US20130022586A1 - Production and use of bacterial histamine - Google Patents

Production and use of bacterial histamine Download PDF

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Publication number
US20130022586A1
US20130022586A1 US13/552,686 US201213552686A US2013022586A1 US 20130022586 A1 US20130022586 A1 US 20130022586A1 US 201213552686 A US201213552686 A US 201213552686A US 2013022586 A1 US2013022586 A1 US 2013022586A1
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Prior art keywords
histamine
histidine
lactic acid
strain
strains
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US13/552,686
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James Versalovic
Carissa Michelle Thomas
Eamonn Connolly
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Biogaia AB
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Priority to US13/552,686 priority Critical patent/US20130022586A1/en
Priority to SI201231427T priority patent/SI2734845T1/sl
Priority to DK12738122.6T priority patent/DK2734845T3/en
Priority to AU2012285657A priority patent/AU2012285657B2/en
Priority to KR1020147004227A priority patent/KR20140047717A/ko
Priority to CN201810062784.9A priority patent/CN109554435A/zh
Priority to CA2842379A priority patent/CA2842379C/en
Priority to RU2014106509A priority patent/RU2628536C2/ru
Priority to EP12738122.6A priority patent/EP2734845B1/en
Priority to UAA201401697A priority patent/UA115864C2/uk
Priority to LTEP12738122.6T priority patent/LT2734845T/lt
Priority to PL12738122T priority patent/PL2734845T3/pl
Priority to TR2018/16432T priority patent/TR201816432T4/tr
Priority to JP2014520684A priority patent/JP6211516B2/ja
Priority to NZ619605A priority patent/NZ619605B2/en
Priority to PT12738122T priority patent/PT2734845T/pt
Priority to ES12738122.6T priority patent/ES2694567T3/es
Priority to BR112014001221-0A priority patent/BR112014001221B1/pt
Priority to CN201280035256.5A priority patent/CN104160276B/zh
Priority to MX2014000844A priority patent/MX358347B/es
Priority to KR1020187032594A priority patent/KR102039289B1/ko
Priority to RS20181329A priority patent/RS57957B1/sr
Priority to GEAP201213351A priority patent/GEP201706730B/en
Priority to PCT/EP2012/064351 priority patent/WO2013011137A1/en
Assigned to BIOGAIA AB reassignment BIOGAIA AB ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CONNOLLY, E., THOMAS, C., VERSALOVIC, J.
Publication of US20130022586A1 publication Critical patent/US20130022586A1/en
Priority to US13/765,947 priority patent/US20130149291A1/en
Priority to IL229959A priority patent/IL229959B/en
Priority to ZA2014/00142A priority patent/ZA201400142B/en
Priority to CL2014000128A priority patent/CL2014000128A1/es
Priority to HK15103998.9A priority patent/HK1203615A1/xx
Priority to US15/289,666 priority patent/US10004770B2/en
Priority to US15/987,210 priority patent/US10898529B2/en
Priority to HRP20181599TT priority patent/HRP20181599T1/hr
Abandoned legal-status Critical Current

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    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
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    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
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    • A—HUMAN NECESSITIES
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    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
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    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
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    • G01N2333/335—Assays involving biological materials from specific organisms or of a specific nature from bacteria from Lactobacillus (G)

Definitions

  • This invention relates to a method of selecting specific probiotic lactic acid bacteria producing histamine and the use of such strains to deliver beneficial effects for the host.
  • probiotics live microorganisms which when administered in adequate amounts confer a health benefit on the host”.
  • probiotics for example, lactic-acid producing bacteria such as strains of Lactobacillus and Bifidobacteria.
  • Lactic-acid producing bacteria are not only used for their beneficial effect on human or animal health, but they are also widely used in the food industry for fermentation processes.
  • the effectiveness of probiotics is strain-specific, and each strain may contribute to host health through different mechanisms.
  • Probiotics can prevent or inhibit the proliferation of pathogens, suppress production of virulence factors by pathogens, or modulate the immune response in a pro-inflammatory or an anti-inflammatory way.
  • Use of different strains of the probiotic lactic-acid producing bacteria Lactobacillus reuteri is a promising therapy for the amelioration of infantile colic, alleviation of eczema, reduction of episodes of workplace illness, and suppression of Helicobacter pylori infection. L.
  • reuteri is considered an indigenous organism of the human gastrointestinal tract and is present for example on the mucosa of the gastric corpus, gastric antrum, duodenum, and ileum. See, for example, U.S. Pat. Nos. 5,439,678, 5,458,875, 5,534,253, 5,837,238, and 5,849,289.
  • L. reuteri cells When L. reuteri cells are grown under anaerobic conditions in the presence of glycerol, they produce the antimicrobial substance known as reuterin ( ⁇ -hydroxy propionaldehyde).
  • Dysbiosis the perturbation of the normal gut microbiome, has been implicated in a wide range of disease processes including those affecting the local gut environment, such as Inflammatory Bowel Disease (IBD) and Irritable Bowel Syndrome (IBS), and disease processes at sites distant to the gut, such as the metabolic syndrome.
  • IBD Inflammatory Bowel Disease
  • IBS Irritable Bowel Syndrome
  • Significant therapeutic potential lies within the gut microbiome, and research is striving towards a future goal of altering the microbial community in order to prevent and/or treat distinct disease processes.
  • the invention herein provides a specific method of locally producing histamine in mammals, especially humans, the local production of histamine includes but are not limited to production in the GI tract, genitourinary (GU) tract, oral cavity, in the lungs and airway on the skin etc, of the mammalian body by selecting certain strains of lactic acid bacteria.
  • the bacteria may be delivered together with certain amino acids and/or sugars, separately administered or already present at the active site.
  • a primary object of the present invention is to select strains that can locally produce histamine in various locations, including the GI tract, GU tract, oral cavity, in the lungs and airways, on the skin etc, of the mammalian body.
  • the present invention thus relates to a new method for selecting lactic acid bacterial cells which are useful as probiotics and in therapy.
  • This new method involves the screening and selection for strains of lactic acid bacteria which have an active histidine operon and are capable of producing histamine.
  • the lactic acid bacterial strains selected by this method are useful as probiotics and in therapy, in particular in producing anti-inflammatory effects, by way of the local production of histamine.
  • the present invention provides a method of selecting a lactic acid bacterial strain for use in the local production of histamine in a mammal, wherein said method comprises screening bacteria for the presence of an active histidine operon and selecting a strain which has an active histidine operon and is capable of producing histamine.
  • the histidine operon comprises three genes (the histidine/histamine antiporter, the histidine decarboxylase pyruvoyl type A (HdcA), and histidine decarboxylase pyruvoyl type B (HdcB)). It is believed that the activity of each of these genes is important for the present invention. Thus, in the screening methods of the invention, candidate bacteria are assessed for the presence of all three genes and strains positive for all three genes are selected. Any appropriate method can be used for the detection of the presence of all three genes, for example genetic methods such as PCR can be used. The production of good levels of histamine can also be an indicator of the presence of all three genes and the presence of an active histidine operon.
  • HdcA histidine decarboxylase pyruvoyl type A
  • HdcB histidine decarboxylase pyruvoyl type B
  • the selection method of the invention also involves the step of selecting a strain which is capable of producing histamine. Strains with high production levels of histamine are preferred. Thus, in preferred embodiments a strain is selected for its ability to produce histamine at a level of greater than 200, preferably greater than 250 or more preferably greater than 300 pg/ml, for example a level of greater than 350, 400, 450, or 500 pg/ml. Such values generally refer to values of histamine measured in the supernatant of strains in culture.
  • the selection method will involve the step of detecting the amount or level of histamine produced by a candidate strain. Because of the downstream uses of the strains which are selected by the methods of the invention, after histamine-producing strains are selected or isolated, other embodiments will involve the further steps of culturing or propagating such strains, or possibly storing such strains for future uses.
  • Such further steps will generally need to be carried out in an appropriate culture medium which supports histamine production.
  • Preferred culture media will contain an appropriate carbon source which will support the production of histamine by said strain.
  • the media will comprise glucose as a carbon source and preferably will not contain sucrose, or at least will only comprise sucrose at such a level which will not significantly compromise histamine production by the strain.
  • Histidine or a histidine analog can also be provided, optionally together with sources or other amino acids.
  • said strain is a strain of Lactobacillus reuteri.
  • an appropriate strain has been selected using the method of the present invention it can then he used for the local production of histamine in a mammal. Said strains thus also have to be capable of local production of histamine in a mammal.
  • a further aspect of the present invention provides a product comprising cells of a lactic acid bacterial strain obtainable by the selection method of the invention, wherein said lactic acid bacterial strain has an active histidine operon and is capable of producing histamine, for use in the local production of histamine in a mammal.
  • preferred uses are in the treatment and/or prophylaxis of inflammatory conditions, or in the treatment and/or prophylaxis of conditions or diseases which will benefit from local histamine production. For example, such local production of histamine can result in an anti-inflammatory effect.
  • Alternative embodiments of the invention provide a lactic acid bacterial strain which is capable of producing histamine for use in the local production of histamine in a mammal, wherein said lactic acid bacterial strain has an active histidine operon. Preferred features of this strain and its uses are described elsewhere herein.
  • Methods of treatment or methods for the local production of histamine in a mammal comprising the administration of a product comprising cells of a lactic acid bacterial strain obtainable by the selection method of the invention, or the administration of a lactic acid bacterial strain wherein said lactic acid bacterial strain has an active histidine operon and is capable of producing histamine, to said mammal in an amount effective to enable local production of histamine in said mammal.
  • Preferred features of the strain and its therapeutic uses are described elsewhere herein.
  • a product comprising cells of a lactic acid bacterial strain obtainable by the selection method of the invention, wherein said lactic acid bacterial strain has an active histidine operon and is capable of producing histamine, in the manufacture of a composition or medicament for use in the local production of histamine in a mammal.
  • Alternative embodiments provide the use of a lactic acid bacterial strain, wherein said lactic acid bacterial strain has an active histidine operon and is capable of producing histamine, in the manufacture of a composition or medicament for use in the local production of histamine in a mammal. Preferred features of the strain and its therapeutic uses are described elsewhere herein.
  • FIG. 1 Quantification of histamine in HILIC-HPLC fractions. Triple quadrupole mass spectrometry was used to quantify histamine present in a select range of HILIC-HPLC fractions. TNF-inhibitory fractions had the highest amounts of histamine out of all the fractions examined.
  • FIG. 2 Purified histamine and histamine from L. reuteri 6475 inhibit TNF production via the histamine H 2 receptor.
  • N 3, *p value ⁇ 0.05 compared to media control, **p value ⁇ 0.05 compared to histamine, ***p value ⁇ 0.05 compared to ATCC 6475 conditioned media (CM)
  • CM conditioned media
  • FIG. 3 The histidine operon is important for the TNF-inhibitory phenotype of L. reuteri 6475.
  • A. The histidine operon consists of three genes, the histidine/histamine antiporter, hdcA, and hdcB.
  • B. Mutation in any one gene in the histidine operon results in a partial loss of TNF suppression by L. reuteri 6475. N 9, *p value ⁇ 0.05 compared to media control. **p value ⁇ 0.05 compared to ATCC PTA 6475.
  • FIG. 4 L. reuteri 6475 significantly reduced weight loss induced by TNBS challenge, the figure represents data from two independent experiments, * p ⁇ 0.05, **p ⁇ 0.01, ***p ⁇ 0.001.
  • FIG. 5 L. reuteri 6475 significantly diminished macroscopic colon damage induced by TNBS challenge, the figure represents data from two independent experiments. *p ⁇ 0.05, ***p ⁇ 0.001.
  • FIG. 6 L. reuteri 6475 significantly reduced SAA concentration induced by TNBS challenge, the figure represents data from two independent experiments, *p ⁇ 0.05, ***p ⁇ 0.001.
  • FIG. 7 hdcA mutant yielded diminished ability to attenuate colitis, the figure represents data from two independent experiments, *p ⁇ 0.05, **p ⁇ 0.01.
  • FIG. 8 hdcA mutant yielded diminished ability to attenuate colitis, the figure represents data from two independent experiments, *p ⁇ 0.01, **p ⁇ 0.001.
  • lactobacilli including certain strains of Lactobacillus reuteri locally produces histamine under specific growth conditions, and that such produced histamine will benefit the host by for example reducing inflammation, reducing certain cancers etc.
  • Histamine is an organic nitrogen compound involved in several health-associated processes of a mammal, including local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter. As part of an immune response to foreign pathogens, histamine is produced by basophils and mast cells. Histamine can be derived from the decarboxylation of the amino acid histidine, a reaction catalyzed by the enzyme L-histidine decarboxylase.
  • Bacteria are capable of producing histamine using histidine decarboxylase enzymes unrelated to those found in eukaryotes.
  • histidine decarboxylase enzymes unrelated to those found in eukaryotes.
  • Scombroid poisoning a form of non-infectious foodborne disease, is due to histamine production by bacteria in spoiled food, particularly fish.
  • Fermented foods and beverages naturally contain small quantities of histamine due to a similar conversion performed by fermenting bacteria or yeasts. Delivery of certain controlled amounts of histamine from selected bacteria can, surprisingly, give beneficial effects rather than detrimental effects as might be expected from the above mentioned studies.
  • Histamine receptors are a class of G protein-coupled receptors with histamine as their endogenous ligand. There are four known histamine receptors; H 1 receptor (H1R), H 2 receptor (H2R), H 3 receptor (H3R) and H 4 receptor (H4R).
  • Vannier et al. Histamine Suppresses Gene Expression and Synthesis of Tumor Necrosis Factor ⁇ via Histamine H 2 Receptors: J Exp Med. 1991 Jul. 1;174(1):281-4
  • LPS-induced synthesis of TNF- ⁇ in peripheral blood mononuclear cells was suppressed by histamine and they further suggest that histamine release from mast cells may limit the extent of inflammatory and immune reactions by suppressing local cytokine synthesis in H 2 receptor-bearing cells.
  • histamine Antagonizes Tumor Necrosis Factor ( TNF ) Signaling by Stimulating TNF Receptor Shedding from the Cell Surface and Golgi Storage Pool: J. Biol. Chem. 278(24): 21751-21760), showing that histamine causes transient loss of surface TNFR1, increased TNFR1 shedding, and mobilization of TNFR1 molecules from the Golgi in cultured human endothelial cells. Histamine injection into human skin engrafted on immunodeficient mice caused shedding of TNFR1 and diminished TNF-mediated induction of endothelial adhesion molecules.
  • TNF Tumor Necrosis Factor
  • Vannier et al. and Wang et al. did not mention anything about using histamine-producing bacterial strains as probiotics nor how to select the strains based on their histamine-producing abilities in order to assure certain health benefits for the host, such as anti-inflammatory effects.
  • Ceplene a pharmaceutical-grade form of histamine dihydrochloride, is used for the prevention of relapse in patients diagnosed with acute myeloid leukemia (AML).
  • Ceplene is administered in conjunction with low doses of the immune-activating cytokine interleukin-2 (IL-2) in the post-remission phase of AML, i.e. when patients have completed the initial chemotherapy.
  • IL-2 immune-activating cytokine interleukin-2
  • the treatment, subcutaneous injections is given in 3-week cycles by the patients at home for 18 months.
  • the side effects of Ceplene include transient flush and headache. It would be advantageous for patients to receive locally produced histamine, when needed, instead of subcutaneous injections; this delivery strategy may be achieved by administering bacterial-derived histamine to the patient using the strains selected according to this invention.
  • Lactobacillus reuteri has previously been associated with histamine production
  • Casas et al. Validation of the Probiotic Concept: Lactobacillus reuteri Confers Broad - spectrum Protection against Disease in Humans and Animals.: 2000, ISSN 0891-060X
  • two strains of L. reuteri in the hands of Straub et.al. Z Lebensm Unters Forsch (1995) 201: 79-82) has been shown to decarboxylate L-histidine to form histamine and the authors warn against using such strains for the fermentation of food and as probiotics.
  • HdcB a novel enzyme catalyzing maturation of pyruvoyl - dependent histidine decarboxylase; Molecular Microbiology (2011) 79(4), 861-871) referring to three types of genetic organization of histidine decarboxylation loci among histamine-producing Gram-positive bacteria. The largest group is found in the lactic acid bacteria including L. hilgardii 0006. L. buchneri B301. L. reuteri F275 and T. halophilus. Lactobacillus hilgardii 0006 has been shown to produce histamine, in a study performed by Lucas et al.
  • Lucas et al. have performed a screening of a collection of wine lactic acid bacteria to identify the genes involved in the histamine-producing pathway of a gram-positive bacterium of wine.
  • a histamine-producing strain of Lactobacillus buchneri has been isolated from Swiss cheese that had been implicated in an outbreak of histamine poisoning (Summer et al. Isolation of histamine - producing Lactobacillus buchneri from Swiss cheese implicated in a food poisoning outbreak; Applied and Environmental Microbiology (1985), Vol. 50, Issue 4, p. 1094-1096).
  • mast cell also known as mastocyte and labrocyte
  • mastocyte and labrocyte is a resident cell of several types of tissues and contains many granules rich in histamine and heparin. Although best known for their role in allergy and anaphylaxis, mast cells play an important protective role as well, being for example intimately involved in wound healing and defense against pathogens.
  • Mast cells are present in most tissues characteristically surrounding blood vessels and nerves, and are especially prominent near the boundaries between the outside world and the internal milieu, such as the skin, mucosa of the lungs and digestive tract, as well as in the mouth, conjunctiva and nose.
  • mast cells In allergic reactions, mast cells remain inactive until an allergen binds to IgE already in association with the cell. Other membrane activation events can either prime mast cells for subsequent degranulation or can act in synergy with FceR1 signal transduction. Histamine from such granulation dilates post capillary venules, activates the endothelium, and increases blood vessel permeability. Histamine release leads to local edema (swelling), warmth, redness, and the attraction of other inflammatory cells to the site of release. It also irritates nerve endings (leading to itching or pain). Cutaneous signs of histamine release are the “flare and wheal”-reaction.
  • mast cells may have a fairly fundamental role in innate immunity—they are capable of elaborating a vast array of important cytokines and other inflammatory mediators such as TNF ⁇ , they express multiple “pattern recognition receptors” thought to be involved in recognizing broad classes of pathogens, and mice without mast cells seem to be much more susceptible to a variety of infections.
  • the relationship between a host and its microbes is complex, as it also is for certain of a mammalian's own cell types, such as mast cells.
  • This host-microbe relationship has been developing over many years of co-evolution; this includes the microbes production of various metabolites that can benefit the host nutritionally, immunologically etc., act as whole or part antagonists, agonist, de-sensitization etc. of specific receptors or other processes.
  • lactobacilli including certain strains of Lactobacillus reuteri locally produces histamine under specific growth conditions. Such locally produced histamine, contrary to earlier belief, will benefit the host in multiple ways including reduction of inflammation, reducing certain cancers etc.
  • Another object of the invention is to provide products containing said strains together with a specific carbon source, in order to have a synbiotic product.
  • Administering the lactic acid bacterial strains, selected accordingly to the present method, to a mammal will result in locally produced histamine that could be beneficial for several reasons.
  • a primary object of the present invention is to provide a method of selecting lactic acid bacterial strains assuring good anti-inflammatory effect.
  • These strains could preferably be used for treatment and/or prophylaxis of inflammatory conditions, since the histidine operon and the production of histamine is essential for the anti-inflammatory capacity of certain lactic acid bacterium.
  • the strains may be used for treatment and/or prophylaxis of inflammatory processes in the GI tract, GU tract, oral cavity, in the lungs and airways, on the skin etc, of the mammalian body, including but not limited to colitis. IBD, IBS, diverticulosis, gingivitis, vaginitis etc.
  • histamine via the H2 receptor can reduce the gene expression of TN F-alpha.
  • mast cells are capable of elaborating a vast array of important cytokines and other inflammatory mediators such as TNF-alpha.
  • histidine operon, and local histamine production of such selected strains could be beneficial to the host and is for example a key factor in selected L. reuteri strains' anti-inflammatory capacity. Neither is it previously known to use L. reuteri selected according to the present method in treatments requiring histamine.
  • Preferred products and strains for the treatment and/or prophylaxis of inflammatory conditions are Lactobacillus reuteri. in particular Lactobacillus reuteri 6475 (ATCC PTA 6475). In other embodiments of the invention the strain used is not Lactobacillus reuteri 6475 (ATCC PTA 6475).
  • the therapeutic uses of the strains, products and compositions of the invention as defined herein generally result in the reduction or alleviation of the relevant disease or symptoms of disease, for example can result in a significant reduction in inflammation levels in the mammal.
  • locally produced histamine may be activating H 2 receptors on intestinal epithelial cells as well as immune cells to suppress host mucosal immunity, e.g. via the inhibition of pro-inflammatory cytokines.
  • the present invention allows for the conversion of a dietary component (histidine) to histamine at the site of activity and local modulation of the host immune response (e.g. in the gut). It can be seen that such local production of histamine provided by the present invention can provide real advantages over for example oral ingestion or other forms of administration of histamine, especially given the fact that such oral ingestion would not be advocated due to the recognized toxic effects and health risks.
  • the therapeutic uses of the strains, products and compositions of the invention can result in significant reduction in ulceration and intestinal damage (e.g. colon damage) measured for example by a standard method such as a Wallace score, a significant reduction in weight loss or a significant reduction in inflammation of the intestine, e.g. the colon.
  • ulceration and intestinal damage e.g. colon damage
  • Such reduction or alleviation of disease or symptoms thereof can be measured by any appropriate assay.
  • the reduction or alleviation of disease or symptoms is statistically significant, preferably with a probability value of ⁇ 0.05.
  • Such reduction or alleviation of disease or symptoms is generally determined compared to an appropriate control individual or population, for example a healthy mammal or an untreated or placebo treated mammal.
  • An appropriate mode of administration and formulation of the strains, etc. is chosen depending on the site where local production of histamine is desired.
  • a preferred mode of administration is oral, however, equally for some treatments topical or some other form of local administration to the skin, rectum, vagina or gums will be appropriate, or intravenous or intramuscular injection will be appropriate.
  • Dietary mixtures comprising histidine may be used to ensure the presence of histidine and thereby increase the efficacy of the bacteria. Histidine may be administered alone or together with the bacteria.
  • histidine rich food including but not limited to soy protein, cheese, egg, chicken and pork.
  • the histidine operon in bacteria has been shown to improve the growth capacity under conditions of low pH or energy source limitation (Calles-Enriquez et al.) but the histidine operon has not been associated with anti-inflammatory features of certain L. reuteri strains.
  • Another object of the present invention is to use the selected strains in order to reduce food allergy, other allergic reactions or other autoimmune diseases.
  • Systemic increases in histamine are as previously known a consequence of allergy by the granulation of mast cells.
  • the locally produced histamine will lead to a desensitization effect that will reduce allergy or other autoimmune diseases.
  • Patients treated with histamine blockers have an increased risk of getting traveler's diarrhea: this increased risk could be neutralized by administrating the lactic acid bacteria selected according to the present method.
  • Yet another object of the present invention is to use the selected strains in treatment of MS. Histamine has been proposed to be an important molecule for developing new treatments for MS and the strains selected accordingly to the present invention will provide the patient with histamine.
  • Yet another object of the present invention is to use histamine-producing bacteria as a skin-anti-inflammatory treatment using available histidine and histidine analogs in the skin. Since histidine is a substrate for urocanic acid which the skin produces by UV irradiation and the urocanic acid has anti-inflammatory properties on the skin.
  • Another object of the invention is to inhibit TNF alpha.
  • Another object of the invention is to reduce inflammation, locally or systemically.
  • Another object of the invention is to enhance synaptic vesicle exocytosis by inhibiting ERK1/2.
  • Another object of the invention is to promote human embryonic stem cell self-renewal by inhibiting ERK1/2.
  • Another object of the invention is to induce macrophage ABCA1 expression and cholesterol efflux by inhibiting ERK1/2.
  • Another object of the invention is to reduce cardiac hypertrophy and heart failure by inhibiting ERK1/2.
  • Another object of the invention is to reduce the proliferation of certain cancers including leukemia (for example AML) or malignant melanoma.
  • cancers including leukemia (for example AML) or malignant melanoma.
  • Another object of the invention is to use selected strains to produce histamine under certain conditions as a neurotransmitter for example in GU tract interactions with the CNS, and also neural signaling in local pain.
  • This role as a neurotransmitter can be extended to effects on intestinal motility (to treat constipation or diarrhea) and to pain signaling in the gut.
  • Another object of the invention is to use selected strains for influencing the gut-brain axis as the selected lactic acid bacteria (LAB) will produce histamine and affect visceral pain perception and signaling in the enteric nervous system.
  • LAB lactic acid bacteria
  • histidine including histidine analogs or histidine contained in products or compositions.
  • a protective capsule for release of the content in the lower GI tract to ensure survival of both the histidine and the bacteria at the site of action.
  • a yet further aspect of the invention provides a product for the therapeutic uses as defined elsewhere herein, wherein said use further comprises the administration of at least one further therapeutic or nutritional agent.
  • the further therapeutic agent can be any further agent which is useful in the treatment of the disease in question, for example is a further anti-inflammatory agent or an immunotherapeutic agent such as for example a chemokine or cytokine (e.g. IL-2).
  • said further agent comprises histidine or a histidine analog, an appropriate carbon source which supports the production of histamine by the bacterial strain, or a combination thereof.
  • Said further agents can be administered together with the strains of the invention or can be administered separately.
  • said further agents can be administered at the same time as the strains of the invention or at different time points. Suitable administration regimes and timings can readily be determined by the skilled person depending on the further agent in question.
  • the present invention also provides a composition comprising:
  • said histidine or histidine analog is in the form of a histidine or histidine analogy contained in a foodstuff or food supplement, or said carbon source comprises glucose.
  • said carbon source will not comprise sucrose, or at least will only comprise sucrose at such a level which will not significantly compromise histamine production by the strain.
  • sources of other amino acids can also be provided.
  • the strains as defined in part (i) can be combined with a further component which is useful in the treatment of the disease in question, i.e. a further therapeutic agent, for example a further anti-inflammatory agent or an immunotherapeutic agent such as for example a chemokine or cytokine (e.g. IL-2).
  • a further therapeutic agent for example a further anti-inflammatory agent or an immunotherapeutic agent such as for example a chemokine or cytokine (e.g. IL-2).
  • Lactobacillus reuteri is a heterofermentative lactic acid bacterial species that naturally inhabits the gut of humans and animals. Specific probiotic L. reuteri strains potently suppress human TNF ⁇ production while other probiotic L. reuteri strains enhance human TNF ⁇ production.
  • L. reuteri strain 6475 The invention herein is made possible by mechanistic studies of probiotic L. reuteri strain 6475 and other strains which have demonstrated their effect upon activated human IS myeloid cells.
  • L. reuteri metabolites were isolated using HILIC-HPLC, and histamine was identified by NMR spectroscopy and mass spectrometry. Quantification of histamine by triple quadrupole MS revealed that L. reuteri strain 6475 produces relatively high concentrations of histamine when grown in a glucose-based minimal media. Previous transcriptomics studies had suggested that two genes in the L. reuteri histidine operon may play a role in TNF inhibition by strain 6475.
  • HdcA histidine/histamine antiporter
  • HdcB histidine/histamine antiporter
  • Histamine is better known for its pro-inflammatory effects in allergy and anaphylaxis, but several studies have demonstrated anti-inflammatory functions of histamine. In vitro studies have shown that histamine can inhibit production of pro-inflammatory cytokines. IL-1, IL-12, and TNF from LPS-stimulated human monocytes and macrophages and this effect is reversed by H 2 receptor antagonists. Additionally, histamine can stimulate production of the anti-inflammatory cytokine, IL-10, via the H 2 receptor. Signalling through the H 2 receptor results in decreased expression of the CD14 receptor, a receptor involved in LPS recognition, on the surface of human monocytes. The TNF receptor is also affected by histamine.
  • H 1 receptor Signalling through the H 1 receptor induces shedding of both the TNFR1 and the TNFR2.
  • a specific H 2 receptor agonist Treatment with dimaprit, a specific H 2 receptor agonist, reduced plasma TNF levels in mouse models of endotoxin shock (LPS challenge) and hepatitis (LPS plus galactosamine challenge). Histamine was protective in an LPS-induced liver injury mouse model, and these effects were attenuated in an H 2 receptor knock-out mouse. In the gut, histamine may help protect against bacterial infection. Signalling through the H 2 receptor in Peyer's patches helps prevent infection by Yersinia enterocolitica.
  • the effect of histamine can be determined by the expression of histamine receptors on the target cell. In T-cells, the effect of histamine is dependent on which histamine receptor is activated.
  • histamine By signalling through the H 1 receptor, histamine enhances T H 1-type responses but suppresses both T H 1 and T H 2 responses via the H 2 receptor.
  • a study was performed looking at histamine receptor expression in the human gastrointestinal tract. Many of the cell types examined expressed multiple histamine receptors. For example, immune cells, including macrophages, highly expressed the H 1 and H 2 receptor and demonstrated low expression of the H 4 receptor. Increased mast cells and histamine have been implicated in the visceral hypersensitivity associated with IBS. The increased number and activity of mast cells near colonic mucosal innervation may result in heightened abdominal pain perception.
  • ketotifen a mast cell stabilizing agent
  • IBS intracellular lung cancer
  • histamine as an anti-inflammatory compound produced by selected probiotic Lactobacillus strains will help determine therapeutic applications for such strains.
  • Mechanistic studies linked the activation of the H 2 receptor on THP-1 cells with histamine and the suppression of ERK activation.
  • ERK activation is involved in many cellular functions besides TNF production.
  • ERK activation is involved in proliferation, tumorigenesis, differentiation, and cell survival.
  • the results suggest a role for selected strains such as L. reuteri 6475 in protecting against cancer by suppressing inflammation, cell proliferation, and apoptosis via inhibition of ERK activation.
  • histamine is a known neurotransmitter.
  • Histidine may be administered together with the bacteria or alone, diets rich in histidine may increase the histamine production as well.
  • the present invention provides certain strains of lactic acid bacteria and a method of selecting such strains and products comprising such strains.
  • the bacteria are selected using a screen for the histidine operon; surprisingly the presence of an active histidine operon has been shown to be essential for various beneficial effects such as the immunomodulatory properties of lactic acid bacterial strains.
  • CFAS cyclopropane fatty acid synthase
  • THFS1 tetrahydrofolate synthase 1
  • THFS2 tetrahydrofolate synthase 2.
  • Lactobacillus reuteri ATCC PTA 6475 is an isolate from Finnish mother's milk (BioGaia AB, Raleigh, N.C.). This strains is available to the public at the American Type Culture Collection (Rockville, Md.) having been deposited there on Dec. 24, 2004. This deposit meets the requirements of the Budapest Treaty.
  • L. reuteri strains ATCC PTA 6475, ATCC 6475 JP577, ATCC 6475 1229, ATCC 6475 1230, and ATCC 6475 1231 will be referred to as strains 6475, JP577, 1229, 1230, and 1231, respectively, throughout this disclosure.
  • L. reuteri strains were cultured under anaerobic conditions for 16-18 h in deMan, Rogosa, Sharpe media (Difco, Franklin Lakes, N.J.), and inoculated into 2 L of a semi-defined media, LDMIII (OD 600 adjusted to 0.1), which has been described previously.
  • the carbon source was either glucose. LDMIIIG, or sucrose, LDMIIIS.
  • the culture was grown for 24 h at 37° C. in an anaerobic workstation (MACS MG-500, Microbiology International, Frederick, Md.) supplied with a mixture of 10% CO), 10% H 2 , and 80% N 2 . Samples were taken at different times to follow the growth by measuring OD 600 . At stationary phase (24 h), the cells were pelleted from the 2 L culture (4000 ⁇ g, 10 min). Cell pellets and bacteria cell-free supernatants were stored at ⁇ 20° C. before further processing for HPLC separation and testing in a TNF inhibition bioassay.
  • MCS MG-500 Microbiology International, Frederick, Md.
  • THP-1 cells human monocytoid cell line, ATCC, Manassas, Va. maintained in RPMI (ATCC) and heat-inactivated fetal bovine serum (Invitrogen, Carlsbad, Calif.) at 37° C., 5% CO 2 .
  • MEK1/2, phospho-MEK1/2, ERK1/2, and phospho-ERK1/2 antibodies and MEK inhibitor U0126 were received from Cell Signaling Technology (Danvers, Mass.), and the ⁇ -Actin antibody was received from Abeam (Cambridge. Mass.). All other reagents were received from Sigma (St. Louis, Mo.) unless otherwise stated.
  • Cell pellets (7 g) from strain 6475 grown in either LDMIIIG or LDMIIIS were washed with 30 mL ice cold 50% acetonitrile/0.1% trifluoroacetic acid (TFA). The cell suspension was centrifuged for 10 min, 4000 ⁇ g at 4° C. Supernatants were filtered through polyvinylidene fluoride (PVDF) membrane filters (0.45 ⁇ m pore size, Millipore, Bedford, Mass.), lyophilized, and resuspended in 10 mL 0.1% formic acid. The resuspended sample was size fractionated with Amicon Ultra-15 centrifugal filter units using ultracel-3 membrane (Millipore, Bedford, Mass.).
  • PVDF polyvinylidene fluoride
  • the filtrate (9 mL) was dried down to 1 mL with a speed vacuum, and 0.75 mL was used for HILIC-HPLC.
  • the sample was dissolved with 100% acetonitrile before running on a PolyLC Hydroxyethyl column with a gradient of 100-0% acetonitrile, 0.1% formic acid.
  • the sample was run for 25 min and 25 fractions (A1-C1) were collected at 10 mL/min/tube. Three milliliters from each fraction was lyophilized, resuspended in 3 mL 0.1% acetic acid, and lyophilized again for testing in a TNF inhibition bioassay.
  • Bacterial supernatants (10 mL) from a 24 h LDMIII culture were filter-sterilized using PVDF membrane filters (0.22 ⁇ m pore size, Millipore) and size fractionated as described above.
  • THP-1 cells (approximately 5 ⁇ 10 4 cells) were stimulated to produce TNF by the addition of 100 ng/mL Pam 3 Cys-SKKKK ⁇ 3 HCl (EMC Microcollections, Tuebingen, Germany) as previously described.
  • Inhibitors H 2 receptor antagonists, ranitidine and cimetidine (10 ⁇ 4 -10 ⁇ 6 M), H 1 receptor antagonist, indomethacin (10 ⁇ 5 -10 ⁇ 6 M), MEK inhibitor, U0126 (10 ⁇ M), and PKA inhibitor, H89 (N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide dihydrochloride) (10 ⁇ 5 M)—were added to the THP-1 cells followed by L. reuteri conditioned media or cell pellet wash fractions (5% v/v), histamine (10 ⁇ 5 M), or dibutyryl cAMP (10 ⁇ 3 -10 ⁇ 7 M). Plates were incubated at 37° C.
  • THP-1 cells were pelleted (3000 ⁇ g, 5 min, 4° C.), and quantitative ELISAs were used to determine TNF quantities in THP-1 cell supernatants according to the manufacturer's instructions (R&D Systems, Minneapolis, Minn.).
  • Bacterial cell pellets were washed to remove compounds loosely associated with the cell surface. Components of the cell pellet wash were separated based on hydrophobicity using HILIC-HPLC, and the resulting 25 fractions were tested for retention of the TNF-inhibitory compound.
  • L. reuteri 6475 grown in a minimal media with glucose as the sole carbon source produces TNF-inhibitory factors that were retained in 3 separate HILIC-HPLC fractions (B3, B5 and B6, data not shown).
  • L. reuteri 6475 grown with sucrose as the sole carbon sources loses the TNF-inhibitory phenotype and served as the negative control. None of the HILIC-HPLC fractions from the 6475 sucrose cell pellet wash demonstrated significant TNF inhibition (data not shown).
  • TNF-inhibitory HILIC-HPLC fraction B3 was analyzed by 1 H NMR and compared to the neighboring non-TNF inhibitory fraction B4. A unique series of peaks with a chemical shift between 7.0-7.5 ppm, which is characteristic of an aromatic compound, was observed in fraction B3 but not fraction B4 (data not shown).
  • This aromatic compound cluster was further analyzed with heteronuclear single quantum coherence (HSQC) 2-dimensional (2D) NMR in order to identify its components.
  • HSQC heteronuclear single quantum coherence
  • 2D 2-dimensional 2-dimensional
  • Histamine is a biogenic amine that is produced from histidine via the histidine decarboxylase by some fermentative bacteria including lactobacilli. Histamine was also identified in fraction B3 using electrospray time-of-flight mass spectrometry (ESI TOF MS). Histamine is not covalently modified based on its fragmentation pattern in MS/MS analysis. Analysis of the corresponding B3 fraction of L. reuteri 6475 grown in a sucrose media with ESI TOF MS did not reveal any histamine. L reuteri 6475 grown in a glucose media produces histamine, which is present in a TNF-inhibitory HILIC-HPLC fraction.
  • ESI TOF MS electrospray time-of-flight mass spectrometry
  • Triple quadrupole mass spectrometry is an established, highly sensitive method of quantifying small molecular compounds. Histamine was quantified in a select range of HILIC-HPLC fractions from L. reuteri 6475 glucose (B2-B7) and sucrose (B2-B9) as well as the bacterial culture supernatant. High levels of histamine (>300 ng/mL) correlated with the ability of the HILIC-HPLC fractions to inhibit TNF ( FIG. 1 ). Low levels of histamine were measured in most fractions examined, including those from 6475 sucrose ( FIG. 1 ). The ability of histamine to inhibit TNF production appears to be concentration dependent.
  • H 1 receptor-specific antagonist indomethacin
  • Histamine blocks TNF production from TLR2-activated THP-1 cells via signaling through the H 2 receptor.
  • L. reuteri 6475 conditioned media containing histamine significantly inhibits TNF compared to the media control, and this effect is partially blocked by H 2 receptor but not H 1 receptor antagonists ( FIG. 2A ).
  • a partial block in TNF suppression indicates that histamine present in 6475 conditioned media is signaling via the H 2 receptor but that other TNF-inhibitory factors that act through alternative mechanisms may also be present in the conditioned media.
  • the cell pellet wash containing histamine of strain 6475 also suppresses TNF production ( FIG.
  • H 2 receptor antagonists As seen with 6475 conditioned media, H 2 receptor antagonists partially block the effect of the 6475 cell pellet wash ( FIG. 2B ), suggesting multiple immunomodulins are present in the unfractionated cell pellet wash. The effects of TNF-inhibitory fraction B3, which contains high amounts of purified histamine, were completely blocked by the addition of H 2 receptor antagonists ( FIG. 2B ).
  • the levels of produced histamine are determined by triple quadrupole mass spectrometry.
  • the strains with highest production of histamine are selected. Histamine production can also be evaluated and quantified by ELISAs or immunoassays.
  • HdcA histidine decarboxylase pyruvoyl type A
  • HdcB histidine decarboxylase pyruvoyl type A
  • Previous transcriptomics studies suggested that the histidine/histamine antiporter gene and HdcA were potentially important for the TNF-inhibitory phenotype of strain 6475.
  • All 3 genes are strongly down-regulated in 6475 grown in a sucrose media (loses TNF inhibition) compared to 6475 grown in a glucose media (Table 2).
  • at least 1 gene in the operon is down-regulated in 2 mutants that lose TNF-inhibition (Table 2).
  • mutants were investigated previously, and even though the gene products didn't have TNF-inhibitory properties, the genes appeared to be important for the anti-inflammatory phenotype of 6475. In contrast, 2 mutants that do not lose TNF inhibition demonstrated no down-regulation of any of the genes in the histidine operon (Table 2). Mutations were made in each of these 3 genes by inserting a premature stop codon into the gene sequence (strains 1229, 1230 and 1231). A mutation was also made in an unrelated gene, the rifampicin resistance gene, to-serve as a negative control (strain JP577).
  • ERK1/2 Activation is Essential for TNF Production by TLR2-Stimulated Monocytoid Cells
  • ERK1/2 is activated by phosphorylation from upstream MAPKK, MEK1/2, and has been shown previously to be important for TNF production.
  • THP-1 cells were treated with a specific MEK1/2 inhibitor.
  • U0126 for varying amounts of time prior to stimulation with a TLR2 agonist to suppress ERK1 /2 activation. Treatment with U0126 for 30 min was sufficient to prevent TNF production (data not shown).
  • ERK1/2 is activated following TLR2 stimulation and important for stimulating TNF production in our model system.
  • the H 2 receptor is a G protein linked receptor that can activate adenylate cyclase and increase intracellular cAMP.
  • TNF can be inhibited at the level of transcription by cAMP and cAMP analogs.
  • THP-1 cells were stimulated with a TLR2 agonist in the presence of a medium control, 6475 supernatant or histamine with or without an H 2 receptor antagonist and intracellular levels of cAMP were measured.
  • L. reuteri 6475 supernatant caused a small but significant increase in cAMP (data not shown).
  • Treatment with an H 2 antagonist blocked this effect.
  • An increase in cAMP was also seen with histamine treatment, and the effect was blocked by an H 2 antagonist (data not shown).
  • dcAMP dibutyryl cAMP
  • PKA Protein Kinase A
  • Increased concentration of cAMP can activate PKA and subsequently inhibit the downstream ERK MAPK signaling pathway.
  • activated THP-1 cells were treated with a specific PKA inhibitor, H89, in the presence of 6475 supernatant, fraction B3, histamine or varying concentrations of dcAMP.
  • H89 partially blocked TNF inhibition by all of these normally TNF-inhibitory compounds (data not shown).
  • PKA activity is important for suppression of TNF by histamine and dcAMP.
  • TLR2-stimulated THP-1 cells with a synthetic analog of cAMP, dcAMP is sufficient to inhibit TNF production.
  • Inhibition of PKA activity partially blocks TNF suppression by previously TNF-inhibitory compounds 6475 conditioned media, fraction B3, histamine, and dcAMP.
  • Treatment of activated THP-1 cells with 6475 conditioned media, histamine, or U0126 suppressed activation of MEK1/2, an effect that was blocked in the presence of ranitidine.
  • Treatment of activated THP-1 cells with 6475 conditioned media, histamine, or U0126 suppressed activation or ERK1/2, an effect that was blocked in the presence of ranitidine.
  • THP-1 cells were lysed in ice-cold lysis buffer consisting of 50 mM Tris, pH 7.4, 250 mM NaCl, 5 mM EDTA, 50 mM NaF, 1 mM Na 3 VO 4 , 1% v/v Nonidet P40, 0.2% v/v NaN 3 , and protease and phosphatase inhibitors. Lysates were incubated on ice for 30 min, vortexed every 10 min, and cleared by centrifugation at 13,000 ⁇ g for 10 min at 4° C. Protein concentrations were measured using the Quant-iTTM Protein Assay kit (Invitrogen) and a Qubit fluorometer according to the manufacturer's instructions. Equal amounts of proteins were loaded onto electrophoresis gels.
  • ERK1/2 activation was performed using specific phospho-ERK1/2 antibodies.
  • Cell extracts were loaded on a 10% SDS-polyacrylamide gel and transferred to polyvinylidene difluoride membranes (Bio-Rad, Hercules, Calif.). Membranes were blocked overnight at 4° C. in blocking buffer (Li-Cor Biosciences, Lincoln, Neb.). After several washes, membranes were probed with ERK1/2, phospho-ERK1/2 or ⁇ -Actin specific antibodies diluted in blocking buffer (Li-Cor) for 1 h at room temperature.
  • blocking buffer Li-Cor
  • membranes were incubated with the appropriate horseradish peroxidase-conjugated secondary antibody for 1 h at room temperature, and blots were then developed using a chemiluminescent detection. Analysis of MEK1/2 activation was performed as described above except primary antibody incubation was overnight at 4° C.
  • Mutants were generated using RecT-mediated oligonucleotide recombineering.
  • L. reuteri expressing RecT (strain RPRB0000) was used to construct mutations in rpoB (locus tag HMPREF0536 — 0828 (ZP — 03961568)) and the target genes located in the histidine decarboxylase gene cluster HMPREF0536 — 1229 (ZP — 03961969), HMPREF0536 — 1230 (ZP — 03961970) and HMPREF0536 — 1231 (ZP — 03961971) to yield strains RPRB3002, RPRB3004, RPRB3005 and RPRB3006, respectively. Mutations were verified by PCR, and the integrity was confirmed by sequence analysis.
  • L. reuteri ATCC PTA 6475 and histidine decarboxylase gene (hdcA) mutant were cultured in deMan, Rogosa, Sharpe (Difco, Franklin Lakes, N.J.) at 37° C. in an anaerobic workstation (MACS MG-500, Microbiology International, Frederick, Md.) supplied with a mixture of 10% CO 2 , 10% H 2 , and 80% N 2 .
  • mice reuteri 6475 or hdcA mutant or MRS (0.2 ml each time) every day for seven days by orogastric gavage after 10 days of acclimatization. All mouse experiments were performed according to an approved protocol (AN-4199; animal facility of Baylor College of Medicine). Mice (45 days old) were received from Harlan Laboratories (Houston, Tex.) and maintained under specific pathogen-free conditions in filter-top cages (5 mice per cage) and had free access to distilled water and Harlan rodent chow 2918. Mice were divided into different groups randomly.
  • Colitis was induced six hours before the sixth gavage. Mice were anesthetized by constant isoflurane inhalation. A 5% TNBS solution in water (Sigma-Aldrich, USA) was diluted with equal volume of absolute ethanol and administered at dose of 100 mg/kg body weight intrarectally. Mice were kept head down in a vertical position for 2 minutes after enema to ensure complete retention of enema in the colon. Procedure control mice received 50% ethanol in PBS. Mice were weighed prior to TNBS administration and two days after TNBS administration. Then mice were sacrificed. Colonic inflammation and damage was determined by weight loss, macroscopic score and serum SAA concentration.
  • SAA Serum Amyloid Protein A
  • SAA Serum amyloid A
  • L. reuteri 6475 The anti-inflammatory effects of L. reuteri 6475 were tested in a TNBS-induced mouse model of acute colitis. Mice that received L. reuteri 6475 by orogastric gavage every day were compared with mice that received the media control. Mice challenged with PBS instead of TNBS were also studied as colitis negative controls.
  • FIGS. 4-6 represent data from two independent experiments.
  • Orogastric gavage with L. reuteri 6475 significantly reduced weight loss, macroscopic inflammation in the colon and serum SAA concentrations, showing that L. reuteri 6475 significantly attenuated colitis.
  • FIGS. 7 and 8 represent data from two independent experiments. Again, orogastric gavage with L. reuteri 6475 significantly reduced weight loss and colon damage compared with media control group. Mice received hdcA mutant significantly increased weight loss and macroscopic inflammation in the colon compared with mice that received wild type bacteria, showing that hdcA mutant yields diminished ability to attenuate colitis.

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US13/552,686 US20130022586A1 (en) 2011-07-21 2012-07-19 Production and use of bacterial histamine
CN201810062784.9A CN109554435A (zh) 2011-07-21 2012-07-20 细菌组胺的产生和应用
CN201280035256.5A CN104160276B (zh) 2011-07-21 2012-07-20 细菌组胺的产生和应用
AU2012285657A AU2012285657B2 (en) 2011-07-21 2012-07-20 Production and use of bacterial histamine
KR1020147004227A KR20140047717A (ko) 2011-07-21 2012-07-20 박테리아성 히스타민의 산물 및 이의 용도
BR112014001221-0A BR112014001221B1 (pt) 2011-07-21 2012-07-20 Método e composição de histamina bacteriana
CA2842379A CA2842379C (en) 2011-07-21 2012-07-20 Production and use of bacterial histamine
RU2014106509A RU2628536C2 (ru) 2011-07-21 2012-07-20 Получение и применение бактериального гистамина
DK12738122.6T DK2734845T3 (en) 2011-07-21 2012-07-20 PRODUCTION AND USE OF BACTERIAL HISTAMINE
UAA201401697A UA115864C2 (uk) 2011-07-21 2012-07-20 Одержання і застосування бактеріального гістаміну
MX2014000844A MX358347B (es) 2011-07-21 2012-07-20 Produccion y uso de histamina bacteriana.
PL12738122T PL2734845T3 (pl) 2011-07-21 2012-07-20 Wytwarzanie i stosowanie histaminy bakteryjnej
TR2018/16432T TR201816432T4 (tr) 2011-07-21 2012-07-20 Bakteriyel histamin üretimi ve kullanımı.
JP2014520684A JP6211516B2 (ja) 2011-07-21 2012-07-20 細菌性ヒスタミンの産生及び使用
NZ619605A NZ619605B2 (en) 2011-07-21 2012-07-20 Production and use of bacterial histamine
PT12738122T PT2734845T (pt) 2011-07-21 2012-07-20 Produção e utilização de histamina bacteriana
ES12738122.6T ES2694567T3 (es) 2011-07-21 2012-07-20 Producción y uso de histamina bacteriana
SI201231427T SI2734845T1 (sl) 2011-07-21 2012-07-20 Proizvodnja in uporaba bakterijskega histamina
EP12738122.6A EP2734845B1 (en) 2011-07-21 2012-07-20 Production and use of bacterial histamine
LTEP12738122.6T LT2734845T (lt) 2011-07-21 2012-07-20 Bakterinio histamino gamyba ir panaudojimas
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CL2014000128A CL2014000128A1 (es) 2011-07-21 2014-01-17 Metodo para seleccionar una cepa de bacteria del acido lactico que comprende detectar bacterias por la presencia de un operon histidina activa y seleccionar una cepa que tenga un operon histidina activa y sea capaz de producir histamina; y producto que comprende celulas de dicha cepa.
HK15103998.9A HK1203615A1 (en) 2011-07-21 2015-04-24 Production and use of bacterial histamine
US15/289,666 US10004770B2 (en) 2011-07-21 2016-10-10 Production and use of bacterial histamine
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CN112168847A (zh) * 2020-09-30 2021-01-05 浙江大学 罗伊氏乳杆菌在制备治疗急性肝衰竭药物中的用途

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US10004770B2 (en) 2011-07-21 2018-06-26 Biogaia Ab Production and use of bacterial histamine
US10898529B2 (en) 2011-07-21 2021-01-26 Biogaia Ab Production and use of bacterial histamine
US20180273895A1 (en) * 2015-01-16 2018-09-27 Biogaia Ab Lactic acid bacteria and their use for the treatment of mastitis
WO2016153422A1 (en) * 2015-03-26 2016-09-29 Biogaia Ab Histamine-producing bacterial strains and their use in cancer
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US11135255B2 (en) * 2016-05-09 2021-10-05 Biogaia Ab Selection of bacterial strains useful in allergy treatment
WO2019115576A1 (en) * 2017-12-13 2019-06-20 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods of treating heart failure

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