NZ613318A - Indirect substrates for microorganisms metabolizing 1,2-propanediol - Google Patents

Indirect substrates for microorganisms metabolizing 1,2-propanediol Download PDF

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NZ613318A
NZ613318A NZ613318A NZ61331812A NZ613318A NZ 613318 A NZ613318 A NZ 613318A NZ 613318 A NZ613318 A NZ 613318A NZ 61331812 A NZ61331812 A NZ 61331812A NZ 613318 A NZ613318 A NZ 613318A
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pectin
rhamnose
fucose
pdu
substance
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NZ613318A
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NZ613318B2 (en
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Stefan Roos
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Biogaia Ab
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Priority claimed from US13/400,735 external-priority patent/US20120263696A1/en
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Publication of NZ613318B2 publication Critical patent/NZ613318B2/en

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Abstract

Disclosed is a composition comprising bacteria having a pdu-operon and a substance that can be metabolised to 1,2-propanediol comprising (a) rhamnose, (b) fucose, (c) pectin having a high percentage of rhamnose, (d) rhamnose in combination with pectin, (e) fucose in combination with pectin, (f) fucoidan having a high percentage of fucose, or (g) a combination of rhamnose, fucose and pectin. Also disclosed is its use for enhancing the activity of probiotic bacteria or increasing the growth of probiotic bacteria having a pdu-operon in the gastrointestinal tract of an individual.

Description

The t invention relates generally to enhancing the activity of certain probiotics in mammals. Moreover this invention relates to preparations comprising substrate components and certain probiotics, the substrate components being specifically designed to enhance the efficacy of said probiotics. The substrate components are selected to generate 1,2- propanediol, which uniquely most Lactobacillus reuleri strains can utilize as a source of energy and/or as an external electron acceptor.
BACKGROUND OF THE INVENTION The Food and Agricultural Organization of the United Nations define probiotics as “live microorganisms which when stered in adequate s confer a health benefit on the host”. Nowadays, a number of different bacteria are used as probiotics for example, lactic acid bacteria such as strains ofLazaro/Bacillus and acterium.
The effectiveness of probiotics is strain-specific, and each strain may contribute to host health h different mechanisms. Different probiotics can prevent or inhibit the proliferation of pathogens, suppress production of virulence factors by pathogens, te the immune response in a pro-inflammatory or an anti—inflammatory way and influence the host in a number of other ways.
Prebiotics are defined as “non-digestible food ingredients that beneficially affect the host by selectively stimulating the growth and/or activity of one, or a limited number of bacteria in the colon that can improve the host health.” Targets for prebiotics are usually bifidob acteria and lactobacilli; r, prebiotics are often not selective, and hence 3O stimulation of beneficial genera or probiotic strains alone may be difficult to achieve. Since it is difficult to find a prebiotic that is selective for certain tics, the inventor of the present invention has discovered how to use specific substrate components (SSC) that indirectly will supply specific probiotics with a source of energy and/or an external electron acceptor that will increase the energy yield.
Lactobacillus i is a heterofennentative lactic acid bacterium and is frequently found in the gastrointestinal tract of humans and other animals. L. reuterz' is considered an W0 2012/1 15588 indigenous organism of the human gastrointestinal tract and is for e present on the mucosa of the gastric corpus, gastric antrum, duodenum, and ileum. See, for example US.
Patent Nos. 5,439,678, 5,458,875, 5,534,253, 5,837,238, and 5,849,289. When L. reuieri cells are grown under anaerobic conditions in the presence of glycerol, they produce the antimicrobial substance known as in (B—hydroxy propionaldehyde), The ability to produce reuterin is due to the ediol ation (pdu) operon. The pdu operon is a metabolic machinery that also enables growth on l,2-propanediol (PD). This pdu operon is a very important feature for L. reuteri when colonizing humans and exploiting the full potential ofthe bacteria. This machinery is rare among other lactobacilli and therefore those Without the pdu—machinery are not able to grow on l,2-PD and neither are they capable of using 1,2— PD as an electron acceptor.
Different L. reuZerz‘ strains have the ability to colonize the intestine, act as a diarrhea therapeutic agent, modulate the gut motility, function as an inhibitor of bacterial pathogens, immunologically modulate the gastrointestinal mucosa, fimction as an nflammatory agent in the stomach etc, In patent application /1 51391, the pdu machinery of L. reuteri is primed with 1,2-PD or glycerol before freeze-drying the bacteria. With this manufacture design the freeze— dried pdu machinery of L. reuterz’ is primed with the capacity to make and store reuterin.
Emma Arskold et, al., Phosphokefolase Pathway Dominates in acz'llzzs reuz‘eri ATCC 55730 Containing Dual ysfor Glycolysis (Journal ofBacteriology, Jan 2008, 206-2l 2) describes that growth performance of L. reuteri on glucose can be improved by adding se as an external electron acceptor. r nothing in this e teaches how to select certain SSCS based on their ability to ctly supply certain tics with 1,2— PD, which may only be utilized by bacteria with the pdu-machinery.
A common problem with oral administration of probiotic bacteria is insufficient amounts and/or activity of the probiotic bacteria in locations of the intestinal tract Where they will assert their effects. This may have as a consequence that the dosage of probiotic bacteria has to be increased and/or more frequent administration is needed and might also result in loss of activity. This leads to unnecessary costs, undesirable frequency of intake and/or decreased health ts. In the present invention the local amounts and/or metabolic activity of for example L. i is enhanced, leading for example to the possibility of lowering the dosage of the probiotic and further that site-directed health benefits are possible. l,2—propanediol D) is a source of energy that can be locally produced by other coexisting microorganisms and utilized, possibly in combination with onal sugars, by W0 2012/1 15588 certain probiotic species, eg. L. renteri. The inventor of the present invention has surprisingly discovered that those coexisting microbes can be stimulated to produce l,2—PD by oral stration of very selective SSCs and thereby indirectly enhance the activity of 1,2-PD utilizing organisms such as L. reuteri.
Pectin is a polysaccharide from plant cell walls. Various pectic polysaccharides can be detected in the cell wall, including homogalacturonan (HG), xylogalacturonan (XGA), apiogalacturonan, galacturonan I (RG1), and rhamnogalacturonan II (RG11). The ratio between HG, XGA, RG1 and RG11 is variable, but typically HG is the most abundant ccharide tuting about 65% of the pectin, while RG1 constitutes 20% to 35%.
XGA and RG11 are minor components, each tuting less than 10%. The different pectic polysaccharides are not separate molecules but covalently linked domains. L—rhamnose is found as a constituent in the pectin structures RG1 and RG11. L-fucose is also found as a constituent in the R611 structure. Bacteria found in the Gl-tract that are able to convert L- rhamnose or L-fucose belong for example to Bacteroides and Enterobacteria genera, ing E. coli bacteria.
Pectin is resistant to human digestion, but is degraded to sugars and then further metabolized, for example to 1,2-propanediol, by bacteria in the small ine and colon.
Pectin stimulates bacterial growth in the small intestine and in the colon. Pectin is used as a remedy for diarrhea, is related to ed intestinal environment and is also known to have anti-cancer properties. Modified citrus pectin (MCP) is citrus pectin that has been degraded to less complex les and is used to support cell growth and proliferation Fucoidan is a ed polysaccharide found mainly in various species of brown algae and brown seaweed such as mozuku, kombu, limu, moui, bladderwrack, wakame and hijiki, variant forms of fucoidan have also been found in animal species, including the sea cucumber.
Galacto—oligosaccharides (GOS) generally comprise a chain of galactose units that arise through consecutive transgalactosylation reactions, with a terminal glucose unit, is classified as a prebiotic.
Lynch MB et al., The eflecz ofdietary Laminaria~derived laminarin oidan on nutrient digestabliligz, nitrogen utilisation, inal microflora and volatilefatty acid tration in pigs (1 Sci Food Agric. 2010 Feb;90(3):430-7) have seen that pigs offered diets containing fucoidan have increased Lactobacillus spp. in the proximal colon and distal colon compared with non-fucoidan diets. Thus it is suggested that fucoidan may provide a dietary means to improve gut health in pigs. The increased acillus tions in feces due to a fucoidan diet have also been seen by JV. O’Doherty et. al., The eflect ofdietary W0 2012/1 15588 Iaminarin andflzcoidan diet offhe weanlingpiglet on performance and selectedfaecal microbialpopulations (Livestock science 2010 September).
However it was not previously known to select, for example, pectin and fucoidan, or fractions thereof, based on the amounts of L-rhamnose and/or L-fucose in order to generate 1,2—PD through bacterial fermentation and to use such compositions with high deoxy sugar content, particularly high L—rhamnose and/or L-fucose t which will lead to high amounts of 1,2-PD thus indirectly supplying certain microorganism, for example L. reuteri with a source of energy and/or an external electron acceptor, which most other microbes are not able to utilize due to lack of the pdu machinery.
Patent application WO20lO/117274 s to a carbohydrate which is able to induce a detectable increase of a C5 and/or a C6 Short Chain Fatty Acid (SCFA). The SCFA has a ve effect on the gastrointestinal health of the subject treated. The carbohydrate used comprises . Even though they chose s that may comprise traces of rhamnose, they do not disclose how to select and use specific pectin high in L-rhamnose or L—fucose to indirectly supply probiotics with the pdu-machinery with a specific source of energy and/or an al electron acceptor thus enhancing their activity.
US. Patent No. 7,101,565 relates to a composition comprising a prebiotic and a tic. The prebiotic may comprise a pectin or pectic polysacchari de. However it is not disclosed in this invention how to select certain s, or use ations with pectin and L—rhamnose or L—fucose, that will te high amounts of 1,2-PD in the gastrointestinal tract, beneficial for probiotics with the pdu machinery.
In US. Patent No. 578 an invention is disclosed that relates to a method of preventing diarrhea associated with infectious agents such as rotavirus, or diarrhea associated with antibiotic therapies by using Lactobacillus, r in this invention Laclobacillus is not associated with additional SSCs for better efficacy.
Nobody has hitherto disclosed how to e the health promoting effects of certain probiotics by administering SSCs, together with a probiotic, eg. L. reuteri, to indirectly supply such probiotics with a unique source of energy and/or an external electron acceptor.
Oral administration of SSCs, with high content ofL-rhamnose and/or L-fucose will secure the supply of 1,2-propanediol and thus indirectly supply certain tics with a source of energy and/or an al electron acceptor. This will increase the local amounts of health promoting microorganisms, eg. L. reuteri, and provide better efficacy, making site directed effects possible.
Even though it has previously been known to use for example pectin together with probiotics, it is not previously known how to select SSCs based on their ability to form 1,2— PD for the indirect supply of certain probiotics with a specific energy source and/or a specific external electron acceptor.
SUMNIARY OF THE INVENTION This invention discloses a method of enhancing the activity of certain probiotics and the manufacturing and use of ts, which comprises substrate components and optionally a probiotic. The products of the present invention can be used to enhance the activity of for example L. rem‘eri in mammals. This product can be used for improving the host health.
Depending on the used probiotic strain, the product can be used for example to improve gastrointestinal health, improve immune~re1ated health, treat and/or prevent diarrhea and constipation, normalize fecal consistency, improve intestinal motility, treat and/or prevent ious diseases, modulate inflammation and anti-pathogenic .
The increased efficacy of probiotics can be achieved by stimulating co—existing es to produce opanediol (1,2-PD). The coexisting es are stimulated with certain specific substrate components (S SC) as described herein. The SSCS will ensure the presence of 1,2-PD in the gastrointestinal tract and indirectly supply n beneficial organisms with 1,2-PD.
The y to utilize 1,2—PD either as an energy source and/or as an external electron acceptor is unique for bacteria with the pdu-machinery and therefore the administration of SSCs will e the activity only of certain probiotics.
The SSCs can be administered together with the tics for enhancing the activity ofthe co-administered probiotics. The SSCs could also be stered alone, for example to increase the activity of previously administered probiotics. 1,2—PD, administered alone or generated by the SSCs, may further be combined with o-oligosaccharides (GOS) or other galactose containing saccharides to give an even better source of energy for the microorganisms.
Heterofermentative lactic acid bacteria produce lactate, ethanol and carbon dioxide using the oketolase pathway (PKP). The PKP has poor energy yield compared to the Embden—Meyerhof pathway (EMP). This disadvantage can be compensated for by addition of external electron acceptors, The inventor has surprisingly found out that by ng the presence of 1,2- propanediol in the gastrointestinal tract, the probiotics will simultaneously be supplied with a suitable external electron or and thereby enhance the activity of the probiotic.
W0 2012/115588 2012/050202 The SSCs ofthe present invention will selectively increase the growth of heterofermentative lactic acid bacteria, such as Lactobacz‘llus rezzteri, since they will provide the bacteria with a suitable electron acceptor enabling an enhanced ty.
L. renter? are dependent on a good on acceptor for growth in certain environments, and the inventor of the present invention has surprisingly found out that 1,2— propanediol will serve as a good electron acceptor and can be ed by the administration of SSCs.
According to one aspect of the invention, a method is provided for enhancing the activity of probiotic bacteria having a pdu—operon, in the gastrointestinal tract of an IO individual, comprising stering a substance to said individual, which substance has the capacity to be metabolized to 1,2—propanediol in the gastrointestinal tract of said individual.
In an embodiment of the method, the substance comprises a deoxy sugar, which has the capacity to be metabolized to 1,2-propanediol in the intestinal tract of said individual. In an embodiment, the deoxy sugar is rhamnose or fucose.
In an embodiment of the method, the substance comprises (a) rhamnose, (b) fucose, (c) pectin having a high percentage of rhamnose, (d) rhamnose in combination with pectin, (e) fucose in combination with pectin, (f) an having a high percentage of fucose, or (g) a combination ofrhamnose, fiicose and pectin, In an embodiment of the invention, pectin having a high tage of rhamnose is defined as comprising 5-15% rhamnose, such as 5, 6, 7, 8, 9, 10, ll, 12, 13, 14 or 15 % se. In an embodiment of the ion, fucoidan having a high percentage of fucose is defined as comprising more than 15 % fucose.
In an embodiment of the method, the substance is administered simultaneously with bacteria having a pdu operon.
In a preferred embodiment of the invention, the substance is stered orally to the individual.
In another red embodiment of the method, the bacteria having the pdu-operon comprise Lactobacilllus reuteri.
In an embodiment of the method, the nce is administered to the individual at a daily dose of 025-25 g, preferably 1-2 g.
In an embodiment of the invention, the method further comprises simultaneously administering a galactooligosaccharide or other sacchandes comprising galactose.
According to a second aspect of the invention, a substance is provided for use in enhancing the activity or increasing the growth of probiotic bacteria having a pdu—operon, in W0 2012/115588 2012/050202 the gastrointestinal tract of an individual, which substance comprises a deoxy sugar that has the capacity to be lized to 1,2—propanediol in the gastrointestinal tract of said individual.
In an embodiment, the deoxy sugar is rhamnose or fucose.
In an embodiment of the invention, the substance comprises (a) rhamnose, (b) , (c) pectin having a high percentage of rhamnose, (d) rhamnose in combination with pectin, (e) fucose in combination with pectin, (f) fucoidan having a high percentage of fucose, or (g) a ation of rhamnose, fucose and pectin.
In an embodiment of the invention, pectin having a high tage of rhamnose is defined as sing 5-15% rhamnose, such as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 % rhamnose. In an embodiment ofthe invention, fucoidan having a high percentage of fucose is defined as comprising more than 15 % fucose.
In a preferred ment relating to the substance, the bacteria having the pdu- operon are Lactobacilllus reuterz‘.
In an ment of the invention, the substance is administered to the individual at a daily dose of 025-25 g, preferably 1-2 g.
In an ment of the invention, the nce is for use in combination with galactooligosacchari des or other saccharides comprising galactose.
According to a third aspect of the invention, a composition is provided comprising (i) bacteria having a pdu—operon and (ii) a substance comprising a deoxy sugar, which deoxy sugar has the capacity to be lized to 1,2-propanediol in the gastrointestinal tract of an individual.
In an embodiment, the composition comprises bacteria having a pdu-operon, in combination with (a) rhamnose, (b) fucose, (c) pectin having a high percentage of rhamnose, (d) rhamnose in combination with pectin, (e) fucose in combination with pectin, (f) fucoidan having a high percentage of fucose, or (g) a combination of rhamnose, fucose and pectin.
In an embodiment of the invention, pectin having a high percentage of rhamnose is defined as comprising 5—15%rhamnose, such as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 % se. In an embodiment of the invention, fucoidan having a high percentage of fucose is defined as comprising more than 15 % fiacose.
In another embodiment, the composition further ses galactooligosaccharides or other saccharides comprising galactose.
In an embodiment relating to the composition, the bacteria having the pdu-operon are Lactobacz’lllus reuteri. 2012/050202 In an embodiment of the ition, the nce is present in an amount such as to give a daily dose of 025—25 g, preferably 1—2 g. ing to another embodiment of the invention, the above-described composition is for use in enhancing the activity or increasing the growth of probiotic bacteria having a pdu—operon, in the gastrointestinal tract of an individual.
BRIEF DESCRIPTION OF THE DRAWING Figure 1 is a graph showing growth of L. reureri DSM 17938 in modified MRS (with no glucose and citrate) with addition of 1,2—PD, ose and a combination thereof.
DETAILED DESCRIPTION OF THE INVENTION AND IS PREFERRED EMBODIMENTS THEREOF The ediol utilization (pdu) machinery of certain probiotics, among them for example Lactobacz‘llus reuteri, enables growth on 1,2-propanediol D) as energy source and enables the ability to use 1,2-PD as an external electron acceptor.
The inventor of the present ion has surprisingly found a way of enhancing the activity of certain probiotics, using certain specific substrate components (SSCs) to indirectly support a c probiotic organism with 1,2~PD that may be utilized as a source of energy or as an external electron acceptor.
The SSC is a substance, According to one embodiment of the invention, the substance is a substrate. In one embodiment, the substance ts of one component only. In another embodiment, the substance comprises two or more components.
Oral administration of these lly selected SSCs stimulates coexisting microbes to produce 1,2~PD, which leads to locally produced 1,2-PD that can serve as a source of energy or as an al electron acceptor for certain microorganisms with the pdu-machinery, such as for example L. rezzterz'. The SSCs may be administered alone or together with the probiotics.
The presence of 1,2-PD will improve the growth ions for certain microorganisms, moreover the inventor has found out that this can be further enhanced in the presence of galacto—oligosaccharides (GOS) or galactose, as can be seen in figure 1.
The SSCS of the present invention are chosen for their ability to indirectly support a specific probiotic with 1,2—PD, which may be used as energy source or as an external electron acceptor. The inventor of this invention has discovered that SSCs with high amounts of L— rhamnose or L—fucose are the most effective when used to enhance the ty of certain probiotics. Therefore the SSCs used in this invention are carefully selected with regards to the amounts of L-rhamnose and L-fucose. s, preferably certain fractions of pectin comprising high percentages ofL— rhamnose, such as rhamnogalacturonan I and II, may be used as SSCS. Preferably, these red fractions of pectin se 5—1596 rhamnose. These ons of pectin will, when degraded, result in more rhamnose than unfractionated pectin, which in the present text may be called pectin, ry pectin, or regular pectin. A certain daily dose of such preferred fractions of pectin, e.g. 2 g, will thus generate higher amounts of 1,2—PD as compared to the same daily dose (2 g) of regular pectin. Ordinary pectin could also be used, if administered together with L-rhamnose or L-fucose to indirectly and in the same manner be advantageous for certain microbes, e. g. L. reuterz’. This combination will, in addition to 1,2-PD, also supply certain probiotics with other substrates, e. g. galactose, arabinose and galacturonic acid as a result of pectin degradation. The inventor of the present invention has shown that 1,2-PD in combination with n pectin constituents, e.g. galactose, arabinose and galacturonic acid will generate a synergistic effect that enhances the ation of 1,2-PD for n tics, e. g. L. reuteri, as seen in figure l, Fucoidan, preferably certain fractions of fucoidan comprising high amounts of L- fucose may be used as SSCs in the t invention, and preferably these fractions of fiicoidan comprise more than 15 % fiicose. These fractions of fucoidan will, when degraded, result in more fucose than ordinary fucoidan and thus generate higher amounts of 1,2—PD.
L-rhamnose or L-fucose alone may also be used alone as SSCs of this invention.
Other SSCs, e.g. gums and other polysaccharides, can be used according to the present invention if they contain L-rhamnose, L—fucose or the like. Gums include, but are not limited to karaya gum and arabic gum. Further, some human milk oligosaccharides (HMO’s) from human breast milk can be used as SSCs in the present invention.
Administering the SSCs of the present invention, either alone or er with a probiotic, e. g. L. reuteri, secures the supply of energy source for a specific probiotic and/or secures the presence of an al electron acceptor that will increase the energy yield, thus enhancing the local activity and efficacy of said probiotic.
In other embodiments and to support this effect it is r possible to add GOS or galactose in order to increase L. reureri’s ability to utilize 1,2-PD.
Depending on the target indication, a number of L. reuterz' strains can be used in the W0 2012/1 15588 invention herein with different ability to colonize the intestine, act as a ea therapeutic agent, modulate the gut motility, on as an inhibitor of bacterial pathogens, immunologically modulate the gastrointestinal mucosa, on as an anti-inflammatory agent in the stomach etc, Pectin, L—rhamnose and L-fUCOSB are resistant to human digestion, but are degraded to sugars and then further lized to for example 1,2—propanediol by co—existing microbes found in humans and available at certain locations of the human GI-tract, for e on the mucosa of the gastric corpus, gastric antrum, duodenum, and small intestine. The invention herein therefore also makes it possible to favor site—directed effects in the human GI—tract. For example by using selected strains of L. reuteri as the probiotic, it is possible to enhance the anti-inflammatory effect of this strain in the ileum.
When using the described system of certain SSC’s in the present invention, with for example a specific strain ofL. reztterz' in humans with a very disturbed ora, including a lack of normally found co-existing microbes able to convert the SSC to l,2~PD, it is also another possibility of the invention herein to actively supply such co-existing microorganisms, eg. Lacrobacillzts rhamnosus, to the recipient ensuring the efficacy of the administered SSCs.
The products comprising the SSCs of this invention, alone or in combination with certain probiotics are preferably formulated as a tablet, capsule, powder sachet or the like. 2O The product can be a food—supplement, a pharmaceutical t or the like. In such a product, the amount of probiotic feed should be in an amount suffi cient to give the wanted effect of the specific strain, now also considering the enhanced effect by the SSC. Such levels are typically, but not limited to lOE+4 CFU to 10E+ll CFU per day, preferably in the range of 10E+6 CFU to 10E+9 CFU of L. reuteri.
The amount ofthe SSC should be in the range of 0.25 to 25 grams (g) per day when using pectins with high amounts of L—rhamnose and/or L-fucose. When using a combination of regular pectin with separate nose and/or L—fucose, the total amount of SSCS should be in the range of 0.25 to 25g per day. In both cases, the daily dose of 025—25 g may for example be 0.25, 0.5, l, 1.5, 2, 5, 10, 15, 20 or 25 g, preferably 1—2 g, such as l, 125, 15, 1.75 or 2 g. The ratio n the regular pectin and either one of L—rhamnose or se, or the combination f, should be in the range of 95:5 to 0:100, but preferably 80:20 to :80 and even more ably 70:30.
Another option when using the invention herein is to alternatively feed the SSC and the probiotic er, and at one or more occasions following the first feeding to feed only the SSC in a kind of shuttle program to lower the cost of treatment.
It is essential for this invention that the probiotics used have the pdu-machinery, since this is essential for the ability to use 1,2-PD as a source of energy and/or as an external electron acceptor. Therefore in another embodiment of the invention the pdu machinery of the probiotics is primed with 1,2-PD during the production of the probiotic strain for enhanced efficacy. This is done by adding 1,2—PD or glycerol and possibly cobalt or vitamin B-12 (since vitamin B-12 and cobalt are important for reuterin production) at the start of the fermentation step when culturing the bacteria. With this manufacture design, the freeze-dried bacteria to be used in the next step are better ed to more y activate the pdu- machinery. This enhanced efficacy of the pdu machinery will in turn enhance the efficacy of the administered SSC of the present invention. Another way of enhancing the efficacy of the administered SSCS is to e them with GOS or ose, and the or has shown that the ation of 1,2-PD and galactose has an unexpected benefit on L. i’s growth.
Since numerous modifications and changes will readily occur to those skilled in the art, it is not desired to limit the invention to the exact construction and operation shown and described, and accordingly, all suitable ations and equivalents may be resorted to, falling within the scope of the invention as defined herein.
EXAMPLE 1 Manufacture ofa sachet ning a composition ofL. reuteri together with pectin, rhamnose and galacto-oligosaccharides.
The composition is made of: L. reuteri DSM 17938: 10E+8 CFU / sachet Pectin (GENU® pectin (citrus) type USP/200, CP Kelco France SARL, France): 840 mg/ sachet L—rhamnose : (Rhamnose monohydrate L-(+), Kaden Biochemicals GmbH, Hamburg, Germany) 360 mg / sachet GOSlS (VIVINAL®, FrieslandCampina Domo, The Netherlands) 800 mg / sachet The composition is filled at t temperature into aluminum foil bags as known in the art with desiccant (10 cm x 12 cm, using packaging material PETlZ/PE/ALU lZ/PE/PE+desiccant/PE from Alcan) in a LAF bench (Holten Laminair Model 8—201 0 1.2 from Heto—Holten A/S, Denmark). To each bag, 2 g of powder with L. reuteri, pectin, L- rhamnose and galacto—oligosaccharides is added using the balance XP-600 from Denver W0 2012/1 15588 Instrument GmbH, Germany. The filled aluminum foil bags are then heat sealed with the film sealing device model F460/2 from Kettenbaum Folienschweisstechnik GmbH & Co. KG, Germany.
E 2 Manufacture ofa sachet containing a composition ofL. reuteri together with rhamnose.
The composition is made of: 2 g L-rhamnose: (Rhamnose monohydrate L—(+), Kaden Biochemicals GmbH, Hamburg, Germany» containing 10E+8 CFU L. reuieri DSM 17938 / sachet The composition is filled into aluminum foil bags as in Example 1.
EXAMPLE 3 Manufacture ofa sachet containing a composition ofL. reuteri together with galacto— oligosaccharides andrhamnose.
The composition is made of: 1 g GOSlS (VIVINAL®, FrieslandCampina Demo, The Netherlands) and 1 g L— se: (Rhamnose monohydrate L-(+), Kaden Biochemicals GmbH, Hamburg, Germany) containing 10E+8 CFU L. reuteri DSM 17938 / sachet The composition is filled into aluminum foil bags as in Example 1.
EXAMPLE 4 cture ofaprimed L. reuteri strain This example describes how to manufacture a freeze-dried powder ofL. reuieri with ted pdu-machinery. The primed L. reuieri strain can then be used When producing the s of examples 1-3.
Fermentation medium composition Dextrose mono hydrate 60 g/l Yeast extract KAV 20 g/l Peptone Type PS (of pig origin) 20 g/l )0 Di ammonium hydrogen e 5 g/l Sodium acetate (x 3 H20) 4.7 g/l Di potassium hydrogen phosphate 2 g/1 0 0.5 g/I Silibione (anti foam) 0.14 g/i W0 2012/1 15588 Magnesium sulphate 0.10 g/l Manganese sulphate 0.03 g/l Zinc sulphate hepta hydrate 0.01 g/l Water q.s.
Centrifuge medium Peptone O—24 Orthana (of pig origin) Cryoprotectants Lactose (of bovine origin) 33 % Gelatin hydrolysate (of bovine origin) 22 % Sodium glutamate 22 % Maltodextrin ll % Ascorbic acid 11 % Production steps offreeze dried Lactobacill’us reuteri powder 1. Twenty ml of the tation medium is inoculated with 0.6 ml of freeze-dried Lacrobacillus rezrteri powder from a g cell bank vial. The tation is performed in a bottle at 37°C for 18 — 20 hours without ng or pH control ILe. static. 2, Two l-liter flasks of the fermentation medium are inoculated with 9 ml cell slurry (from step 1) per liter of . The fermentation is performed at 37°C for 20 — 22 hours t stirring or pH control 1'. e. static. 3. The two one liter cell slurries from step no. 2 are used to inoculate the 600-liter vessel containing 600 liters fermentation medium. The fermentation is performed at 370C for 13 hours with stirring and pH control. At the start of the fermentation the pH is 6.5. The pH control starts when the pH drops below 5.4 using a 20% sodium hydroxide solution. The pH control is set to pH 5.5. 4. The fourth and final fermentation step is performed in a 15,000-liter vessel with the inoculation from step no. 3. The fermentation is performed at 37°C for 9 to 12 hours with stirring and pH control. At the start of the fermentation the pH is 6.5. The pH control starts when the pH drops below 5.4 using a 20% sodium hydroxide solution. The pH control is set to pH 5.5. 100 mM glycerol is added in the final phase of the femientation, just before the culture reaches the nary phase. The fermentation is complete when the culture reaches the stationary phase, which can be seen by the ion ofthe addition of the sodium W0 2012/115588 hydroxide solution. Roughly 930 liters of the sodium hydroxide on is added to the ,200 liters of media and 600 liters of inoculum during the fermentation.
The cell slurry from the final fermentation (step 4) is separated at 10°C twice in a continuous fuge from Alfa Laval. By the first centrifugation the volume of the cell slurry is reduced from roughly 11,730 liters to 1200 liters. This volume is washed with 1200 liters of a peptone ne 0-24, Orthana) solution in a 3000—1iter vessel and is separated again before the mixing with the cryoprotectants (see below). The washing step with peptone is performed to avoid any freezing—point reduction in the freeze-drying process.
By the second centrifugation the volume of the cell slurry is reduced to 495 liters. This volume is mixed with 156 kg of the cryoprotectant solution to reach roughly 650 liters of the cell sluny.
The cell slurry is pumped to a 1000-liter vessel. The vessel is then transported to the freeze—drying plant.
At the freeze-drying plant, exactly 2 liters of the cell slurry is poured on each plate in the freeze dryer. The maximum capacity of the freeze dryer is 600 liters and all ive cell slurry volume is thrown away.
The cell slurry ofLactobacillus i has a dry matter content of 18 % and is freeze dried for four to five days.
During the freeze-drying process, the pressure in the process is between 0.176 mbar and 0.42 mbar. The vacuum pump is started when the pressure reaches 0.42 mbar. The PRT urizing test) is used to determine when the process is complete. If the PRT or the se of pressure is less then 002 mbar after 120 seconds, the process is stopped.
EXANIPLE 5 Combination of], 2-PD andgalactose generates a synergistic effect enhancing the activity ofL. reuteri L. reuteri DSM 17938 was grown in modified MRS broth (with no glucose and citrate) with addition of 1,2-PD (0.3%), galactose (0.3%) or a combination of the two. The bacteria were grown for 24 h at 37°C. L. i grown in the presence of both 1,2-PD and galactose singly showed a significantly higher growth than the growth on the separate sub stances as seen in figure 1.
W0 2012/1 15588 EXAMPLE 6 Example ofshuttle program to befed Thanks to the enhanced activity ofL. reuteri induced by the SSCs described in this application it is possible to alternate the s of example 1 (sachet A) with s where L. rezaeri is excluded but otherwise manufactured according to example 1 (sachet B) in a shuttle program. This shuttle program does not reduce the efficiency ofL. i and may lower the treatment cost.
Sachet A is administered to the recipient at day 1, at day 2 and 3 the ent is given sachet B. This administration scheme is repeated during the whole treatment .
EXAMPLE 7 Intestinal colonization in vivo in humans A comparison between the intestinal colonization by L. reuteri alone and the same L. renteri administered together with SSC is made in a clinical study. 12 healthy volunteers are divided into two groups (A and B) with 6 participants in each group. Group A receives the powder sachets of example 1, containing a composition ofL. reuteri together with SSCs in the form of pectin, rhamnose and galacto-oligosaccharides. Group B receives the same L. reuteri strain but none of the above SSCs. Both groups are given lOE+8 CFU of L. reuzeri per day during 60 days. The quantitative evaluation of inal zation by strains given alone or together with the SSCs is made by fecal sample examination at the ing of the study, and after 30 and 60 days of the treatment period. Fecal L. renterz' is counted and the fecal amounts of group A and B are compared.
A significant increase in the fecal amounts ofL. reuteri is seen in patients Where L. reuterz' is administered together with SSCs, compared to patients where L. reuteri is administered alone, as seen in table 1. The values are given as the average loglo CFU per gram of feces i SEM.
Table 1 study group L. reuteri count (n) before day 30 day 60 groupA (6) ND. 5.54502 5.81-03 group B (6) ND. 42 i 0.3 4.5 i 0.4

Claims (18)

1. A non-therapeutic method for enhancing the activity of probiotic bacteria having a pdu- operon, in the gastrointestinal tract of an individual, comprising stering a substance to said dual, wherein said substance comprises (a) rhamnose, (b) fucose, (c) pectin having a high percentage of rhamnose, (d) rhamnose in combination with pectin, (e) fucose in combination with pectin, (f) fucoidan having a high percentage of , or (g) a ation of rhamnose, fucose and pectin. 10
2. The non-therapeutic method of claim 1 wherein the substance is administered simultaneously with bacteria having a pdu operon.
3. The non-therapeutic method of claim 1 or 2, wherein the bacteria having the pdu-operon comprise Lactobacilllus reuteri.
4. The non-therapeutic method of any one of the preceding claims, wherein the substance is stered to the individual at a daily dose of 025—25 g.
5. The non-therapeutic method of claim 4, wherein the substance is administered to the 20 dual at a daily dose of 1-2 g.
6. The non-therapeutic method of any one of the preceding claims, further comprising aneously administering a galactooligosaccharide or other saccharides comprising galactose.
7. Use of a substance comprising (a) rhamnose, (b) fucose, (c) pectin having a high percentage of rhamnose, (d) rhamnose in combination with pectin, (e) fucose in combination with pectin, (f) fucoidan having a high percentage of fucose, or (g) a combination of rhamnose, fucose and pectin in the manufacture of a medicament for enhancing the activity or 30 increasing the growth of probiotic ia having a pdu-operon in the gastrointestinal tract of an individual.
8. The use of claim 7 wherein the ia having the pdu-operon are Lactobacilllus reuteri.
9. The use of claim 7 or 8, wherein the substance is ated for administration at a daily dose of 025-25 g.
10. The use of claim 9, n the substance is formulated for administration at a daily dose of 1-2 g.
11. The use of any one of claims 7 to 10, which is for use in combination with galactooligosaccharides or other saccharides comprising galactose. 10
12. A composition comprising bacteria having a pdu—operon and a substance that can be metabolised to 1,2-propanediol comprising (a) rhamnose, (b) fucose, (c) pectin having a high percentage of rhamnose, (d) se in combination with pectin, (e) fucose in combination with pectin, (f) fucoidan having a high tage of fucose, or (g) a combination of rhamnose, fucose and pectin.
13. The composition of claim 12 r comprising galactooligosaccharides or other saccharides comprising galactose.
14. The composition of claims 12 or 13 wherein the bacteria having the pdu-operon are 20 Lactobacilllus reuterz’.
15. The composition of any one of claims 12 to 14 wherein the composition is formulated as a daily dosage form comprising 0.25-25 g of the substance. 25
16. The composition of claim 15, wherein the composition is formulated as a daily dosage form comprising 1-2 g of the substance.
17. The composition of any one of claims 12 to 16 for use in enhancing the activity or increasing the growth of probiotic ia having a pdu—operon, in the gastrointestinal tract of 30 an dual.
18. The non-therapeutic method of claim 1, substantially as herein described with reference to the
NZ613318A 2011-02-23 2012-02-23 Indirect substrates for microorganisms metabolizing 1,2-propanediol NZ613318B2 (en)

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US61/463,846 2011-02-23
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US13/400,735 2012-02-21
US13/400,735 US20120263696A1 (en) 2011-04-14 2012-02-21 Indirect Substrates for Microorganisms Metabolizing 1,2-Propanediol
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