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WO2016035043A1 - Composition probiotique - Google Patents

Composition probiotique Download PDF

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Publication number
WO2016035043A1
WO2016035043A1 PCT/IB2015/056754 IB2015056754W WO2016035043A1 WO 2016035043 A1 WO2016035043 A1 WO 2016035043A1 IB 2015056754 W IB2015056754 W IB 2015056754W WO 2016035043 A1 WO2016035043 A1 WO 2016035043A1
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WO
WIPO (PCT)
Prior art keywords
human
effective amount
infection
broad
probiotic composition
Prior art date
Application number
PCT/IB2015/056754
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English (en)
Inventor
Tiaan De Jager Heunis
Leon Milner Theodore Dicks
Kyle KLOPPER
Original Assignee
SMITH, Jerome Shelsley
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by SMITH, Jerome Shelsley filed Critical SMITH, Jerome Shelsley
Publication of WO2016035043A1 publication Critical patent/WO2016035043A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/745—Bifidobacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/747—Lactobacilli, e.g. L. acidophilus or L. brevis

Definitions

  • This invention relates to a probiotic composition.
  • Probiotic microorganisms favourably alter the intestinal microbiota balance, promote intestinal integrity and mobility, inhibit the growth of harmful bacteria and increase resistance to infection in humans.
  • Probiotics can be used for the treatment of acute conditions, such as gastroenteritis, which develops as a result of stress and infection.
  • probiotics can be included in the diet at any time to improve the body's microbial balance.
  • HIV human immunodeficiency virus
  • AIDS acquired immunodeficiency syndrome
  • the present invention seeks to provide a probiotic composition that can be safely administered to individuals with an HIV infection.
  • a broad-spectrum probiotic composition comprising one or more selected from the group of:
  • the broad-spectrum probiotic may only include a pharmaceutically effective amount of the strain Lactobacillus plantarum D4.
  • the broad-spectrum probiotic may be in the form of a tablet, a capsule, a liquid, a gel, in an edible form, or may be included into foodstuff.
  • the invention further provides a substance or composition for use in a method of treating and/or preventing a secondary infection in a human with an existing early to intermediate human immunodeficiency virus (HIV) infection, said substance or composition comprising the probiotic composition of the invention, and said method comprising administering a therapeutically effective amount of the substance or composition to the human.
  • HIV human immunodeficiency virus
  • the broad-spectrum probiotic composition may be suitable for administration to humans with acquired immunodeficiency syndrome (AIDS).
  • AIDS acquired immunodeficiency syndrome
  • the broad-spectrum probiotic composition may be used to reduce pathogenic bacteria or viruses causing the secondary infection in the human.
  • the secondary infection may be gastroenteritis.
  • the invention further provides for the use of the probiotic composition of the invention in the manufacture of a medicament for treating and/or preventing a secondary infection in a human with an existing early to intermediate human immunodeficiency virus (HIV) infection.
  • HIV human immunodeficiency virus
  • the broad-spectrum probiotic composition may be suitable for administration to humans with acquired immunodeficiency syndrome (AIDS).
  • AIDS acquired immunodeficiency syndrome
  • the broad-spectrum probiotic composition may be used to reduce pathogenic bacteria or viruses causing the secondary infection in the human in the human.
  • the secondary infection may be gastroenteritis.
  • a method of inhibiting the growth of bacterial species causing a secondary infection in a human with an existing early to intermediate human immunodeficiency virus (HIV) infection comprising the step of exposing the bacterial species to an effective amount of the broad-spectrum probiotic composition as herein described.
  • HIV human immunodeficiency virus
  • a method of treating and/or preventing a secondary infection in a human with an existing early to intermediate human immunodeficiency virus (HIV) infection including the step of administering a therapeutically effective amount of the broad-spectrum probiotic composition in accordance with the invention.
  • HIV human immunodeficiency virus
  • the human may have acquired immunodeficiency syndrome (AIDS).
  • AIDS immunodeficiency syndrome
  • the broad-spectrum probiotic composition may be used to reduce pathogenic bacteria or viruses causing the secondary infection in the human in the human.
  • the probiotic composition may be used to treat various forms of gastroenteritis.
  • a method of treating and/or preventing an infection in a human including the step of administering a therapeutically effective amount of the broad-spectrum probiotic composition in accordance with the invention.
  • Figure 1 is a table showing the antibiotics used to compile an antibiogram.
  • Figure 2 is a table showing the antibiotic sensitivity spectrum of L. plantarum D4, compared to reference strains L. plantarum 423 and L. reuteri DSM 17938.
  • Figure 3 is a photograph of the growth of acid-producing colonies on modified MRS agar plates supplemented with 1 % w/v bile, 0.5% w/v CaCO3 and 0.001 % w/v cyclohexamide.
  • Figure 4 is a photograph of the haemolytic activity of L. plantarum D4, compared to reference strains W. confusa B10, L. plantarum 423 and L. reuteri DSM 17938.
  • L. plantarum 423 and Lactobacillus reuteri DSM 17938, used as reference strains, are both a-haemolytic (A and B, respectively).
  • L. plantarum D4 is a-haemolytic (C)
  • W. confusa B10 a reference strain
  • is ⁇ -haemolytic with clear halo's visible around the colonies (D).
  • Figure 5 is a graphic representation of the auto aggregation of L. plantarum D4 (red line); compared to reference strains L. plantarum 423 (blue line) and L. reuteri DSM 17938 (green line).
  • Figure 6 is a table showing the effect of pH on the viability of L. plantarum D4 compared to a reference strain L. reuteri DSM 17938.
  • Figure 7 is a graphic representation of the tolerance to simulated gastric juice, expressed as percentage survival of L. plantarum D4, L. plantarum 423 and L. reuteri DSM 17938; L. plantarum 423 and Lactobacillus reuteri DSM 17938 were used as reference strains.
  • Figure 8 is a graphic representation of the response of L plantarum D4 and reference strains to bile stress.
  • L plantarum 423 and Lactobacillus reuteri DSM 17938 were used as reference strains.
  • Figure 9 is a graphic representation of the adhesion of L plantarum D4, L plantarum 423 and L reuteri DSM 17938 to mucus (red bars) and BSA (blue bars).
  • L. plantarum 423 and Lactobacillus reuteri DSM 17938 were used as reference strains.
  • Figure 10 is a photograph of antimicrobial activity of L plantarum D4 against Listeria monocytogenes EGDe.
  • the invention describes use of one or more of the strains of Lactobacillus paracasei HFI-K1 , Lactobacillus reuteri C4, Lactobacillus reuteri C5, Lactobacillus plantarum D4, Bifidobacterium longum HFI- ⁇ , Bifidobacterium longum HFI-P3, Bifidobacterium longum HFI- ⁇ , Lactobacillus casei HFI-y2 and Lactobacillus rhamnosus HFI-k2, in the manufacture of a broad-spectrum probiotic composition.
  • the broad-spectrum probiotic composition can be used to treat and/or prevent a secondary infection in a human with an existing early to intermediate human immunodeficiency virus (HIV) infection.
  • HIV human immunodeficiency virus
  • strains Lactobacillus paracasei HFI-K1 , Lactobacillus reuteri C4, Lactobacillus reuteri C5, Lactobacillus plantarum D4, Bifidobacterium longum HFI- ⁇ , Bifidobacterium longum HFI-P3, Bifidobacterium longum HFI- ⁇ , Lactobacillus casei HFI-y2 and Lactobacillus rhamnosus HFI-k2 were all isolated from the faeces of healthy humans.
  • Lactobacillus plantarum D4 was screened for bile resistance, pH sensitivity (HCI), antibiotic resistance, mucus binding, antimicrobial peptide production, and hydrophobicity.
  • a strain should preferably have the properties of competitive exclusion, production of antimicrobial peptides, and stimulation of mucosal immunity to exert probiotic properties in humans with human immunodeficiency virus (HIV) infection.
  • HIV human immunodeficiency virus
  • Lactic acid bacteria were isolated from faecal samples collected from healthy individuals and plated onto modified De Man Rogosa and Sharpe (MRS) agar containing 1 .0% (w/v) bile, 0.5% (w/v) calcium carbonate and 0.001 % (w/v) cyclohexamide to prevent yeast growth.
  • the plates were incubated aerobically at 37°C for 24-48 h.
  • a duplicate set of plates was incubated under the same conditions in an anaerobic chamber (Annaero-pack, Davies Diagnostics). Colonies were selected based on differences in morphology and size of the surrounding halos, and then streaked to purity.
  • Bile sensitivity was tested by streaking the strains onto modified MRS agar, supplemented with 2% (w/v), 1 % (w/v) and 0.3% (w/v) ox bile, respectively. Plates were incubated at 37°C for 48 h and changes in growth recorded.
  • Bile tolerance was tested by culturing the strains in MRS broth that contained either 1 .0% ,0.3% or 0% (w/v) ox bile. Incubation was at 37°C for 24 h and samples were taken at regular intervals.
  • the PCR (DNA amplification) conditions were: Initial denaturing at 94°C for 5 min, followed by 25 cycles of denaturing (94°C for 1 min), annealing (50°C for 1 min) and elongation (72°C for 1 min), with a final elongation step at 72°C for 7 min.
  • recombinase A gene was amplified using primers AmpF (5' -G C C CTAAAAAARATYG AAAAG AAHTTYG GTAAAG G-3' ) and AmpR (5'- AATGGTGGCGCYACYTTGTTTTTHACAACTTT-3').
  • the 16S rDNA and recA amplicons were purified, using the QIAquick PCR purification kit (Qiagen, Hilden, Germany).
  • the purified PCR amplicons were cloned into the pGEM-T Easy vector (Promega, Madison, Wl, USA) and transformed into chemically competent Escherichia coli DH5a. Plasmids were isolated using the PureYield plasmid miniprep system (Promega, Madison, Wl, USA) and sequenced using the universal M13 forward and M13 reverse primer pair.
  • Haemolytic activity of the selected cultures was determined by streaking onto sheep blood (5%) agar, followed by incubation at 37°C for 24 to 48 h.
  • Figure 1 shows a table of the antibiotics used to compile an antibiogram.
  • Antibiotic sensitivity of the selected strains was determined with antibiotic disks listed in Figure 2 as described by Bauer et al. (Bauer A, Kirby W, Sherris JC, Turck M. 1966. Antibiotic susceptibility testing by a standardized single disk method. Am. J. Clin. Pathol. 45:493).
  • MMiiccrroobbiiaall aaddhheessiioonn ttoo ssoollvveennttss ((MMAATTSS)) wwaass aasssseesssseedd aaccccoorrddiinngg ttoo RRoosseennbbeerrgg eett aall.. ((RRoosseennbbeerrgg MM,, GGuuttnniicckk DD,, RRoosseennbbeerrgg EE.. 11998800..
  • Simulated gastric juice was prepared by suspending pepsin (2000 mg/L, Sigma-Aldrich, Inc. St. Louis, MO, USA) into 0.5% (w/v) saline. The pH was adjusted to 3.0. Strains were grown for 24 h in MRS broth, after which 15 ⁇ of the cell suspension was added to 1 .0 ml of the simulated gastric juice and 485 ⁇ 0.5% (w/v) saline. Incubation was at 37°C for 2 h. Samples were drawn after 30 min, 60 min and 120 min of inoculation and plated onto MRS agar. Percentage survival was expressed after calculating the difference in cell numbers before and after exposure to simulated gastric juice.
  • the strains were cultured for 18 h at 37°C, harvested (13,000 rpm, 10 min), washed twice with HH-buffer and resuspended in HH-buffer. Immobilised mucus in the wells were covered with 1 .0 ml of resuspended cells and incubated at 37°C for 1 h. The wells were then rinsed twice with 1 .0 ml HH-buffer to remove unbound bacteria. Mucus-bound bacteria were removed from the wells, serially diluted with HH-buffer and plated onto MRS ager to determine number of cells that adhered to the mucus.
  • Antimicrobial peptide production was determined by using the agar-well diffusion method. Strains were grown in 5 ml MRS broth for 24 h, the cells harvested (13,000 rpm, 10 min) and cell-free supernatants equilibrated to pH 6.5 to 7.5 with 1 M NaOH. The cell-free supernatants were heat-treated at 80°C for 10 min and antimicrobial activity accessed using soft agar plates (1 %, w/v, agar). Wells were punched into the soft agar and cell-free supernatant (50 ⁇ ) placed into each of the wells. The wells were incubated at optimal growth temperatures of the target organism. The proteinaceous nature of the antimicrobial substances was confirmed by treating the cell-free supernatant with 10mg/ml proteinase K and trypsin, respectively.
  • Reference strains used in comparative studies were Lactobacillus plantarum 423 and Lactobacillus reuteri DSM 17938. Unpaired t-tests, two tailed, were used for data obtained from hydrophobicity and mucus binding assays, and pH viability tests. Auto aggregation data and tolerance to simulated gastric juice were compared using analysis of variance (ANOVA). When a significant ANOVA test was obtained, Fisher's least significant difference (LSD) multiple comparison tests were conducted to ascertain which means differed significantly. IBM SPSS 22.0 software was used for all determinations and a p-value of ⁇ 0.05 was considered significant.
  • ANOVA analysis of variance
  • Figure 3 shows modified MRS agar plates. The growth of acid-producing colonies are evident when grown on modified MRS agar plates supplemented with 1 % w/v bile, 0.5% (w/v) CaC03 and 0.001 % (w/v) cyclohexamide. Fifty-one (51 ) bacteria with a halo surrounding each colony were isolated from the modified MRS agar plates.
  • Gram reaction and catalase tests narrowed the 51 isolates down to 25 lactic acid bacteria. Of the 25 lactic acid bacteria, only 3 strains were resistant to bile concentrations of at 0.3% (w/v). Seven strains were resistant to 1 .0 % (w/v) bile and 6 strains were resistant to 2.0 % (w/v) bile (Table 2).
  • Figure 5 shows the Haemolytic activity of L piantarum D4, and the controls, W. confusa B10, L piantarum 423 and L. reuteri DSM 17938.
  • the strains were streaked onto 5% (v/v) sheep blood agar and incubated overnight.
  • L piantarum 423 and Lactobacillus reuteri DSM 17938, used as reference strains, are both a-haemollytic (A and B, respectively).
  • L piantarum D4 is ⁇ -haemollytic (C)
  • W. confusa B10 is ⁇ -haemolytic, with clear halo's visible around the colonies (D).
  • Haemolytic activity tests have shown that ⁇ N. confusa (numbered strain B10) is ⁇ - haemolytic and L. piantarum (numbered strain D4) a-hemolytic. Strains with ⁇ - haemolytic activity may be pathogenic.
  • L. piantarum D4 has the ability to auto- aggregate with the formation of a distinct clear upper phase.
  • Figure 5 shows the auto-aggregation, expressed as a percentage value, of L. piantarum D4 (red line), compared to the control cultures, L. piantarum 423 (blue line) and L. reuteri DSM 17938 (green line).
  • L. piantarum D4 The ability of L. piantarum D4 to tolerate simulated gastric juice is not significantly different from the ability of the two reference strains to tolerate gastric juice.
  • Figure 7 shows the tolerance to simulated gastric juice expressed as percentage survival.
  • the survival rate of L. piantarum D4 and the reference strain L. piantarum 423 over the first 60 min were simlar with no signifficant difference being observed. However, after 120 min of exposure to simulated gastric juice L. piantarum D4 exhibited a significantly better survival rate than L. piantarum 423. The survival of L. piantarum D4 from 60 min to 120 min was significantly better than the reference strain L. reuteri DSM 17938.
  • Bile tolerance of L. plantarum D4 compared to reference strains L. plantarum 423 and L. reuteri DSM 17938 were assessed by monitoring growth patterns in the presence of different bile concentrations.
  • Figure 8 shows the response of L.plantarum D4 and reference strains to bile stress.
  • plantarum D4 was 0.558 h ⁇ 1 in the presence of 1 .0% (w/v) ox bile, compared to 0.506 h ⁇ 1 for L.plantarum 423 and 0.453 IT 1 for Lreuteri DSM 17938.
  • L. plantarum D4 produces an antimicrobial peptide with activity against Gram- positive bacteria.
  • Figure 10 shows the antimicrobial activity of L. plantarum D4 against L. monocytogenes EGDe.
  • lactic acid bacteria from human faecal samples provided a large number of isolates. However, only twenty five (25) of the isolates were lactic acid bacteria. Further selection based on resistance to acid and bile, binding to mucus, aggregation properties and haemolytic activity excluded most of the strains to be used as probiotics in the gastrointestinal tract (GIT) of HIV individuals. Survival in stomach acid, excessive gastric juice, excessive bile salts and adhesion to mucous are essential characteristics for such a strain to prevail and colonise the GIT. The isolation of a L. plantarum strain (D4) is of significant importance, as a previous study has found that children, who were HIV-positive, had lost all L.
  • D4 L. plantarum strain
  • L plantarum D4 is resistant to antibiotics inhibiting protein synthesis (amikacin, kanamycin and streptomycin) and nucleic acid synthesis (sulphamethoxazole and trimethoprim). Resistance exhibited by L plantarum D4 is in line with results obtained for reference strains L plantarum 423 and L reuteri DSM 17938. Since both these strains are used in commercial preparations, resistance shown by L. plantarum D4 is not unusual and the strain is considered safe.
  • Strain L. plantarum D4 has excellent auto-aggregation properties. Probiotics with high auto-aggregating abilities is essential in the case of HIV-positive individuals with a largely dysfunctional GIT ( Perez PF, Minnaard Y, Disalvo EA, De Antoni GL. 1998. Surface properties of bifidobacteria! strains of human origin. Appl. Environ. Microbiol. 64:21 -26). A correlation exists between auto-aggregation potential of bacteria and their adhesion to solvents (Collado et al., 2008, supra). Hydrophobicity correlates with auto-aggregation. According to the MATS assay, the cell surface hydrophobicity of L. plantarum D4 is much higher than that recorded for the reference strain L. reuteri DSM 17938.
  • L. plantarum D4 would be capable of colonising the GIT of HIV-positive individuals.
  • Mucus is a vital part of the GIT, especially HIV-positive people. Mucus protects the stomach lining against acid and entraps pathogens, but also provides adhesion sites for beneficial microorganisms Finlay BB, Falkow S. 1997. Common themes in microbial pathogenicity revisited. Microbiol. Mol. Biol. Rev. 61 : 136-169.).
  • Previous studies conducted on probiotics (Ouwehand A, Isolauri E, Kirjavainen P, Salminen S. 2000.
  • Strain D4 would thus stabilize the intestinal mucosa and protect HIV-positive individuals from bacterial infections.
  • Production of an antimicrobial peptide is an added advantage in the exclusion of pathogens.

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  • Pharmacology & Pharmacy (AREA)
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Abstract

L'invention concerne une composition probiotique à large spectre destinée à être utilisée dans le traitement d'une infection secondaire chez un être humain atteint d'une infection par le virus de l'immunodéficience humaine (VIH) précoce à intermédiaire et du syndrome d'immunodéficience acquise (SIDA).
PCT/IB2015/056754 2014-09-04 2015-09-04 Composition probiotique WO2016035043A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023120547A1 (fr) * 2021-12-22 2023-06-29 株式会社明治 Composition pour prévenir des maladies sexuellement transmissibles secondaires ou réduire le risque de développer celles-ci

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE20202562U1 (de) * 2002-02-19 2002-05-23 Orthomol pharmazeutische Vertriebs GmbH, 40764 Langenfeld Mikronährstoffkombinationsprodukt mit Pro- und Prebiotika
EP2060257A1 (fr) * 2007-11-08 2009-05-20 Nestec S.A. Prévention et traitement d'infections secondaires à la suite d'une infection virale
WO2015160314A1 (fr) * 2014-04-16 2015-10-22 SCHWARTZ, I. Sandford Mélange nutraceutique pour stimuler le système immunitaire

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE20202562U1 (de) * 2002-02-19 2002-05-23 Orthomol pharmazeutische Vertriebs GmbH, 40764 Langenfeld Mikronährstoffkombinationsprodukt mit Pro- und Prebiotika
EP2060257A1 (fr) * 2007-11-08 2009-05-20 Nestec S.A. Prévention et traitement d'infections secondaires à la suite d'une infection virale
WO2015160314A1 (fr) * 2014-04-16 2015-10-22 SCHWARTZ, I. Sandford Mélange nutraceutique pour stimuler le système immunitaire

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DUPONT H.L.: "Prevention of diarrhea by the probiotic, Lactobacillus GG", J. PEDIATR, vol. 134, no. 1-2, 1999, pages 1 - 2, XP027487363, DOI: doi:10.1016/S0022-3476(99)70360-4 *
RUBEN HUMMELEN ET AL.: "Lactobacillus rhamnosus GR -1 and L. reuteri RC-14 to prevent or cure bacterial vaginosis among women with HIV", INT. J. OF GYNECOLOGY AND OBSTETRICS, vol. 111, 2010, pages 245 - 248, XP027457588, DOI: doi:10.1016/j.ijgo.2010.07.008 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023120547A1 (fr) * 2021-12-22 2023-06-29 株式会社明治 Composition pour prévenir des maladies sexuellement transmissibles secondaires ou réduire le risque de développer celles-ci

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