CN107736614A - Nutritional preparation containing butyric acid - Google Patents
Nutritional preparation containing butyric acid Download PDFInfo
- Publication number
- CN107736614A CN107736614A CN201710757264.5A CN201710757264A CN107736614A CN 107736614 A CN107736614 A CN 107736614A CN 201710757264 A CN201710757264 A CN 201710757264A CN 107736614 A CN107736614 A CN 107736614A
- Authority
- CN
- China
- Prior art keywords
- butyric acid
- nec
- preparation
- butyrate
- nutritional preparation
- Prior art date
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- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 title claims abstract description 345
- 238000002360 preparation method Methods 0.000 title claims abstract description 116
- 235000016709 nutrition Nutrition 0.000 title claims abstract description 104
- -1 butyric acid compound Chemical class 0.000 claims abstract description 47
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 claims abstract description 36
- 150000004648 butanoic acid derivatives Chemical class 0.000 claims abstract description 34
- 239000000203 mixture Substances 0.000 claims abstract description 19
- 230000012010 growth Effects 0.000 claims abstract description 17
- 235000013350 formula milk Nutrition 0.000 claims description 42
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 41
- 201000010099 disease Diseases 0.000 claims description 36
- 235000013305 food Nutrition 0.000 claims description 34
- MFBOGIVSZKQAPD-UHFFFAOYSA-M sodium butyrate Chemical group [Na+].CCCC([O-])=O MFBOGIVSZKQAPD-UHFFFAOYSA-M 0.000 claims description 29
- 239000011248 coating agent Substances 0.000 claims description 28
- 238000000576 coating method Methods 0.000 claims description 28
- 230000035764 nutrition Effects 0.000 claims description 26
- 235000013336 milk Nutrition 0.000 claims description 22
- 239000008267 milk Substances 0.000 claims description 22
- 210000004080 milk Anatomy 0.000 claims description 22
- 210000000481 breast Anatomy 0.000 claims description 18
- 239000003814 drug Substances 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 15
- 239000000843 powder Substances 0.000 claims description 13
- 239000002253 acid Substances 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 9
- 238000002347 injection Methods 0.000 claims description 9
- 239000007924 injection Substances 0.000 claims description 9
- 235000016236 parenteral nutrition Nutrition 0.000 claims description 9
- 150000004652 butanoic acids Chemical class 0.000 claims description 7
- 230000000474 nursing effect Effects 0.000 claims description 7
- 238000009472 formulation Methods 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 235000020256 human milk Nutrition 0.000 claims description 5
- 210000004251 human milk Anatomy 0.000 claims description 5
- 235000018102 proteins Nutrition 0.000 claims description 5
- 108090000623 proteins and genes Proteins 0.000 claims description 5
- 102000004169 proteins and genes Human genes 0.000 claims description 5
- 239000000243 solution Substances 0.000 claims description 5
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 4
- PQLMXFQTAMDXIZ-UHFFFAOYSA-N isoamyl butyrate Chemical compound CCCC(=O)OCCC(C)C PQLMXFQTAMDXIZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000008101 lactose Substances 0.000 claims description 4
- 235000015097 nutrients Nutrition 0.000 claims description 4
- HNAGHMKIPMKKBB-UHFFFAOYSA-N 1-benzylpyrrolidine-3-carboxamide Chemical compound C1C(C(=O)N)CCN1CC1=CC=CC=C1 HNAGHMKIPMKKBB-UHFFFAOYSA-N 0.000 claims description 3
- JXPHLUCMHXXHEJ-UHFFFAOYSA-N 2-(aminomethyl)-4-bromoaniline Chemical compound NCC1=CC(Br)=CC=C1N JXPHLUCMHXXHEJ-UHFFFAOYSA-N 0.000 claims description 3
- 206010061958 Food Intolerance Diseases 0.000 claims description 3
- 206010067508 Low birth weight baby Diseases 0.000 claims description 3
- 102000014171 Milk Proteins Human genes 0.000 claims description 3
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- 206010036600 Premature labour Diseases 0.000 claims description 3
- 235000020616 amino acid formula Nutrition 0.000 claims description 3
- 150000001413 amino acids Chemical class 0.000 claims description 3
- OBNCKNCVKJNDBV-UHFFFAOYSA-N butanoic acid ethyl ester Natural products CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 claims description 3
- FYPVXEILSNEKOO-UHFFFAOYSA-L calcium;butanoate Chemical compound [Ca+2].CCCC([O-])=O.CCCC([O-])=O FYPVXEILSNEKOO-UHFFFAOYSA-L 0.000 claims description 3
- 235000013339 cereals Nutrition 0.000 claims description 3
- 235000009508 confectionery Nutrition 0.000 claims description 3
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- 125000005456 glyceride group Chemical group 0.000 claims description 3
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- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 3
- 235000020214 lactose-free milk formula Nutrition 0.000 claims description 3
- 239000002960 lipid emulsion Substances 0.000 claims description 3
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- 229940094941 isoamyl butyrate Drugs 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims 1
- 239000003978 infusion fluid Substances 0.000 claims 1
- 239000011591 potassium Substances 0.000 claims 1
- 229910052700 potassium Inorganic materials 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 1
- 206010051606 Necrotising colitis Diseases 0.000 abstract description 167
- 208000004995 necrotizing enterocolitis Diseases 0.000 abstract description 167
- 201000006195 perinatal necrotizing enterocolitis Diseases 0.000 abstract description 167
- 230000000968 intestinal effect Effects 0.000 abstract description 41
- 210000000987 immune system Anatomy 0.000 abstract description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 81
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- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 208000004232 Enteritis Diseases 0.000 description 2
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- MBMBGCFOFBJSGT-KUBAVDMBSA-N all-cis-docosa-4,7,10,13,16,19-hexaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCC(O)=O MBMBGCFOFBJSGT-KUBAVDMBSA-N 0.000 description 2
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- 235000020669 docosahexaenoic acid Nutrition 0.000 description 2
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 2
- 230000001146 hypoxic effect Effects 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- 238000002386 leaching Methods 0.000 description 2
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- 230000007774 longterm Effects 0.000 description 2
- 230000035790 physiological processes and functions Effects 0.000 description 2
- RWMKSKOZLCXHOK-UHFFFAOYSA-M potassium;butanoate Chemical compound [K+].CCCC([O-])=O RWMKSKOZLCXHOK-UHFFFAOYSA-M 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 239000002356 single layer Substances 0.000 description 2
- 210000000813 small intestine Anatomy 0.000 description 2
- 238000012453 sprague-dawley rat model Methods 0.000 description 2
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- DVSZKTAMJJTWFG-SKCDLICFSA-N (2e,4e,6e,8e,10e,12e)-docosa-2,4,6,8,10,12-hexaenoic acid Chemical compound CCCCCCCCC\C=C\C=C\C=C\C=C\C=C\C=C\C(O)=O DVSZKTAMJJTWFG-SKCDLICFSA-N 0.000 description 1
- GZJLLYHBALOKEX-UHFFFAOYSA-N 6-Ketone, O18-Me-Ussuriedine Natural products CC=CCC=CCC=CCC=CCC=CCC=CCCCC(O)=O GZJLLYHBALOKEX-UHFFFAOYSA-N 0.000 description 1
- 206010002660 Anoxia Diseases 0.000 description 1
- 241000976983 Anoxia Species 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
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- 101100136092 Drosophila melanogaster peng gene Proteins 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
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- 108010054147 Hemoglobins Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010022680 Intestinal ischaemia Diseases 0.000 description 1
- 206010022699 Intestinal stenosis Diseases 0.000 description 1
- 108010055717 JNK Mitogen-Activated Protein Kinases Proteins 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- 108010059881 Lactase Proteins 0.000 description 1
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
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- 230000006837 decompression Effects 0.000 description 1
- CYQFCXCEBYINGO-IAGOWNOFSA-N delta1-THC Chemical compound C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 CYQFCXCEBYINGO-IAGOWNOFSA-N 0.000 description 1
- 230000000249 desinfective effect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 229940090949 docosahexaenoic acid Drugs 0.000 description 1
- KAUVQQXNCKESLC-UHFFFAOYSA-N docosahexaenoic acid (DHA) Natural products COC(=O)C(C)NOCC1=CC=CC=C1 KAUVQQXNCKESLC-UHFFFAOYSA-N 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
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- 208000037902 enteropathy Diseases 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
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- 230000004720 fertilization Effects 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
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- 239000000499 gel Substances 0.000 description 1
- 235000004554 glutamine Nutrition 0.000 description 1
- 230000034659 glycolysis Effects 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
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- 210000000214 mouth Anatomy 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 235000020660 omega-3 fatty acid Nutrition 0.000 description 1
- 229940012843 omega-3 fatty acid Drugs 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000009984 peri-natal effect Effects 0.000 description 1
- 206010034674 peritonitis Diseases 0.000 description 1
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- 239000006041 probiotic Substances 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23C—DAIRY PRODUCTS, e.g. MILK, BUTTER OR CHEESE; MILK OR CHEESE SUBSTITUTES; MAKING THEREOF
- A23C9/00—Milk preparations; Milk powder or milk powder preparations
- A23C9/152—Milk preparations; Milk powder or milk powder preparations containing additives
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Landscapes
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Food Science & Technology (AREA)
- Polymers & Plastics (AREA)
- Mycology (AREA)
- Health & Medical Sciences (AREA)
- Nutrition Science (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention provides a kind of nutritional preparation containing butyric acid, including alimentation composition and butyric acid compound, concentration of the butyric acid compound in nutritional preparation is 0.5~200mM (mmol/L).The butyric acid compound is selected from least one of butyric acid, butyrate, butanoic acid derivative.The present invention in alimentation composition by adding butyric acid compound, available for preventing and treating necrotizing enterocolitis, while has the function that to promote growth, developing immune system and intestinal growth ripe.
Description
Technical field
The present invention relates to food technology field, specifically, is related to a kind of nutritional preparation containing butyric acid, specifically includes containing fourth
The nutritional preparation of at least one of acid, butyrate and butanoic acid derivative, available for preventing and treating necrotizing enterocolitis.
Background technology
Necrotizing enterocolitis (necrotizing enterocolitis, NEC) is a kind of intestines for jeopardizing infant life
Tract disease, it is one of major reason of neonatal death, clinically there is no effectively preventing means at present.With perinatal medicine skill
The progress of art, the birth rate and survival rate of premature improve constantly, especially along with joint embryo transfer technology in vitro fertilization
Application, the NEC incidence of disease is in increase trend in recent years.The long-term final result of NEC infants is undesirable, and the death rate is up to 15%-50%,
Even if still often there are the complication such as intestinal stenosis enterostenosis, short bowel syndrome after successfully carrying out operative treatment, the survival of infant is had a strong impact on
Rate and life quality.Therefore, the problem of searching safely and effectively prophylactico-therapeutic measures turns into clinically urgent need to resolve, and clinically
One big difficult point.
Although necrotizing enterocolitis is nominally similar to enteritis, but with traditional enteritis and inflammatory
The entirely different disease of enteropathy, the cause of disease and pathogenesis are different, and prevention and controls are also entirely different.Generally believe that NEC is one at present
Disease caused by kind is multifactor, premature is taken place mostly in, therefore prematurity enteron aisle is the basis that NEC occurs.Occurring NEC's
Generally there are three factors to occur in infant small intestine：Lasting intestine ischemia Hypoxic, substrate (such as enteral nursing), bacterium in enteric cavity
Field planting.Intestinal ischemia Hypoxic can destroy Gut barrie r, cause enteron aisle easily by bacteria attack.With the progress of lesion, can cause
Necrosis, perforation, peritonitis, septicemia and the death of flood intestinal wall.Compared with other intestines problems, NEC morbidity it is more dangerous,
Progress is rapid and the moment jeopardizes infant life.At present, the expectant treatment measure for NEC be mainly fasting, it is gastrointestinal decompression, enough
The use of antibiotic and intravenous nutrition supportive treatment etc..It is however, heavy dose of for a long time and repeated multiple times easy using antibiotic
Infant whole body internal organs are caused damage, it also occur that the problems such as antibiotics resistance and suprainfection.Intravenous nutrition is for existing
NEC risks or infant with NEC are particularly important even unique nutritional supportive paths.But long-term use of intravenous nutrition
Support, also occur that complication causes to be reduced or disable intravenous nutrition.
Due to being faced with many problems in NEC treatment, researchers both domestic and external, which have carried out, largely experimentally to grind
Study carefully with clinical research to explore preventing and treating NEC method.Researchers employ different medicines for each link of NEC mechanisms of causing a disease
Thing or nutriment are intervened, such as growth factor, arginine, glutamine, probiotics, prebiotics, IL-10, how unsaturated
Aliphatic acid etc., although some medicines achieve certain effect in zoopery, due to lacking security and validity
Foundation limits its clinical practice.On the other hand, because artificial feeding is another important risk factor that NEC occurs, manually
Nursing is more easy to that NEC occurs compared with breast-feeding.There are many protective factors, therefore lot of domestic and foreign in breast milk compared with formula milk
Researcher is directed to exploring preventing and treating NEC method by studying the dominant component in breast milk, but effect is not notable.
Butyric acid is the natural component in mammal milk, but content is relatively low, and the metabolite of gut flora in vivo
One of.The one kind of butyric acid as short chain fatty acids, played an important role in terms of enteron aisle normal physiological function is maintained.At some
In intestines problem such as ulcerative colitis, Crohn disease, butyric acid has the function that to alleviate disease symptomses.However, grind for a long time
Study carefully and think that effect of the butyric acid in premature and neonate's enteron aisle is really not so.Premature and neonate have its special physiology
Feature, such as intestinal growth are immature, enterocinesia is poor, alactasia and are frequently accompanied by infecting and suffocating history.Due to stomach and intestine
The shortage of power causes the food residence time to be grown, and easily causes bacterial growth；On the other hand, because small enteral lactase lacks relatively
It is weary, in enteron aisle bacterium by substantial amounts of lactose glycolysis into short chain fatty acids, so as to produce excessive short chain fatty acids and be accumulated in intestines
Intracavitary can not be removed in time.And premature and neonate's intestinal growth are not yet ripe, intestinal barrier function is not perfect enough, high concentration
Short chain fatty acids can cause or aggravate intestinal mucosal injury.Numerous studies confirm excess generation or storage in premature and neonate's enteric cavity
Long-pending short chain fatty acids such as butyric acid is a major reason for causing NEC.For example, research finds to give acetic acid, butyric acid through enteron aisle
Newborn rat is acted on etc. short chain fatty acids, both cause enteron aisle to produce the infringement of NEC samples (Lin J, et with concentrationdependent manner
a1.Variable effects of short chain fatty acidsand lactic acid in inducing
Intestinal mucosal injury in newborn rats.J Pediatr Gastroenterol Nutr.2002,
35(4)：545-550.).The researchs such as Peng find that high concentration butyric acid may cause intestines by increasing the apoptosis rate of enterocyte
Destruction (Peng L, the et a1.Effects of butyrate on intestinal barrier functionin of barrier
A Caco-2cell monolayer model of intestinal barrier.Pediatr Res.2007,61 (1)：37-
41.).Carbonaro etc. has found that high concentration butyric acid causes the rise of its permeability then to cause in enteric cavity by damaging intestinal mucosal barrier
Bacterial translocation (Carbonaro CA, et a1.A bacterial pathogenicity determinant associated
With necrotizing enterocolitis.Microb Pathog.1988,5 (6)：427-436.).Therefore, based on this
A little results of study, short chain fatty acids butyric acid is considered as a key factor for causing NEC for a long time.
In the prior art, Application No. 200880120656.X patent document discloses a kind of improvement gastrointestinal function
Preparation.The patent provides the enteral nutrition rich in protein of addition glutamine, docosahexaenoic acid (DHA) and butyric acid
Formula, for improving gastrointestinal function.High protein can improve enteral nutriment and barrier function in the formula；Add glutamy
Amine is preventing the Apoptosis that intestines source property inflammation and regulation stress be related；Omega-3 fatty acid, such as DHA are added, to prevent intestines
The propagation of source property inflammation；And short chain fatty acids butyric acid is added, to improve intestinal barrier function.The patent is by adding several nutrition
Composition is used to improve gastrointestinal function, and being not directed to also no evidence confirms work of the formula in necrotizing enterocolitis is prevented and treated
With.It is volatile and butyric acid is weak acid, and carry stink.Butyric acid is added directly in enteral nutritional prescription by the patent, not only can
Bring niff into, it is often more important that acidulous material may not have too big influence for normal and ripe enteron aisle, but
Directly adding acidulous material stimulates the immature enteron aisle of newborn individual, especially in the presence of suffering from necrotizing enterocolitis risk
Individual, enteron aisle may be accelerated to be damaged.
Because necrotizing enterocolitis takes place mostly in infant, therefore it is also primarily most that the security of prevention and controls, which is,
Important Consideration, and may cause certain side effect if using conventional medicament intervene, especially as prevention
It is difficult to the accreditation of father and mother or medical worker for obtaining these young objects during purposes.Therefore, it is anti-to find safely and effectively method
Control a big technical barrier of necrotizing enterocolitis.
The content of the invention
The technical problem to be solved in the present invention is, in view of the shortcomings of the prior art, providing a kind of battalion containing butyric acid compound
Preparation is supported, available for preventing and treating necrotizing enterocolitis (NEC).
The present invention is analyzed by the research to prior art, finds some problems.First, although in premature's enteric cavity
Bacterial overgrowth can cause to produce a large amount of short chain fatty acids, but there is no definite clinical evidence to confirm these short-chain fats at present
Specific composition in acid and its effect in NEC.Secondly, research reports that butyric acid can induce enterocyte apoptosis so as to lead
Gut barrie r is caused to destroy (Peng L, et a1.Effects of butyrate on intestinal barrier
functionin a Caco-2cell monolayer model of intestinal barrier.Pediatr
Res.2007,61 (1)：37-41.) (Ruemmele FM, et a1.Butyrate induced Caco-2cell
Apoptosisis mediated via the mitochondrial pathway.Gut.2003,52 (1)：94-100.),
But enterocytes for using is Caco-2 cell lines in these researchs, the cell line derives from colon adenocarcinoma cell, and butyric acid
Originally there is anticancer property can suppress the propagation of cancer cell and promote cancer cell-apoptosis (Mandal M1, et a1.Butyric
acid induces apoptosis by up-regulating Bax expression via stimulation of the
c-Jun N-terminal kinase/activation protein-1pathway in human colon cancer
cells.Gastroenterology.2001Jan；120(1):71-8.).Therefore, on the butyric acid increase intestines that these researchs are drawn
The conclusion of endothelial apoptosis may not be set up on normal enterocyte.Finally, research carries out animal using high concentration butyric acid
Experiment, causes intestinal mucosa and Gut barrie r is damaged (Lin J, et a1.Variable effects of short chain
fatty acids and lactic acid in inducing intestinal mucosal injury in newborn
Rats.J Pediatr Gastroenterol Nutr.2002,35 (4)：545-550.), but butyric acid is originally faintly acid thing
Matter, directly it is administered with butyric acid stoste and is likely to result in damage chemically for immature enteron aisle, it is original so as to mask its
Physiological function.
In the present invention, we are used to prevent and treat gangrenosum acne a kind of innovative nutritional preparation containing butyric acid compound that provides
Enterocolitis, technology prejudice present in above-mentioned existing research is overcome, the technical barrier for solving NEC preventing and treatings, be NEC's
Preventing and treating provides a kind of safe, economic and effective method.Wherein, butyric acid compound include butyrate, butanoic acid derivative and
Butyric acid.Butyrate and butanoic acid derivative are not acidic materials, therefore enteron aisle will not be caused to damage；In the present invention, butyric acid class
Added when compound is butyric acid in the form of coating, can not only prevent high concentration butyric acid from directly contacting intestinal mucosa and causing to damage, and
Niff will not be brought into influences nutritional preparation mouthfeel.Also, the present invention considers premature and neonate's intestinal growth not
The characteristics of ripe, not by the way of being directly administered, but butyrate, butanoic acid derivative, coating butyric acid are configured at formula milk
In the alimentation compositions such as powder, the damage chemically caused by the reasons such as osmotic pressure, pH value are to enteron aisle is on the one hand avoided, on the other hand
To contain in butyric acid compound addition nutritional preparation can make it slow transit through enteron aisle with food preferably to play a role, thus
NEC can effectively be prevented and treated.
Secondly as intravenous nutrition is particularly important even unique for NEC risks or infant with NEC be present
Nutritional supportive path.In the present invention, we are innovative is added to butyric acid compound in parenteral nutrition preparation, is NEC
Preventing and treating new and more reliable intervention is provided.
The purpose of the present invention is achieved through the following technical solutions：
The invention provides a kind of nutritional preparation containing butyric acid, including alimentation composition and butyric acid compound, the fourth
Concentration of the acid compounds in nutritional preparation is 0.5~200mM (mmol/L).
Preferably, the butyric acid compound is selected from least one of butyric acid, butyrate, butanoic acid derivative.
Preferably, the butyrate is selected from least one of sodium butyrate, calcium butyrate, magnesium butyrate, potassium butyrate.
Preferably, the butanoic acid derivative be selected from glycerol monobutyralte, butyric acid list double glyceride, ethyl butyrate, methylbutanoic acid,
At least one of isoamyl butyrate, butyric acid cyclodextrin complexes.
Preferably, the butyric acid compound is butyric acid and/or butyrate, and butyric acid and/or butyrate are in nutritional preparation
Concentration be 1~200mM.
It is highly preferred that the butyric acid compound is butyric acid and/or butyrate, butyric acid and/or butyrate are in nutritional preparation
In concentration be 1~100mM；Most preferable concentrations are 50~100mM.Nutritional preparation containing the concentration butyric acid and/or butyrate can
Effectively prevention NEC generation, promotes growth, developing immune system and gut maturation.
It is highly preferred that the butyric acid compound is butyric acid and/or butyrate, butyric acid and/or butyrate are in nutritional preparation
In concentration be 100~200mM.The nutritional preparation of butyric acid and/or butyrate containing the concentration can effectively treat NEC.
Preferably, the butyric acid compound is butanoic acid derivative, and concentration of the butanoic acid derivative in nutritional preparation is 0.5
~200mM.
It is highly preferred that the butyric acid compound is butanoic acid derivative, concentration of the butanoic acid derivative in nutritional preparation is
0.5~100mM；Most preferable concentrations are 50~100mM.The nutritional preparation of butanoic acid derivative containing the concentration can effectively prevent NEC.
Preferably, the butyric acid compound is butanoic acid derivative, and concentration of the butanoic acid derivative in nutritional preparation is 100
~200mM.The nutritional preparation of butanoic acid derivative containing the concentration can effectively treat NEC.
Preferably, the alimentation composition is selected from conventional formulation food, special medicine purposes formula food, parenteral nutrition system
At least one of agent, enteral nutrition preparation.
Preferably, the conventional formulation food include babies ' formula milk powder, baby formulas milk powder, cereal milk powder, growth breast,
Pregnancy period and nursing period formula milk；The special medicine purposes formula food include premature labor/low birth weight baby formula milk,
Lactose-free formula or Low lactose milk formula milk, milk protein part hydrolyzed formulas milk powder, lactoprotein depth hydrolysis formula or amino acid
Formula milk, the hardening agent of breast milk and dispensed food for baby or nutritious supplementary pharmaceutical, suitable for food intolerance, abnormal anti-
Should, the formula food of disease or dysfunction；The parenteral nutrition preparation includes fat emulsion injection, All-In-One nutrient solution, quiet
Arteries and veins parenteral solution；The enteral nutrition preparation includes amino acid pattern enteral nutrition preparation, short peptide type enteral nutrition preparation, whole protein type
Enteral nutrition preparation, assembly type enteral nutrition preparation.
Special medicine purposes formula food (Food for Special Medical Purpose, FSMP), it is in order to full
Foot feed is limited, the special requirement of Disorder of Digestion and A orption, metabolic disorder or particular disease states crowd to nutrient or meals, specially
The formula food that door processing is formulated.Such product must in the case where doctor or clinical nutrition teacher instruct, it is individually edible or and its
His food is matched.Special medicine purposes formula food belongs to food for special foods.When target group can not feed commonly
Meals or when can not meet its nutritional need with ordinary meal, special medicine purposes formula food can be used as a kind of nutritional supplementation
Approach, it is treated, rehabilitation and body function maintain etc. to play important nutritional support effect.
Present invention also offers a kind of preparation method of the nutritional preparation containing butyric acid, the preparation method includes：By butyric acid
Class compound is proportionally added into the alimentation composition, is well mixed, you can；The butyric acid compound is selected from butyric acid, fourth
At least one of hydrochlorate, butanoic acid derivative.
Preferably, when the butyric acid compound is butyric acid, butyric acid compound by coating or it is coated in the form of add.
It should be noted that in the present invention, the butyric acid compound includes the compound of butyric acid form of ownership, this hair
It is bright to be applicable not only to foregoing each butyric acid compound, apply also for the compound of other butyric acid forms.The butyric acid is included just
Butyric acid and isobutyric acid.
It should be noted that the administration form of butyric acid is inessential in the present invention, by the material containing butyric acid such as butyric acid and/or fourth
Hydrochlorate and/or butanoic acid derivative are added to conventional formulation food, special medicine purposes formula food, parenteral nutrition preparation, enteral
In nutritional preparation, as long as preventing and treating NEC effect can be achieved using effective dose.
The alternative solution applied as formula milk, butyric acid of the invention, butyrate and butanoic acid derivative can conducts
Replenishers are applied rather than are incorporated into formula food.For example, butyric acid, butyrate and butanoic acid derivative can be with pill, tablet, glue
Capsule, caplet, powder, liquid or gel form intake.For example, butyric acid, butyrate and butanoic acid derivative can be mended with other nutrition
Fill agent and combine intake.
Compared with prior art, the present invention has following beneficial effect：
1. the present invention in nutritional preparation by adding active ingredient --- butyric acid compound, can very effective preventing and treating
Necrotizing enterocolitis, including the obvious morbidity and mortality for reducing necrotizing enterocolitis, shortening gangrenosum acne small intestine
The duration of colitis, reduce its complication and/or mitigate its order of severity.There is enhancing development, siberian crabapple simultaneously
The ripe effect with intestinal growth of system.
The butyric acid compound added in the present invention has advantages below：
First, as the direct energy source of intestinal epithelial cell, have the function that to promote intestinal growth；
Secondly, the development of newborn individual immune system and perfect is promoted；
Finally, butyric acid compound also has an easily ignored critical function, and it, which has, promotes hemoglobin synthesis
Effect, so as to strengthen body oxygen delivery capacity come damage of intestines caused by resisting hypoxic-ischemic, and this point is small for preventing and treating gangrenosum acne
Intestines colitis plays vital effect.
2. butyric acid is the natural component being present in mammal milk and enteron aisle, from the perspective of clinical practice, with
The medicine of other preventing and treating necrotizing enterocolitis is compared, safer.Butyric acid compound can be with the shape of coating in this research
Formula is added, and will not influence to apply because of the acidity and stink of butyric acid.
3. intravenous nutrition is particularly important even unique nutrition branch for NEC risks or infant with NEC be present
Hold approach.In the present invention, we are innovative is added to butyric acid compound in parenteral nutrition preparation, is NEC preventing and treating
New and more reliable intervention is provided.
Brief description of the drawings
The detailed description made by reading with reference to the following drawings to non-limiting example, further feature of the invention,
Objects and advantages will become more apparent upon：
Fig. 1 is neonate rat oral trachea cannula artificial feeding schematic diagram；
Fig. 2 is neonate rat intestinal tube general form figure；Wherein,
Fig. 2 a are NEC model groups；
Fig. 2 b are NEC modelings+butyric acid (100mM, non-coating directly add) intervention group；
Fig. 2 c are that NEC modelings+butyric acid (100mM, adds) intervention group with capsule form；
Fig. 2 d are NEC modelings+sodium butyrate (100mM) intervention group；
Fig. 2 e are NEC modelings+glycerol monobutyralte (50mM) intervention group；
Fig. 2 f are NEC modelings+butyric acid (200mM, non-coating directly add) treatment group；
Fig. 2 g are that NEC modelings+butyric acid (200mM, adds) treatment group with capsule form；
Fig. 2 h are NEC modelings+sodium butyrate (200mM) treatment group；
Fig. 2 i are NEC modelings+glycerol monobutyralte (200mM) treatment group；
Fig. 3 is neonate rat intestinal tissue pathological change figure (200 ×)；Wherein,
Fig. 3 a are NEC model groups；
Fig. 3 b are NEC modelings+butyric acid (100mM, non-coating directly add) intervention group；
Fig. 3 c are that NEC modelings+butyric acid (100mM, adds) intervention group with capsule form；
Fig. 3 d are NEC modelings+sodium butyrate (100mM) intervention group；
Fig. 3 e are NEC modelings+glycerol monobutyralte (50mM) intervention group；
Fig. 3 f are NEC modelings+butyric acid (200mM, non-coating directly add) treatment group；
Fig. 3 g are that NEC modelings+butyric acid (200mM, adds) treatment group with capsule form；
Fig. 3 h are NEC modelings+sodium butyrate (200mM) treatment group；
Fig. 3 i are NEC modelings+glycerol monobutyralte (200mM) treatment group.
Embodiment
With reference to specific embodiment, the present invention is described in detail.Following examples will be helpful to the technology of this area
Personnel further understand the present invention, but the invention is not limited in any way.It should be pointed out that the ordinary skill to this area
For personnel, without departing from the inventive concept of the premise, some changes and improvements can also be made.These belong to the present invention
Protection domain.
Following examples provide a kind of nutritional preparation containing butyric acid, including alimentation composition and butyric acid compound, institute
It is 0.5~200mM (mmol/L) to state concentration of the butyric acid compound in nutritional preparation.
The butyric acid compound is selected from least one of butyric acid, butyrate, butanoic acid derivative.
The butyrate is selected from least one of sodium butyrate, calcium butyrate, magnesium butyrate, potassium butyrate.
It is different that the butanoic acid derivative is selected from glycerol monobutyralte, butyric acid list double glyceride, ethyl butyrate, methylbutanoic acid, butyric acid
At least one of pentyl ester, butyric acid cyclodextrin complexes.
The butyric acid compound is butyric acid and/or butyrate, and the concentration of butyric acid and/or butyrate in nutritional preparation is
1~200mM.
When the concentration of the butyric acid and/or butyrate in nutritional preparation is 1~100mM, especially preferred concentration is 50
During~100mM, the nutritional preparation containing the concentration butyric acid and/or butyrate can effectively prevent NEC generation, promote growth, be immunized
Systematic growth and gut maturation.It is dense containing this when the concentration of the butyric acid and/or butyrate in nutritional preparation is 100~200mM
The butyric acid of degree and/or the nutritional preparation of butyrate can effectively treat NEC.
The butyric acid compound is butanoic acid derivative, concentration of the butanoic acid derivative in nutritional preparation is 0.5~
200mM。
When concentration of the butanoic acid derivative in nutritional preparation is 0.5~100mM, especially preferred concentration be 50~
During 100mM, the nutritional preparation of the butanoic acid derivative containing the concentration can effectively prevent NEC.The butanoic acid derivative is in nutritional preparation
In concentration when being 100~200mM, the nutritional preparation of the butanoic acid derivative containing the concentration can effectively treat NEC.
The alimentation composition is selected from conventional formulation food, special medicine purposes formula food, parenteral nutrition preparation, enteral
At least one of nutritional preparation.
The conventional formulation food include babies ' formula milk powder, baby formulas milk powder, cereal milk powder, growth breast, the pregnancy period and
Nursing period formula milk；The special medicine purposes formula food includes premature labor/low birth weight baby formula milk, lactose-free
Formula or Low lactose milk formula milk, milk protein part hydrolyzed formulas milk powder, lactoprotein depth hydrolysis formula or amino acid formula milk
Powder, the hardening agent of breast milk and dispensed food for baby or nutritious supplementary pharmaceutical, suitable for food intolerance, allergy, disease
Or the formula food of dysfunction；The parenteral nutrition preparation includes fat emulsion injection, All-In-One nutrient solution, intravenous injection
Liquid；The enteral nutrition preparation includes amino acid pattern enteral nutrition preparation, short peptide type enteral nutrition preparation, whole protein type enteral battalion
Support preparation, assembly type enteral nutrition preparation.
Embodiment 1
A kind of nutritional preparation containing sodium butyrate and preparation method thereof is present embodiments provided, methods described is：By food-grade
Or injection stage sodium butyrate is added in nutritional preparation, it is well mixed, produces.The concentration of sodium butyrate is in the nutritional preparation of the preparation
1~100mM.
Embodiment 2
A kind of nutritional preparation containing sodium butyrate and preparation method thereof is present embodiments provided, methods described is：By food-grade
Or injection stage sodium butyrate is added in nutritional preparation, it is well mixed, produces.The concentration of sodium butyrate is in the nutritional preparation of the preparation
100~200mM.
Embodiment 3
A kind of nutritional preparation containing glycerol monobutyralte and preparation method thereof is present embodiments provided, methods described is：Will food
Grade or injection stage glycerol monobutyralte are added in nutritional preparation, are well mixed, are produced.Butyric acid is sweet in the nutritional preparation of the preparation
The concentration of grease is 0.5~100mM.
Embodiment 4
A kind of nutritional preparation containing glycerol monobutyralte and preparation method thereof is present embodiments provided, methods described is：Will food
Grade or injection stage glycerol monobutyralte are added in nutritional preparation, are well mixed, are produced.Butyric acid is sweet in the nutritional preparation of the preparation
The concentration of grease is 100~200mM.
Embodiment 5
A kind of nutritional preparation containing butyric acid and preparation method thereof is present embodiments provided, methods described is：By food-grade fourth
Acid or injection stage butyric acid are added in nutritional preparation with capsule form, are well mixed, are produced.Butyric acid in the nutritional preparation of the preparation
Concentration be 1~100mM.
Embodiment 6
A kind of nutritional preparation containing butyric acid and preparation method thereof is present embodiments provided, methods described is：By food-grade fourth
Acid or injection stage butyric acid are added in nutritional preparation with capsule form, are well mixed, are produced.Butyric acid in the nutritional preparation of the preparation
Concentration be 100~200mM.
Nutritional preparation containing butyric acid made from above example can effectively prevent and treat NEC, while have promotion body weight increase, be immunized
The effect of system maturation and intestinal growth.
Animal experiment compliance test result：Effect of the nutritional preparation containing butyric acid in NEC is prevented and treated
1. experimental animal and packet
Cleaning grade new life Sprague-Dawley (SD) rat, it is born the 1st day, male and female are unlimited, body weight about 5-6g, purchased from upper
Western pul-Bi Kai experimental animals the Co., Ltd in sea.Raised in Xinhua Hospital Attached to Medical School, Shanghai Jiaotong Univ.'s animal experimental center
Support.Mouse breast substitute is prepared with reference to Nancy Auestad etc. and the report in Gail Besner laboratories.
2. processing method
Artificial feeding control group：Neonate rat separates with dams, is placed in incubator, artificial feeding mouse breast substitute
The timing of 0.15ml/6h/ days is fed；
NEC model groups：Neonate rat separates with dams, is placed in incubator, artificial feeding mouse breast substitute 0.15ml/
6h/ days, timing are fed；After artificial feeding 1 day, give anoxic and cold stimulation twice daily, continue three days；
NEC modelings+butyric acid (non-coating directly adds) intervention group：Neonate rat separates with dams, is placed in incubator, people
Work feeds the mouse breast substitute 0.15ml/6h/ days timing nursing for adding non-coating butyric acid；After artificial feeding 1 day, give anoxic and
Cold stimulation twice daily, continues three days；
NEC modelings+butyric acid (adds) intervention group with capsule form：Neonate rat separates with dams, is placed in incubator, people
The mouse breast substitute 0.15ml/6h/ days timing that work feeds addition coating butyric acid is fed；After artificial feeding 1 day, give anoxic and cold
Stimulate twice daily, continue three days；
NEC modelings+sodium butyrate intervention group：Neonate rat separates with dams, is placed in incubator, artificial feeding addition butyric acid
The mouse breast substitute 0.15ml/6h/ days timing of sodium is fed；After artificial feeding 1 day, give anoxic and cold stimulation twice daily, hold
It is continuous three days；
NEC modelings+glycerol monobutyralte intervention group：Neonate rat separates with dams, is placed in incubator, artificial feeding addition
The mouse breast substitute 0.15ml/6h/ days timing of glycerol monobutyralte is fed；After artificial feeding 1 day, give anoxic and cold stimulation is daily
Twice, three days are continued；
NEC modelings+butyric acid (non-coating directly adds) treatment group：Neonate rat separates with dams, is placed in incubator, people
Work is fed the timing of mouse breast substitute 0.15ml/6h/ days and fed；After artificial feeding 1 day, hold with anoxic and cold stimulation twice daily
Continuous three days, and use instead and add the mouse breast substitute of non-coating butyric acid and treated；
NEC modelings+butyric acid (adds) treatment group with capsule form：Neonate rat separates with dams, is placed in incubator, people
Work is fed the timing of mouse breast substitute 0.15ml/6h/ days and fed；After artificial feeding 1 day, hold with anoxic and cold stimulation twice daily
It is continuous three days, and the mouse breast substitute for using addition coating butyric acid instead is treated；
NEC modelings+sodium butyrate treatment group：Neonate rat separates with dams, is placed in incubator, and artificial feeding mouse breast substitutes
The timing of product 0.15ml/6h/ days is fed；After artificial feeding 1 day, continue three days, and use instead and add with anoxic and cold stimulation twice daily
The mouse breast substitute of sodium butyrate is added to be treated；
NEC modelings+glycerol monobutyralte treatment group：Neonate rat separates with dams, is placed in incubator, artificial feeding mouse breast
The timing of substitute 0.15ml/6h/ days is fed；After artificial feeding 1 day, give anoxic and cold stimulation twice daily, continue three days, and
The mouse breast substitute for using addition glycerol monobutyralte instead is treated；
(Fig. 1) is fed with cleaning PICC pipes oral trachea cannula, skin around neonate rat oral cavity is cleaned with physiological saline before feeding
Skin.After nursing terminates, after PICC is cleaned and with 75% alcohol disinfecting.
3. modeling method
Anoxic and cold stimulation：Oxygen analyser is returned to zero, is connected on airtight anoxia case.Nitrogen is connected, it is about to control flow
15L/min.Oxygen concentration starts timing when being down to zero, neonate rat is taken out after 90 seconds, is immediately placed in 4 DEG C of refrigerators 10 minutes.
Daily row anoxic and cold stimulation are handled 2 times, are sent back to after processing in incubator.
After establishing model, the feed of close observation neonate rat, defecation, belly situation and activity reaction etc..In experiment before and
The body weight of neonate rat is weighed after modeling daily.When there is obvious clinical symptoms (serious abdominal distension, bloody stool and cyanosis) or in making
Put to death neonate rat within (96 hours) the 4th day after mould, observe the general form of rat intestinal tube, collect intestinal tube and blood preparation.
4. intestinal tissue pathological examination
Intestines distal end 2cm intestinal tubes are fetched, gives cold saline flushing rapidly, after removing intestinal contents, is placed in tissue and fixes
24-48 hours are fixed in liquid.It is independent by pathologists in light Microscopic observation intestinal tissue morphological change after HE is dyed
Carry out pathological score (double-blind study).
The standards of grading used with reference to Michael Caplan and Gail Besner：
0 point：Intestinal mucosa fine hair is complete, and institutional framework is normal.
1 point：Slight submucosa and/or lamina propria separation.
2 points：Moderate submucosa and/or lamina propria separation, or submucosa and muscle layer oedema.
3 points：Serious submucosa and/or lamina propria separation, or submucosa and muscle layer Severe edema, local fine hair take off
Fall.
4 points：Intestinal villus disappears with the necrosis of intestinal wall holostrome.
Ping Fen≤2 point are thought of as NEC.
5. result
5.1 growing state：
Control group：Rats eating and defecation are normal, and active situation is good, the symptom such as no abdominal distension, bloody stool, body in experimentation
Increase again, do not occur death；
NEC model groups：Rat engenders different degrees of abdominal distension, enters the reduction of milk amount, be slow in reacting, living after modeling
Dynamic degree declines, slow in action, body cyanosis, and row's kermesinus is just, and body weight substantially mitigates after modeling, and partial rat is after modeling
It is dead in 72 hours；
NEC modelings+butyric acid (100mM, non-coating directly add) intervention group：There is abdominal distension after modeling in rat, action is delayed
Slowly, body cyanosis, and just etc. symptom, partial rat are dead during modeling for row's kermesinus.
NEC modelings+butyric acid (100mM, adds) intervention group with capsule form：Rat defecation is normal, activity in order, body
Body is ruddy, and no abdominal distension is had blood in stool, and body weight increase is very fast before modeling, and body weight slightly mitigates after modeling；
NEC modelings+sodium butyrate (100mM) intervention group：Rat defecation is normal, and in order, body is ruddy, no abdominal distension for activity
Have blood in stool, body weight increase is very fast before modeling, and body weight slightly mitigates after modeling；
NEC modelings+glycerol monobutyralte (50mM) intervention group：Rat defecation is normal, and in order, body is ruddy, nothing for activity
Abdominal distension is had blood in stool, and body weight increase is very fast before modeling, and body weight slightly mitigates after modeling；
NEC modelings+butyric acid (200mM, non-coating directly add) treatment group：There is abdominal distension after modeling in rat, action is delayed
Slowly, body cyanosis, and just etc. symptom, most of rat are dead during modeling for row's kermesinus.
NEC modelings+butyric acid (200mM, adds) treatment group with capsule form：Activity situation is preferable during rat modeling, body
Body is ruddy, and without having blood in stool, body weight slightly mitigates after modeling；
NEC modelings+sodium butyrate (200mM) treatment group：Activity situation is preferable during rat modeling, and body is ruddy, and nothing is had blood in stool,
Body weight slightly mitigates after modeling；
NEC modelings+glycerol monobutyralte (200mM) treatment group：Occur abdominal distension during rat modeling once in a while, activity situation compared with
Good, body is ruddy, and without having blood in stool, body weight slightly mitigates after modeling.
5.2 intestinal tube situations (Fig. 2)：
Control group：Rat intestinal tube color and luster is ruddy, and elasticity is good；
NEC model groups：Rat intestinal wall oedema, hyperemia, necrosis, in reddish black, it is seen that tapering, narrow or even obstruction；
As shown in Figure 2 a；
NEC modelings+butyric acid (100mM, non-coating directly add) intervention group：Rat intestinal wall oedema, hyperemia, necrosis, in red
Black, tapering, narrow or even obstruction；As shown in Figure 2 b；
NEC modelings+butyric acid (100mM, adds) intervention group with capsule form：Rat intestinal tube color and luster is normal, no congested necrosis,
Without attenuate it is narrow, with control group compared with intestinal tube compared with slightly, form it is normal, as shown in Figure 2 c；
NEC modelings+sodium butyrate (100mM) intervention group：Rat intestinal tube color and luster is normal, no congested necrosis, narrow without attenuating, with
Control group compared to intestinal tube compared with it is thick, form is normal, as shown in Figure 2 d；
NEC modelings+glycerol monobutyralte (50mM) intervention group；Rat intestinal tube is relatively thick, narrow without attenuating, and form is normal, intestinal tube
It is downright bad without hyperemia, as shown in Figure 2 e；
NEC modelings+butyric acid (200mM, non-coating directly add) treatment group：Rat intestinal wall oedema, hyperemia, necrosis, in red
Black, it is seen that tapering, narrow or even obstruction, as shown in figure 2f；
NEC modelings+butyric acid (200mM, adds) treatment group with capsule form：Intestinal tube color and luster is normal, no congested necrosis, no change
Thin narrow, form is normal, as shown in Figure 2 g；
NEC modelings+sodium butyrate (200mM) treatment group：Intestinal tube color and luster is normal, and no congested necrosis, narrow without attenuating, form is just
Often, intestinal tube is thicker, as shown in fig. 2h；
NEC modelings+glycerol monobutyralte (200mM) treatment group：Intestinal tube color and luster is normal, no congested necrosis, without narrow, the shape that attenuates
State is normal, as shown in fig. 2i.
5.3 pathologic conditions (Fig. 3)：
Control group：Ileum fluff structures are complete, epithelium is continuous, body of gland queueing discipline；
NEC model groups：There is different degrees of mucous layer and submucosa hyperemia, oedema in ileum, and part villus shedding is bad
Extremely, body of gland arrangement disorder, muscularis mucosae slightly separate to moderate, and muscle layer is thinning or even is broken, inflammatory cell such as neutrophil leucocyte,
Lymphocytic infiltration, severe patient's intestinal villus disappears with bowel necrosis, similar with the pathological change of clinically NEC infants；Such as Fig. 3 a institutes
Show；
NEC modelings+butyric acid (100mM, non-coating directly add) intervention group:There is mucous layer and muscle layer separation in ileum, glues
Film layer and submucosa hyperemia, oedema, the necrosis of part villus shedding, body of gland arrangement disorder, inflammatory cell such as neutrophil leucocyte, leaching
Bar cellular infiltration, disappears and bowel necrosis with intestinal villus, as shown in Figure 3 b；
NEC modelings+butyric acid (100mM, adds) intervention group with capsule form：Ileum fluff structures are complete, fine hair is long, crypts
It is relatively deep, epithelium is continuous, body of gland queueing discipline, lamina propria blood vessel without expansion, without mucous membrane it is congested, without obvious inflammatory cell infiltration, such as
Shown in Fig. 3 c；
NEC modelings+sodium butyrate (100mM) intervention group：Ileum fluff structures are complete, fine hair is long, crypts is relatively deep, epithelium connects
Continuous, body of gland queueing discipline, lamina propria blood vessel without expansion, without mucous membrane it is congested, without obvious inflammatory cell infiltration, as shown in Figure 3 d；
NEC modelings+glycerol monobutyralte (50mM) intervention group：Ileum fluff structures are complete, fine hair is long, crypts is relatively deep, epithelium
Continuously, body of gland queueing discipline, lamina propria blood vessel without expansion, without mucous membrane it is congested, without obvious inflammatory cell infiltration, as shown in Figure 3 e；
NEC modelings+butyric acid (200mM, non-coating directly add) treatment group：There is mucous layer and muscle layer separation in ileum, glues
Film layer and submucosa hyperemia, oedema, the necrosis of part villus shedding, body of gland arrangement disorder, inflammatory cell such as neutrophil leucocyte, leaching
Bar cellular infiltration, disappears and bowel necrosis with intestinal villus, as illustrated in figure 3f；
NEC modelings+butyric acid (200mM, adds) treatment group with capsule form：Ileum fluff structures are complete, fine hair is long, crypts
It is relatively deep, epithelium is continuous, body of gland queueing discipline, lamina propria blood vessel without expansion, without obvious mucous membrane is congested and inflammatory cell infiltration, such as scheme
Shown in 3g；
NEC modelings+sodium butyrate (200mM) treatment group：Ileum fluff structures are complete, fine hair is long, crypts is relatively deep, epithelium connects
Continuous, body of gland queueing discipline, lamina propria blood vessel without expansion, without mucous membrane is congested and inflammatory cell infiltration, as illustrated in figure 3h；
NEC modelings+glycerol monobutyralte (200mM) treatment group：Ileum fluff structures are complete, fine hair is long, crypts is relatively deep, epithelium
Continuously, body of gland queueing discipline, lamina propria blood vessel without expansion, without obvious mucous membrane is congested and inflammatory cell infiltration, as shown in figure 3i.
5.4 developing immune system situations：
Because the immune system of neonate rat is not yet reached maturity, it is poor that it adjusts the ability of immunity of organism inflammatory reaction.
And after sodium butyrate, glycerol monobutyralte, the intervention of coating butyric acid and treatment, the maturation of neonate rat immunocyte is promoted with increasing
Grow, ratio is horizontal closer to adult rats.
5.5 incidence and mortality：
Control group：The NEC incidence of disease 0%, survival rate 100%.
NEC modeling groups：The NEC incidence of disease 100%, survival rate is less than 20%.
Intervention group incidence and mortality：
NEC modelings group+butyric acid (100mM, non-coating directly add) intervention group：The NEC incidence of disease 100%, survival rate is not
To 5%.
NEC modelings group+butyric acid (100mM, adds) intervention group with capsule form：The NEC incidence of disease is down to 15%, survival rate
Reach 90%.
NEC modelings group+butyric acid (50mM, adds) intervention group with capsule form：The NEC incidence of disease is down to 20%, survival rate
Reach 85%.
NEC modelings group+butyric acid (1mM, adds) intervention group with capsule form：The NEC incidence of disease is 80%, and survival rate is
35%.
NEC modelings+sodium butyrate (100mM) intervention group：The NEC incidence of disease is down to 10%, and survival rate has reached 95%.
NEC modelings+sodium butyrate (50mM) intervention group：The NEC incidence of disease is down to 15%, and survival rate has reached 90%.
NEC modelings+sodium butyrate (1mM) intervention group：The NEC incidence of disease is declined slightly as 85%, survival rate 35%.
NEC modelings+glycerol monobutyralte (100mM) intervention group：The NEC incidence of disease is down to 15%, and survival rate has reached 95%.
NEC modelings+glycerol monobutyralte (50mM) intervention group：The NEC incidence of disease is down to 20%, and survival rate has reached 90%.
NEC modelings+glycerol monobutyralte (0.5mM) intervention group：The NEC incidence of disease is 90%, survival rate 30%.
Treatment group's incidence and mortality：
NEC modelings group+butyric acid (200mM, non-coating directly add) treatment group：The NEC incidence of disease 100%, survival rate is not
To 10%.
NEC modelings group+butyric acid (100mM, adds) treatment group with capsule form：The NEC incidence of disease is down to 20%, survival rate
Reach 80%.
NEC modelings group+butyric acid (200mM, adds) treatment group with capsule form：The NEC incidence of disease is down to 15%, survival rate
Reach 85%.
NEC modelings group+butyric acid (300mM, adds) treatment group with capsule form：The NEC incidence of disease is 25%, and survival rate is
80%.
NEC modelings+sodium butyrate (100mM) treatment group：The NEC incidence of disease is down to 20% or so, and survival rate has reached 85%.
NEC modelings+sodium butyrate (200mM) treatment group：The NEC incidence of disease is down to 15% or so, and survival rate has reached 90%.
NEC modelings+sodium butyrate (300mM) treatment group：The NEC incidence of disease is 20%, survival rate 85%；
NEC modelings+glycerol monobutyralte (100mM) treatment group：The NEC incidence of disease is down to 20%, and survival rate has reached 85%.
NEC modelings+glycerol monobutyralte (200mM) treatment group：The NEC incidence of disease is down to 15%, and survival rate has reached 90%.
NEC modelings+glycerol monobutyralte (300mM) treatment group：The NEC incidence of disease is 20%, and survival rate has reached 85%.
In summary, NEC models are built by artificial feeding joint anoxic and the method for cold stimulation, using non-coating fourth
Acid, coating butyric acid, butyrate or butanoic acid derivative are intervened or treated.As a result show, directly add non-coating butyric acid and carry out
Intervene, because its faintly acid has aggravated the NEC state of an illness on the contrary, the death rate rises；And use coating butyric acid is intervened and treatment has
The morbidity and mortality for reducing NEC of effect.Addition butyrate and butanoic acid derivative very effective can equally prevent and control
Treat NEC.The incidence of disease of NEC model groups is 100%, and survival rate is less than 20%.Butyric acid compound through effective dose carries out pre-
After anti-intervention, the NEC incidences of disease are minimum to be down to 10%, and survival rate can reach 95%.Using the butyric acid class of effective dose
After compound is treated, the NEC incidences of disease are minimum to be down to 15%, and survival rate can reach 90%.NEC model group rats occur
Intestinal wall oedema, hyperemia, necrosis, in reddish black, and NEC modelings+butyric acid compound intervention or treatment group's rat intestinal tube color and luster
Normally, no congested necrosis, has no obvious lesion.Pathological examination shows that hyperemia, oedema, inflammation occurs in NEC model group rats ileum
Cellular infiltration, the necrosis of part villus shedding, body of gland arrangement disorder, muscularis mucosae slightly separate to moderate, and muscle layer is thinning or even disconnected
The pathological change such as split；And NEC modelings+butyric acid compound intervention or treatment group's rat ileum fluff structures are complete, fine hair is long, hidden
Nest is relatively deep, epithelium is continuous, body of gland queueing discipline, lamina propria blood vessel without expansion, without obvious mucous membrane is congested and inflammatory cell infiltration.Cause
This, effect of the short chain fatty acids-butyric acid in NEC pathogenic processes for a long time has been overturned in our research, it was confirmed that butyric acid class
Significant effect of the compound on prevention and treatment NEC is better than the other drugs reported at present, while butyric acid compound also has
Play the role of to promote neonate rat growth, the development of immune system and intestinal growth ripe.Also, butyric acid is mammalian milk
Natural component in juice, it is safer compared with other drugs from the perspective of clinical practice.Therefore, butyric acid class is added
Compound effective method as a kind of safe, economic into nutritional preparation, has great importance for preventing and treating NEC.
The specific embodiment of the present invention is described above.It is to be appreciated that the invention is not limited in above-mentioned
Particular implementation, those skilled in the art can make a variety of changes or change within the scope of the claims, this not shadow
Ring the substantive content of the present invention.In the case where not conflicting, the feature in embodiments herein and embodiment can any phase
Mutually combination.
Claims (10)
- A kind of 1. nutritional preparation containing butyric acid, it is characterised in that including alimentation composition and butyric acid compound, the butyric acid class Concentration of the compound in nutritional preparation is 0.5~200mM.
- 2. the nutritional preparation according to claim 1 containing butyric acid, it is characterised in that the butyric acid compound is selected from fourth At least one of acid, butyrate, butanoic acid derivative.
- 3. the nutritional preparation according to claim 2 containing butyric acid, it is characterised in that the butyrate is selected from sodium butyrate, fourth At least one of sour potassium, calcium butyrate, magnesium butyrate.
- 4. the nutritional preparation according to claim 2 containing butyric acid, it is characterised in that it is sweet that the butanoic acid derivative is selected from butyric acid At least one in grease, butyric acid list double glyceride, ethyl butyrate, methylbutanoic acid, isoamyl butyrate, butyric acid cyclodextrin complexes Kind.
- 5. the nutritional preparation according to claim 2 containing butyric acid, it is characterised in that the butyric acid compound is butyric acid And/or butyrate, the concentration of butyric acid and/or butyrate in nutritional preparation are 1~200mM.
- 6. the nutritional preparation containing butyric acid according to claim 2 or 4, it is characterised in that the butyric acid compound is fourth Acid derivative, concentration of the butanoic acid derivative in nutritional preparation are 0.5~200mM.
- 7. the nutritional preparation according to claim 1 containing butyric acid, it is characterised in that the alimentation composition is selected from conventional match somebody with somebody At least one of square food, special medicine purposes formula food, parenteral nutrition preparation, enteral nutrition preparation.
- 8. the nutritional preparation according to claim 7 containing butyric acid, it is characterised in that the conventional formulation food includes baby Formula milk, baby formulas milk powder, cereal milk powder, growth breast, pregnancy period and nursing period formula milk；The special medicine purposes is matched somebody with somebody Square food includes premature labor/low birth weight baby formula milk, lactose-free formula or Low lactose milk formula milk, milk protein part water Solve formula milk, lactoprotein depth hydrolysis formula or amino acid formula milk, breast milk and dispensed food for baby hardening agent or Nutritious supplementary pharmaceutical, the formula food suitable for food intolerance, allergy, disease or dysfunction；The parenteral nutrition Preparation includes fat emulsion injection, All-In-One nutrient solution, intravenous fluid；The enteral nutrition preparation includes amino acid pattern enteral Nutritional preparation, short peptide type enteral nutrition preparation, whole protein type enteral nutrition preparation, assembly type enteral nutrition preparation.
- A kind of 9. preparation method of the nutritional preparation according to claim 1 containing butyric acid, it is characterised in that the preparation side Method includes：Butyric acid compound is proportionally added into the alimentation composition, is well mixed, you can；The butyric acid class chemical combination Thing is selected from least one of butyric acid, butyrate, butanoic acid derivative.
- 10. the preparation method of the nutritional preparation according to claim 9 containing butyric acid, it is characterised in that the butyric acid class When compound is butyric acid, butyric acid compound by coating or it is coated in the form of add.
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