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  • Y10S435/822—Microorganisms using bacteria or actinomycetales
  • Y10S435/853—Lactobacillus

Definitions

• the invention relates to the use of strains of Lactobacillus salivarius.
• Innate defence mechanisms include the low pH of the stomach, bile salts, peristalsis, mucin layers and anti-microbial compounds such as lysozyme (D.C. Savage, 'Microbial Ecology of the Gut', Academic Press, London, 1997, p.278.).
• Immunological mechanisms include specialised lymphoid aggregates, underlying M cells, called peyers patches which are distributed throughout the small intestine and colon (M.F. Kagnoff. Gastroenterol. 1993, 105, 1275). Luminal antigens presented at these sites result in stimulation of appropriate T and B cell subsets with establishment of cytokine networks and secretion of antibodies into the gastrointestinal tract (M.R. Neutra and J-P Kraehenbuhl, 'Essentials of mucosal immunology', Academic Press, San Diego, 1996, p.29., M.E. Lamm. Ann. Rev.
• control mechanisms must be capable of distinguishing non-pathogenic adherent bacteria from invasive pathogens which would cause significant damage to the host.
• the intestinal flora contributes to defence of the host by competing with newly ingested potentially pathogenic micro-organisms.
• Bacteria present in the human gastrointestinal tract can promote inflammation. Aberrant immune responses to the indigenous microflora have been implicated in certain disease states, such as inflammatory bowel disease (Brandzeag P. et al. Springer Semin. Immunopathol, 1997, 18, 555). Antigens associated with the normal flora usually lead to immunological tolerance and failure to achieve this tolerance is a major mechanism of mucosal inflammation (Stallmach A. et al., Immunol. Today, 1998, 19, 438). Evidence for this breakdown in tolerance includes an increase in antibody levels directed against the gut flora in patients with IBD.
• WO-A-98/35014 describes strains of Lactobacillus salivarius isolated from resected and washed human gastrointestinal tract which inhibits a broad range of Gram positive and Gram negative microorganisms and which secretes a product having anti-microbial activity into a cell-free supernatant.
• the immune system is designed to defend host tissue and destroy invading pathogens. Upon recognition of the presence of a bacterial cell, cells of the immune system become activated and eliminate the bacterial threat. The production of inflammatory mediators promote cellular activation and pathogen destruction.
• strains of Lactobacillus salivarius elicit an anti- inflammatory effect in vitro and in vivo.
• the immune perception of Lactobacillus salivarius results in the suppression of inflammatory activity.
• the deliberate consumption in large numbers of Lactobacillus salivarius results in the suppression of inflammatory activity.
• the invention is therefore of major potential therapeutic value in the prophylaxis or treatment of undesirable inflammatory responses, such as inflammatory bowel disease.
• Lactobacillus salivarius is a commensal microorganism originally isolated from the microbial flora within the human gastrointestinal tract.
• the immune system within the gastrointestinal tract cannot have a pronounced reaction to members of this flora as the resulting inflammatory activity would also destroy host cells and tissue function. Therefore, some mechanism(s) exist whereby the immune system can recognise commensal non-pathogenic members of the gastrointestinal flora as being different to pathogenic organisms. This ensures that damage to host tissues is restricted and a defensive barrier is still maintained.
• use of a strain of Lactobacillus salivarius 'in the prophylaxis and/or treatment of undesirable inflammatory activity is provided.
• the undesirable inflammatory activity may be undesirable gastrointestinal inflammatory activity such as inflammatory bowel disease, eg. Crohns disease, ulcerative colitis, irritable bowel syndrome, pouchitis or post infection colitis.
• the gastrointestinal inflammatory activity may also be diarrhoeal disease.
• the diarrhoeal disease may be associated by Clostridium difficile or be associated with Rotovirus.
• the diarrhoeal disease may also be post infective diarrhoeal disease.
• the inflammatory activity may be due to gastrointestinal cancer or systemic inflammatory disease such as rheumatoid arthritis.
• the undesirable inflammatory activity may be due to an autoimmune disorder.
• the undesirable inflammatory activity may be due to cancer.
• the invention provides use of a strain of Lactobacillus salivarius the prophylaxis of cancer.
• the invention provides use of a strain of Lactobacillus salivarius wherein the Lactobacillus salivarius is contained in a formulation.
• the formulation includes another probiotic material.
• the formulation includes a prebiotic material.
• the formulation includes an ingestable carrier.
• the ingestable carrier may be a pharmaceutically acceptable carrier such as a tablet, capsule or powder.
• the ingestable carrier is a protein and/or a peptide, in particular proteins and/or peptides that are rich in glutamine/glutamate; a lipid; a carbohydrate; a vitamin; mineral and/or trace element.
• the ingestable carrier is a food product such as acidified milk, yoghurt, frozen yoghurt, milk powder, milk concentrate, cheese spreads, dressings or beverages.
• Lactobacillus salivarius is present in the formulation at more than 10 6 cfu per gram of delivery system.
• the formulation includes an adjuvant.
• the formulation may include a bacterial component.
• the formulation may alternatively or additionally include a drug entity.
• the formulation may also include a biological compound.
• the invention provides use of a strain of Lactobacillus salivarius wherein the strain or formulation is for administration to animals.
• the animal is a mammal, most preferably a human.
• the invention provides use of a strain of Lactobacillus salivarius wherein the Lactobacillus salivarius effects changes in an immunological marker when introduced into a system comprising cells which interact with the immune system and cells of the immune system.
• the cells which interact with the immune system are epithelial cells.
• the immunological marker is a cytokine especially TNF ⁇ .
• the cells which interact with the immune system and the immune system cells are of matched origin.
• the cells which interact with the immune system are of gastrointestinal, respiratory or genitourinary origin.
• the cells of the immune system are of gastrointestinal, respiratory or genitourinary origin.
• the invention provides use of a strain of Lactobacillus salivarius wherein the Lactobacillus saliva ⁇ us strain is Lactobacillus salivarius subspecies salivarius.
• the Lactobacillius salivarius is of human origin, most preferably from resected and washed human gastrointestinal tract.
• Lactobacillus salivarius inhibits a broad range of Gram positive and
• Gram negative micro-organisms Most preferably it secretes a product having anti-microbial activity into a cell-free supernatant, said activity being produced only by growing cells and being destroyed by proteinase K and pronase E.
• Lactobacillus salivarius is Lactobacillus salivarius strain UCC 188 or mutant or variant thereof.
• Lactobacillus salivarius strain UCC 118 was made at the NCIMB on November 27, 1996 and accorded the accession number NCIMB 40829. The strain of Lactobacillus salivarius is described in WO-A-98/35014.
• the Lactobacillus salivarius may be a genetically modified mutant or it may be a naturally occurring variant of Lactobacillus salivarius.
• the Lactobacillus salivarius is in the form of viable cells.
• the Lactobacillus salivarius may be in the form of non-viable cells.
• Fig. 1 is a graph of C. perfringens levels in the mice consuming UCC118 compared to a placebo group ⁇ 0.05). Results are plotted as the mean log values ⁇ standard error for each of the groups
• Fig. 2 is a bar chart of inflammatory scores for mice consuming UCC118 in comparison to control mice. Results are shown as the mean ⁇ standard error for each of the groups.
• Fig. 4 is a graph of CDAI scores for patients consuming UCC118 over the course of probiotic feeding. CDAI scores decreased from an average of 180 to 160.
• Fig. 5 is a graph of cytokine production in vitro following exposure to UCC118, Results are expressed as pg/ml.
• Fig. 6 is bar chart of extracellular TNF ⁇ , IL-1RA, IL-6, sIL-6R, and IFN ⁇ levels following exposure to Lactobacillus salivarius UCC118.
• Fig. 7 is a gene array with specific gene sequences for 268 cytokines and related molecules to examine the immune response to UCC 118.
• the bottom panel illustrates the control culture while the top panel illustrates cytokine gene expression by PBMCs following exposure to UCC 118;
• Fig. 8 is a bar chart of TNF ⁇ levels in the presence of various bacterial strains. Detailed Description
• probiotic bacteria in the form of viable cells.
• non-viable cells such as killed cultures or compositions containing beneficial factors expressed by the probiotic bacteria. This could include thermally killed micro-organisms or micro-organisms killed by exposure to altered pH or subjection to pressure.
• non- viable cells product preparation is simpler, cells may be incorporated easily into pharmaceuticals and storage requirements are much less limited than viable cells.
• Lactobacillus caseiYYI 9018 offers an example of the effective use of heat killed cells as a method for the treatment and/or prevention of tumour growth as described in US Patent No. US4347240.
• LPS lipopolysaccharide
• Example 1 Detailed description of the in vivo demonstration of the anti- inflammatory effects of Lactobacillus salivarius especially subspecies salivarius UCC118.
• C57BL/6 Interleukin-10 knockout mice are predisposed to developing enterocolitis in the presence of an enteric bacterial flora.
• IL-10 knock out mice do not develop the disease (Kuhn R., et al. Cell, 1993, 75, 263). Since the pathogenesis of this disease has been linked with the enteric flora, elimination of specific components of this flora may have a beneficial effect on the severity of this disease.
• Lactobacillus salivarius subsp. salivarius UCC118 is a probiotic bacteria, which was isolated from a healthy human ileum. It is suited to gastrointestinal colonization as it fulfills many criteria set down for the selection of probiotic strains. These include traits such as bile tolerance, acid resistance and in vitro adherence to human colonic cell lines. Feeding trials in healthy humans have been conducted and considerable modification of the gastrointestinal flora was noted. In addition, UCC118 was perceived by the mucosal immune system resulting in the production and secretion of IgA specific to UCC 118.
• UCC118 survives passage through the gastrointestinal tract, modulates the gut flora and is perceived by the mucosal immune system.
• the influence of this probiotic bacteria in modulating inflammatory responses within the gastrointestinal tract was examined using a murine model of enterocolitis.
• UCC118 in reducing the rate of neoplastic change within the gastrointestinal tract.
• IL-10 KO mice Twenty IL-10 KO mice were studied (ten consumed probiotic organisms in milk and 10 consumed unmodified milk) for 16 weeks. Fecal microbial analysis was performed weekly to enumerate excretion of lactobacilli, Clostridium perffingens, bacteroides, coliforms, bifidobacteria and enterococci. At sacrifice, small and large bowel were microbiologically and histologically assessed.
• Test animal mucosal inflammation consistently scored lower than that of the control mice ( Figure 2).
• the reduction in tumour incidence following consumption of UCC118 may be related to the reduced level of inflammation within the gastrointestinal tract or may be due to elimination of pro-carcinogenic members of the gastrointestinal flora (Rumney C.J., et al. Carcinogen esis, 1993,
• Example 2 Human Trial with UCC118 in patients with active Crohn's disease.
• IBD Inflammatory bowel disease
• UCC118 Patients suffering from active Crohn's disease have been treated with UCC 118. Briefly, UCC118 was consumed in a fermented milk product for 6 weeks by 22 patients. Microbiological and immunological determinations were made at week 0, week 1, week 3 and week 6. This was not a placebo-controlled trial.
• TNF ⁇ tumour necrosis factor ⁇
• CDAI Crohn's Disease Activity Index
• Example 3 Detailed description of the in vitro demonstration of the mechanisms underlying the anti-inflammatory effects of Lactobacillus salivarius especially subspecies salivarius UCCl IS.
• tumour necrosis factor ⁇ has been targeted, due to its clinical importance, and suppression of the production of this cytokine, following exposure to UCCl 18, has been noted using all three methodologies.
• TNF ⁇ Intracellular staining for TNF ⁇ confirmed the ELISA result as TNF ⁇ levels were lower in the UCCl 18 stimulated sample compared to controls.
• Figure 6 demonstrates the tricellular signalling that occurs. Co-incubation of PBMCs and Lactobacillus salivarius strain UCCl 18 results in the stimulation of
• UCCl 18 is capable of inducing Th2 type cytokines (i.e. IL-6 and LL-6 soluble receptor) while suppressing the production of inflammatory cytokines such as TNF ⁇ and IL-l ⁇ .
• Th2 type cytokines i.e. IL-6 and LL-6 soluble receptor
• Example 4 Test for anti-inflammatory bacterial strains
• lactic acid bacteria which have been isolated from the human gastrointestinal tract, were examined in this novel assay system for anti- inflammatory effect. All bacterial strains were taken from -20°C glycerol stocks and incubated anaerobically overnight in MRS broth and washed in antibiotic containing medium. Epithelial cell monolayers were grown for 6 weeks prior to the addition of PBMCs and bacterial cells.
• Inflammation is the term used to describe the local accumulation of fluid, plasma proteins and white blood cells at a site that has sustained physical damage, infection or where there is an ongoing immune response. Control of the inflammatory response is exerted on a number of levels (for review see Henderson B., and Wilson M. 1998. In “Bacteria-Cytokine interactions in health and disease. Portland Press, 79-130).
• the controlling factors include cytokines, hormones (e.g. hydrocortisone), prostaglandins, reactive intermediates and leukotrienes. Cytokines are low molecular weight biologically active proteins that are involved in the generation and control of immunological and inflammatory responses, while also regulating development, tissue repair and haematopoiesis.
• TNF ⁇ is a pivotal proinflammatory cytokine as it initiates a cascade of cytokines and biological effects resulting in the inflammatory state. Therefore, agents which inhibit TNF ⁇ are currently being used for the treatment of inflammatory diseases, e.g. infliximab.
• Pro-inflammatory cytokines are thought to play a major role in the pathogenesis of many inflammatory diseases, including inflammatory bowel disease (IBD).
• IBD inflammatory bowel disease
• Current therapies for treating IBD are aimed at reducing the levels of these pro- inflammatory cytokines, including IL-8 and TNF ⁇ .
• Such therapies may also play a significant role in the treatment of systemic inflammatory diseases such as rheumatoid arthritis.
• systemic inflammatory diseases such as rheumatoid arthritis.
• NSAIDs non-steroid anti-inflammatory drugs
• Infliximab Infliximab.
• the barrier function of the intestinal epithelium can be diminished during nervous (acetylcholine) and immune (histamine) mediated secretion.
• Certain bacterial toxins may also induce Ca2+ and PKC dependent secretion and thereby can disturb the epithelial barrier (Ganguly NK and Kaur T. Indian J Med Res 1996;104:28-37, Groot JA. Vet Q 1998;20(S3):45-9).
• Several studies have examined the prevention and treatment of diarrhoea using probiotic bacteria.
• Lactobacillus salivarius may also produce an anti-diarrhoeal effect, possibly medicated via cAMP modulation.
• Cyclic AMP-dependent Cl-secretion is the major secretory pathway in the human intestine (Brzuszczak IM, et al., J. Gastroenterol. Hepatol.
• the anti-diarrhoeal effect may not be restricted just to diarrhoea resulting from gastrointestinal inflammation, but can be applied to the general treatment of diarrhoeal disease.
• Autoimmune Disease may not be restricted just to diarrhoea resulting from gastrointestinal inflammation, but can be applied to the general treatment of diarrhoeal disease.
• the immune system has a large repertoire of specificities expressed by B and T cells. Some of these specificities will be directed to self-components. Self- recognition is normally controlled by clonal deletion and inactivation of self- reactive lymphocytes. However, there is a constant background of autoimmunity with antibodies to many proteins being found in serum. A breakdown in the self- nonself recognition system results in autoimmunity. When autoimmune disease does occur, the resulting immune response damages the tissue bearing the offending antigen. Immune complex deposition, type II hypersensitivity and cell- mediated reactions are the most important mechanisms by which immunopathological damage occurs.
• autoimmune diseases include, but are not limited to, systemic lupus erythematosus, rheumatoid arthritis, insulin dependent diabetes mellitus, myasthenia gravis and pernicious anaemia.
• Lactobacillus salivarius is an immunomodulatory bacterium.
• consumption either as a single component or in combination with other bacteria by patients suffering from autoimmune disease may restrict organ damage and help restore normal body homeostasis.
• Toxicology of the colon role of the intestinal microflora. In: Gibson G.R. (ed). Human colonic bacteria: role in nutrition, physiology and pathology, pp 155-174. Boca Raton CRC Press).
• species of Lactobacillus have low activities of xenobiotic metabolising enzymes compared to other populations within the gut such as bacteroides, eubacteria and clostridia (Saito Y., et al., Microb. Ecol.
• probiotic organisms are accomplished by the ingestion of the microorganism in a suitable carrier. It would be advantageous to provide a medium that would promote the growth of these probiotic strains in the large bowel.
• oligosaccharides, polysaccharides, or other prebiotics enhances the growth of lactic acid bacteria in the gastrointestinal tract
• Prebiotics refers to any non- viable food component that is specifically fermented in the colon by indigenous bacteria thought to be of positive value, e.g. bifidobacteria, lactobacilli.
• Types of prebiotics may include those which contain fructose, xylose, soya, galactose, glucose and mannose.
• the combined administration of a probiotic strain with one or more prebiotic compounds may enhance the growth of the administered probiotic in vivo resulting in a more pronounced health benefit, and is termed synbiotic.
• Lactobacillus salivarius may be administered prophylactically or as a method of treatment either on its own or with other probiotic and/or prebiotic materials as described above.
• the bacteria may be used as part of a prophylactic or treatment regime using other active materials such as those used for treating inflammation or other disorders, especially those of the gastrointestinal tract.
• Such combinations may be administered in a single formulation or as separate formulations administered at the same or different times and using the same or different routes of administration.

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• 2000
  • 2000-01-15 ID IDW00200101531A patent/ID29150A/id unknown
  • 2000-01-17 EP EP00900788A patent/EP1143985B1/en not_active Expired - Lifetime
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  • 2000-01-17 JP JP2000593317A patent/JP2004502633A/ja active Pending
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  • 2000-01-17 AU AU30717/00A patent/AU3071700A/en not_active Abandoned
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  • 2000-01-17 DK DK00900788T patent/DK1143985T3/da active
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  • 2000-01-17 MX MXPA01007144A patent/MXPA01007144A/es not_active Application Discontinuation
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  • 2000-01-17 DE DE60028003T patent/DE60028003T2/de not_active Expired - Lifetime
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  • 2000-01-17 BR BR0007550-7A patent/BR0007550A/pt not_active Application Discontinuation
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  • 2000-01-17 AT AT00900788T patent/ATE367820T1/de not_active IP Right Cessation
  • 2000-01-17 WO PCT/IE2000/000009 patent/WO2000042429A2/en not_active Ceased
  • 2000-01-17 CA CA002360243A patent/CA2360243A1/en not_active Abandoned
  • 2000-01-17 CN CNB00802829XA patent/CN1245994C/zh not_active Expired - Fee Related
  • 2000-01-17 CA CA2359334A patent/CA2359334C/en not_active Expired - Lifetime
  • 2000-01-17 CN CNB008040893A patent/CN100552016C/zh not_active Expired - Lifetime
  • 2000-01-17 IL IL14418500A patent/IL144185A0/xx unknown
  • 2000-01-17 WO PCT/IE2000/000008 patent/WO2000042168A2/en not_active Ceased
  • 2000-01-17 EP EP06009910A patent/EP1688481A1/en not_active Withdrawn
  • 2000-01-17 ES ES00900789T patent/ES2265331T3/es not_active Expired - Lifetime
• 2001
  • 2001-07-05 IL IL144185A patent/IL144185A/en not_active IP Right Cessation
  • 2001-07-10 NO NO20013429A patent/NO327792B1/no not_active IP Right Cessation
  • 2001-07-12 NO NO20013467A patent/NO20013467L/no unknown
  • 2001-07-13 US US09/903,681 patent/US20020006432A1/en not_active Abandoned
• 2002
  • 2002-09-12 US US10/241,797 patent/US20030166257A1/en not_active Abandoned
• 2003
  • 2003-03-03 US US10/376,602 patent/US20030170217A1/en not_active Abandoned
  • 2003-03-17 US US10/388,652 patent/US20030215467A1/en not_active Abandoned
• 2004
  • 2004-02-23 US US10/783,020 patent/US7195906B2/en not_active Expired - Lifetime
  • 2004-03-19 US US10/804,223 patent/US20050084482A1/en not_active Abandoned
  • 2004-10-04 US US10/956,330 patent/US20050214272A1/en not_active Abandoned
  • 2004-10-29 US US10/975,353 patent/US20060002908A1/en not_active Abandoned
• 2005
  • 2005-12-20 US US11/311,632 patent/US20060292133A1/en not_active Abandoned
• 2006
  • 2006-06-29 US US11/478,545 patent/US20070141039A1/en not_active Abandoned
• 2007
  • 2007-01-29 US US11/699,115 patent/US20080057109A1/en not_active Abandoned
• 2008
  • 2008-05-19 US US12/123,052 patent/US20080311080A1/en not_active Abandoned
• 2009
  • 2009-06-05 US US12/479,364 patent/US20100112003A1/en not_active Abandoned

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