CN111728111B - 一种缓解焦虑或抑郁的益生菌组合物及其应用 - Google Patents
一种缓解焦虑或抑郁的益生菌组合物及其应用 Download PDFInfo
- Publication number
- CN111728111B CN111728111B CN202010601490.6A CN202010601490A CN111728111B CN 111728111 B CN111728111 B CN 111728111B CN 202010601490 A CN202010601490 A CN 202010601490A CN 111728111 B CN111728111 B CN 111728111B
- Authority
- CN
- China
- Prior art keywords
- lactobacillus
- probiotic
- depression
- anxiety
- cgmcc
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 239000006041 probiotic Substances 0.000 title claims abstract description 97
- 235000018291 probiotics Nutrition 0.000 title claims abstract description 97
- 230000000529 probiotic effect Effects 0.000 title claims abstract description 75
- 208000019901 Anxiety disease Diseases 0.000 title claims abstract description 41
- 230000036506 anxiety Effects 0.000 title claims abstract description 38
- 239000000203 mixture Substances 0.000 title claims abstract description 30
- 241001134770 Bifidobacterium animalis Species 0.000 claims abstract description 15
- 244000199866 Lactobacillus casei Species 0.000 claims abstract description 15
- 235000013958 Lactobacillus casei Nutrition 0.000 claims abstract description 15
- 229940118852 bifidobacterium animalis Drugs 0.000 claims abstract description 15
- 229940017800 lactobacillus casei Drugs 0.000 claims abstract description 15
- 240000006024 Lactobacillus plantarum Species 0.000 claims abstract description 14
- 235000013965 Lactobacillus plantarum Nutrition 0.000 claims abstract description 14
- 241000218588 Lactobacillus rhamnosus Species 0.000 claims abstract description 14
- 229940072205 lactobacillus plantarum Drugs 0.000 claims abstract description 14
- 240000001046 Lactobacillus acidophilus Species 0.000 claims abstract description 12
- 235000013956 Lactobacillus acidophilus Nutrition 0.000 claims abstract description 12
- 241000186604 Lactobacillus reuteri Species 0.000 claims abstract description 12
- 229940039695 lactobacillus acidophilus Drugs 0.000 claims abstract description 12
- 229940001882 lactobacillus reuteri Drugs 0.000 claims abstract description 12
- 241001608472 Bifidobacterium longum Species 0.000 claims abstract description 10
- 229940009291 bifidobacterium longum Drugs 0.000 claims abstract description 10
- 240000002605 Lactobacillus helveticus Species 0.000 claims abstract description 9
- 235000013967 Lactobacillus helveticus Nutrition 0.000 claims abstract description 9
- 229940054346 lactobacillus helveticus Drugs 0.000 claims abstract description 9
- 239000000843 powder Substances 0.000 claims description 41
- 238000004321 preservation Methods 0.000 claims description 27
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 claims description 16
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 claims description 8
- DATAGRPVKZEWHA-YFKPBYRVSA-N N(5)-ethyl-L-glutamine Chemical compound CCNC(=O)CC[C@H]([NH3+])C([O-])=O DATAGRPVKZEWHA-YFKPBYRVSA-N 0.000 claims description 8
- 229960003692 gamma aminobutyric acid Drugs 0.000 claims description 8
- 239000002994 raw material Substances 0.000 claims description 5
- 235000020183 skimmed milk Nutrition 0.000 claims description 5
- HEBKCHPVOIAQTA-NGQZWQHPSA-N d-xylitol Chemical compound OC[C@H](O)C(O)[C@H](O)CO HEBKCHPVOIAQTA-NGQZWQHPSA-N 0.000 claims description 4
- FTSSQIKWUOOEGC-RULYVFMPSA-N fructooligosaccharide Chemical compound OC[C@H]1O[C@@](CO)(OC[C@@]2(OC[C@@]3(OC[C@@]4(OC[C@@]5(OC[C@@]6(OC[C@@]7(OC[C@@]8(OC[C@@]9(OC[C@@]%10(OC[C@@]%11(O[C@H]%12O[C@H](CO)[C@@H](O)[C@H](O)[C@H]%12O)O[C@H](CO)[C@@H](O)[C@@H]%11O)O[C@H](CO)[C@@H](O)[C@@H]%10O)O[C@H](CO)[C@@H](O)[C@@H]9O)O[C@H](CO)[C@@H](O)[C@@H]8O)O[C@H](CO)[C@@H](O)[C@@H]7O)O[C@H](CO)[C@@H](O)[C@@H]6O)O[C@H](CO)[C@@H](O)[C@@H]5O)O[C@H](CO)[C@@H](O)[C@@H]4O)O[C@H](CO)[C@@H](O)[C@@H]3O)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@@H](O)[C@@H]1O FTSSQIKWUOOEGC-RULYVFMPSA-N 0.000 claims description 4
- 229940107187 fructooligosaccharide Drugs 0.000 claims description 4
- 235000021255 galacto-oligosaccharides Nutrition 0.000 claims description 4
- 150000003271 galactooligosaccharides Chemical class 0.000 claims description 4
- 229940026510 theanine Drugs 0.000 claims description 4
- UQZIYBXSHAGNOE-USOSMYMVSA-N Stachyose Natural products O(C[C@H]1[C@@H](O)[C@H](O)[C@H](O)[C@@H](O[C@@]2(CO)[C@H](O)[C@@H](O)[C@@H](CO)O2)O1)[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@H](CO[C@@H]2[C@@H](O)[C@@H](O)[C@@H](O)[C@H](CO)O2)O1 UQZIYBXSHAGNOE-USOSMYMVSA-N 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- UQZIYBXSHAGNOE-XNSRJBNMSA-N stachyose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO[C@@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO[C@@H]3[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O3)O)O2)O)O1 UQZIYBXSHAGNOE-XNSRJBNMSA-N 0.000 claims description 3
- 235000020660 omega-3 fatty acid Nutrition 0.000 claims description 2
- 235000021122 unsaturated fatty acids Nutrition 0.000 claims description 2
- 150000004670 unsaturated fatty acids Chemical class 0.000 claims description 2
- DLRVVLDZNNYCBX-RTPHMHGBSA-N isomaltose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)C(O)O1 DLRVVLDZNNYCBX-RTPHMHGBSA-N 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 19
- 230000000968 intestinal effect Effects 0.000 abstract description 19
- 235000013406 prebiotics Nutrition 0.000 abstract description 15
- 239000000126 substance Substances 0.000 abstract description 11
- 208000027534 Emotional disease Diseases 0.000 abstract description 7
- 230000002195 synergetic effect Effects 0.000 abstract description 6
- 230000009286 beneficial effect Effects 0.000 abstract description 5
- 208000037976 chronic inflammation Diseases 0.000 abstract description 2
- 230000006020 chronic inflammation Effects 0.000 abstract description 2
- 206010027940 Mood altered Diseases 0.000 abstract 1
- 239000000047 product Substances 0.000 description 39
- 235000013361 beverage Nutrition 0.000 description 32
- 239000007787 solid Substances 0.000 description 24
- 235000013618 yogurt Nutrition 0.000 description 22
- 238000012360 testing method Methods 0.000 description 18
- 241000699670 Mus sp. Species 0.000 description 14
- 230000036541 health Effects 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- 241000699666 Mus <mouse, genus> Species 0.000 description 8
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 8
- 239000003814 drug Substances 0.000 description 7
- 230000006870 function Effects 0.000 description 7
- 230000036651 mood Effects 0.000 description 7
- 210000001035 gastrointestinal tract Anatomy 0.000 description 6
- 244000005700 microbiome Species 0.000 description 6
- 239000002131 composite material Substances 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 230000001965 increasing effect Effects 0.000 description 5
- 230000001737 promoting effect Effects 0.000 description 5
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 235000021552 granulated sugar Nutrition 0.000 description 4
- 230000007413 intestinal health Effects 0.000 description 4
- 238000009629 microbiological culture Methods 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 238000012216 screening Methods 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 241000186660 Lactobacillus Species 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 235000013305 food Nutrition 0.000 description 3
- 238000004108 freeze drying Methods 0.000 description 3
- 229940039696 lactobacillus Drugs 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000002207 metabolite Substances 0.000 description 3
- 230000008520 organization Effects 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 230000004622 sleep time Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 2
- 208000020401 Depressive disease Diseases 0.000 description 2
- 206010012735 Diarrhoea Diseases 0.000 description 2
- 229920001202 Inulin Polymers 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 244000199885 Lactobacillus bulgaricus Species 0.000 description 2
- 235000013960 Lactobacillus bulgaricus Nutrition 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- MUPFEKGTMRGPLJ-RMMQSMQOSA-N Raffinose Natural products O(C[C@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O[C@@]2(CO)[C@H](O)[C@@H](O)[C@@H](CO)O2)O1)[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 MUPFEKGTMRGPLJ-RMMQSMQOSA-N 0.000 description 2
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 2
- 241000194020 Streptococcus thermophilus Species 0.000 description 2
- MUPFEKGTMRGPLJ-UHFFFAOYSA-N UNPD196149 Natural products OC1C(O)C(CO)OC1(CO)OC1C(O)C(O)C(O)C(COC2C(C(O)C(O)C(CO)O2)O)O1 MUPFEKGTMRGPLJ-UHFFFAOYSA-N 0.000 description 2
- 240000008866 Ziziphus nummularia Species 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 230000009102 absorption Effects 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 2
- 229960004373 acetylcholine Drugs 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 230000029087 digestion Effects 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 230000008451 emotion Effects 0.000 description 2
- 230000001804 emulsifying effect Effects 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 238000003304 gavage Methods 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 210000000987 immune system Anatomy 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 206010022437 insomnia Diseases 0.000 description 2
- 230000003871 intestinal function Effects 0.000 description 2
- JYJIGFIDKWBXDU-MNNPPOADSA-N inulin Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)OC[C@]1(OC[C@]2(OC[C@]3(OC[C@]4(OC[C@]5(OC[C@]6(OC[C@]7(OC[C@]8(OC[C@]9(OC[C@]%10(OC[C@]%11(OC[C@]%12(OC[C@]%13(OC[C@]%14(OC[C@]%15(OC[C@]%16(OC[C@]%17(OC[C@]%18(OC[C@]%19(OC[C@]%20(OC[C@]%21(OC[C@]%22(OC[C@]%23(OC[C@]%24(OC[C@]%25(OC[C@]%26(OC[C@]%27(OC[C@]%28(OC[C@]%29(OC[C@]%30(OC[C@]%31(OC[C@]%32(OC[C@]%33(OC[C@]%34(OC[C@]%35(OC[C@]%36(O[C@@H]%37[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O%37)O)[C@H]([C@H](O)[C@@H](CO)O%36)O)[C@H]([C@H](O)[C@@H](CO)O%35)O)[C@H]([C@H](O)[C@@H](CO)O%34)O)[C@H]([C@H](O)[C@@H](CO)O%33)O)[C@H]([C@H](O)[C@@H](CO)O%32)O)[C@H]([C@H](O)[C@@H](CO)O%31)O)[C@H]([C@H](O)[C@@H](CO)O%30)O)[C@H]([C@H](O)[C@@H](CO)O%29)O)[C@H]([C@H](O)[C@@H](CO)O%28)O)[C@H]([C@H](O)[C@@H](CO)O%27)O)[C@H]([C@H](O)[C@@H](CO)O%26)O)[C@H]([C@H](O)[C@@H](CO)O%25)O)[C@H]([C@H](O)[C@@H](CO)O%24)O)[C@H]([C@H](O)[C@@H](CO)O%23)O)[C@H]([C@H](O)[C@@H](CO)O%22)O)[C@H]([C@H](O)[C@@H](CO)O%21)O)[C@H]([C@H](O)[C@@H](CO)O%20)O)[C@H]([C@H](O)[C@@H](CO)O%19)O)[C@H]([C@H](O)[C@@H](CO)O%18)O)[C@H]([C@H](O)[C@@H](CO)O%17)O)[C@H]([C@H](O)[C@@H](CO)O%16)O)[C@H]([C@H](O)[C@@H](CO)O%15)O)[C@H]([C@H](O)[C@@H](CO)O%14)O)[C@H]([C@H](O)[C@@H](CO)O%13)O)[C@H]([C@H](O)[C@@H](CO)O%12)O)[C@H]([C@H](O)[C@@H](CO)O%11)O)[C@H]([C@H](O)[C@@H](CO)O%10)O)[C@H]([C@H](O)[C@@H](CO)O9)O)[C@H]([C@H](O)[C@@H](CO)O8)O)[C@H]([C@H](O)[C@@H](CO)O7)O)[C@H]([C@H](O)[C@@H](CO)O6)O)[C@H]([C@H](O)[C@@H](CO)O5)O)[C@H]([C@H](O)[C@@H](CO)O4)O)[C@H]([C@H](O)[C@@H](CO)O3)O)[C@H]([C@H](O)[C@@H](CO)O2)O)[C@@H](O)[C@H](O)[C@@H](CO)O1 JYJIGFIDKWBXDU-MNNPPOADSA-N 0.000 description 2
- 229940029339 inulin Drugs 0.000 description 2
- 229940004208 lactobacillus bulgaricus Drugs 0.000 description 2
- 235000013336 milk Nutrition 0.000 description 2
- 239000008267 milk Substances 0.000 description 2
- 210000004080 milk Anatomy 0.000 description 2
- MUPFEKGTMRGPLJ-ZQSKZDJDSA-N raffinose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO[C@@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O2)O)O1 MUPFEKGTMRGPLJ-ZQSKZDJDSA-N 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000000284 resting effect Effects 0.000 description 2
- 230000033764 rhythmic process Effects 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- 229940076279 serotonin Drugs 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- AHOUBRCZNHFOSL-YOEHRIQHSA-N (+)-Casbol Chemical compound C1=CC(F)=CC=C1[C@H]1[C@H](COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-YOEHRIQHSA-N 0.000 description 1
- WVXRAFOPTSTNLL-NKWVEPMBSA-N 2',3'-dideoxyadenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@H]1CC[C@@H](CO)O1 WVXRAFOPTSTNLL-NKWVEPMBSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 241000186000 Bifidobacterium Species 0.000 description 1
- 241000167854 Bourreria succulenta Species 0.000 description 1
- 206010010774 Constipation Diseases 0.000 description 1
- 206010013954 Dysphoria Diseases 0.000 description 1
- 208000000059 Dyspnea Diseases 0.000 description 1
- 206010013975 Dyspnoeas Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 238000012449 Kunming mouse Methods 0.000 description 1
- 240000003394 Malpighia glabra Species 0.000 description 1
- 235000014837 Malpighia glabra Nutrition 0.000 description 1
- 208000019022 Mood disease Diseases 0.000 description 1
- 101100370002 Mus musculus Tnfsf14 gene Proteins 0.000 description 1
- 240000008790 Musa x paradisiaca Species 0.000 description 1
- 235000018290 Musa x paradisiaca Nutrition 0.000 description 1
- GIYXAJPCNFJEHY-UHFFFAOYSA-N N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]-1-propanamine hydrochloride (1:1) Chemical compound Cl.C=1C=CC=CC=1C(CCNC)OC1=CC=C(C(F)(F)F)C=C1 GIYXAJPCNFJEHY-UHFFFAOYSA-N 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 206010033557 Palpitations Diseases 0.000 description 1
- AHOUBRCZNHFOSL-UHFFFAOYSA-N Paroxetine hydrochloride Natural products C1=CC(F)=CC=C1C1C(COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-UHFFFAOYSA-N 0.000 description 1
- 239000001888 Peptone Substances 0.000 description 1
- 108010080698 Peptones Proteins 0.000 description 1
- 201000001880 Sexual dysfunction Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 239000005862 Whey Substances 0.000 description 1
- 102000007544 Whey Proteins Human genes 0.000 description 1
- 108010046377 Whey Proteins Proteins 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 230000006400 anxiety behaviour Effects 0.000 description 1
- 230000007529 anxiety like behavior Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000007640 basal medium Substances 0.000 description 1
- 235000015278 beef Nutrition 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 229940041514 candida albicans extract Drugs 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 235000019693 cherries Nutrition 0.000 description 1
- 235000020247 cow milk Nutrition 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007357 depressive behavior Effects 0.000 description 1
- 230000007267 depressive like behavior Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000015872 dietary supplement Nutrition 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 230000004970 emotional disturbance Effects 0.000 description 1
- 230000002996 emotional effect Effects 0.000 description 1
- 230000010482 emotional regulation Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 229960000389 fluoxetine hydrochloride Drugs 0.000 description 1
- 235000013373 food additive Nutrition 0.000 description 1
- 239000002778 food additive Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 230000008821 health effect Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 235000008216 herbs Nutrition 0.000 description 1
- 230000007124 immune defense Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000007102 metabolic function Effects 0.000 description 1
- 239000005445 natural material Substances 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 229960002296 paroxetine Drugs 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 235000019319 peptone Nutrition 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 235000003784 poor nutrition Nutrition 0.000 description 1
- 235000021489 probiotic drink Nutrition 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000009103 reabsorption Effects 0.000 description 1
- 229960002073 sertraline Drugs 0.000 description 1
- VGKDLMBJGBXTGI-SJCJKPOMSA-N sertraline Chemical compound C1([C@@H]2CC[C@@H](C3=CC=CC=C32)NC)=CC=C(Cl)C(Cl)=C1 VGKDLMBJGBXTGI-SJCJKPOMSA-N 0.000 description 1
- 231100000872 sexual dysfunction Toxicity 0.000 description 1
- 230000007958 sleep Effects 0.000 description 1
- 208000019116 sleep disease Diseases 0.000 description 1
- 208000020685 sleep-wake disease Diseases 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 210000001082 somatic cell Anatomy 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- YWYZEGXAUVWDED-UHFFFAOYSA-N triammonium citrate Chemical compound [NH4+].[NH4+].[NH4+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O YWYZEGXAUVWDED-UHFFFAOYSA-N 0.000 description 1
- 239000001393 triammonium citrate Substances 0.000 description 1
- 235000011046 triammonium citrate Nutrition 0.000 description 1
- 235000008939 whole milk Nutrition 0.000 description 1
- 239000012138 yeast extract Substances 0.000 description 1
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
- A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
- A23L2/38—Other non-alcoholic beverages
-
- 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
- A23C9/12—Fermented milk preparations; Treatment using microorganisms or enzymes
- A23C9/13—Fermented milk preparations; Treatment using microorganisms or enzymes using additives
- A23C9/1307—Milk products or derivatives; Fruit or vegetable juices; Sugars, sugar alcohols, sweeteners; Oligosaccharides; Organic acids or salts thereof or acidifying agents; Flavours, dyes or pigments; Inert or aerosol gases; Carbonation methods
-
- 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
- A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
- A23L2/385—Concentrates of non-alcoholic beverages
- A23L2/39—Dry compositions
-
- 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
- A23L33/135—Bacteria or derivatives thereof, e.g. probiotics
-
- 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
- A23L33/20—Reducing nutritive value; Dietetic products with reduced nutritive value
- A23L33/21—Addition of substantially indigestible substances, e.g. dietary fibres
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/74—Bacteria
- A61K35/741—Probiotics
- A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
- A61K35/745—Bifidobacteria
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/74—Bacteria
- A61K35/741—Probiotics
- A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
- A61K35/747—Lactobacilli, e.g. L. acidophilus or L. brevis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- 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
-
- 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
- A23V2400/00—Lactic or propionic acid bacteria
- A23V2400/11—Lactobacillus
- A23V2400/113—Acidophilus
-
- 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
- A23V2400/00—Lactic or propionic acid bacteria
- A23V2400/11—Lactobacillus
- A23V2400/125—Casei
-
- 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
- A23V2400/00—Lactic or propionic acid bacteria
- A23V2400/11—Lactobacillus
- A23V2400/147—Helveticus
-
- 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
- A23V2400/00—Lactic or propionic acid bacteria
- A23V2400/11—Lactobacillus
- A23V2400/169—Plantarum
-
- 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
- A23V2400/00—Lactic or propionic acid bacteria
- A23V2400/11—Lactobacillus
- A23V2400/173—Reuteri
-
- 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
- A23V2400/00—Lactic or propionic acid bacteria
- A23V2400/11—Lactobacillus
- A23V2400/175—Rhamnosus
-
- 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
- A23V2400/00—Lactic or propionic acid bacteria
- A23V2400/51—Bifidobacterium
- A23V2400/515—Animalis
-
- 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
- A23V2400/00—Lactic or propionic acid bacteria
- A23V2400/51—Bifidobacterium
- A23V2400/533—Longum
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Mycology (AREA)
- Polymers & Plastics (AREA)
- Food Science & Technology (AREA)
- Microbiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Nutrition Science (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Molecular Biology (AREA)
- Epidemiology (AREA)
- Pain & Pain Management (AREA)
- Psychiatry (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Coloring Foods And Improving Nutritive Qualities (AREA)
Abstract
本发明公开了一种缓解焦虑或抑郁的益生菌组合物及其应用。所述益生菌组合物包含益生元、K‑KLJ益生菌组合和功能性物质,所述K‑KLJ益生菌组合含有植物乳杆菌、罗伊氏乳杆菌、干酪乳杆菌、瑞士乳杆菌中的至少一种,或者还包括鼠李糖乳杆菌、嗜酸乳杆菌、动物双歧杆菌、长双歧杆菌中的至少一种。本专利发明的益生菌组合物可以显著提升肠道有益菌群的数量,改善肠道不适,减少慢性炎症,从而减少不良的情绪,防治抑郁和焦虑等情绪疾病。而且本专利发明的益生菌株组合之间,以及益生元,益生菌菌株与功能性物质之间具有显著的协同增强作用。
Description
技术领域
本发明属于生物医药领域,具体涉及通过调节肠道菌群缓解焦虑或抑郁的益生菌组合物及其应用。
背景技术
人体肠道为微生物提供了良好的栖息环境,成人肠道内的微生物数量高达1014,接近人体体细胞数量的10倍;质量达到1.2kg,接近人体肝脏的质量;其包含的基因数目约是人体自身的100倍,具有人体自身不具备的代谢功能。作为人体最庞大、最复杂的微生态系统,肠道微生物本身及其代谢产物不仅能调节人体健康,更在膳食和宿主之间起到了重要的桥梁作用,是人体健康系统中非常重要的组成部分。
肠道不仅是人体消化吸收的重要场所,同时也是最大的免疫器官,在维持正常免疫防御功能中发挥着极其重要的作用。人体的健康与肠道内环境微生物有密不可分的联系,正常身体状态下,肠道菌群通过与肠道的相互作用调控宿主的免疫系统,维持动态平衡。一旦这种平衡被打破,肠道生态环境失衡,有害菌数量增多,就会导致疾病。现代快节奏的生活,以及高强度的工作,给人们带来越来越多的压力,压力会引起失眠,晚上入睡时间越来越晚,睡眠时间短,焦虑和抑郁的患病率越来越高。近年来的科学研究发现,60%以上的抑郁和焦虑患者均存在至少一种的肠道功能疾病,如腹泻,便秘,营养吸收功能差,肠道炎症等,肠道功能不适会给患者带来情绪障碍,如易焦虑,发怒,脾气差,情绪压抑,抑郁等。抑郁和焦虑患者的肠道菌群与正常人相比,多样性上有显著差异,此外“菌-肠-脑轴”的发现,证实了肠道菌群与人的情绪关系密切,肠道菌群的代谢产物(如5-羟色胺,γ-氨基丁酸,乙酰胆碱,等),也参与了神经系统的功能。通过肠道菌群生态的重建,是预防和缓解情绪相关疾病的新手段。
目前临床上常用的抗抑郁药物多是通过改善五羟色胺功能起作用的,如盐酸氟西汀、帕罗西汀、舍曲林等调节五羟色胺的重吸收,尽管这些药物在抑郁症治疗中起到重要作用,但也存在副作用较大的缺点,常引发头痛头昏、恶心腹泻、性功能障碍及血压/体重异常等,且治疗费用高,仅限制其在一些病情严重的患者人群使用,不适合轻度症状的患者使用,也不能用于敏感人群抑郁症的预防。因此,寻找副作用小、价格经济且适合预防敏感人群抑郁症发生的产品,非常的必要和紧迫。
近年来,益生菌在调节肠道菌群生态,缓解情绪异常的作用越来越被重视,大量的科学研究表明,益生菌与肠道细胞具有紧密的联系和调控作用,除了诱导免疫系统外,其代谢产物也与情绪调节密切相关,如5-羟色胺,γ-氨基丁酸,乙酰胆碱,多巴胺,等。最近的许多研究结果表明,许多中草药的药效,是通过肠道菌群代谢后成为活性物质发挥作用的。因为不同病人的肠道菌群不同,从而导致相同的中药方,在不同的病人身上的效果会存在差异。调整菌群,重建肠道微生态,是一种安全的,无毒副作用的提升亚健康人群的健康状况的方式。
然而,当前市场上的益生菌产品,多仅为补充益生菌为目标的,没有深入研究益生菌株的功能与人体亚健康状态以及益生菌菌株间的协同作用,又或者仅把益生菌当做助消化或者增加风味的作用,如灭活常温酸奶,乳酸菌风味饮料,乳酸菌风味蛋糕等,对人体肠道菌群生态的调节和对健康的有益效果不显著,也远远低估了益生菌的作用。开发具有缓解情绪障碍的健康功能的益生菌产品,帮助亚健康人群恢复健康状态,可减少患病风险,提升人民的生活质量,具有显著的社会意义,也具有巨大市场应用价值。
发明内容
针对上述现有技术的不足,本发明的目的在于提供一种缓解焦虑或抑郁的益生菌组合物。本发明的益生菌组合物可以显著提升肠道有益菌群的数量,改善肠道不适,减少慢性炎症,从而减少不良的情绪,防治抑郁和焦虑等情绪疾病。而且本发明的益生菌株组合之间,以及益生元,益生菌菌株与功能性物质之间具有显著的协同增强作用。
本发明的另一目的在于提供缓解焦虑或抑郁的益生菌组合物在制备缓解焦虑或抑郁的产品中的应用。
为实现上述目的,本发明的技术方案为:
本发明的第一方面,提供一种口服的缓解抑郁和焦虑的益生菌组合物,含有益生元、K-KLJ益生菌组合和功能性物质,所述K-KLJ益生菌组合含有植物乳杆菌、罗伊氏乳杆菌、干酪乳杆菌、瑞士乳杆菌中的至少一种。
优选的,所述K-KLJ益生菌组合还包括鼠李糖乳杆菌、嗜酸乳杆菌、动物双歧杆菌、长双歧杆菌中的至少一种。
优选的,所述益生菌组合物中的总活菌数≥1.0*108CFU/g,其中,植物乳杆菌、罗伊氏乳杆菌、干酪乳杆菌、瑞士乳杆菌中的单一益生菌的活菌数≥2.0*107CFU/g,鼠李糖乳杆菌、嗜酸乳杆菌、动物双歧杆菌、长双歧杆菌中的单一益生菌的活菌数≥0.5*107CFU/g。
优选的,所述益生元为低聚果糖、低聚半乳糖、低聚木糖、棉子糖、水苏糖中的至少一种。
优选的,所述功能性物质为γ-氨基丁酸、ω-3不饱和脂肪酸、茶氨酸、脱脂乳粉、酸枣仁粉或酸枣仁提取物、针叶樱桃粉中的至少一种。
进一步优选的,所述益生菌组合物含有低聚果糖或菊粉、低聚半乳糖、低聚木糖、植物乳杆菌,干酪乳杆菌、罗伊氏乳杆菌、嗜酸乳杆菌、鼠李糖乳杆菌、动物双歧杆菌、瑞士乳杆菌、长双歧杆菌、脱脂乳粉、γ-氨基丁酸、茶氨酸;所述植物乳杆菌为保藏编号CGMCCNo.19710的植物乳杆菌(Lactobacillus plantarum)、干酪乳杆菌为保藏编号CGMCCNo.19708的干酪乳杆菌(Lactobacillus casei)、罗伊氏乳杆菌为保藏编号CGMCCNo.18700的罗伊氏乳杆菌(Lactobacillus reuteri)、鼠李糖乳杆菌为保藏编号CGMCCNo.19711的鼠李糖乳杆菌、动物双歧杆菌为保藏编号CGMCC No.19712的动物双歧杆菌(Bifidobacterium animalis)。
第二方面,提供上述益生菌组合物在制备缓解焦虑或抑郁的产品中的应用。
优选的,上述应用中,所述缓解焦虑或抑郁的产品为食品、保健品、特医食品、药品中的任一种。
优选的,上述应用中,所述缓解焦虑或抑郁的产品为固体饮料、酸奶、益生菌饮料、酸奶块。
在整个公开内容中,术语“K-KLJ益生菌组合”为有助于缓解焦虑或抑郁的益生菌组合。
本发明的有益效果:
本发明经过多轮的益生菌株功能的筛选和菌株组合优化,辅配协同增强益生菌效果的天然物质,并在动物体内和受试人群验证其健康效果。本发明的益生菌组合物较常规的市售益生菌粉,其生长效率增加630%以上,可以显著提升肠道有益菌群的数量。经动物试验验证,本发明的益生菌组合物可改善焦虑与抑郁样行为,且多种益生菌组合的效果优于单一益生菌效果,证明本发明的益生菌组合之间具有协同增强的效果。受试人群服用后从可显著减少压力(如考试,等)带来的焦虑情绪的剧烈波动以及睡眠障碍,防治抑郁和焦虑等情绪疾病。本发明的益生菌株组合物,可以缓解当下社会中快节奏,高压力生活节奏下带来的情绪障碍,具有巨大的社会意义和经济价值。
生物保藏说明
植物乳杆菌(Lactobacillus plantarum),保藏于中国微生物菌种保藏管理委员会普通微生物中心,保藏地址北京市朝阳区北辰西路1号院3号,保藏机构简称:CGMCC,保藏日期为2020年04月23日,生物保藏编号为CGMCC No.19710,菌株编号:KLpl-5。
干酪乳杆菌(Lactobacillus casei),保藏于中国微生物菌种保藏管理委员会普通微生物中心,保藏地址北京市朝阳区北辰西路1号院3号,保藏机构简称:CGMCC,保藏日期为2020年04月23日,生物保藏编号为CGMCC No.19708,菌株编号:KLca-10。
罗伊氏乳杆菌(Lactobacillus reuteri),保藏于中国微生物菌种保藏管理委员会普通微生物中心,保藏地址北京市朝阳区北辰西路1号院3号,保藏机构简称:CGMCC,保藏日期为2019年10月17日,生物保藏编号为CGMCC No.18700,菌株编号:KLR-3。
鼠李糖乳杆菌(Lactobacillus rhamnosus),保藏于中国微生物菌种保藏管理委员会普通微生物中心,保藏地址北京市朝阳区北辰西路1号院3号,保藏机构简称:CGMCC,保藏日期为2020年04月23日,生物保藏编号为CGMCC No.19711,菌株编号:KLrh-10。
动物双歧杆菌(Bifidobacterium animalis),保藏于中国微生物菌种保藏管理委员会普通微生物中心,保藏地址北京市朝阳区北辰西路1号院3号,保藏机构简称:CGMCC,保藏日期为2020年04月23日,生物保藏编号为CGMCC No.19712,菌株编号:KBla-22。
具体实施方式
通过以下详细说明可以进一步理解本发明的特点和优点。所提供的实施例仅是对本发明方法的说明,而不以任何方式限制本发明揭示的其余内容。
以下实施例中所用到的原料和益生菌粉,除特别注明外,均为市售产品或湖北康肽药业有限公司生产的益生菌粉。功效性物质添加量参照了相应的国家标准:GB 2760-2014《食品添加剂使用标准》;GB 14880-2012《食品营养强化剂使用标准》;相应的行业标准和国家卫生部等主管部门颁布的最新的新食品原料使用规范等,配料添加量均符合相应的法规规定。
以下实施例中鼠李糖乳杆菌、嗜酸乳杆菌、动物双歧杆菌、长双歧杆菌中的单一益生菌的活菌数≥2.0*107CFU/g,鼠李糖乳杆菌、嗜酸乳杆菌、动物双歧杆菌、长双歧杆菌中的单一益生菌的活菌数≥0.5*107CFU/g。
实施例1:筛选对K-KLJ复合益生菌的促进作用益生元
本实施例针对K-KLJ益生菌组合进行了促增长益生元的筛选,从而获得促进益生菌的益生元组合。以MRS培养基(牛肉膏10.0g,酵母膏5.0g,蛋白胨10.0g,葡萄糖20.0g,K2HPO4 2.0g,醋酸钠5.0g,MgSO4·7H2O 0.2g,MnSO4·4H2O0.05g,吐温80 1.0g,柠檬酸三铵2.0g,琼脂15.0g,加蒸馏水至1000ml)为基础培养基,分别添加候选的益生元或益生元组合至终浓度为10%。按相同的接种量接入K-KLJ复合益生菌冻干粉(植物乳杆菌冻干粉20%,干酪乳杆菌冻干粉20%,罗伊氏乳杆菌冻干粉15%;鼠李糖乳杆菌冻干粉15%,长双歧杆菌冻干粉5%,动物双歧杆菌冻干粉5%,嗜酸乳杆菌冻干粉10%,瑞士乳杆菌冻干粉10%),厌氧培养箱静置培养6h,测定菌体生长的OD600值,筛选促进益生菌生长的益生元组合物。筛选结果(表.1)显示,菊粉(低聚果糖)、低聚半乳糖、低聚木糖、棉子糖、水苏糖等益生元的促进益生菌生长的效果较好,促进效果较基础培养基提高102%-204%,可提高在肠道内的益生菌数量。
表1.促进K-KLJ复合益生菌生长的益生元筛选
实施例2:缓解抑郁/焦虑情绪的固体饮料
本实施例提供一种能够维持肠道健康和改善抑郁/或焦虑情绪的益生菌固体饮料,各辅料的组成如表2所示,精确称量原料后,进行梯度混匀,最终分装为10g/袋。经检测(参考GB4789.35-2016方法描述),该固体饮料的益生菌活菌数为1.8-8.5×108CFU/g。
表2.缓解抑郁/焦虑情绪的固体饮料
实施例3:缓解抑郁/焦虑情绪的酸奶
本实施例提供一种能够维持肠道健康和改善抑郁/或焦虑情绪的的功能性益生菌发酵酸奶,是由下列重量的组分组成:鲜牛乳100g,白砂糖12g,酸枣仁提取物500mg,γ-氨基丁酸200mg,95℃灭菌5min后冷却至40℃,接种K-KLJ复合益生菌发酵剂0.18g(嗜热链球菌冻干粉20%,保加利亚乳杆菌冻干粉15%,植物乳杆菌冻干粉15%,干酪乳杆菌冻干粉25%,长双歧乳杆菌冻干粉10%,嗜酸乳杆菌冻干粉5%,瑞士乳杆菌冻干粉10%),密封后置于酸奶机在40℃发酵7-12h,然后置于4℃冰箱中12h。经检测(参考GB4789.35-2016方法描述),该固体饮料的益生菌活菌数为2.7×108CFU/g。
实施例4:缓解抑郁/焦虑情绪的益生菌饮料
本实施例提供一种能够维持肠道健康和缓解抑郁/焦虑情绪的功能性益生菌饮料,是由下列重量的组分组成:每100g的益生菌饮料中含有脱脂乳粉8g,食用白砂糖12g和K-KLJ复合益生菌混合益生菌0.82g(干酪乳杆菌冻干粉10%、长双歧杆菌冻干粉20%、鼠李糖乳杆菌冻干粉10%、嗜酸乳杆菌冻干粉30%、动物双歧杆菌冻干粉30%)。混合均匀后无菌分装,于4-8℃储存。经检测(参考GB4789.35-2016方法描述),该固体饮料的益生菌活菌数为2.8×108CFU/g。
实施例5:缓解抑郁/焦虑情绪的酸奶块
本实施例提供一种能够维持肠道健康和提高免疫力的功能性益生菌饮料,首先是酸奶发酵,将鲜牛乳1000g,白砂糖90g混合均匀,加热至80-90℃维持10分钟,降温至40℃以下,加入K-KLJ复合益生菌发酵剂1g(嗜热链球菌冻干粉20%,保加利亚乳杆菌冻干粉15%,植物乳杆菌冻干粉15%,干酪乳杆菌冻干粉25%,长双歧乳杆菌冻干粉10%,嗜酸乳杆菌冻干粉5%,瑞士乳杆菌冻干粉10%)并搅拌均匀,密封后置于酸奶机在40℃发酵7-12h使酸奶凝固,然后置于4℃冰箱中12h。将酸奶与辅料按以下重量分混合:酸奶30%、白砂糖7%、全脂奶粉7%、乳清粉7%、柠檬酸7%、淀粉1%、果胶1%、水30%份、香蕉水果粒10%,茶氨酸2%,γ-氨基丁酸1%。所有物料混合均匀后,倒入乳化罐中乳化30分钟,装入酸奶块制备不锈钢格板,放入冷冻干燥机冻干,冻干程序如表1所示,经检测(参考GB4789.35-2016方法描述),酸奶块的活菌数为5.5×109CFU/g。
表3.益生菌酸奶块冻干程序
序号 | 温度(℃) | 保温时间(h) |
1 | -40 | 3 |
2 | -25 | 7 |
3 | -15 | 3 |
4 | -5 | 3 |
5 | 5 | 2 |
6 | 15 | 2 |
7 | 25 | 4 |
实施例6:小鼠焦虑与抑郁样行为学检测
100只昆明小鼠,雌雄各半,6-8周龄,体重20-25g,经一周适应后,随机分为10组。受试样品为实施例2-5的配方产品,对照组采用等量的脱脂乳粉。以人体推荐剂量为10g/天(以体重60kg计)计算,在该试验中受试样品剂量为1.7g/kg·bw/d(相当于受试样品人体推荐摄入量的10倍),以等量的脱脂乳粉为空白对照。受试样品用无菌水配制,配制浓度分别为500g/L,经口每日分三次给予小鼠相应剂量的受试物,小鼠总灌胃量为3.4mL/kg·bw,连续灌胃30天。干预结束后,采用明暗箱试验和悬尾试验测试不同实施例组样品与空白对照组的小鼠的焦虑与抑郁样行为的影响。
(1)明暗箱试验
参考文献[Premysl bercik,Gastroenterology,2010]的描述设计和执行明暗箱实验。实验需要在安静环境下进行,将受试小鼠放入长宽高分别为80*80*40cm的箱内(一半有遮挡为暗箱,一半无遮挡为明箱),将小鼠放入敞箱后开始测定,每次计时10min,记录单位时间内小鼠在亮箱中停留的总时间。小鼠在亮处停留时间越长说明小鼠越不焦虑。结果(表4)显示,与不含K-KLJ益生菌的对照组相比,本发明的益生菌组合物的干预组的小鼠在亮箱中的停留明显延长,表明其焦虑状态得到改善。发酵酸奶组的小鼠比益生菌饮料组的小鼠在明箱中的停留时间更长,说明酸枣仁,γ-氨基丁酸等物质对组合物的缓解焦虑情绪是有增强作用的。固体饮料产品1、9和10比较可发现,只含益生菌组合(产品9)或者仅含功能性物质(产品10),其效果均弱于同时含益生元、益生菌和功能性物质的组合(产品1);固体饮料产品1、2、6、8的效果显示,多种益生菌的组合产品较单一益生菌的产品效果好,说明所选的菌株之间有协同作用。
表4.明暗箱测试益生菌组合物的效果
组别 | 小鼠明箱中的停留时间(秒) |
固体饮料(实施例2中产品1) | 260±56# |
固体饮料(实施例2中产品2) | 229±49 |
固体饮料(实施例2中产品6) | 237±51* |
固体饮料(实施例2中产品8) | 245±45* |
固体饮料(实施例2中产品9) | 233±53* |
固体饮料(实施例2中产品10) | 225±52 |
发酵酸奶(实施例3) | 253±76# |
益生菌饮料(实施例4) | 242±43* |
益生菌酸奶块(实施例5) | 286±63# |
对照组 | 210±56 |
注:与对照组比较,*:p<0.05;#:p<0.01
(2)悬尾试验
参考文献[徐立,中国中药杂志,2005]的实验方法描述进行悬尾实验,当被悬挂的小鼠静止不动则视为抑郁。将小鼠尾端1cm的部位贴在一铁架夹上,头朝下,使小鼠前后左右均无攀抓的地方,一段时间后小鼠因绝望而活动减少,记录小鼠6min内后4min的不动时间。结果(表5)显示,与对照组相比,本发明的益生菌组合物的干预组的小鼠静止时间明显缩短,表明其抑郁状态得到改善。固体饮料产品1、9和10比较可发现,只含益生菌组合(产品9)或者仅含功能性物质(产品10),其效果均弱于同时含益生元,益生菌和功能性物质的组合(产品1);固体饮料产品1、2、6、8的效果显示,多种益生菌的组合产品较单一益生菌的产品效果好,说明所选的菌株之间有协同作用。
表5.悬尾试验测试益生菌组合物的效果
组别 | 小鼠静止时间(秒) |
固体饮料(实施例2中产品1) | 104±31# |
固体饮料(实施例2中产品2) | 143±34 |
固体饮料(实施例2中产品6) | 135±38* |
固体饮料(实施例2中产品8) | 130±35* |
固体饮料(实施例2中产品9) | 125±32* |
固体饮料(实施例2中产品10) | 138±36 |
发酵酸奶(实施例3) | 113±26# |
益生菌饮料(实施例4) | 132±33* |
益生菌酸奶块(实施例5) | 93±37# |
对照组 | 152±28 |
注:与对照组比较,*:p<0.05;#:p<0.01
实施例7:大学生考试前焦虑的效果测试
选取100名学生作为志愿者,随机分为5组,于期末考试前两个月开始分别服用固体饮料10g/天,发酵酸奶100g/天,益生菌饮料100g/天,酸奶块10g/天,对照组A服用按照实施例1制作的不含有益生菌的安慰剂,每日1次,每次1袋;持续至期末考试结束。志愿者汇报考试前一周的焦虑状况(包括学习注意力不集中,莫名的烦躁,心慌和呼吸困难,等异常状况),以及智能手环采集到的睡眠时间的数据。
表6.对学生考试前焦虑的及睡眠情况改善效果测试
注:与对照组比较,*:p<0.05;#:p<0.01
从上表6可以看出,服用本发明产品组与对照组相比,睡眠时间明显上升,其情绪焦虑的次数也显著下降,说明本发明提供的配方制备的功能性益生菌产品,具有缓解压力带来的焦虑情绪障碍以及失眠的效果。
Claims (2)
1.一种口服的缓解抑郁或焦虑的益生菌组合物,其特征在于,所述益生菌组合物由下列质量百分含量的原料组成:低聚果糖7%、低聚异麦芽糖7%、低聚半乳糖32%、低聚木糖10%、水苏糖10%、保藏编号CGMCC No.19710的植物乳杆菌2%、保藏编号CGMCC No.19708的干酪乳杆菌2%、保藏编号CGMCC No.18700的罗伊氏乳杆菌1.5%、嗜酸乳杆菌1%、保藏编号CGMCC No.19711的鼠李糖乳杆菌1.5%、保藏编号CGMCC No.19712的动物双歧杆菌0.5%、瑞士乳杆菌0.5%、长双歧杆菌0.5%、脱脂奶粉15%、γ-氨基丁酸1%、茶氨酸1.5%、酸枣仁2%、ω-3不饱和脂肪酸5%,其中,植物乳杆菌、罗伊氏乳杆菌、干酪乳杆菌、瑞士乳杆菌中的单一益生菌的活菌数≥2.0*107CFU/g,鼠李糖乳杆菌、嗜酸乳杆菌、动物双歧杆菌、长双歧杆菌中的单一益生菌的活菌数≥0.5*107CFU/g,所述益生菌组合物中的总活菌数为8.5*108CFU/g。
2.权利要求1所述的益生菌组合物在制备缓解焦虑或抑郁的产品中的应用。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010601490.6A CN111728111B (zh) | 2020-06-28 | 2020-06-28 | 一种缓解焦虑或抑郁的益生菌组合物及其应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010601490.6A CN111728111B (zh) | 2020-06-28 | 2020-06-28 | 一种缓解焦虑或抑郁的益生菌组合物及其应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN111728111A CN111728111A (zh) | 2020-10-02 |
CN111728111B true CN111728111B (zh) | 2023-01-17 |
Family
ID=72651509
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202010601490.6A Active CN111728111B (zh) | 2020-06-28 | 2020-06-28 | 一种缓解焦虑或抑郁的益生菌组合物及其应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN111728111B (zh) |
Families Citing this family (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR101951919B1 (ko) * | 2018-12-07 | 2019-02-25 | (주)에이투젠 | 도파민 분비 증진 기능이 있는 신규한 락토바실러스 루테리 atg-f4 균주, 이를 함유하는 정신질환의 예방 또는 치료용 조성물 |
CN109588726B (zh) * | 2019-01-31 | 2021-11-30 | 山东环亿生物科技有限公司 | 一种用于改善睡眠的干酪乳杆菌组合物及其制备方法 |
CN112336753A (zh) * | 2020-11-20 | 2021-02-09 | 深圳市融思生物科技有限公司 | 一种肠道菌群胶囊及其制备方法和应用 |
CN112375713B (zh) * | 2020-11-25 | 2022-07-05 | 山东向日葵生物工程有限公司 | 一株长双岐乳杆菌sf-b-27及其应用 |
EP4265297A1 (en) * | 2020-12-16 | 2023-10-25 | Meiji Co., Ltd | Composition for improving inflammation of brain tissue |
CN112655800A (zh) * | 2020-12-21 | 2021-04-16 | 上海诺德生物实业有限公司 | 一种含茶叶茶氨酸益生菌的巧克力及其制备方法 |
CN112999246A (zh) * | 2021-01-22 | 2021-06-22 | 绍兴市第七人民医院 | 一种益生菌组合物及其产品和应用 |
CN112889871A (zh) * | 2021-02-03 | 2021-06-04 | 广州悦芯科技有限公司 | 一种含益生菌的奶茶伴侣饼干及其制备方法和应用 |
CN113337428B (zh) * | 2021-06-03 | 2023-06-06 | 海南大学 | 一株植物乳杆菌hnu082及其用途 |
CN113430135B (zh) * | 2021-07-01 | 2022-04-26 | 杭州娃哈哈科技有限公司 | 一种有改善抑郁作用的瑞士乳杆菌菌株及其应用 |
TWI810645B (zh) * | 2021-09-06 | 2023-08-01 | 景岳生物科技股份有限公司 | 乳桿菌組合物及其改善抗生素造成之焦慮症的用途 |
CN114081184B (zh) * | 2021-11-25 | 2022-11-11 | 江苏新申奥生物科技有限公司 | 一种具有预防抑郁和焦虑行为形成的益生菌剂及其应用 |
CN114525218B (zh) * | 2021-12-30 | 2024-05-07 | 美益添生物医药(武汉)有限公司 | 一种长双歧杆菌及其培养方法和其在高产γ-氨基丁酸和5-羟色胺中的应用 |
CN115521883B (zh) * | 2022-02-16 | 2024-02-20 | 广东益可维生物技术有限公司 | 一种具有缓解压力和改善睡眠功能的益生菌 |
CN115154488B (zh) * | 2022-03-31 | 2024-04-26 | 合肥工业大学 | 一种鼠李糖乳杆菌改善记忆损伤的用途 |
CN115838653A (zh) * | 2022-07-11 | 2023-03-24 | 四川维创天益生物科技有限公司 | 一种改善不良情绪的植物乳杆菌gm11及其用途 |
CN116076734B (zh) * | 2022-10-26 | 2024-04-26 | 健码制药(广东)有限公司 | 一种抗氧化和抗抑郁的中药/益生菌/益生元微生态制剂及其制备与应用 |
CN116138457A (zh) * | 2022-12-14 | 2023-05-23 | 温州医科大学 | 一种具有缓解抑郁样症状作用的复合营养组合物 |
CN116676225B (zh) * | 2023-05-23 | 2024-01-05 | 河北源民生物科技有限公司 | 一株具有安神助眠功效的鼠李糖乳杆菌lr-28菌株、发酵产物、嘉眠菌群组合剂及应用 |
CN116676226B (zh) * | 2023-05-23 | 2024-04-26 | 河北源民生物科技有限公司 | 缓解焦虑的植物乳杆菌lp-28、酸奶及应用 |
CN116420831B (zh) * | 2023-06-01 | 2023-08-22 | 山东向日葵生物工程有限公司 | 一种鼠李糖乳杆菌sf-l30在制备改善机体血清素水平发酵饮品中的应用 |
CN116850213B (zh) * | 2023-07-24 | 2024-04-30 | 青岛东海药业有限公司 | 一种益生菌组合物及其应用 |
CN117887646B (zh) * | 2024-03-18 | 2024-05-14 | 微康益生菌(苏州)股份有限公司 | 一种抗焦虑和抑郁的复合益生菌及其应用 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107744017A (zh) * | 2017-06-27 | 2018-03-02 | 中食月太(北京)健康科技有限公司 | 一种含水解酪蛋白的益生菌固体饮料及其制备方法 |
CN108004189A (zh) * | 2018-01-18 | 2018-05-08 | 北京科拓恒通生物技术股份有限公司 | 一种复合益生乳酸菌粉剂及其制备方法与应用 |
CN110101722A (zh) * | 2019-06-10 | 2019-08-09 | 北京科拓恒通生物技术股份有限公司 | 一种复合益生菌菌剂用于制备治疗溃疡性结肠炎产品的用途 |
CN110140968A (zh) * | 2019-06-18 | 2019-08-20 | 广州康泽医疗科技有限公司 | 一种缓解焦虑、抑郁,调节情绪偏差、减压助眠的益生菌组合物及其制备方法和应用 |
CN110141585A (zh) * | 2019-07-02 | 2019-08-20 | 北京科拓恒通生物技术股份有限公司 | 一种用于调节肠道菌群的复合益生菌发酵菌剂及其制备方法 |
-
2020
- 2020-06-28 CN CN202010601490.6A patent/CN111728111B/zh active Active
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107744017A (zh) * | 2017-06-27 | 2018-03-02 | 中食月太(北京)健康科技有限公司 | 一种含水解酪蛋白的益生菌固体饮料及其制备方法 |
CN108004189A (zh) * | 2018-01-18 | 2018-05-08 | 北京科拓恒通生物技术股份有限公司 | 一种复合益生乳酸菌粉剂及其制备方法与应用 |
CN110101722A (zh) * | 2019-06-10 | 2019-08-09 | 北京科拓恒通生物技术股份有限公司 | 一种复合益生菌菌剂用于制备治疗溃疡性结肠炎产品的用途 |
CN110140968A (zh) * | 2019-06-18 | 2019-08-20 | 广州康泽医疗科技有限公司 | 一种缓解焦虑、抑郁,调节情绪偏差、减压助眠的益生菌组合物及其制备方法和应用 |
CN110141585A (zh) * | 2019-07-02 | 2019-08-20 | 北京科拓恒通生物技术股份有限公司 | 一种用于调节肠道菌群的复合益生菌发酵菌剂及其制备方法 |
Also Published As
Publication number | Publication date |
---|---|
CN111728111A (zh) | 2020-10-02 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN111728111B (zh) | 一种缓解焦虑或抑郁的益生菌组合物及其应用 | |
CA2745341C (en) | Means and methods for activating vagus nerve | |
WO2013127146A1 (zh) | 一种能够缓解铅毒性的植物乳杆菌及其用途 | |
CN112056399A (zh) | 一种增强免疫力的益生菌组合物及其应用 | |
CZ300143B6 (cs) | Kmen Lactobacillus, jeho použití a výrobek jej obsahující | |
CN102174450B (zh) | 一种抗幽门螺杆菌感染的植物乳杆菌及其用途 | |
TWI739495B (zh) | 可促進排便的組合物及其用途 | |
CN111264737A (zh) | 助睡眠益生菌固体饮料及其制备方法 | |
CN103271274B (zh) | 一种营养保健粥 | |
CN111671079A (zh) | 一种复合益生菌粉组合物及其制备方法 | |
CN111557404A (zh) | 助消化益生菌固体饮料及其制备方法 | |
CN110679813A (zh) | 一种用于减重的益生菌保健饮料 | |
CN105661230A (zh) | 小扁豆发酵生产益生菌功能性饮料和食品 | |
KR20040027180A (ko) | 비만 또는 당뇨병의 예방 및 치료 효과를 갖는 유산균발효 유제품 및 그 제조방법 | |
WO2017047777A1 (ja) | ストレス負荷解放後のセロトニン欠乏改善剤 | |
CN111635875A (zh) | 一种长双歧杆菌cz70及其制备活菌型黑莓果浆的方法 | |
Astashkina et al. | Microbiological quality control of probiotic products | |
CN111685328B (zh) | 那曲4580及其制剂在调节情绪的食品中的应用 | |
CN111642747B (zh) | 那曲4580及制剂在改善睡眠质量的食品中的应用 | |
CN109207389B (zh) | 一种消栓降脂益生复合菌中药口服液及其制备方法 | |
CN106472670B (zh) | 一种运动营养型发酵乳及其制备方法 | |
CN112616932A (zh) | 保护口腔健康的羊奶片及其制备方法 | |
CN112544707A (zh) | 调整肠道助睡眠的固体饮料及其制备方法 | |
Georgieva et al. | Probiotics: past, present, and future challenges | |
TW202242090A (zh) | 具減少脂肪與提升運動表現的乳酸菌組合物及其用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |