talc, sodium aluminosilicate, potassium aluminosilicate, calcium aluminosilicate, bentonite, aluminum silicate, stearic acid, and dimethicone. In this context, it is preferred that the capsule comprises magnesium stearate and silicon dioxide as anti-caking agents.

[0402] In certain embodiments, the capsule comprising the multi-strain preparation of the application has the following composition:

[0403] Table 3: Composition of exemplary capsules of the application

[0404] Ingredients mg / capsule Function Probiotic mixture 144.443 Active ingredient Corn starch 110.517 Filling agent Magnesium stearate 9.990 Anti-caking agent Silicon dioxide 0.050 Anti-caking agent Hydroxypropyl methylcellulose 60 Capsule shell

[0405] .

[0406] In certain embodiments, each capsule comprises 10 8 to 10 12 live bacteria (CFU), preferably 10 8 to 10 11 live bacteria (CFU), more preferably 10 9 to 10 11 live bacteria (CFU), even more preferably 10 10 to 10 11 live bacteria (CFU), most preferably about 5 x 10 10 live bacteria (CFU).

[0407] Preferably, each capsule comprises 10 9 to 10 11 live bacteria (CFU), wherein the content of the bacterial strains Bifidobacterium animalis lactis subsp. biol and / or Paracaseicobacter paracasei subsp. paracasei IMC 502 is 108 to 8 x 10 10 CFU. Even more preferably, each capsule comprises 10 9 to 10 11 viable bacteria (CFU), wherein the content of the bacterial strain Bifidobacterium animalis lactis Bii and / or Paracasei subsp. paracasei IMC 502 is 10 8 to 8 x 10 10 CFU, respectively, and the content of the other bacterial strains listed in Table 1 is 10 4 to 10 8 CFU, respectively.

[0408] In a particularly preferred embodiment, each capsule comprises 10 10 to 10 11 viable bacteria (CFU), wherein the content of the bacterial strain Bifidobacterium animalis lactis Bii and / or Paracasei subsp. paracasei IMC 502 is 5 x 10 9 to 5 x 10 10 CFU, respectively, and the content of the other bacterial strains listed in Table 1 is 1 x 10 5 to 1 x 10 7 CFU, respectively.

[0409] In a most preferred embodiment, each capsule comprises the amounts of all 53 bacterial strains indicated in Table 4 for the formulation "SYN-AR-A".

[0410] In certain embodiments, the capsules further comprise vitamins. In a preferred embodiment, the capsules comprise vitamin B7 (biotin). In certain embodiments, each capsule can comprise 1 to 1000 pg vitamin B7 (biotin), preferably 10 to 500 pg vitamin B7 (biotin), more preferably 10 to 100 pg vitamin B7 (biotin), most preferably 50 pg vitamin B7 (biotin).

[0411] Medical use

[0412] According to the present application, the multi-strain formulation of the present application or a composition comprising the same can be used in therapy (i.e. for use as a medicament). To this end, the multi-strain formulation of the present application can take any suitable form which allows it to be suitable for a patient and to exert its therapeutic potential. For example, the multi-strain formulation of the present application can be formulated into any of the compositions as described above, including a pharmaceutical composition, a cosmetic composition, a prebiotic composition or a food composition.

[0413] The multi-strain preparation of the application or the composition comprising the same can be used in therapy, for example, for the treatment or prevention of an immunological disease / disorder, in particular for the treatment or prevention of an allergic disease / disorder. Accordingly, the present application relates to a multi-strain preparation (or a composition comprising the same) for use in the treatment or prevention of an immunological disease / disorder, in particular for the treatment or prevention of an allergic disease / disorder. The present application also relates to the use of a multi-strain preparation (or a composition comprising the same) for the manufacture of a medicament (or a pharmaceutical composition) for the treatment or prevention of an immunological disease / disorder, in particular for the treatment or prevention of an allergic disease / disorder. Furthermore, the present application also provides a method of treating or preventing a disease / disorder, in particular an immunological disease / disorder or an allergic disease / disorder, the method comprising administering a multi-strain preparation (or a composition comprising the same) to a subject in need thereof. It will be appreciated that the method comprises administering a therapeutically effective amount (or dose) of the multi-strain preparation.

[0414] The allergic disease / disorder treated or prevented according to the present application is preferably selected from the group consisting of allergic rhinitis, allergic conjunctivitis, allergic rhinoconjunctivitis, atopic dermatitis, contact urticaria, allergic bronchial asthma, anaphylactic shock, and gastrointestinal conditions associated with an allergic reaction (e.g., nausea, vomiting, abdominal pain, meteorism or diarrhea). More preferably, the disease / disorder treated or prevented is allergic rhinitis, allergic conjunctivitis or allergic rhinoconjunctivitis. Most preferably, the disease / disorder treated or prevented is allergic rhinoconjunctivitis.

[0415] In the context of the present application, it was surprisingly found that the novel multi-strain probiotic preparation provided herein efficiently alleviates ARC symptoms in a double-blind, randomized, placebo-controlled clinical trial in ARC patients, as shown in Example 1. The efficiency of this novel multi-strain probiotic preparation is an unexpected result, as it is well known and widely accepted in the art that the effectiveness of multi-strain preparations is highly strain-specific and, thus, unpredictable.

[0416] The subject or patient treated according to the present application can be an animal (e.g., a non-human animal). Preferably, the subject / patient is a mammal. More preferably, the subject / patient is a human (e.g., a male human or a female human) or a non-human mammal (e.g., a guinea pig, a hamster, a rat, a mouse, a rabbit, a dog, a cat, a horse, a monkey, an ape, a marmoset, a baboon, a gorilla, a chimpanzee, an orangutan, a gibbon, a sheep, a cow or a pig). Most preferably, the subject / patient treated according to the present application is a human.

[0417] As used herein, unless the context indicates otherwise, the term "treatment" (of a disease or disorder) means curing, alleviating, reducing or preventing one or more symptoms or clinically relevant manifestations of the disease or disorder, or alleviating, reversing or eliminating the disease or disorder, or preventing the disease or disorder from occurring, or preventing, reducing or delaying the progression of the disease or disorder. For example, "treatment" of a subject or patient who has not yet been found to have symptoms or clinically relevant manifestations of the corresponding disease or disorder is a prophylactic or preventative treatment, whereas "treatment" of a subject or patient who has been found to have symptoms or clinically relevant manifestations of the corresponding disease or disorder can be, for example, curative or palliative treatment. Each of these forms of treatment can be considered a distinct aspect of the present application. "Treatment" of a disease or disorder can, for example, result in a halt of the progression of the disease or disorder (e.g. the symptoms do not worsen) or a delay of the progression of the disease or disorder (if the halt of progression is only temporary). "Treatment" of a disease or disorder can also result in a partial response (e.g. improvement of symptoms) or a complete response (e.g. disappearance of symptoms) of a subject / patient having the disease or disorder. Thus, "treatment" of a disease or disorder can also refer to an improvement of the disease or disorder, which can, for example, result in a halt of the progression of the disease or disorder or a delay of the progression of the disease or disorder. After such a partial or complete response, a relapse can occur. It will be appreciated that a subject / patient can have a broad range of responses to the treatment (e.g. the exemplary responses described herein above). Treatment of a disease or disorder can in particular include curative treatment of the disease or disorder (preferably resulting in a complete response and eventually curing the disease or disorder), palliative treatment (including alleviation of symptoms) or prophylactic treatment (including prevention).

[0418] Dosage regimen

[0419] As mentioned above, the present application in particular provides the multi-strain preparation of the present application (or a composition comprising said multi-strain preparation) for use in therapy, more preferably for use in the treatment or prevention of an allergic disease / disorder. It will be appreciated that a therapeutically effective amount of the multi-strain preparation should be used for this purpose.

[0420] It will be appreciated that the dosage required to observe a change, and the time interval for a response to occur after treatment, can vary from one specific medical use to another. The specific amounts and times can be determined by routine testing well known to the person skilled in the art.

[0421] For example, for a pharmaceutical composition, the dosage regimen will generally be determined by the attending physician and will depend upon a variety of factors, including the stage of the disease, the patient's size, age, health, and response to the drugs, the type of composition to be administered, the time and route of administration, and the judgment of the treating physician. The therapeutically effective amount for a given situation can be readily determined by routine experimentation and is within the skill of the ordinary clinician or physician. For oral administration to humans (weighing about 70 kg), a suggested, but not limiting, dosage can be from 0.05 to 2000 mg, preferably from 0.1 mg to 1000 mg, more preferably from 1 mg to 1000 mg, even more preferably from 10 to 1000 mg, and most preferably from 100 to 1000 mg of active ingredient per unit dose. The unit dose can be administered, for example, from 1 to 3 times per day for a period of 3 consecutive days. The 3-day treatment cycle can be repeated at intervals of, for example, 1 to 4 weeks. Similar amounts and dosing intervals are applicable for other types of compositions, such as prebiotic compositions or food compositions.

[0422] It is understood that routine adjustments can need to be made according to the age, body weight, and medical condition of the patient / subject, and the severity of the disease, to practice this method of treatment or prevention. The exact dosage and route of administration will be determined by the attending medical / veterinary practitioner.

[0423] According to the present application, it is especially preferred that the multi-strain preparation is administered via the oral route in an amount of at least about 10 5 CFU per week. More preferably, the multi-strain preparation is administered via the oral route in an amount of at least about 10 6 CFU per week, such as at least about 10 7 CFU, at least about 10 8 CFU, at least about 10 9 CFU, or at least about 10 10 CFU, more preferably in an amount of at least about 10 11 CFU per week, even more preferably in an amount of at least about 3 x 10 11 CFU per week, and most preferably in an amount of about 4.5 x 10 11 CFU per week.

[0424] Any suitable dosage regimen can be employed to achieve this weekly amount. That is, the multi-strain preparation of the application, or a composition comprising the multi-strain preparation of the application, can be administered once or more times per week until the weekly amount defined herein is achieved.

[0425] According to current scientific understanding, for optimal effect, a daily intake of the probiotic preparation is required, at a daily dose of 1 x 10 7 to 1 x 1010 CFU for several weeks, preferably months. This current treatment regimen is often a major problem in daily clinical practice, as many patients are not able to adhere to the treatment long term, or only take the medication irregularly, which leads to poor treatment efficacy and eventually to treatment discontinuation.

[0426] In contrast to this general approach in the prior art, it was surprisingly found that by an easy to follow treatment regimen, i.e. the administration of a high dose of the multi-strain preparation of the present application within only three days, a significant improvement compared to placebo can be achieved. As shown in Example 1, three treatment cycles, each of which a multi-strain preparation of about 4.5 x 1010 11 CFU, is sufficient to significantly improve ARC symptoms compared to placebo. If necessary, several three-day cycles can be repeated at intervals of, e.g., 1 to 4 weeks. In contrast, conventional probiotic preparations have to be taken daily for several weeks or even better for several months and at least 100 daily doses are required to achieve a similar effect.

[0427] Without being bound by theory, the surprisingly good efficacy of this treatment regimen stems from the unique composition of the novel multi-strain preparation of the present application, which comprises 5 (preferably 53) specific bacterial strains, combined with a high dose administered within a short period of time, which makes this treatment regimen particularly suitable for restoring the repeatedly occurring altered intestinal microbiota composition in ARC patients.

[0428] Thus, the multi-strain preparation (or the composition comprising the multi-strain preparation) according to the present application is preferably administered according to a treatment or intake regimen comprising one or more (e.g., one to ten, in particular one, two, three, four or five) consecutive short-term treatment cycles. Each short-term treatment cycle can last, e.g., a time period of 1 day and not more than 5 days, e.g., 2 to 4 days, preferably 3 days (this is also referred to as "3-day treatment cycle"). While the duration of each short-term treatment cycle can be the same or different (i.e., can be independently selected from the above-mentioned time periods), it is preferred that all short-term treatment cycles have the same duration. Any two or more consecutive short-term treatment cycles can be separated by an interval period ("rest period") of at least 2 days, in particular days, weeks or months (e.g., 3 days, 5 days, 7 days (i.e., 1 week), 2 weeks, 3 weeks, 4 weeks, 1 month or 2 months; preferably at least 3 days, more preferably 4 days), during which the multi-strain preparation (or the corresponding composition) is not administered. Preferably, the multi-strain preparation (or the composition comprising the multi-strain preparation) is administered at least once per day (e.g., once, twice or three times per day, in particular once a day) during each day of each short-term treatment cycle. The daily dose of the multi-strain preparation (or the composition comprising the multi-strain preparation) administered (preferably by the oral route) can be, e.g., at least about 10 5 CFU, preferably at least about 106 CFU, at least about 10 7 CFU, at least about 10 8 CFU, at least about 10 9 CFU, or at least about 10 10 CFU, more preferably at least about 10 11 CFU, even more preferably at least about 1.5 x 10 11 CFU (in relation to the total viable cell count of the bacterial strains of the multi-strain preparation).

[0429] In one particular embodiment, the short-term treatment cycle lasts 3 days, and the daily dose of the multi-strain preparation (or composition comprising the multi-strain preparation) administered (preferably orally) is about 1.5 x 10 11 CFU (in relation to the total viable cell count of the bacterial strains of the multi-strain preparation). Preferably, 4 days are allowed to elapse between each 3-day treatment cycle.

[0430] Alternatively, the multi-strain preparation of the application, or a composition comprising the multi-strain preparation, can be administered daily. For daily administration, the administered dose of the multi-strain preparation (or composition comprising the multi-strain preparation) can be, for example, at least about 10 5 CFU, preferably at least about 10 6 CFU, at least about 10 7 CFU, at least about 10 8 CFU, at least about 10 9 CFU, more preferably at least about 10 10 CFU, even more preferably at least about 0.2 x 10 11 CFU (in relation to the total viable cell count of the bacterial strains of the multi-strain preparation). When the multi-strain preparation of the application, or a composition comprising the multi-strain preparation, is administered daily, it is preferred that vitamin B7 (biotin) is administered concurrently, as described elsewhere herein.

[0431] The multi-strain preparation or composition of the application can be administered as a monotherapy (e.g. without the administration of any other therapeutic agent, or without the administration of any other therapeutic agent directed against the same disease as the disease to be treated or prevented by the multi-strain preparation or composition of the application). However, the multi-strain preparation or composition of the application can also be administered in combination with one or more other therapeutic agents. If the multi-strain preparation or composition of the application is used in combination with a second therapeutic agent active against the same disease or condition, the dosage of each agent can be different from that when the respective agent is used alone, in particular, a lower dosage of each agent can be used. The combination of the multi-strain preparation or composition of the application with one or more other therapeutic agents can include simultaneous / concurrent administration of the multi-strain preparation or composition of the application and the other therapeutic agent(s) (in a single pharmaceutical preparation or in separate pharmaceutical preparations), or sequential / separate administration of the multi-strain preparation or composition of the application and the other therapeutic agent(s). If administration is sequential, either the multi-strain preparation or composition of the application or the other therapeutic agent(s) can be administered first. If administration is simultaneous, the other therapeutic agent(s) can be included in the same pharmaceutical preparation as the multi-strain preparation or composition of the application, or can be administered in two or more different (separate) pharmaceutical preparations.

[0432] Preparation of the multi-strain formulation

[0433] To provide a sufficient number of bacteria, they can be cultivated and expanded using methods known in the art, for example, as described in "Probiotics and Health Claims", Wolfgang Kneifel, Seppo Salminen, John Wiley & Sons, 1st Edition (January 7, 2011). For example, the living cells can be cultivated in a protein-rich liquid medium. Typically, a suitable medium for cultivating and / or fermenting bacterial strains comprises at least water, glucose, yeast extract, and minerals. It is clear to the person skilled in the art that other media can also be used to cultivate, ferment, and precultivate bacterial organisms. Typically, at least 200 milliliters, preferably at least 300 milliliters, more preferably at least 400 milliliters, even more preferably at least 500 milliliters, most preferably at least 600 milliliters of a standard medium are inoculated with at least one cell of a bacterial strain and the culture is grown under anaerobic conditions overnight, for example, at 37 °C and 220 rpm. Additional fermentation steps can be performed, for example, in larger volumes. Further processing comprises one or more further method steps, for example, for harvesting and / or purification. Methods and means for such harvesting and / or purification steps are well known in the art and include, for example, centrifugation, for example, using a disc centrifuge or a separator (for example, provided by GEA Westfalia Separator Group GmbH (Oelde, Germany)). The cells can then be stabilized, freeze-dried, ground, and sieved using standard methods and means. All of the above methods are known in the art and have been described in the literature, for example, in "Probiotics and Health Claims" (Wolfgang Kneifel, Seppo Salminen, John Wiley & Sons, 1st Edition, January 7, 2011); "Modelling microorganisms in food" (Stanley Brul, Suzanne Van Gerwen, Marcel Zwietering, 1st Edition, 2007); and "Probiotic bacteria: fundamentals, therapy, and technological aspects" (J. Paulo Sousa e Silva and Ana C. Freitas, 1st Edition, 2014).

[0434] Finally, different strains, preferably 53 strains listed in Table 1 above, are mixed to make a homogeneous mixture of live bacteria. Then, these cells can be optionally mixed with one or more prebiotic compounds and / or one or more members selected from the group consisting of pharmaceutically acceptable compounds, ingestible carriers, adjuvants, bacterial ingredients, drug entities, biological compounds and / or proteins and / or peptides and / or mixtures thereof, in particular proteins and / or peptides rich in glutamine / glutamate, lipids, carbohydrates, vitamins, minerals and / or trace elements; optionally, the at least one pharmaceutically acceptable compound is a member selected from the group consisting of one or more vitamins, such as B vitamins; one or more minerals, such as calcium or magnesium; one or more carbohydrates, such as lactose, maltodextrin, inulin, glucose, mannitol, maltose, dextrin, sorbitol, fructose and mixtures thereof in different amounts.

[0435] The terms "a," "an," and "the" as used herein, unless otherwise clear from the context, are used interchangeably with "one or more" or "at least one." Thus, for example, a composition including "a" particular compound (e.g., a carrier) can be interpreted to mean a composition that includes "one or more" of the particular compound (e.g., one or more carriers).

[0436] The term "about" as used herein, preferably means ± 10% of the indicated numerical value, more preferably ± 5% of the indicated numerical value, and in particular the exact indicated numerical value. If the term "about" is used in connection with an end point of a range, it preferably means a range from the lower end point - 10% of the indicated numerical value thereof to the upper end point + 10% of the indicated numerical value thereof, more preferably a range from the lower end point - 5% to the upper end point + 5%, and even more preferably a range defined by the exact numerical values of the lower and upper end points. If the term "about" is used in connection with an end point of an open-ended range, it preferably means the respective range starting from the lower end point - 10% or from the upper end point + 10%, more preferably a range starting from the lower end point - 5% or from the upper end point + 5%, and even more preferably an open-ended range defined by the exact numerical values of the respective end points. If the term "about" is used in connection with a parameter quantified in whole numbers, the number corresponding to ± 10% or ± 5% of the indicated numerical value should be rounded to the nearest whole number (using the rule of "rounding").

[0437] As used herein, the term "comprising" (or "comprise", "comprises", "include", "including" or "includes") has the meaning associated with "including, but not limited to", unless specifically indicated otherwise or otherwise distinctly limited by context. In addition to this, the term includes the narrower meanings of "consisting essentially of" and "consisting of". For example, the term "A comprises B and C" has the meaning "A including, but not limited to, B and C", where A can include other optional elements (e.g. "A comprises B, C and D" is also contemplated), but the term also includes the meaning "A consists essentially of B and C" and "A consists of B and C" (i.e. A does not include any other components than B and C).

[0438] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. If there is a conflict between the patent specification (including definitions) and the art then the specification (including definitions) controls. It should be understood that the application specifically relates to each and every combination of the features and embodiments described herein, including any combination of general and / or preferred features / embodiments.

[0439] Similarly, and where options are not recited in independent and / or dependent claims, it is to be understood that if a dependent claim refers to multiple prior claims, then any combination of the subject matter of the claims thus covered is hereby expressly disclosed. For example, if there is an independent claim 1, a dependent claim 2 referring to claim 1, and a dependent claim 3 referring to claims 1 and 2, then the combination of the subject matter of claim 3 and claim 1 is clearly and expressly disclosed, as is the combination of the subject matter of claim 3, claim 2 and claim 1. If there is another dependent claim 4 referring to any of claims 1-3, then the combination of the subject matter of claim 4 and claim 1, the combination of the subject matter of claim 4, claim 2 and claim 1, the combination of the subject matter of claim 4, claim 3 and claim 1, and the combination of the subject matter of claim 4, claim 3, claim 2 and claim 1 are expressly disclosed. The above considerations apply mutatis mutandis to all the appended claims.

[0440] It is to be understood that where a range of values is provided / covered herein, all values and sub-ranges encompassed by the range of values are intended to be included within the scope of the application. Thus, the application specifically and expressly relates to each and every value and sub-range encompassed by the ranges of values disclosed herein.

[0441] In this specification, several documents including patents and scientific literature are cited. The disclosure of these documents, in their entirety, are hereby incorporated by reference into this document. More specifically, all cited references are incorporated by reference as if each individual document was specifically and individually indicated to be incorporated by reference.

[0442] The mention of any prior publication (or information derived from it) in this specification should not be taken as an admission that the prior publication (or information derived from it) constitutes prior art in relation to the technology described in this specification.

[0443] The present application particularly relates to the following items:

[0444] 1. A multi-strain preparation comprising:

[0445] - Bifidobacterium bifidum BB02;

[0446] - Lactobacillus rhamnosus SP1;

[0447] - Bifidobacterium animalis lactis subspecies Bi1;

[0448] - Paracaseicobacter paracasei subspecies IMC 502; and

[0449] - Lactobacillus casei LC11.

[0450] 2. The multi-strain preparation according to item 1, further comprising:

[0451] - Bifidobacterium bifidum SP9;

[0452] - Bifidobacterium adolescentis SP77;

[0453] - Lactobacillus casei BGP93;

[0454] - Lactobacillus rhamnosus LR92;

[0455] - Bifidobacterium breve Bbr8;

[0456] - Bifidobacterium breve BL10;

[0457] - Lactobacillus crispatus SP28;

[0458] - Lactobacillus rhamnosus LB21;

[0459] - Lactobacillus rhamnosus IMC 501;

[0460] - Lactobacillus rhamnosus LR1;

[0461] - Lactobacillus acidophilus LA3;

[0462] - Lactobacillus acidophilus LA1 ;

[0463] - Lactobacillus plantarum subsp. plantarum 14D;

[0464] - Lactobacillus plantarum subsp. plantarum LB931 ;

[0465] - Lactobacillus plantarum subsp. plantarum BG112;

[0466] - Lactobacillus plantarum subsp. plantarum LP48;

[0467] - Pediococcus acidilactici PA09;

[0468] - Pediococcus pentosaceus PP02;

[0469] - Lactobacillus brevis SP48;

[0470] - Lactobacillus delbrueckii subsp. lactis LL82;

[0471] - Bifidobacterium longum subsp. longum SP54;

[0472] - Mucilaginibacter ferus LF2;

[0473] - Mucilaginibacter ferus CS57;

[0474] - Lactobacillus salivarius SP2;

[0475] - Bifidobacterium animalis subsp. lactis BLC1 ;

[0476] - Lactococcus lactis subsp. lactis SP38;

[0477] - Lactococcus lactis subsp. lactis SP47;

[0478] - Lactococcus lactis subsp. lactis SD13;

[0479] - Lactobacillus helveticus SP27;

[0480] - Lactobacillus helveticus LH102;

[0481] - Streptococcus thermophilus SP4;

[0482] - Streptococcus thermophilus Z57;

[0483] - Streptococcus thermophilus ST628;

[0484] - Lactobacillus buchneri subsp. buchneri LBC01 ;

[0485] - Lactobacillus delbrueckii subsp. bulgaricus LB2;

[0486] - Lactobacillus delbrueckii subsp. bulgaricus LB284;

[0487] - Paracaseicilus casei subsp. paracasei 101 / 37;

[0488] - Paracaseicilus casei subsp. paracasei BGP1 ;

[0489] - Paracaseicilus casei subsp. paracasei BGP2;

[0490] - Lactobacillus sakei subsp. sakei LSK04;

[0491] - Lactobacillus sakei subsp. sakei LSK14;

[0492] - Lactobacillus casei LC10;

[0493] - Lactobacillus rhamnosus LRH01 ;

[0494] - Lactobacillus rhamnosus LRH05;

[0495] - Lactobacillus rhamnosus LRH14;

[0496] - Lactobacillus rhamnosus LRH58;

[0497] - Paracaseicilus casei subsp. paracasei LPC43; and

[0498] - Lactococcus lactis subsp. lactis SL97.

[0499] 3. A composition comprising the multi-strain preparation according to item 1 or 2.

[0500] 4. The composition according to item 3, wherein the composition is a probiotic composition.

[0501] 5. The composition according to item 3 or 4, wherein the composition can be a pharmaceutical composition, a food supplement composition or a food composition.

[0502] 6. The composition according to any one of items 3-5, wherein the composition further comprises biotin.

[0503] 7. The multi-strain preparation according to item 1 or 2 or the composition according to any one of items 3-6 for use in therapy.

[0504] 8. The multi-strain preparation according to item 1 or 2 or the composition according to any one of items 3-6 for use in the treatment or prevention of an immunological disease / disorder.

[0505] 9. The multi-strain preparation of item 1 or 2 or the composition of any one of items 3-6 for use in the treatment or prevention of an allergic disease / disorder.

[0506] 10. The multi-strain preparation for use of item 9 or the composition for use of item 9, wherein the allergic disease / disorder is selected from the group consisting of allergic rhinitis, allergic conjunctivitis, allergic rhinoconjunctivitis, atopic dermatitis, contact urticaria, allergic bronchial asthma, anaphylactic shock, and a gastrointestinal disorder associated with an allergic reaction.

[0507] 11. The multi-strain preparation for use of item 9 or the composition for use of item 9, wherein the allergic disease / disorder is allergic rhinitis, allergic conjunctivitis, or allergic rhinoconjunctivitis.

[0508] 12. The multi-strain preparation for use of any one of items 7 to 11 or the composition for use of any one of items 7 to 11, wherein the multi-strain preparation or the composition is for administration in accordance with a treatment or intake regimen comprising one or more consecutive short-term treatment periods, wherein each short-term treatment period independently has a duration of greater than 1 day and less than 5 days, and wherein all consecutive short-term treatment periods are separated by a rest period of at least 2 days.

[0509] 13. The multi-strain preparation for use of item 12 or the composition for use of item 12, wherein each short-term treatment period has a duration of 3 days.

[0510] 14. The multi-strain preparation for use of item 12 or 13 or the composition for use of item 12 or 13, wherein the multi-strain preparation or the composition is administered at least once per day of each short-term treatment period.

[0511] 15. The multi-strain preparation for use of any one of items 12 to 14 or the composition for use of any one of items 12 to 14, wherein the multi-strain preparation or the composition is administered in a daily dose of at least about 1 x 10 11 CFU.

[0512] 16. The multi-strain preparation for use of any one of items 12 to 15 or the composition for use of any one of items 12 to 15, wherein all consecutive short-term treatment periods are separated by a rest period of 4 days.

[0513] 17. The multi-strain preparation for use according to any one of items 7 to 11 or the composition for use according to any one of items 7 to 11, wherein the multi-strain preparation or the composition is administered daily.

[0514] 18. The multi-strain preparation for use according to item 17 or the composition for use according to item 17, wherein the multi-strain preparation or the composition is administered in a daily dose of at least about 1 x 10 10 CFU.

[0515] 19. The multi-strain preparation for use according to any one of items 7 to 18 or the composition for use according to any one of items 7 to 18, wherein the multi-strain preparation or the composition is administered orally. BRIEF DESCRIPTION OF DRAWINGS

[0516] The present application is also described by the following exemplary figures. The figures show:

[0517] Figure 1 : Treatment cycle and exposure schedule during the clinical study described in Example 1.

[0518] Figure 2: Mean total symptom score (TSS) during V1 (a) and V3 (b) for the SYN-AR-A, SYN-AR-B, SYN-AR-C and placebo groups.

[0519] Figure 3: Difference in total symptom score (TSS) at V3 from baseline exposure at V1 for the SYN-AR-A, SYN-AR-B, SYN-AR-C and placebo groups.

[0520] The present application will be described below with reference to the following examples, which are for illustrative purposes only and should not be construed as limiting the scope of the present application. EXAMPLE

[0521] Example 1 : Study of the benefit of SYN-AR in three different compositions in the treatment of patients with allergic rhinoconjunctivitis caused by grass pollen and their associated symptoms, relative to placebo

[0522] A double-blind, single-center, randomized, placebo-controlled, four-arm study to evaluate the efficacy of the multi-strain probiotic preparation SYN-AR in three different compositions - SYN-AR-A, SYN-AR-B and SYN-AR-C - in patients with allergic rhinoconjunctivitis (ARC).

[0523] SYN-AR-A is a mixture composed of 53 probiotic bacterial strains with a high concentration (5 x 10 10SYN-AR-B contains the same mixture of 53 probiotic bacterial strains as SYN-AR-A, but with an increased concentration of Lactobacillus rhamnosus SP1 and a lower overall concentration (6 x 10 9 CFU per capsule). SYN-AR-C contains the 4 core probiotic bacterial strains of the above mixture with a high concentration (4 x 10 10 CFU per capsule). Finally, the placebo does not contain any probiotic bacteria, but only excipients (corn starch, magnesium stearate and silicon dioxide).

[0524] The present study aimed to investigate the benefit of three different compositions (SYN-AR-A, SYN-AR-B and SYN-AR-C) on ARC patients and associated symptoms (mild and severe) due to grass pollen exposure during grass pollen exposure in an allergen exposure chamber (AEC) and in comparison to placebo. Furthermore, the study compared the importance of the composition and concentration of the probiotic bacterial mixture for the relief of allergic symptoms associated with ARC.

[0525] Participants were exposed to allergens in an allergen exposure chamber (AEC). The study was conducted in Berlin, Germany.

[0526] 1.1 Study design

[0527] The entire study consisted of a screening period (V0) for the selection of suitable subjects, a baseline exposure (V1) in the AEC including a follow-up safety telephone call (V2), 3 treatment periods of 3 days per week for 3 weeks each, a final exposure (V3) in the AEC including a follow-up safety telephone call (V4) and a subject-based follow-up questionnaire on the overall treatment effect (V5). An overview of the study timeline is shown in Figure 1 .

[0528] The AEC allowed participants to be exposed to a defined amount of a specific allergen under controlled conditions. The AEC was developed to cope with the typical problems in pollen season clinical trials, i.e. the variability of natural allergen exposure in terms of concentration, duration and purity. All AEC exposures used standardized grass pollen provided by Stallergenes Greer (Lenoir, USA). At each exposure, participants were exposed to 4000 grass pollen / m 3 for 120 minutes at room temperature (20°C) and 55% relative humidity. During the 120 minutes of exposure time, participants recorded the severity of symptoms every 10 minutes.

[0529] The treatment period starts at least 1 week after the baseline exposure (V1) and lasts 3 weeks. Participants receive 3 treatment cycles (one per week), each lasting 3 days. In each treatment cycle, participants receive SYN-AR-A, SYN-AR-B, SYN-AR-C or placebo treatment, respectively, 3 capsules per day for 3 consecutive days, with daily doses of 1.5 x 107 11 , 1.8 x 107 10 , 1.2 x 107 11 and 0 CFU, respectively. The final exposure (V3) is performed one week after the final treatment cycle (see Figure 1 ).

[0530] 1.2 Study population

[0531] The study population is individuals affected by seasonal grass pollen ARC. Only individuals between 18 and 65 years of age with a known history of grass pollen allergy of at least 2 years and a positive skin prick test to grass pollen (wheal diameter > 3 mm and test time not more than 8 months) are included. In addition, clinical relevant sensitization to grass pollen is assessed by exposure in the AEC. The final study population only includes participants with a maximum total symptom score TSS MAX > 6 after the AEC allergen exposure at baseline (V1) (see section 1.4 for TSS definition).

[0532] Exclusion criteria are: acute infection, current diagnosis of cancer, autoimmune disease, gastrointestinal disease leading to decreased metabolism of oral substances or severe type of the following chronic diseases: neurological disease, metabolic disease, severe asthma, severe lung obstruction, congenital heart or gastrointestinal or lung abnormalities. In addition, individuals with a psychological disease (e.g. depression), eating disorder (e.g. bulimia), alcohol or drug addiction, allergy to any of the ingredients of the tested formulation as well as contraindication to epinephrine or any other rescue medication (especially cetirizine) are excluded. Pregnant or lactating women, heavy smokers, individuals who received specific immunotherapy in the past 5 years, individuals who participated in a clinical trial in the past 3 months and persons currently placed in a custodial institution by court order are also excluded. Individuals with a forced expiratory volume in the first second (FEV1) of less than 60% (predicted) before allergen exposure are also excluded. In addition, participants are asked to stop the use of the following medications before and during the study: decongestant nose drops (3 days), antihistamines (5 days), antiallergic eye and nose sprays (1 week), topical steroids (2 weeks), systemic corticosteroids (3 weeks), probiotics (4 weeks), antibiotics (4 weeks).

[0533] Subjects were also excluded if one or more of the exclusion criteria occurred or were detected during the study, if a UE and / or SUE attributable to the investigational product occurred, if pregnancy was discovered, if the investigator and the subject permanently lost contact, if there was a serious violation of the study protocol, if surgery occurred that made it impossible to ensure intake of the study product and AEC exposure due to the extent of the surgery and the length of sick leave.

[0534] 1.3 Study product

[0535] The investigational product is a multi-strain, multi-species product. For SYN-AR-A, the product contains 53 probiotic bacterial strains at a concentration of at least 5 x 10 10 CFU per capsule; for SYN-AR-B, the product contains 53 probiotic bacterial strains, including an increased amount of Lactobacillus rhamnosus SP1, at a concentration of at least 6 x 10 9 CFU per capsule; for SYN-AR-C, the product contains 4 probiotic bacterial strains at a concentration of at least 4 x 10 10 CFU per capsule (see Table 4 for more details). The total dose per treatment cycle for SYN-AR-A, SYN-AR-B and SYN-AR-C is at least 4.5 x 10 11 , 5.4 x 10 10 and 3.6 x 10 11 CFU per week, respectively. Further ingredients are listed in Table 5.

[0536] The placebo contains only corn starch as a filler, magnesium stearate and silicon dioxide as anti-caking agents, and hypromellose as a capsule shell. The packaging of the investigational product and the placebo is similar, and there is no difference in appearance and taste.

[0537] Table 4: Composition of the probiotic mixtures SYN-AR-A, SYN-AR-B and SYN-AR-C used in the clinical study (“CFU”: colony forming units)

[0538]

[0539] .

[0540] Table 5: Composition of one capsule of SYN-AR-A, SYN-AR-B, SYN-AR-C and placebo used in the clinical trial

[0541]

[0542] .

[0543] 1.4 Endpoints

[0544] The Total Symptom Score (TSS), described by Pfaar et al. (Pfaar O et al., Allergy, 2014, 69(7): 854-867, doi: 10.1111 / all.12383), was used to determine symptom severity every 10 minutes during a 120-minute AEC allergen exposure. The TSS consisted of the Total Ocular Symptom Score (TESS) and the Total Nasal Symptom Score (TNSS), for a total of 24 points. Each of the TESS and TNSS contained four symptoms (see Tables 6 and 7 below). The severity of each symptom was assessed on a scale of 0 to 3 (0 = asymptomatic; 1 = mild symptoms; 2 = moderate symptoms; 3 = severe symptoms), with a maximum total score of 12 points for both the TESS and TNSS.

[0545] Table 6: Detailed description of symptoms covered by the Total Ocular Symptom Score (TESS)

[0546]

[0547] .

[0548] Table 7: Detailed description of symptoms covered by the Total Nasal Symptom Score (TNSS)

[0549]

[0550] .

[0551] For each exposure in AEC, TSS MAX The maximum TSS recorded at any time point during the specified 120-minute exposure period was determined. To determine the effectiveness of the treatment, the TSS during the post-treatment exposure period (V3) was determined. MAX TSS recorded at baseline exposure (V1) MAX Differences (d_TSS) MAX ).

[0552] TSS from baseline exposure (V1) to post-treatment exposure (V3) MAX The changes are calculated as follows:

[0553]

[0554] Statistical methods: d_TSS obtained for SYN-AR-A, SYN-AR-B and SYN-AR-C MAX The (V1,V3) values, used with the Wilcoxon rank-sum test, were compared with placebo in the modified intention-to-treat (ITT) population (see below). MAX The (V1, V3) test was performed. A significance level of p < 0.05 was considered statistically significant. All statistical data analyses were performed by independent biostatisticians.

[0555] 1.5 Results:

[0556] 1.5.1 Research Group:

[0557] A total of 247 patients were screened in this study. Only 166 patients fully met all inclusion criteria and were randomly assigned to four groups: placebo (41 patients), SYN-AR-A (42 patients), SYN-AR-B (41 patients), and SYN-AR-C (42 patients). Of these 166 patients, n=8 withdrew during the study for various reasons unrelated to treatment, leaving only 158 patients eligible for the final exposure (V3) visit. A revised ITT dataset was generated: placebo (39 patients), SYN-AR-A (37 patients), SYN-AR-B (41 patients), and SYN-AR-C (41 patients).

[0558] Of the 166 patients, 113 were female; the overall median age was 33 years, and the weight ranged from 45 to 178 kg (12% were obese). There were no significant differences in baseline characteristics (i.e., age, sex, and BMI) among the four groups.

[0559] A total of 15 adverse events were reported in the entire study population (11 mild, 3 moderate, and 1 severe). However, none of the adverse events were related to the study product.

[0560] 1.5.2 Therapeutic efficacy:

[0561] TSS at baseline exposure (V1) MAX Compared to TSS with a second exposure (V3) after treatment. MAX The changes were significantly greater in the SYN-AR-A group than in the placebo group (d_TSS). MAX [Mean ± StD]: -5.19 ± 4.86 vs. -2.82 ± 4.90; p = 0.0335). However, compared with V1, the V3 TSS of the SYN-AR-B group (-2.27 ± 4.15, p = 0.8544) and the SYN-AR-C group (-3.41 ± 3.33, p = 0.3387) was significantly lower. MAX The changes were not significantly higher than those in the placebo group (-2.82±4.90), meaning the p-values ​​for the SYN-AR-B and SYN-AR-C groups were > 0.05 (see also Table 8).

[0562] Table 8: Shows the maximum total symptom score difference (d_TSS) from baseline to post-treatment in the four groups. MAX Data are presented as mean ± StD. Wilcoxon rank-sum test was used, p < 0.05.

[0563]

[0564] .

[0565] The mean TSS values during the exposure visit (every 10 minutes of the 120 minutes exposure period in AEC) further support the effectiveness of SYN-AR-A. (See also Figure 2).

[0566] 1.5.3 Conclusion:

[0567] The present study shows that the new combination of 53 specific bacterial strains according to the present application, in particular SYN-AR-A, offers a new treatment option for patients with ARC, which is not only very effective, but also very well tolerated.

[0568] In addition, the study also shows that the use of the given multi-strain, multi-species preparation SYN-AR-A, over 3 treatment cycles of 3 days / week, i.e. only nine days of drug intake, is sufficient to reduce the typical symptoms of ARC compared to placebo. This finding is very important, considering that it was previously thought that probiotic preparations had to be taken continuously and daily for several weeks or months to achieve a good effect.

[0569] Thus, it has been proven that the new multi-strain, multi-species preparation according to the present application, in particular SYN-AR-A, is not only highly effective and well tolerated, but also allows a particularly advantageous short-term treatment regimen.

[0570] Example 2: Multi-strain probiotic preparation

[0571] Three other exemplary multi-strain probiotic preparations according to the present application were prepared as described below:

[0572] Formulation (i):

[0573] The composition comprises the following strains in an amount of at least 1x10 6 CFU / unit of each probiotic strain: Bifidobacterium bifidum BB02, Lactobacillus rhamnosus SP1, Bifidobacterium animalis lactis subspecies Bi1, Paracaseicobacter paracasei subspecies IMC 502 and Lactobacillus casei LC11. The term "unit" is defined as a preselected form of intake, for example a capsule. Other optional ingredients include 120 mg of corn starch as a filler, and 10 mg of magnesium stearate and 0.05 mg of silicon dioxide as an anti-caking agent. The capsule shell and the probiotic mixture weigh 60 mg and 144 mg, respectively.

[0574] Formulation (ii):

[0575] The composition comprises the following strains in an amount of at least 1x10 6CFU / unit amount comprising strains Bifidobacterium bifidum BB02, Lactobacillus rhamnosus SP1, Bifidobacterium animalis lactis subspecies Bi1, Paracaseicobacter paracasei subsp. paracasei IMC502, Caseobacter casei LC11, Lactococcus lactis subspecies SL97, Lactobacillus helveticus SP27, Lactobacillus brevis SP48, Streptococcus thermophilus SP4, Bifidobacterium longum longum subspecies SP54 and Bifidobacterium adolescentis SP77. The term "unit" is defined as a preselected form of ingestion, for example a capsule. Other optional ingredients include 120 mg of corn starch as a filler, and 10 mg of magnesium stearate and 0.05 mg of silicon dioxide as an anti-caking agent. The capsule shell and probiotic mixture weigh 60 mg and 144 mg, respectively.

[0576] Formulation (iii):

[0577] The composition is in an amount of at least 1 x 1010CFU / unit for each strain 6 CFU / unit amount comprising strains Bifidobacterium bifidum BB02, Lactobacillus rhamnosus SP1, Bifidobacterium animalis lactis subspecies Bi1, Paracaseicobacter paracasei subsp. paracasei IMC502, Caseobacter casei LC11, Lactobacillus helveticus LH102, Lactobacillus brevis SP48, Streptococcus thermophilus SP4, Lactobacillus rhamnosus LRH14, Paracaseicobacter paracasei subsp. paracasei LPC43, Caseobacter casei LC10, Mucilaginobacter fermentans CS57 and Lactobacillus rhamnosus IMC 501. The term "unit" is defined as a preselected form of ingestion, for example a capsule. Other optional ingredients include 120 mg of corn starch as a filler, and 10 mg of magnesium stearate and 0.05 mg of silicon dioxide as an anti-caking agent. The capsule shell and probiotic mixture weigh 60 mg and 144 mg, respectively.

[0578] The therapeutic effectiveness of the above exemplary multi-strain formulations (i), (ii) and (iii) on ARC can be verified by the same clinical protocol described in Example 1.

Claims

1. A multi-strain preparation comprising: - Bifidobacterium bifidum BB02; - Lactobacillus rhamnosus SP1; - Bifidobacterium animalis lactis Bi1; - Lactobacillus casei LC11; and - Paracaseicloacter paracasei subsp. paracasei IMC 502.

2. The multi-strain preparation according to claim 1, further comprising: - Bifidobacterium bifidum SP9; - Bifidobacterium adolescentis SP77; - Lactobacillus casei BGP93; - Lactobacillus rhamnosus LR92; - Bifidobacterium breve Bbr8; - Bifidobacterium breve BL10; - Lactobacillus crispatus SP28; - Lactobacillus rhamnosus LB21; - Lactobacillus rhamnosus IMC 501; - Lactobacillus rhamnosus LR1; - Lactobacillus acidophilus LA3; - Lactobacillus acidophilus LA1; - Lactobacillus plantarum subsp. plantarum 14D; - Lactobacillus plantarum subsp. plantarum LB931; - Lactobacillus plantarum subsp. plantarum BG112; - Lactobacillus plantarum subsp. plantarum LP48; - Pediococcus acidilactici PA09; - Pediococcus pentosaceus PP02; - Lactobacillus brevis SP48; - Lactobacillus delbrueckii subsp. lactis LL82; - Bifidobacterium longum subsp. longum SP54; - Lactobacillus fermentum LF2; - Lactobacillus fermentum CS57; - Lactobacillus salivarius SP2; - Bifidobacterium animalis lactis BLC1; - Lactococcus lactis subsp. lactis SP38; - Lactococcus lactis subsp. lactis SP47; - Lactococcus lactis subsp. lactis SD13; - Lactobacillus helveticus SP27; - Lactobacillus helveticus LH102; - Streptococcus thermophilus SP4; - Streptococcus thermophilus Z57; - Streptococcus thermophilus ST628; - Lactobacillus buchneri subsp. buchneri LBC01; - Lactobacillus delbrueckii subsp. bulgaricus LB2; - Lactobacillus delbrueckii subsp. bulgaricus LB284; - Paracaseicloacter paracasei subsp. paracasei 101 / 37; - Paracaseicloacter paracasei subsp. paracasei BGP1; - Paracaseicloacter paracasei subsp. paracasei BGP2; - Lactobacillus sake LS K04; - Lactobacillus sake LS K14; - Lactobacillus casei LC10; - Lactobacillus rhamnosus LRH01; - Lactobacillus rhamnosus LRH05; - Lactobacillus rhamnosus LRH14; - Lactobacillus rhamnosus LRH58; - Paracaseicloacter paracasei subsp. paracasei LPC43; and - Lactococcus lactis subsp. lactis SL97.

3. A composition comprising the multi-strain preparation according to claim 1 or 2.

4. The composition according to claim 3, wherein the composition is a probiotic composition.

5. The composition according to claim 3 or 4, wherein the composition is a pharmaceutical composition, a food supplement composition or a food composition.

6. The composition according to any one of claims 3-5, wherein the composition further comprises biotin.

7. The multi-strain preparation according to claim 1 or 2 or the composition according to any one of claims 3-6 for use in therapy.

8. The multi-strain preparation according to claim 1 or 2 or the composition according to any one of claims 3-6 for use in the treatment or prevention of an immunological disease / condition.

9. The multi-strain preparation according to claim 1 or 2 or the composition according to any one of claims 3-6 for use in the treatment or prevention of an allergic disease / condition.

10. The multi-strain preparation for use according to claim 9 or the composition for use according to claim 9, wherein the allergic disease / condition is selected from the group consisting of allergic rhinitis, allergic conjunctivitis, allergic rhinoconjunctivitis, atopic dermatitis, contact urticaria, allergic bronchial asthma, anaphylactic shock and a gastrointestinal disorder associated with an allergic reaction.

11. The multi-strain preparation for use according to claim 9 or the composition for use according to claim 9, wherein the allergic disease / condition is allergic rhinitis, allergic conjunctivitis or allergic rhinoconjunctivitis.

12. The multi-strain preparation for use according to any one of claims 7 to 11 or the composition for use according to any one of claims 7 to 11, wherein the multi-strain preparation or the composition is for administration according to a treatment or intake regimen comprising one or more consecutive short-term treatment periods, wherein each short-term treatment period independently has a duration of greater than 1 day and less than 5 days, and wherein all consecutive short-term treatment periods are separated by a rest period of at least 2 days.

13. The multi-strain preparation for use according to claim 12 or the composition for use according to claim 12, wherein: - each short-term treatment period has a duration of 3 days; and / or - the multi-strain preparation or the composition is administered at least once per day of each short-term treatment period; and / or -The multi-strain preparation or the composition is administered at a daily dose of at least about 1 x 10 11 CFU administration; and / or - all consecutive short-term treatment periods are separated by a rest period of 4 days.

14. The multi-strain preparation for use according to any one of claims 7 to 11 or the composition for use according to any one of claims 7 to 11, wherein the multi-strain preparation or the composition is administered daily.

15. The multi-strain preparation for use of claim 14 or the composition for use of claim 14, wherein the multi-strain preparation or the composition is administered in a daily dose of at least about 1 x 10 10 CFU.

15. The multi-strain preparation for use of claim 14 or the composition for use of claim 14, wherein the multi-strain preparation or the composition is administered in a daily dose of at least about 1 x 10 10 CFU.

15. The multi-strain preparation for use of claim 14 or the composition for use of claim 14, wherein the multi-strain preparation or the composition is administered 16. The multi-strain preparation for use according to any one of claims 7 to 15 or the composition for use according to any one of claims 7 to 15, wherein the multi-strain preparation or the composition is administered orally.

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