Use of heat-killed lactic acid bacterial strains for the manufacture of a medicament for the treatment and / or prevention of particulate matter-induced lung injury

Abstract

The present invention relates to the use of heat-killed lactic acid bacterial strains for the manufacture of a medicament for the treatment and / or prevention of particulate matter-induced lung injury. It has been discovered that heat-killed lactic acid bacterial strains can be used to treat and / or prevent particulate matter-induced lung injury.

Description

Technical Field

[0001] This invention relates to the use of heat-killed lactic acid bacteria strains to treat and / or prevent particulate matter-induced lung injury. Background Technology

[0002] Atmospheric particulate matter (PM) is a major form of air pollution, referring to tiny solid particles suspended in the atmosphere. It can be distinguished based on its aerodynamic diameter; for example, PM 10 and PM 2.5 represent particulate matter with an aerodynamic diameter of ≤10μm and ≤2.5μm, respectively.

[0003] Particulate matter comprises aromatic hydrocarbons, metals, minerals, and organic toxins, which can adversely affect the human respiratory and circulatory systems. For example, particulate matter with an aerodynamic diameter of approximately 5 to 10 μm accumulates in the bronchi, while particulate matter with an aerodynamic diameter of approximately 1 to 5 μm can invade the alveoli and enter the circulatory system through the alveolar capillaries, causing systemic inflammation. When the lungs are exposed to particulate matter for extended periods, it can cause lung injury [including inflammatory damage], leading to serious symptoms such as bronchial fibrosis, worsening of respiratory function, and impairment of the lung immune systems.

[0004] The Food and Agriculture Organization of the United Nations (FAO) and the World Health Organization (WHO) define probiotics as: live microorganisms that, when administered in appropriate quantities, confer a health benefit on a host. Currently, many types of microorganisms can be used as probiotics, such as *Lactobacillus*, *Bifidobacterium*, *Bacillus*, *Lactococcus*, *Enterococcus*, *Saccharomyces*, and *Streptococcus*, especially species from the first two genera.

[0005] Previous studies have indicated a close relationship between changes in gut microbiota species and metabolites and alterations in immune responses, inflammation, and the progression of lung-related diseases. For example, gut microbiota diversity can alleviate lung inflammation symptoms by regulating the Th1 / Th2 balance. Therefore, researchers in this field have explored the application of probiotics with gut microbiota-modulating properties in the treatment and / or prevention of lung-related diseases.

[0006] However, after oral administration, a certain number of these probiotics are usually destroyed by gastric acid and bile salts in the stomach and duodenum. Furthermore, before they can exert their effects, they must compete with harmful bacteria in the gut to successfully colonize and proliferate, making it difficult to maintain the necessary bacterial count for effectiveness. Additionally, as a live microbial ingredient, probiotics are also difficult to preserve. Summary of the Invention

[0007] In developing drugs that can effectively combat particulate matter-induced lung injury, the applicant unexpectedly discovered that, unlike existing technologies that use live microorganisms, the heat-killed lactic acid bacteria strains of this invention [i.e., heat-killed strains of the genus *Lactobacillus* and genus *Bifidobacterium*] can effectively reduce the concentration of immunoglobulin E (IgE) in lung tissue and increase the Th1 / Th2 cytokine secretion ratios in lung tissue in mice with particulate matter-induced lung injury, thereby achieving therapeutic and / or preventive effects against particulate matter-induced lung injury.

[0008] Therefore, in a first aspect, the present invention provides a heat-killing lactic acid bacteria strain for use in the preparation of pharmaceuticals for treating and / or preventing particulate matter-induced lung injury, wherein the lactic acid bacteria strain is a strain of the genus *Lactobacillus* and / or the genus *Bifidobacterium*.

[0009] In a second aspect, the present invention provides a method for treating and / or preventing particulate matter-induced lung injury, comprising administering, to an individual requiring treatment and / or prevention of particulate matter-induced lung injury, a heat-killing strain of lactic acid bacteria as described above.

[0010] Preferably, the lactic acid bacteria strain is selected from the group consisting of: Lactobacillus plantarum, Lactobacillus acidophilus, Bifidobacterium longum, Bifidobacterium lactis, and combinations thereof.

[0011] Preferably, the pharmaceutical product further comprises probiotics selected from the group consisting of: *Lactobacillus* species, *Bifidobacterium* species, *Bacillus* species, *Streptococcus* species, *Lactococcus* species, *Abiotrophia* species, *Aerococcus* species, *Carnobacterium* species, *Enterococcus* species, *Leuconostoc* species, *Oenococcus* species, *Pediococcus* species, *Tetragenococcus* species, *Vagococcus* species, and *Weissella* species. spp.), species of the genus Saccharomyces spp., species of the genus Kluyveromyces spp., species of the genus Staphylococcus spp., species of the genus Propionibacterium spp., and combinations thereof.

[0012] More preferably, the probiotic is selected from the group consisting of Bacillus coagulans, Lactobacillus paracasei, and combinations thereof.

[0013] Preferably, the pharmaceutical product further comprises a pharmaceutically acceptable carrier.

[0014] Preferably, the pharmaceutical product is in a dosage form for oral administration.

[0015] Information on the Preservation of Biological Materials

[0016] Accession number: DSM 33893

[0017] Classification and nomenclature: Bacillus coagulans CB85

[0018] Date of preservation: June 9, 2021

[0019] Preservation Institution: German Center for Microbial Culture Collection

[0020] Address of the depositary: Braunschweig, 7B D-38124, Germany

[0021] Accession number: DSM 33894

[0022] Classification and nomenclature: Lactobacillus plantarum CB102

[0023] Date of preservation: June 9, 2021

[0024] Preservation Institution: German Center for Microbial Culture Collection

[0025] Address of the depositary: Braunschweig, 7B D-38124, Germany

[0026] Accession number: DSM 33895

[0027] Classification and nomenclature: Bifidobacterium longum CB108

[0028] Date of preservation: June 9, 2021

[0029] Preservation Institution: German Center for Microbial Culture Collection

[0030] Address of the depositary: Braunschweig, 7B D-38124, Germany Attached Figure Description

[0031] The present invention will now be described in detail with reference to the accompanying drawings and embodiments. Therefore, the present invention, as well as other objects and features, will become more apparent from the following description and accompanying figures, in which:

[0032] Figure 1 The IgE concentration measured in the lung tissue of mice in each group is shown.

[0033] Figure 2 The Th1 / Th2 cytokine secretion rate measured in the lung tissue of mice in each group is shown.

[0034] Figure 3 The IgE concentration measured in the lung tissue of mice in each group is shown; and

[0035] Figure 4 The display shows the Th1 / Th2 cytokine secretion rates measured in the lung tissue of mice in each group. Detailed Implementation

[0036] In this invention, it will be clearly understood that the word "comprising" means "including but not limited to," and the word "comprises" has a corresponding meaning. The terms "A and / or B" in this invention refer to A, B, or a combination of A and B.

[0037] Unless otherwise defined, all technical and scientific terms used herein have the meaning commonly understood by those skilled in the art. Those skilled in the art will recognize many similar or equivalent methods and materials that can be used to practice the invention. Of course, the invention is by no means limited to the methods and materials described.

[0038] This invention provides a heat-killed lactic acid bacteria strain for use in the preparation of pharmaceuticals for the treatment and / or prevention of particulate matter-induced lung injury, wherein the lactic acid bacteria strain is a strain of the genus *Lactobacillus* spp. and / or the genus *Bifidobacterium* spp.

[0039] Preferably, the lactic acid bacteria strain is selected from Lactobacillus species in the group consisting of: Lactobacillus plantarum, Lactobacillus acidophilus, and combinations thereof.

[0040] Preferably, the lactic acid bacteria strain is selected from Bifidobacterium species in the group consisting of: Bifidobacterium longum, Bifidobacterium lactis, and combinations thereof.

[0041] As used herein, the terms “heat-killing” and “heat-inactivation” may be used interchangeably and refer to killing probiotics through heat treatment for a predetermined period of time.

[0042] According to the present invention, the heat-killed lactic acid bacteria strain can be prepared using techniques well known and commonly used by those skilled in the art. In this regard, references may be made, for example, to Segawa S. et al. (2008), Int. J. Food Microbiol., 128:371-377 and Ben Othman M. et al. (2020), Food Res. Int., doi:10.1016 / j.foodres.2019.108792.

[0043] According to the present invention, the thermal death can be achieved by heating at a temperature of 60°C to 140°C for 1 second to 30 minutes. In a preferred embodiment of the present invention, the thermal death is achieved by heating at 73±2°C for 15 seconds.

[0044] According to the present invention, the heat-killed lactic acid bacteria strain can be further subjected to a drying process. This drying process can be carried out using techniques well-known and commonly used by those skilled in the art, including, but not limited to, spray-drying treatment, lyophilization treatment, vacuum evaporation treatment, and combinations thereof. In a preferred embodiment of the present invention, the heat-killed lactic acid bacteria strain is subjected to a spray-drying treatment.

[0045] According to the present invention, the heat-killed lactic acid bacteria strain undergoes a separation process to remove the culture medium before being subjected to the drying process.

[0046] Preferably, the separation process is selected from the group consisting of centrifugation treatment, filtration treatment, and combinations thereof. In a preferred embodiment of the invention, the separation process is centrifugation treatment.

[0047] As used herein, the terms “treating” or “treatment” for particulate-induced lung injury mean that the severity or symptoms of the lung injury have been reduced, or that the lung injury has been partially or entirely eliminated.

[0048] As used herein, the terms “preventing” or “prevention” for particulate matter-induced lung injury refer to the elimination or reduction of the incidence of such lung injury in an individual before they are diagnosed with it, as well as the likelihood or probability of slowing, delaying, controlling, or decreasing the incidence of such lung injury.

[0049] As used herein, the term “particulate matter-induced lung injury” refers to injury or damage to the lungs of an organism caused by exposure to particulate matter, including, but not limited to, inflammatory cell infiltration, interstitial thickening, structural distortion, abnormal collagen deposition, and pulmonary fibrosis.

[0050] According to the present invention, the pharmaceutical product can be manufactured into a dosage form suitable for oral administration using techniques known to those skilled in the art, including, but not limited to: sterile powders, tablets, troche, lozenges, pellets, capsules, dispersible powders or granules, solutions, suspensions, emulsions, syrups, elixirs, slurries, and the like.

[0051] According to the present invention, the pharmaceutical product may further comprise a pharmaceutically acceptable carrier widely used in drug manufacturing techniques. For example, the pharmaceutically acceptable carrier may comprise one or more reagents selected from the following: solvent, buffer, emulsifier, suspending agent, decomposer, disintegrating agent, dispersing agent, binding agent, excipient, stabilizing agent, chelating agent, diluent, gelling agent, preservative, wetting agent, lubricant, absorption delaying agent, liposome, and the like. The selection and quantity of these reagents fall within the scope of professional competence and routine practice of those skilled in the art.

[0052] According to the present invention, the pharmaceutical product may further comprise probiotics selected from the group consisting of: *Lactobacillus* species, *Bifidobacterium* species, *Bacillus* species, *Streptococcus* species, *Lactococcus* species, *Abiotrophia* species, *Aerococcus* species, *Carnobacterium* species, *Enterococcus* species, *Leuconostoc* species, *Oenococcus* species, *Pediococcus* species (also known as *Pediococcus* species), *Tetragenococcus* species, and *Vagococcus* species. species of the genera *Weissella*, *Saccharomyces*, *Kluyveromyces*, *Staphylococcus*, *Propionibacterium*, and combinations thereof.

[0053] Preferably, the probiotic is selected from the group consisting of Bacillus coagulans, Lactobacillus paracasei, and combinations thereof.

[0054] As used herein, the terms “probiotics” and “probiotic microbes” may be used interchangeably and refer to preparations of live microorganisms that, when ingested by a human or animal, remain and survive in the gastrointestinal tract and are able to exert desired effects (e.g., gut microbiota regulation, preventative or therapeutic effects, etc.).

[0055] According to the present invention, in the pharmaceutical product, the ratio of the number of probiotics to the number of heat-killed lactic acid bacteria strains can fall within the range of 1:0.5 to 1:5.

[0056] The present invention also provides a method for treating and / or preventing particulate matter-induced lung injury, comprising administering to an individual requiring treatment and / or prevention of particulate matter-induced lung injury a heat-killing lactic acid bacteria strain as described above.

[0057] As used herein, the terms “administration” and “administration” may be used interchangeably and mean introducing, providing, or delivering a predetermined active ingredient to an individual by any suitable means to perform its intended effect.

[0058] As used in this article, the term "subject" refers to any mammal of interest, such as humans, mice, and rats.

[0059] According to the present invention, the dosage and frequency of administration of the heat-killed lactic acid bacteria strain will vary depending on the following factors: the severity of the disease to be improved, the route of administration, and the individual's weight, age, physical condition, and response. The selection of the dosage and frequency of administration falls within the scope of the professional competence and routine techniques of those skilled in this art.

[0060] The present invention will be further described with reference to the following embodiments, but it should be understood that the embodiments are for illustrative purposes only and should not be construed as limiting the implementation of the present invention.

[0061] <Example>

[0062] General experimental materials:

[0063] 1. The probiotic strains used in the following examples were obtained from the Microbiology Laboratory of the Department of Food Science and Biotechnology at Chung Hsing University and are listed in Table 1 below.

[0064] Table 1. Various probiotic strains

[0065]

[0066] Among the probiotic strains mentioned, *Lactobacillus acidophilus* JCM1132, *Lactobacillus paracasei* JCM8130, and *Bifidobacterium lactis* JCM10602 are all commercially available. *Lactobacillus plantarum* CB102 and *Bifidobacterium longum* CB108 were deposited on May 8, 2019, with accession numbers BCRC 910893 and BCRC 910894 respectively, at the Bioresource Collection and Research Center (BCRC) of the Food Industry Research and Development Institute (FIRDI), Taiwan (No. 331, Food Rd., Hsinchu City, Taiwan 300). *Bacillus coagulans* CB85 was also deposited on July 23, 2020, with accession number BCRC 911010, at the same center. In addition, Lactobacillus plantarum CB102, Bifidobacterium longum CB108, and Bacillus coagulans CB85 were deposited on June 9, 2021, with accession numbers DSM 33894, DSM 33895, and DSM 33893, respectively, in accordance with the provisions of the Budapest Treaty at the German Center for Microbial Collection (Deutsche Sammlung von Mikroorganismen und ZellkulturenGmbH, DSMZ).

[0067] 2. Preparation of live lactic acid bacteria culture:

[0068] The six probiotic strains mentioned in item 1 above were inoculated into MRS broth medium (trade name BDDifco Lactobacilli MRS Broth, catalog number DF0881-17-5) and cultured at 37°C for 16 hours to obtain the bacterial suspensions of each live lactic acid bacteria strain.

[0069] 3. Preparation of heat-killed lactic acid bacteria strain powder:

[0070] First, the bacterial suspensions of *Lactobacillus plantarum* CB102, *Lactobacillus acidophilus* JCM1132, *Bifidobacterium longum* CB108, and *Bifidobacterium lactis* JCM10602 obtained in step 2 above were heat-killed at 73±2℃ for 15 seconds, followed by centrifugation at 10,000 rpm for 15 minutes at 25℃. After discarding the supernatant, the resulting precipitates were spray-dried to obtain the bacterial powders of each heat-killed lactic acid bacteria strain.

[0071] 4. Laboratory animals:

[0072] The male C57BL / 6J mice (6 weeks old, weighing approximately 20±1g) used in the following examples were purchased from Lesco Biotechnology Co., Ltd. All experimental animals were housed in an independently air-conditioned animal room with 12 hours of light and 12 hours of darkness, a room temperature maintained at 22±1°C, and a relative humidity maintained at 55±5%, and adequate water and feed were provided. The animal housing environment, handling, and all experimental procedures complied with the Institutes of Health's Guide for the Care and Use of Laboratory Animals (2011).

[0073] 5. Preparation of suspensions of particulate matter (PM):

[0074] Apply an appropriate amount of Standard Reference Material (SRM) purchased from Sigma-Aldrich's National Institute of Standards and Technology (NIST). The 2783 filter membrane was sheared into fragments and soaked in phosphate-buffered saline (PBS), followed by ultrasonic treatment for 15 minutes and centrifugation at 1,000 rpm for 5 minutes. The supernatant was then collected and dried under reduced pressure, and then dissolved in PBS to obtain the PM suspension.

[0075] Example 1. Evaluation of the efficacy of heat-killed lactic acid bacteria strains in combating PM-induced lung injury.

[0076] In this embodiment, the applicant used the expression levels of immunoglobulin E (IgE), interferon-γ (IFN-γ), and interleukin-4 (IL-4) as inflammatory markers to evaluate the efficacy of heat-killed lactic acid bacteria strains in combating PM-induced lung injury.

[0077] Experimental methods:

[0078] A. Administration of heat-killed lactic acid bacteria strains and treatment of PM:

[0079] First, male C57BL / 6J mice were randomly divided into 6 groups (n=6 per group), including one normal control group, one pathological control group, and four heat-killed bacteria groups (i.e., heat-killed bacteria groups 1 to 4). Next, the heat-killed *Lactobacillus plantarum* CB102, *Bifidobacterium longum* CB108, *Lactobacillus acidophilus* JCM1132, and *Bifidobacterium lactis* JCM10602 powders obtained in section 3 of the "General Experimental Materials" section were orally administered to mice in heat-killed bacteria groups 1 to 4 via oral gavage (dose: 1.0 × 10⁻⁶). 7 CFU / day (prepared in PBS). The medication was administered once daily for a total of 14 days. Mice in the normal control and pathological control groups received no treatment.

[0080] On day 15 after the start of drug administration, mice in the pathological control group and each heat-killed bacteria group were administered 100 μL of the PM suspension obtained in item 5 of the "General Experimental Materials" section above (dose: 0.16 mg PM / mouse) via intranasal administration. The administration was once daily for a total of 3 days. Mice in the normal control group received no treatment.

[0081] B. Determination of IgE, IFN-γ, and IL-4 concentrations in lung tissue:

[0082] On day 18 after drug administration, mice in each group were sacrificed using CO2, and their lungs were then removed. The lungs were then placed in PBS and ultrasonically shaken five times at 4°C for 10 seconds each time, followed by cooling on ice. After centrifugation at 1,000 rpm for 15 minutes at 4°C, the supernatant was collected, and the concentrations of IgE, IFN-γ, and IL-4 were determined using an IgE ELISA kit (BD Biosciences, catalog number 555248), an IFN-γ ELISA kit (BD Biosciences, catalog number 555138), and an IL-4 ELISA kit (BD Biosciences, catalog number 555232), respectively. Each measured absorbance value was converted into its concentration (pg / mg) based on a standard curve prepared in advance using standards of IgE, IFN-γ and IL-4 with different known concentrations relative to their own absorbance values.

[0083] Then, the IFN-γ concentration of each group was divided by its respective IL-4 concentration to calculate the Th1 / Th2 cytokine secretion ratio, also known as the pro- / anti-inflammatory cytokine secretion ratio.

[0084] result:

[0085] Figure 1 This shows the IgE concentration measured in the lung tissue of mice in each group. Figure 1 As can be seen, the IgE concentration in the pathological control group was significantly increased compared with the normal control group, indicating that PM successfully induced an inflammatory response in the lungs of mice. In contrast, the IgE concentrations in heat-killed bacteria groups 1 through 4 all showed a significant decrease compared with the pathological control group.

[0086] Figure 2 This shows the Th1 / Th2 cytokine secretion rates measured in the lung tissue of mice in each group. Figure 2 As can be seen, compared with the normal control group, the Th1 / Th2 cytokine secretion rate of the pathological control group was significantly reduced, indicating that PM successfully induced an inflammatory response in the lungs of mice. Compared with the pathological control group, the Th1 / Th2 cytokine secretion rates of groups 1 to 4 of the heat-killing bacteria group all showed a significant increase.

[0087] These experimental results show that pretreatment of mice with heat-killed strains of Lactobacillus or Bifidobacterium effectively protects them against PM-induced lung inflammation. Therefore, heat-killed strains of Lactobacillus or Bifidobacterium are expected to have therapeutic and / or preventative effects against PM-induced lung injury.

[0088] Example 2. Evaluation of the efficacy of a combination of heat-killed lactic acid bacteria strains and live probiotic strains in combating PM-induced lung injury.

[0089] Experimental methods:

[0090] First, male C57BL / 6J mice were randomly divided into 12 groups (n=6 per group), including one normal control group, one pathological control group, two live bacteria groups (i.e., live bacteria groups 1 and 2), and eight mixed groups (i.e., mixed groups 1 to 8). Next, according to the dosages shown in Table 2 below, live Bacillus coagulans CB85 and Lactobacillus paracasei JCM8130 bacterial suspensions obtained in section 2 of "General Experimental Materials" above, and heat-killed Lactobacillus plantarum CB102, Bifidobacterium longum CB108, Lactobacillus acidophilus JCM1132, and Bifidobacterium lactis JCM10602 bacterial powders obtained in section 3 of "General Experimental Materials" above, were prepared in PBS and administered orally to the mice in each live bacteria group and each mixed group via tube feeding. Administered once daily for a total of 14 days. The mice in the normal control and pathological control groups received no treatment.

[0091] Table 2. Probiotic strains and dosages (CFU / day) administered orally to mice in each group

[0092]

[0093] On day 15 after the start of drug administration, mice in the pathological control group, each live bacteria group, and each mixed group were administered 100 μL of the PM suspension obtained in item 5 of the "General Experimental Materials" section above (dose: 0.16 mg PM / mouse) intranasally. The medication was administered once daily for a total of 3 days. Mice in the normal control group received no treatment.

[0094] Next, the concentrations of IgE, IFN-γ, and IL-4 in lung tissue and the Th1 / Th2 cytokine secretion rate were measured according to the method described in item B of Example 1 above.

[0095] result:

[0096] Figure 3This shows the IgE concentration measured in the lung tissue of mice in each group. Figure 3 As can be seen, the IgE concentration in the pathological control group was significantly increased compared to the normal control group, indicating that PM successfully induced an inflammatory response in the lungs of mice. In contrast, the IgE concentrations in live bacteria groups 1 and 2, as well as mixed groups 1 to 8, all showed a significant decrease compared to the pathological control group. Notably, the IgE concentrations in mixed groups 1 to 8 were similar to those in the normal control group.

[0097] Figure 4 This shows the Th1 / Th2 cytokine secretion rates measured in the lung tissue of mice in each group. Figure 4 As can be seen, compared with the normal control group, the Th1 / Th2 cytokine secretion rate of the pathological control group was significantly reduced, indicating that PM successfully induced an inflammatory response in the lungs of mice. Compared with the pathological control group, the Th1 / Th2 cytokine secretion rates of live bacteria groups 1 and 2, as well as mixed groups 1 to 8, all showed significantly increased levels. In particular, the increase in Th1 / Th2 cytokine secretion rates in mixed groups 1 to 8 was even more pronounced.

[0098] In addition, from Figure 3 and Figure 4 The experimental results also showed that the decrease in IgE concentration and the increase in Th1 / Th2 cytokine secretion rate in mixed groups 1, 3, 5, and 7 compared to the pathological control group were significantly higher than those in live bacteria group 1 compared to the pathological control group. Similarly, the decrease in IgE concentration and the increase in Th1 / Th2 cytokine secretion rate in mixed groups 2, 4, 6, and 8 compared to the pathological control group were significantly higher than those in live bacteria group 2 compared to the pathological control group. This indicates that using heat-killed lactic acid bacteria strains to replace similar amounts of live bacteria strains can significantly enhance the efficacy of live bacteria strains in inhibiting lung inflammation in mice.

[0099] These experimental results show that pretreatment with a combination of heat-killed lactic acid bacteria strains (i.e., heat-killed strains of the genus *Lactobacillus* or *Bifidobacterium*) and live strains effectively protects mice against PM-induced lung inflammation. Therefore, this combination is also expected to have therapeutic and / or preventative effects against PM-induced lung injury.

[0100] All patents and documents cited in this specification are incorporated herein by reference in their entirety. In the event of any conflict, the detailed description herein (including its definitions) shall prevail.

[0101] Although the invention has been described with reference to the specific examples described above, it is apparent that many modifications and variations can be made without departing from the scope and spirit of the invention. Therefore, it is intended that the invention be limited only to the claims appended herein.

Claims

1. A heat-killable lactic acid bacteria strain for use in the preparation of a pharmaceutical product for the prevention of particulate matter-induced lung injury, wherein the lactic acid bacteria strain is selected from the group consisting of: *Lactobacillus plantarum* (…). Lactobacillus plantarum CB102, Lactobacillus acidophilus ( Lactobacillus acidophilus JCM1132, Bifidobacterium longum ( Bifidobacterium longum CB108, Bifidobacterium lactis ( Bifidobacterium lactis JCM10602 and the aforementioned combination, Lactobacillus plantarum CB102 and Bifidobacterium longum CB108 are deposited at the German Microbiological Collection Center with accession numbers DSM 33894 and DSM 33895, respectively.

2. Use according to claim 1, characterized in that: The pharmaceutical product further comprises probiotic bacteria selected from the group consisting of Bacillus coagulans Bacillus coagulans , Lactobacillus paracasei Lactobacillus paracasei , and combinations of the foregoing.

3. Use according to claim 1, characterized in that: The pharmaceutical further comprises a pharmaceutically acceptable carrier.

4. Use according to claim 1, characterized in that: The pharmaceutical is in a dosage form for oral administration.

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