CN103402377A - Indirect substrates for microorganisms metabolizing 1,2-propanediol - Google Patents

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

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CN103402377A
CN103402377A CN2012800099181A CN201280009918A CN103402377A CN 103402377 A CN103402377 A CN 103402377A CN 2012800099181 A CN2012800099181 A CN 2012800099181A CN 201280009918 A CN201280009918 A CN 201280009918A CN 103402377 A CN103402377 A CN 103402377A
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rhamnose
pectin
fucose
probio
pdu
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斯蒂芬·罗斯
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Biogaia AB
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Biogaia AB
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Abstract

The present invention generally relates to enhanced activity of certain probiotics. The increased efficacy is achieved by using certain substrate components that indirectly supply the probiotics with a specific source of energy. The substrate components are specifically designed to stimulate 1,2-propanediol production. The substrate is exemplified with rhamnose, fucose, pectin with a high percentage of rhamnose, and fucodian having a high percentage of fucose.

Description

Indirect matrix for the microbial metabolism 1,2-PD
Technical field
The present invention relates generally to improve the activity of some probio in mammal.In addition, the present invention relates to comprise the preparation of matrix components and some probio, this matrix components is designed to improve the effect of described probio especially.Select matrix components to produce 1,2-PD, most of lactobacillus reuteris (Lactobacillus reuteri) bacterial strain can utilize 1,2-PD as energy source and/or external electrical acceptor.
Background technology
United Nations Food and Agriculture Organization is defined as probio " when using enough quantity, being conducive to the active microorganism of host's health ".Nowadays, many different bacteriums are used as probio, for example, and such as the Bacillus acidi lactici of lactobacillus (Lactobacillus) bacterial strain and Bifidobacterium (Bifidobacterium) bacterial strain.
The validity of probio is that bacterial strain is specific, and each bacterial strain all can be beneficial to by different mechanism host's health.Different probios can stop or suppress pathogen propagation, stop the pathogen virulence factor generation, be adjusted in the immune response in proinflammatory mode or anti-inflammatory mode and affect the host in multiple other modes.
Prebiotics is defined as " stodgy dietary supplements, growth and/or the activity of the bacterium in colon that can improve host health of its or limited quantity a kind of by selective stimulating, and affect valuably the host.”。For the target of prebiotics normally Bifidobacterium and Bacillus acidi lactici; Therefore yet prebiotics is not often optionally, may be difficult to realize the spread effect of useful Pseudomonas or independent probiotics strain.Owing to being difficult to find to some probio prebiotics selectively, therefore the present inventor has found how to use specific matrix components (SSC), and this specific matrix components indirectly provides energy source for specific probio and/or can increase the external electrical acceptor of energy yield.
Lactobacillus reuteri is a kind of Bacillus acidi lactici of heterofermentation, and it is found in the intestines and stomach of the be everlasting mankind and other animals.Lactobacillus reuteri is considered to a kind of intrinsic organism in human gastrointestinal tract, on the mucous membrane that is present in body of stomach, stomach hole, duodenum and ileum.Refer to for example U.S. Patent number 5439678,5458875,5534253,5837238 and 5849289.While under there is the oxygen free condition of glycerine in the lactobacillus reuteri cell, growing, their produce the antibacterial material that is called as reuterin (beta-hydroxy propionic aldehyde).The ability that produces reuterin is utilized the pdu operon owing to propane diols.This pdu operon is a kind of metabolic mechanism that also can grow on 1,2-PD (PD).In the people and while excavating whole potential of bacterium, this pdu operon is very important feature for lactobacillus reuteri when bacterial reproduction.This mechanism is rare in other Bacillus acidi lacticis, so those do not have the Bacillus acidi lactici of pdu mechanism in the upper growth of 1,2-PD, can not use 1,2-PD as electron acceptor.
Different lactobacillus reuteri bacterial strains have the ability of breeding in enteron aisle, as the inhibitor of bacterial pathogens, play a part the diarrhea treatment agent and regulating intestinal canal is wriggled, and are gastrointestinal tract mucous etc. as the immunological regulation of stomach antiinflammatory.
In patent application WO2009/151391, before lyophilised bacteria, with 1,2-PD or glycerine, cause the pdu mechanism of lactobacillus reuteri.According to this designing for manufacturing, the pdu mechanism of the lactobacillus reuteri of freeze-drying has the primer ability that produces and store reuterin.
Emma
Figure BPA0000175378860000031
Deng the people at " control of phosphoketolase path to the lactobacillus reuteri 55730 that contains the glycolysis dual path " (Journal of Bacteriology, Jan2008, described the growth performance that can improve the lactobacillus reuteri on glucose as the fructose of external electrical acceptor by adding in p.206-212).Yet, this piece article not instruction based on some SSC of ability How to choose of 1,2-PD is provided for some probio indirectly, this 1, the bacterium that 2-PD can only be had pdu mechanism utilizes.
The FAQs of probiotic oral is, probio, remains the quantity of probio in their enteron aisle of effect and/or active not enough.Therefore, people may have to increase the consumption of probio and/or needs administration of probiotics more continually, and may also can cause loss of activity.The health advantages that has caused so unnecessary cost, unwanted absorption frequency and/or reduction.In the present invention, improve local amount and/or metabolic activity such as lactobacillus reuteri, caused such as the possibility that reduces the probio consumption, made further the health advantages of site guiding become possibility.
1,2-PD (1,2-PD) be a kind of energy source, this energy source can produce and utilize by other microorganisms that coexist are local, or by some probio kind, for example the carbohydrate of lactobacillus reuteri and interpolation is used in combination.The present inventor finds surprisingly by oral very selectively SSC, can stimulate those microorganisms 1 that coexists, 2-PD, and then indirectly utilize for example activity of lactobacillus reuteri organism raising 1,2-PD.
Pectin is a kind of polysaccharide from plant cell wall.In cell membrane, multiple pectin polysaccharide be can detect, homotype galacturonic acid glycan (HG), xylogalacturonase (XGA), apiose galacturonic acid glycan (apiogalacturonan), rhamnose galacturonic acid glycan I (RGI) and rhamnose galacturonic acid glycan II (RGII) comprised.Ratio between HG, XGA, RGI and RGII is variable, but usually, HG is the abundantest polysaccharide, and it comprises about 65% pectin, and RGI comprises 20% to 35%, and XGA and RGII are microcomponent, respectively comprise less than 10%.Different pectin polysaccharides is not independent molecule, but the territory that covalent bond is connected.Find that the L-rhamnose is as the composition in pectin structure RGI and RGII.Also find that L-fucose is as the composition in the RGII structure.The bacterium that can change L-rhamnose or L-fucose of finding in intestines and stomach belongs to for example Bacteroides and Enterobacter, comprises the Escherichia coli bacterium.
Pectin is anti-human body digestion, the saccharogenesis but it can be degraded, then by the bacterial metabolism in small intestine and colon, be further 1,2-PD.Pectin stimulates the growth of bacterium in small intestine and colon.Pectin uses as treatment diarrhoea, with to improve intestinal environment relevant, and also has as everyone knows anti-cancer properties.The citrus pectin (MCP) of improvement is the citrus pectin that can be biodegradable into not too complicated molecule, and for growth and the propagation of supportint cell.
Fucoidin is a kind of controlling sulfate polyose, it is mainly in different types of brown seaweed and brown seaweed, in for example deliver vegetables in sea, sea-tangle, multitude mother, millet (moui), bladder-wrack, undaria pinnitafida and sheep dwell dish, find, comprise the variant form of also having found fucoidin in the animal species of sea cucumber.Galactooligosaccharide (GOS) with terminal glucose unit generally includes a series of by the galactose units that occurs in continuous Transglycosylation, and galactooligosaccharide is classified as to beneficial rhzomorph.
The people such as Lynch MB are at " but the derivative laminarin of the sea-tangle of diet and fucoidin are on impact of the nutrition digestion of pig and absorbability, nitrogen utilization, stomach microbiologic population, Vfa Concentration " (J Sci Food Agric.2010Feb; 90 (3): 430-7), find to provide the pig that comprises the fucoidin diet, with the pig that does not contain the fucoidin diet, compare, the Bacillus acidi lactici that has increased in proximal colonic and lower distal colon.Show that thus fucoidin can provide a kind of diet style to improve the intestinal health of pig.Based on lactobacillus in the excreta of fucoidin meals increase, also by people such as J.V.O ' Doherty, in " weanling piggy diet laminarin and fucoidin are on performance and the selected overall impact of excremental microorganism group " (Livestock science2010September), found.
Yet, people did not know that quantity based on L-rhamnose and/or L-fucose was to produce 1 by bacterial fermentation in the past, 2-PD selects, for example pectin and fucoidin or its fragment, do not know to use this high desoxysugar content that has yet, the composition of especially high L-rhamnose and/or L-fucose content, can cause 1 of high-load, 2-PD, thereby be certain microorganism indirectly, for example lactobacillus reuteri provides energy source and/or external electrical acceptor, and most other microorganisms can not utilize this external electrical acceptor owing to lacking pdu mechanism.
Patent application WO2010/117274 relates to a kind of carbohydrate, and this carbohydrate can be induced the detectable increase of C5 and/or C6 SCFA (SCFA).This SCFA has good effect on treatment experimenter's gastrointestinal health.The carbohydrate that uses comprises pectin.Even they select to comprise the pectin of micro-rhamnose, they are How to choose and use specific pectin with high-load L-rhamnose or L-fucose indirectly to provide specific energy source and/or external electrical acceptor as the probio with pdu mechanism openly also, thereby improves their activity.
U.S. Patent number 7101565 relates to a kind of composition that comprises prebiotics and probio, and this prebiotics can comprise pectin or pectin polysaccharide.Yet should invention disclose some pectin of How to choose or combining pectin and L-rhamnose or L-fucose use, and can in intestines and stomach, produce 1 of high-load, 2-PD, be of value to the probio with pdu mechanism.
U.S. Patent number 5902578 disclose relate to a kind of by using for example relevant diarrhoea of rotavirus of Bacillus acidi lactici prevention and infectious agent, or the method for the diarrhoea relevant with antibiotherapy.Yet Bacillus acidi lactici is irrelevant with the SSC that adds for better curative effect in this invention.
Nobody openly, how by with probio, for example using SSC to improve the health promotion effect of some probio together with lactobacillus reuteri, provides unique energy source and/or external electrical acceptor for this probio indirectly up to now; Oral SSC can guarantee the supply of 1,2-PD together with the L-rhamnose of high-load and/or L-fucose, thereby indirectly for some prebiotics, provides the energy and/or external electrical acceptor.This will increase sanatory microorganism, the local quantity of lactobacillus reuteri for example, and better curative effect is provided, make the site guide effect become possibility.
Even known before that same probio used for example pectin together, but in the past and do not know how based on the ability that forms 1,2-PD, to select SSC, be used to some probio that specific energy source and/or specific external electrical acceptor are provided indirectly.
Summary of the invention
The invention discloses a kind of the improve method of some probiotic active and manufacture and the use of product, described product comprises matrix components and probio arbitrarily.Product of the present invention can be used for improving the activity of the lactobacillus reuteri in mammal for example.Described product can be used for improving host's health.According to the probiotics strain that uses; described product can be used for for example improving gastrointestinal health; improve and Ia health; treat and/or prevent diarrhoea and constipation; make excremental denseness normalization; promote gastrointestinal peristalsis, treat and/or prevent communicable disease, regulate inflammation and antiviral effect.
By stimulation coexist microorganism with produce 1,2-PD (1,2-PD) can realize the raising of probiotic effect.The microorganism that coexists is stimulated by certain specific matrix components (SSC) described here.Described SSC guarantees in intestines and stomach 1, the existence of 2-PD, and indirectly for some beneficial organism body, provide 1,2-PD.
For the bacterium with pdu mechanism, utilize 1,2-PD as the energy and/or be unique as the ability of external electrical acceptor, so SSC use the activity that only can improve some probio.
SSC can use together with probio, for improving the activity of the probio of jointly using.SSC also can use separately, for example in order to improve the activity of the probio of using before.
Use separately 1,2-PD or by SSC produce 1,2-PD, can further be combined with galactooligosaccharide (GOS) or other galactolipins that contains carbohydrate, thereby provide better energy source for microorganism.
The Bacillus acidi lactici of heterofermentation uses phosphoketolase path (PKP) to produce lactic acid, ethanol and carbon dioxide.With Embden-Meyerhof path (EMP), compare, PKP has low energy yield.This defect can make up by adding the external electrical acceptor.
The wonderful discovery of the inventor, by guaranteeing in intestines and stomach, there is 1,2-PD, can be simultaneously for probio provides suitable external electrical acceptor, thereby improve the activity of probio.
SSC of the present invention optionally improves for example growth of lactobacillus reuteri of Bacillus acidi lactici of heterofermentation, and being provides a kind of and can carry highly active suitable external electrical acceptor because SSC can be bacterium.
Lactobacillus reuteri relies on good electron acceptor for growth under some environment, the present inventor is surprised to find 1,2-PD can serve as a kind of good electron acceptor, and provides by using SSC.
According to an aspect of the present invention, provide a kind of side that has the probiotic active of pdu operon for improving intestines and stomach at individuality to wash, described method comprises to individuality uses a kind of material, and described material has the ability that is metabolised to 1,2-PD in the intestines and stomach of individuality.
In an embodiment of described method, described material comprises desoxysugar, and described desoxysugar has the ability that is metabolised to 1,2-PD in the intestines and stomach of individuality.In this embodiment, described desoxysugar is rhamnose or fucose.
In an embodiment of described method, described material comprises that (a) rhamnose, (b) fucose, (c) have the rhamnose of the pectin of a high proportion of rhamnose, (d) combining pectin, the fucose of (e) combining pectin, (f) and have the fucoidin of a high proportion of fucose or (g) combination of rhamnose, fucose and pectin.
In one embodiment of the invention, the pectin that will have a high proportion of rhamnose is defined as the rhamnose that comprises 5-15%, for example 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% or 15% rhamnose.In one embodiment of the invention, will have the fucoidin of the algae sugar of rock at high proportion and be defined as the fucose that comprises over 15%.
In an embodiment of described method, described material is used simultaneously with the bacterium with pdu operon.
In a preferred embodiment of the invention, individual oral described material.
In another preferred embodiment of described method, the bacterium with pdu operon comprises lactobacillus reuteri.
In an embodiment of described method, it is 0.25-25g that described material is administered to individual daily dose, preferred 1-2g.
In one embodiment of the invention, described method further comprises other carbohydrate of using simultaneously galactooligosaccharide or comprising galactolipin.
According to a second aspect of the invention, a kind of material is provided, described material has the growth of the probio of pdu operon for the active or increase that improves the probio with pdu operon, described probio is in the intestines and stomach of individuality, described material comprises having the desoxysugar that is metabolised to the ability of 1,2-PD in the intestines and stomach of individuality.
In one embodiment, described desoxysugar is rhamnose or fucose.
In one embodiment of the invention, described material comprises that (a) rhamnose, (b) fucose, (c) have the rhamnose of the pectin of a high proportion of rhamnose, (d) combining pectin, the fucose of (e) combining pectin, (f) and have the fucoidin of a high proportion of fucose or (g) combination of rhamnose, fucose and pectin.
In one embodiment of the invention, the pectin that will have a high proportion of rhamnose is defined as the rhamnose that comprises 5-15%, for example 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% or 15% rhamnose.The fucoidin that in one embodiment of the invention, will have an a high proportion of fucose is defined as and comprises and surpass 15% fucose.
In relating to a preferred embodiment of described material, the bacterium of the described pdu of having operon is lactobacillus reuteri.
In one embodiment of the invention, it is 0.25-25g that described material is administered to individual daily dose, preferred 1-2g.
In one embodiment of the invention, described material is with galactooligosaccharide or comprise that other carbohydrate of galactolipin is combined with.
According to a third aspect of the invention we, provide a kind of composition, described composition comprises that (i) has the bacterium of pdu operon and (ii) material of desoxysugar, and described desoxysugar has the ability that is metabolised to 1,2-PD in the intestines and stomach of individuality.
In one embodiment, described composition comprises the bacterium with pdu operon, and pectin, the rhamnose of (d) combining pectin, the fucose of (e) combining pectin, (f) that described bacterium and (a) rhamnose, (b) fucose, (c) have an a high proportion of rhamnose has the fucoidin of a high proportion of fucose or (g) the combining of combination of rhamnose, fucose and pectin.
In one embodiment of the invention, the pectin that will have a high proportion of rhamnose is defined as the rhamnose that comprises 5-15%, for example 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% or 15% rhamnose.The fucoidin that in one embodiment of the invention, will have an a high proportion of fucose is defined as and comprises and surpass 15% fucose.
In another embodiment, described composition further comprises galactooligosaccharide or comprises other carbohydrate of galactolipin.
In an embodiment relevant with described composition, the bacterium of the described pdu of having operon is lactobacillus reuteri.
In an embodiment of composition, the daily dose of using of described material is 0.25-25g, is preferably 1-2g.
According to another embodiment of the invention, above-mentioned composition has the growth of the probio of pdu operon for the active or increase that improves the probio with pdu operon, and described probio is in the intestines and stomach of individuality.
The accompanying drawing explanation
Fig. 1 is being added with 1 for showing lactobacillus reuteri DSM17938, the chart of growth in the MRS of the improvement of 2-PD, galactolipin and composition thereof (without glucose and citrate).
The specific embodiment
Some probio, wherein for example propane diols utilization (pdu) mechanism of lactobacillus reuteri can the 1,2-PD as energy source (1,2-PD) upper growth, and make it have the ability of 1,2-PD as the external electrical acceptor of utilizing.
The present inventor is surprisingly found out that a kind of method that improves some probiotic active, the method uses some specific matrix components (SSC) indirectly to provide 1 as specific probiotic organism, 2-PD, 1,2-PD can be used as energy source or external electrical acceptor.
SSC is a kind of material.According to one embodiment of present invention, this material is a kind of matrix.In one embodiment, this material only has a kind of component to form.In another embodiment, this material comprises two or more components.
Oral well-chosen SSC stimulation coexists microorganism to produce 1,2-PD, and this causes local 1, the 2-PD of generation, and 1,2-PD can be used as some microorganism with pdu mechanism, for example the energy source of lactobacillus reuteri or external electrical acceptor.SSC can use separately, or uses together with probio.
As shown in Figure 1, the existence of 1,2-PD has improved the growth conditions of certain micro-organisms, and the inventor finds that the existence of galactooligosaccharide (GOS) or galactolipin can further improve the microbial growth condition in addition.
SSCs of the present invention is chosen as and can indirectly for specific probio provides, can be used as 1 of energy source or external electrical acceptor, 2-PD.The present inventor finds that it is the most effective having the L-rhamnose of high-load and the SSC of L-fucose when improving some probio active.Therefore the SSC that uses in the present invention considers the content of L-rhamnose and L-fucose and well-chosen.
Pectin, preferably some comprises the pectin fragments of a high proportion of L-rhamnose, for example rhamnose galacturonic acid glycan I and II, can be used as SSC and use.Preferably, these preferred pectin fragments comprise the rhamnose of 5-15%.When degraded, these pectin fragments produce than the more rhamnose of unsegregated pectin, and unsegregated pectin is called pectin, common pectin or conventional pectin in this article.Certain daily dose such as the 2g of this preferred pectin fragments, with comparing of the identical daily dose of conventional pectin, can produce 1 of high-load more, 2-PD.If, while together with L-rhamnose or L-fucose, using, also can use common pectin, indirectly and in an identical manner to be of value to certain micro-organisms, for example lactobacillus reuteri.Except outside 1,2-PD, this combination also can be for some probio provides other matrix, for example as galactolipin, arabinose and the galacturonic of pectin degrading result.As shown in Figure 1, the present inventor demonstrates 1,2-PD and some pectin composition, for example galactolipin, arabinose and galacturonic combine and have produced cooperative effect, and this cooperative effect is for some probio, for example lactobacillus reuteri, improved 1,2-PD utilization rate.
Fucoidin, preferably some fucoidin fragment with L-fucose of high-load is used in the present invention as SSC.Preferably, these fucoidin fragments comprise the fucose over 15%.When the fucoidin segment degradation, these fucoidin fragments produce more fucose than common fucoidin, thereby produce 1 of greater number, 2-PD.
Independent L-rhamnose or L-fucose also can be used as SSC of the present invention and use separately.
If according to the present invention, comprise L-rhamnose, L-fucose or analog, can use other SSC, for example natural gum and other polysaccharide.Natural gum include but not limited to karaya and Arabic gum.In addition, from the human milk oligosaccharides (HMO ' s) can use in the present invention as SSC of mankind's breast milk.
The present invention namely can use separately SSC, also can the same probio, for example lactobacillus reuteri is used together, to guarantee the existing of external electrical acceptor that provides and/or guarantee to improve energy yield for the energy source of specific probio, thereby improve activity and the effect of described probio.
In other embodiments, in order to support this effect, can also add GOS or galactolipin and to improve lactobacillus reuteri, utilize the ability of 1,2-PD.
According to target indication, in this present invention, used and multiplely had different reproductive in the lactobacillus reuteri bacterial strain of enteron aisle ability, serve as the diarrhea treatment agent, regulating intestinal canal is wriggled; As the bacterial pathogen inhibitor, immunological regulation is gastrointestinal tract mucous, under one's belt as antiinflammatory etc.
Pectin, L-rhamnose and L-fucose are anti-human body digestion, the saccharogenesis but it is degraded, further by the microbial metabolism that coexists, be for example 1 again, the 2-propane diols, in human body and may be in some position of human gastrointestinal tract, for example on the mucous membrane of body of stomach, stomach hole, duodenum and small intestine, find to coexist microorganism.Therefore the invention enables the site guide effect that is supported in human gastrointestinal tract to become possibility.For example use selected lactobacillus reuteri bacterial strain as probio, can improve the antiinflammatory action of this bacterial strain in ileum.
When using certain SSC system of describing in the present invention, for example has the very interior a kind of specific lactobacillus reuteri bacterial strain of human body of abnormal microbial flora, comprise lack normal discovery SSC can be converted into to 1, the microorganism that coexists of 2-PD, this be also of the present invention another may be with energetically by this microorganism that coexists, for example rhamnose lactic acid bacteria offers the recipient of the effect of guaranteeing the SSC that uses.
To comprise or independent or preferably make tablet, capsule, pulvis bag or analog in conjunction with the product of the SSC of the present invention of some probio.This product can be food supplement, pharmaceutical products or analog.In this product, the quantity of probiotic feed should be the quantity that enough realizes this specific bacterial strain Expected Results and consider the effect that improves by SSC.This standard normally, but is not limited to 10E+4CFU to 10E+11CFU every day, and preferably the scope of lactobacillus reuteri is 10E+6CFU to 10E+9CFU.
When use had the pectin of the L-rhamnose of high-load and/or L-fucose, the amount of SSC should be in the scope of 0.25 to 25 gram (g) every day.When using the composition of conventional pectin and independent L-rhamnose and/or L-fucose, the total amount of SSC should be in the scope of every day 0.25 to 25g.In above-mentioned two situations, the daily dose of 0.25-25g can be for example 0.25,0.5,1,1.5,2,5,10,15,20 or 25g, is preferably 1-2g, for example 1,1.25,1.5,1.75 or 2g.Any in conventional pectin and L-rhamnose or L-fucose, or the ratio of its composition should be in the scope of 95:5 to 0:100, but be preferably 80:20 to 20:80, more preferably 70:30.
When using another selection when of the present invention, be alternative supply SSC and probio together, and according to the first mode of supplying with, with ALP, only supply with SSC in one or more occasions, thereby reduce treatment cost.
For the present invention, the probio of use has pdu mechanism and also is absolutely necessary, because this is necessary for using 1,2-PD as the ability of energy source and/or external electrical acceptor.Therefore in another embodiment of the present invention, in the process that probiotics strain is produced, with 1,2-PD, cause the pdu mechanism of probio to improve effect.This is when culture of bacteria, and when fermentation step started, 1,2-PD or glycerine and possible cobalt or vitamin B-12 (because vitamin B-12 and cobalt are very important to producing reuterin) realized by adding.According to this designing for manufacturing, the bacterium of the freeze-drying that will will use in lower step is better prepared to activate more quickly pdu mechanism.The effect of this enhancing of pdu mechanism can improve the effect of the SSC that the present invention uses in turn.The another kind of method that improves the effect of the SSC that uses is to be combined with GOS or galactolipin, and the growth in conjunction with to lactobacillus reuteri that the present invention has demonstrated 1,2-PD and galactolipin has beyond thought benefit.
Due to many modifications with change those skilled in the art is easily expected, therefore do not wish to limit the invention to concrete structure and operation shown and that describe, therefore, the equivalent of all modifications that are suitable for and employing all falls in the scope of the present invention of appending claims restriction.
Embodiment 1
Contain lactobacillus reuteri and pectin, rhamnose and galactooligosaccharide composition the bag manufacture
The composition of composition:
Lactobacillus reuteri DSM17938:10E+8CFU/ bag
Pectin ( Pectin (plant of citrus) USP/200 type, France, Si Bikai can the French CP Kelco France SARL of Co., Ltd): the 840mg/ bag
L-rhamnose: (card is stepped on the Kaden Biochemicals GmbH of biochemicals limited company for rhamnose monohydrate L-(+), Hamburg, Germany) 360mg/ bag
GOS15 (
Figure BPA0000175378860000152
Dutch royal Fei Shilan Dairy Company FrieslandCampina Domo) 800mg/ bag
(10cm x12em uses in packaging material PET12/PE/ALU12/PE/PE+ drier from ALCAN(Aluminium Company of Canada (Alcan)/PE) in LAF workbench (from Horton tabular molding (the Holten Laminair Model) S-20101.2 of Denmark Heto-Holten A/S), at room temperature composition and drier to be loaded into to aluminium foil bag well known in the art.The XP-600 balance that uses German Denver instrument limited company (Denver Intrument GmbH) is to the powder that adds lactobacillus reuteri, pectin, L-rhamnose and the galactooligosaccharide of 2g in each sack.Then by German Kettenbaum Folienschweisstechnik GmbH& The aluminium foil bag that the diaphragm seal device model F460/2 heat-seal of Co.KG is filled in.
Embodiment 2
Contain lactobacillus reuteri and rhamnose composition the bag manufacture
The composition of composition:
2g L-rhamnose: (card is stepped on the Kaden Biochemicals GmbH of biochemicals limited company for rhamnose monohydrate L-(+), Hamburg, Germany) every bag contained 10E+8CFU lactobacillus reuteri DSM17938
The mode of composition by embodiment 1 is loaded in aluminium foil bag.
Embodiment 3
Contain lactobacillus reuteri and galactooligosaccharide and rhamnose composition the bag manufacture
The composition of composition:
1g GOS15 (
Figure BPA0000175378860000161
Dutch royal Fei Shilan Dairy Company FrieslandCampina Domo) and 1g L-rhamnose: (rhamnose monohydrate L-(+), Hamburg, Germany, card is stepped on the Kaden Biochemicals GmbH of biochemicals limited company) every bag contain 10E+8CFU lactobacillus reuteri DSM17938.
The mode of composition by embodiment 1 is loaded in aluminium foil bag.
Embodiment 4
The manufacture of the lactobacillus reuteri bacterial strain that causes
The present embodiment has been described the freeze dried powder of lactobacillus reuteri how to manufacture the pdu mechanism with activation.When bag of production example 1-3, can use the lactobacillus reuteri bacterial strain of initiation.
Fermentation medium forms
Dextrose monohydrate 60g/l
Yeast extract KAV20g/l
PS type peptone (the pig source) 20g/l
Diammonium hydrogen citrate 5g/l
Sodium acetate (x3H 2O) 4.7g/l
Dipotassium hydrogen phosphate 2g/l
Tween 80 0.5g/l
Silibione (anti-foam) 0.14g/l
Magnesium sulfate 0.10g/l
Manganese sulfate 0.03g/l
ZINC SULFATE HEPTAHYDRATE 0.01g/l
Suitable quantity of water
Centrifugal medium
Peptone 0-24Orthana (the pig source)
Antifreezing agent
Lactose (Niu Laiyuan's) 33%
Gelatin hydrolysied matter (Niu Laiyuan's) 22%
Sodium glutamate 22%
Maltodextrin 11%
Ascorbic acid 11%
The production stage of the lactobacillus reuteri pulvis of freeze-drying
1, the lactobacillus reuteri pulvis inoculation of the fermentation medium of 20ml from the 0.6ml freeze-drying of working cardial cell storehouse bottle.At 37 ℃ of 18-20 hour that ferment in bottle, do not stir or the control of pH value, that is, static.
2, the fermentation medium of two 1 liter of flasks is inoculated with every liter of 9ml cell slurries (from step 1).Fermentation is carried out 20-22 hour at 37 ℃, do not stir or the control of pH value, that is, static.
3, will be used for being inoculated into 600 liters of containers that contain 600 liters of fermentation mediums from two one liter of cell slurries of step 2.Fermentation was carried out 13 hours at 37 ℃, with stirring and the control of pH value.When fermentation started, the pH value was 6.5.When the pH value is brought down below 5.4, utilize 20% sodium hydroxide solution to start the pH value and control.The pH value is controlled and is arranged on pH5.5.
4, the 4th and final fermentation step with the inoculum of step 3, in 15000 liters of containers, carry out.At 37 ℃, fermented 9 to 12 hours, with stirring and the control of pH value.When fermentation started, the pH value was 6.5.When the pH value is brought down below 5.4, utilize 20% sodium hydroxide solution to start the pH value and control.The pH value is controlled and is set to pH5.5.Before culture was about to reach stationary phase, 100mM glycerine added among the latter stage of fermentation.When culture arrives stationary phase, fermentation completes, and can find out by the reduction that sodium hydroxide solution adds stationary phase.During fermentation, the sodium hydroxide solution of about 930 liters adds in the inoculum of the culture medium of 10200 liters and 600 liters.
Cell slurries from final fermentation (step 4) separate twice under 10 ℃ in the continuous centrifuge from Alfa Laval.By centrifugal first, the volume of cell slurries from approximately 11730 liters be reduced to 1200 liters.This volume in 3000 liters of containers with 1200 liters of peptones (Peptone0-24, Orthana) solution washing, with again separate before antifreezing agent (seeing below) mixes.Carry out the washing step of peptone to avoid any freezing point in freeze-drying process to reduce.
By centrifugal for the second time, the volume of cell slurries is reduced to 495 liters.This volume mixes with the antifreezing agent solution of 156kg, reaches the cell slurries of about 650 liters.
The cytoplasm liquid pump is delivered in 1000 liters of containers.Then this container is transported to freeze-drying factory.
In freeze-drying factory, just the cell slurries of 2 liters are poured on each flat board of freeze-dryer.The heap(ed) capacity of freeze-dryer is 600 liters, and all too much cell slurry volume are discarded.
The cell slurries dry matter content of lactobacillus reuteri is 18%, freeze-drying four to five days.
In freeze-drying process, the pressure in described process is between 0.176mbar and 0.42mbar.When reaching 0.42mbar, opens pressure vavuum pump.When process completes, use PRT (sealing test) to measure.If the raising of PRT or pressure lower than 0.02mbar, stopped this process after 120 seconds.
Embodiment 5
The composition of 1,2-PD and galactolipin produces the synergy of the activity that improves lactobacillus reuteri
Lactobacillus reuteri DSM17938 is growth in the MRS meat soup (not containing glucose and citrate) of the improvement of having added 1,2-PD (0.3%), galactolipin (0.3%) or the composition of the two.Bacterium was 37 ℃ of growths 24 hours.As shown in Figure 1, at 1,2-PD and galactolipin, all exist the lactobacillus reuteri of lower growth to demonstrate significantly higher growth than the lactobacillus reuteri of growing in independent material.
Embodiment 6
The embodiment of the ALP of supplying with
Due to the raising of the described lactobacillus reuteri activity of being induced by SSC of the application, make in ALP the sack of embodiment 1 (A bag) and the sack that does not contain lactobacillus reuteri of otherwise manufacturing according to embodiment 1 (B bag) are alternately become to possibility.This ALP can not reduce the effect of lactobacillus reuteri, and can reduce treatment cost.
At the 1st day, to the recipient, use the A bag, at the 2nd day and the 3rd day, to the recipient, use the B bag.During whole treatment, repeat this application program.
Embodiment 7
Enteron aisle breeding in human body
In clinical research, done one in the comparison of independent lactobacillus reuteri with enteron aisle breeding between identical lactobacillus reuteri and SSC use together.The volunteer of 12 health is become to two groups (A group and B groups) take 6 participants as a component.A group is accepted the sack of embodiment 1, and this sack comprises lactobacillus reuteri and with the composition of the SSC of pectin, rhamnose and galactooligosaccharide form.The B group is accepted identical lactobacillus reuteri bacterial strain but be there is no above-mentioned SSC.Every day, each organized the lactobacillus reuteri of taking 10E+8CFU in 60 days.While by the research during treating, starting, after 30 days and after 60 days to faecal samples inspection make and giving separately or the quantitative assessment of enteron aisle breeding while giving bacterial strain together with SSC.By excremental lactobacillus reuteri counting, and the excremental amount that relatively A organizes and B organizes.
As shown in table 1, with the patient who only uses lactobacillus reuteri, to compare, the excremental amount of lactobacillus reuteri of using the patient of lactobacillus reuteri together with SSC demonstrates significant increase.The average log of the every gram excreta ± SEM of the numeric representation that provides 10The value of CFU.
Table 1
Figure BPA0000175378860000211

Claims (17)

1. method of activity that has the probio of pdu operon for improving intestines and stomach at individuality, described method comprises to individuality uses a kind of material, and described material has the ability that is metabolised to 1,2-PD in the intestines and stomach of individuality.
2. method according to claim 1, wherein, described material comprises that (a) rhamnose, (b) fucose, (c) have the rhamnose of the pectin of a high proportion of rhamnose, (d) combining pectin, the fucose of (e) combining pectin, (f) and have the fucoidin of a high proportion of fucose or (g) combination of rhamnose, fucose and pectin.
3. method according to claim 1 and 2, wherein, described material is applied simultaneously with the bacterium with pdu operon.
4. according to arbitrary described method in aforementioned claim, wherein, the bacterium of the described pdu of having operon comprises lactobacillus reuteri.
5. according to arbitrary described method in aforementioned claim, wherein, it is 0.25-25g that described material is administered to individual daily dose, preferred 1-2g.
6. according to arbitrary described method in aforementioned claim, described method further comprises other carbohydrate of using simultaneously galactooligosaccharide or comprising galactolipin.
7. material that has probio active of pdu operon or increase the growth of the probio with pdu operon for improving intestines and stomach at individuality, described material comprises a kind of desoxysugar that is metabolised to the ability of 1,2-PD in the intestines and stomach of individuality that has.
8. material according to claim 7, described material comprise that (a) rhamnose, (b) fucose, (c) have the rhamnose of the pectin of a high proportion of rhamnose, (d) combining pectin, the fucose of (e) combining pectin, (f) and have the fucoidin of a high proportion of fucose or (g) combination of rhamnose, fucose and pectin.
9. arbitrary described material according to claim 7 to 8, wherein, the bacterium of the described pdu of having operon is lactobacillus reuteri.
10. it is 0.25-25g that arbitrary described material according to claim 7 to 9, described material are administered to individual daily dose, preferred 1-2g.
11. arbitrary described material according to claim 7 to 10, described material are with galactooligosaccharide or comprise that other carbohydrate of galactolipin is combined with.
12. a composition, described composition comprise the bacterium with pdu operon and the material that comprises desoxysugar, described desoxysugar has the ability that is metabolised to 1,2-PD in the intestines and stomach of individuality.
13. composition according to claim 12, described composition comprises the bacterium with pdu operon, and has the fucoidin of a high proportion of fucose or (g) combination of rhamnose, fucose and pectin with pectin, the rhamnose of (d) combining pectin, the fucose of (e) combining pectin, (f) that (a) rhamnose, (b) fucose, (c) have an a high proportion of rhamnose.
14. according to claim 12 or 13 described compositions, described composition further comprise galactooligosaccharide or comprise other carbohydrate of galactolipin.
15. according to claim 12 to arbitrary described composition in 14, wherein, the bacterium of the described pdu of having operon is lactobacillus reuteri.
16. according to claim 12 to arbitrary described composition in 15, wherein, described material use daily dose 0.25-25g, be preferably 1-2g.
17. according to claim 12 to arbitrary described composition in 16, the growth that described composition has probio active of pdu operon or increases the probio with pdu operon for improving intestines and stomach at individuality.
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