US20230119720A1 - Synthetic composition for treating metabolic disorders - Google Patents
Synthetic composition for treating metabolic disorders Download PDFInfo
- Publication number
- US20230119720A1 US20230119720A1 US18/082,793 US202218082793A US2023119720A1 US 20230119720 A1 US20230119720 A1 US 20230119720A1 US 202218082793 A US202218082793 A US 202218082793A US 2023119720 A1 US2023119720 A1 US 2023119720A1
- Authority
- US
- United States
- Prior art keywords
- diabetes
- composition
- infant
- precursor condition
- obesity
- 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.)
- Pending
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 91
- 208000030159 metabolic disease Diseases 0.000 title claims abstract description 25
- 238000011282 treatment Methods 0.000 claims abstract description 45
- 238000000034 method Methods 0.000 claims abstract description 42
- 229920001542 oligosaccharide Polymers 0.000 claims abstract description 35
- 150000002482 oligosaccharides Chemical class 0.000 claims abstract description 35
- 208000008589 Obesity Diseases 0.000 claims abstract description 34
- 235000020824 obesity Nutrition 0.000 claims abstract description 34
- 235000020256 human milk Nutrition 0.000 claims abstract description 33
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims abstract description 32
- 210000004251 human milk Anatomy 0.000 claims abstract description 30
- 239000002243 precursor Substances 0.000 claims abstract description 29
- IEQCXFNWPAHHQR-UHFFFAOYSA-N lacto-N-neotetraose Natural products OCC1OC(OC2C(C(OC3C(OC(O)C(O)C3O)CO)OC(CO)C2O)O)C(NC(=O)C)C(O)C1OC1OC(CO)C(O)C(O)C1O IEQCXFNWPAHHQR-UHFFFAOYSA-N 0.000 claims abstract description 27
- 229940062780 lacto-n-neotetraose Drugs 0.000 claims abstract description 27
- RBMYDHMFFAVMMM-PLQWBNBWSA-N neolactotetraose Chemical compound O([C@H]1[C@H](O)[C@H]([C@@H](O[C@@H]1CO)O[C@@H]1[C@H]([C@H](O[C@H]([C@H](O)CO)[C@H](O)[C@@H](O)C=O)O[C@H](CO)[C@@H]1O)O)NC(=O)C)[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O RBMYDHMFFAVMMM-PLQWBNBWSA-N 0.000 claims abstract description 27
- AXQLFFDZXPOFPO-UHFFFAOYSA-N UNPD216 Natural products O1C(CO)C(O)C(OC2C(C(O)C(O)C(CO)O2)O)C(NC(=O)C)C1OC(C1O)C(O)C(CO)OC1OC1C(O)C(O)C(O)OC1CO AXQLFFDZXPOFPO-UHFFFAOYSA-N 0.000 claims abstract description 25
- AXQLFFDZXPOFPO-UNTPKZLMSA-N beta-D-Galp-(1->3)-beta-D-GlcpNAc-(1->3)-beta-D-Galp-(1->4)-beta-D-Glcp Chemical compound O([C@@H]1O[C@H](CO)[C@H](O)[C@@H]([C@H]1O)O[C@H]1[C@@H]([C@H]([C@H](O)[C@@H](CO)O1)O[C@H]1[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O1)O)NC(=O)C)[C@H]1[C@H](O)[C@@H](O)[C@H](O)O[C@@H]1CO AXQLFFDZXPOFPO-UNTPKZLMSA-N 0.000 claims abstract description 25
- USIPEGYTBGEPJN-UHFFFAOYSA-N lacto-N-tetraose Natural products O1C(CO)C(O)C(OC2C(C(O)C(O)C(CO)O2)O)C(NC(=O)C)C1OC1C(O)C(CO)OC(OC(C(O)CO)C(O)C(O)C=O)C1O USIPEGYTBGEPJN-UHFFFAOYSA-N 0.000 claims abstract description 25
- 210000000577 adipose tissue Anatomy 0.000 claims abstract description 23
- 206010061218 Inflammation Diseases 0.000 claims abstract description 21
- SNFSYLYCDAVZGP-UHFFFAOYSA-N UNPD26986 Natural products OC1C(O)C(O)C(C)OC1OC1C(OC2C(OC(O)C(O)C2O)CO)OC(CO)C(O)C1O SNFSYLYCDAVZGP-UHFFFAOYSA-N 0.000 claims abstract description 21
- 230000004054 inflammatory process Effects 0.000 claims abstract description 21
- 206010018429 Glucose tolerance impaired Diseases 0.000 claims abstract description 19
- 230000002503 metabolic effect Effects 0.000 claims abstract description 19
- 201000009104 prediabetes syndrome Diseases 0.000 claims abstract description 19
- 208000001280 Prediabetic State Diseases 0.000 claims abstract description 18
- SNFSYLYCDAVZGP-OLAZETNGSA-N 2'-fucosyllactose Chemical compound O[C@H]1[C@H](O)[C@H](O)[C@H](C)O[C@H]1O[C@H]1[C@H](O[C@@H]2[C@H](OC(O)[C@H](O)[C@H]2O)CO)O[C@H](CO)[C@H](O)[C@@H]1O SNFSYLYCDAVZGP-OLAZETNGSA-N 0.000 claims abstract description 16
- 208000037487 Endotoxemia Diseases 0.000 claims abstract description 16
- FZIVHOUANIQOMU-YIHIYSSUSA-N alpha-L-Fucp-(1->2)-beta-D-Galp-(1->3)-beta-D-GlcpNAc-(1->3)-beta-D-Galp-(1->4)-D-Glcp Chemical compound O[C@H]1[C@H](O)[C@H](O)[C@H](C)O[C@H]1O[C@H]1[C@H](O[C@@H]2[C@H]([C@H](O[C@@H]3[C@H]([C@H](O[C@@H]4[C@H](OC(O)[C@H](O)[C@H]4O)CO)O[C@H](CO)[C@@H]3O)O)O[C@H](CO)[C@H]2O)NC(C)=O)O[C@H](CO)[C@H](O)[C@@H]1O FZIVHOUANIQOMU-YIHIYSSUSA-N 0.000 claims abstract description 16
- 238000011161 development Methods 0.000 claims abstract description 16
- FZIVHOUANIQOMU-UHFFFAOYSA-N lacto-N-fucopentaose I Natural products OC1C(O)C(O)C(C)OC1OC1C(OC2C(C(OC3C(C(OC4C(OC(O)C(O)C4O)CO)OC(CO)C3O)O)OC(CO)C2O)NC(C)=O)OC(CO)C(O)C1O FZIVHOUANIQOMU-UHFFFAOYSA-N 0.000 claims abstract description 16
- 230000035699 permeability Effects 0.000 claims abstract description 16
- LKOHREGGXUJGKC-UHFFFAOYSA-N Lactodifucotetraose Natural products OC1C(O)C(O)C(C)OC1OC1C(OC2C(C(O)C(O)OC2CO)OC2C(C(O)C(O)C(C)O2)O)OC(CO)C(O)C1O LKOHREGGXUJGKC-UHFFFAOYSA-N 0.000 claims abstract description 14
- LKOHREGGXUJGKC-GXSKDVPZSA-N alpha-L-Fucp-(1->3)-[alpha-L-Fucp-(1->2)-beta-D-Galp-(1->4)]-beta-D-Glcp Chemical compound C[C@@H]1O[C@@H](O[C@@H]2[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]2O[C@@H]2[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]2O[C@@H]2O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]2O)[C@@H](O)[C@H](O)[C@@H]1O LKOHREGGXUJGKC-GXSKDVPZSA-N 0.000 claims abstract description 14
- WJPIUUDKRHCAEL-UHFFFAOYSA-N 3FL Natural products OC1C(O)C(O)C(C)OC1OC1C(OC2C(C(O)C(O)C(CO)O2)O)C(CO)OC(O)C1O WJPIUUDKRHCAEL-UHFFFAOYSA-N 0.000 claims abstract description 11
- 241000736262 Microbiota Species 0.000 claims abstract description 11
- 241000186018 Bifidobacterium adolescentis Species 0.000 claims abstract description 7
- 241000282412 Homo Species 0.000 claims abstract description 7
- 230000002496 gastric effect Effects 0.000 claims abstract description 7
- 229940062827 2'-fucosyllactose Drugs 0.000 claims abstract description 6
- HWHQUWQCBPAQQH-UHFFFAOYSA-N 2-O-alpha-L-Fucosyl-lactose Natural products OC1C(O)C(O)C(C)OC1OC1C(O)C(O)C(CO)OC1OC(C(O)CO)C(O)C(O)C=O HWHQUWQCBPAQQH-UHFFFAOYSA-N 0.000 claims abstract description 6
- 210000001035 gastrointestinal tract Anatomy 0.000 claims description 24
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 claims description 14
- 101800000221 Glucagon-like peptide 2 Proteins 0.000 claims description 14
- TWSALRJGPBVBQU-PKQQPRCHSA-N glucagon-like peptide 2 Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(O)=O)[C@@H](C)CC)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)CC)C1=CC=CC=C1 TWSALRJGPBVBQU-PKQQPRCHSA-N 0.000 claims description 14
- 101710198884 GATA-type zinc finger protein 1 Proteins 0.000 claims description 13
- 102400000326 Glucagon-like peptide 2 Human genes 0.000 claims description 13
- 230000002829 reductive effect Effects 0.000 claims description 12
- 238000012423 maintenance Methods 0.000 claims description 9
- HWHQUWQCBPAQQH-BWRPKUOHSA-N 2-fucosyllactose Chemical compound O[C@H]1[C@H](O)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@H]([C@H](O)CO)[C@H](O)[C@@H](O)C=O HWHQUWQCBPAQQH-BWRPKUOHSA-N 0.000 claims description 8
- 108010088406 Glucagon-Like Peptides Proteins 0.000 claims description 8
- 238000011221 initial treatment Methods 0.000 claims description 8
- 239000002552 dosage form Substances 0.000 claims description 7
- 230000007935 neutral effect Effects 0.000 claims description 4
- 102400000322 Glucagon-like peptide 1 Human genes 0.000 claims 3
- 235000016709 nutrition Nutrition 0.000 description 28
- 150000001720 carbohydrates Chemical class 0.000 description 21
- 235000014633 carbohydrates Nutrition 0.000 description 19
- 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 18
- 241000699670 Mus sp. Species 0.000 description 16
- 210000004369 blood Anatomy 0.000 description 16
- 239000008280 blood Substances 0.000 description 16
- 206010012601 diabetes mellitus Diseases 0.000 description 16
- 239000008103 glucose Substances 0.000 description 16
- 239000000047 product Substances 0.000 description 16
- 102100040918 Pro-glucagon Human genes 0.000 description 14
- 239000002158 endotoxin Substances 0.000 description 13
- 235000013305 food Nutrition 0.000 description 12
- 229920006008 lipopolysaccharide Polymers 0.000 description 12
- 206010022489 Insulin Resistance Diseases 0.000 description 11
- 108090000623 proteins and genes Proteins 0.000 description 11
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 10
- 230000003870 intestinal permeability Effects 0.000 description 10
- 239000007788 liquid Substances 0.000 description 10
- 150000002772 monosaccharides Chemical class 0.000 description 10
- SQVRNKJHWKZAKO-UHFFFAOYSA-N beta-N-Acetyl-D-neuraminic acid Natural products CC(=O)NC1C(O)CC(O)(C(O)=O)OC1C(O)C(O)CO SQVRNKJHWKZAKO-UHFFFAOYSA-N 0.000 description 9
- 239000003629 gastrointestinal hormone Substances 0.000 description 9
- 235000018102 proteins Nutrition 0.000 description 9
- 102000004169 proteins and genes Human genes 0.000 description 9
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 8
- 241000186000 Bifidobacterium Species 0.000 description 8
- 108020004414 DNA Proteins 0.000 description 8
- TYALNJQZQRNQNQ-JLYOMPFMSA-N alpha-Neup5Ac-(2->6)-beta-D-Galp-(1->4)-beta-D-Glcp Chemical compound O1[C@@H]([C@H](O)[C@H](O)CO)[C@H](NC(=O)C)[C@@H](O)C[C@@]1(C(O)=O)OC[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O)[C@H](O)O[C@@H]2CO)O)O1 TYALNJQZQRNQNQ-JLYOMPFMSA-N 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- SQVRNKJHWKZAKO-OQPLDHBCSA-N sialic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@](O)(C(O)=O)OC1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-OQPLDHBCSA-N 0.000 description 8
- DVGKRPYUFRZAQW-UHFFFAOYSA-N 3 prime Natural products CC(=O)NC1OC(CC(O)C1C(O)C(O)CO)(OC2C(O)C(CO)OC(OC3C(O)C(O)C(O)OC3CO)C2O)C(=O)O DVGKRPYUFRZAQW-UHFFFAOYSA-N 0.000 description 7
- 102000004127 Cytokines Human genes 0.000 description 7
- 108090000695 Cytokines Proteins 0.000 description 7
- 230000037396 body weight Effects 0.000 description 7
- 244000005709 gut microbiome Species 0.000 description 7
- 150000002632 lipids Chemical class 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- OIZGSVFYNBZVIK-FHHHURIISA-N 3'-sialyllactose Chemical compound O1[C@@H]([C@H](O)[C@H](O)CO)[C@H](NC(=O)C)[C@@H](O)C[C@@]1(C(O)=O)O[C@@H]1[C@@H](O)[C@H](O[C@H]([C@H](O)CO)[C@H](O)[C@@H](O)C=O)O[C@H](CO)[C@@H]1O OIZGSVFYNBZVIK-FHHHURIISA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- SHZGCJCMOBCMKK-UHFFFAOYSA-N D-mannomethylose Natural products CC1OC(O)C(O)C(O)C1O SHZGCJCMOBCMKK-UHFFFAOYSA-N 0.000 description 6
- SHZGCJCMOBCMKK-DHVFOXMCSA-N L-fucopyranose Chemical compound C[C@@H]1OC(O)[C@@H](O)[C@H](O)[C@@H]1O SHZGCJCMOBCMKK-DHVFOXMCSA-N 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 238000009547 dual-energy X-ray absorptiometry Methods 0.000 description 6
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 6
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 6
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 6
- 230000002757 inflammatory effect Effects 0.000 description 6
- 235000020978 long-chain polyunsaturated fatty acids Nutrition 0.000 description 6
- 229940068196 placebo Drugs 0.000 description 6
- 239000000902 placebo Substances 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 229940088594 vitamin Drugs 0.000 description 6
- 229930003231 vitamin Natural products 0.000 description 6
- 235000013343 vitamin Nutrition 0.000 description 6
- 239000011782 vitamin Substances 0.000 description 6
- 108020004465 16S ribosomal RNA Proteins 0.000 description 5
- AUNPEJDACLEKSC-ZAYDSPBTSA-N 3-fucosyllactose Chemical compound O[C@H]1[C@H](O)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@H](OC(O)[C@H](O)[C@H]2O)CO)O[C@H](CO)[C@@H]1O AUNPEJDACLEKSC-ZAYDSPBTSA-N 0.000 description 5
- 102000004877 Insulin Human genes 0.000 description 5
- 108090001061 Insulin Proteins 0.000 description 5
- 239000000090 biomarker Substances 0.000 description 5
- 235000008504 concentrate Nutrition 0.000 description 5
- 239000012141 concentrate Substances 0.000 description 5
- 235000005911 diet Nutrition 0.000 description 5
- 230000037213 diet Effects 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- -1 etc.) Chemical compound 0.000 description 5
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 5
- 229940125396 insulin Drugs 0.000 description 5
- 210000000936 intestine Anatomy 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 235000019198 oils Nutrition 0.000 description 5
- 229920002401 polyacrylamide Polymers 0.000 description 5
- 239000006041 probiotic Substances 0.000 description 5
- 235000018291 probiotics Nutrition 0.000 description 5
- 238000012216 screening Methods 0.000 description 5
- KBPHJBAIARWVSC-XQIHNALSSA-N trans-lutein Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CC(O)CC1(C)C)C=CC=C(/C)C=CC2C(=CC(O)CC2(C)C)C KBPHJBAIARWVSC-XQIHNALSSA-N 0.000 description 5
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 4
- 108020000946 Bacterial DNA Proteins 0.000 description 4
- 229920002498 Beta-glucan Polymers 0.000 description 4
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- PNNNRSAQSRJVSB-UHFFFAOYSA-N L-rhamnose Natural products CC(O)C(O)C(O)C(O)C=O PNNNRSAQSRJVSB-UHFFFAOYSA-N 0.000 description 4
- UPYKUZBSLRQECL-UKMVMLAPSA-N Lycopene Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1C(=C)CCCC1(C)C)C=CC=C(/C)C=CC2C(=C)CCCC2(C)C UPYKUZBSLRQECL-UKMVMLAPSA-N 0.000 description 4
- JEVVKJMRZMXFBT-XWDZUXABSA-N Lycophyll Natural products OC/C(=C/CC/C(=C\C=C\C(=C/C=C/C(=C\C=C\C=C(/C=C/C=C(\C=C\C=C(/CC/C=C(/CO)\C)\C)/C)\C)/C)\C)/C)/C JEVVKJMRZMXFBT-XWDZUXABSA-N 0.000 description 4
- 108010046377 Whey Proteins Proteins 0.000 description 4
- 102000007544 Whey Proteins Human genes 0.000 description 4
- 102000044820 Zonula Occludens-1 Human genes 0.000 description 4
- 108700007340 Zonula Occludens-1 Proteins 0.000 description 4
- 230000002411 adverse Effects 0.000 description 4
- OENHQHLEOONYIE-UKMVMLAPSA-N all-trans beta-carotene Natural products CC=1CCCC(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C OENHQHLEOONYIE-UKMVMLAPSA-N 0.000 description 4
- RQNFGIWYOACERD-OCQMRBNYSA-N alpha-L-Fucp-(1->4)-[alpha-L-Fucp-(1->2)-beta-D-Galp-(1->3)]-beta-D-GlcpNAc-(1->3)-beta-D-Galp-(1->4)-D-Glcp Chemical compound O[C@H]1[C@H](O)[C@H](O)[C@H](C)O[C@H]1O[C@H]1[C@H](O[C@H]2[C@@H]([C@@H](CO)O[C@@H](O[C@@H]3[C@H]([C@H](O[C@@H]4[C@H](OC(O)[C@H](O)[C@H]4O)CO)O[C@H](CO)[C@@H]3O)O)[C@@H]2NC(C)=O)O[C@H]2[C@H]([C@H](O)[C@H](O)[C@H](C)O2)O)O[C@H](CO)[C@H](O)[C@@H]1O RQNFGIWYOACERD-OCQMRBNYSA-N 0.000 description 4
- 230000004888 barrier function Effects 0.000 description 4
- 235000013734 beta-carotene Nutrition 0.000 description 4
- 239000011648 beta-carotene Substances 0.000 description 4
- TUPZEYHYWIEDIH-WAIFQNFQSA-N beta-carotene Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C)C=CC=C(/C)C=CC2=CCCCC2(C)C TUPZEYHYWIEDIH-WAIFQNFQSA-N 0.000 description 4
- 229960002747 betacarotene Drugs 0.000 description 4
- 230000036772 blood pressure Effects 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 235000021466 carotenoid Nutrition 0.000 description 4
- 150000001747 carotenoids Chemical class 0.000 description 4
- 235000010418 carrageenan Nutrition 0.000 description 4
- 229920001525 carrageenan Polymers 0.000 description 4
- 239000000679 carrageenan Substances 0.000 description 4
- 229940113118 carrageenan Drugs 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 235000013399 edible fruits Nutrition 0.000 description 4
- 235000019197 fats Nutrition 0.000 description 4
- 239000012527 feed solution Substances 0.000 description 4
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 4
- 230000037406 food intake Effects 0.000 description 4
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 description 4
- 230000000968 intestinal effect Effects 0.000 description 4
- RQNFGIWYOACERD-UHFFFAOYSA-N lacto-N-Difucosylhexaose I Natural products OC1C(O)C(O)C(C)OC1OC1C(OC2C(C(CO)OC(OC3C(C(OC4C(OC(O)C(O)C4O)CO)OC(CO)C3O)O)C2NC(C)=O)OC2C(C(O)C(O)C(C)O2)O)OC(CO)C(O)C1O RQNFGIWYOACERD-UHFFFAOYSA-N 0.000 description 4
- OQIUPKPUOLIHHS-UHFFFAOYSA-N lacto-N-difucohexaose I Natural products OC1C(O)C(O)C(C)OC1OC1C(OC2C(C(CO)OC(OC3C(C(OC(C(O)CO)C(O)C(O)C=O)OC(CO)C3O)O)C2NC(C)=O)OC2C(C(O)C(O)C(C)O2)O)OC(CO)C(O)C1O OQIUPKPUOLIHHS-UHFFFAOYSA-N 0.000 description 4
- 235000012680 lutein Nutrition 0.000 description 4
- 229960005375 lutein Drugs 0.000 description 4
- 239000001656 lutein Substances 0.000 description 4
- KBPHJBAIARWVSC-RGZFRNHPSA-N lutein Chemical compound C([C@H](O)CC=1C)C(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\[C@H]1C(C)=C[C@H](O)CC1(C)C KBPHJBAIARWVSC-RGZFRNHPSA-N 0.000 description 4
- ORAKUVXRZWMARG-WZLJTJAWSA-N lutein Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C)C=CC=C(/C)C=CC2C(=CC(O)CC2(C)C)C ORAKUVXRZWMARG-WZLJTJAWSA-N 0.000 description 4
- 235000012661 lycopene Nutrition 0.000 description 4
- 229960004999 lycopene Drugs 0.000 description 4
- 239000001751 lycopene Substances 0.000 description 4
- OAIJSZIZWZSQBC-GYZMGTAESA-N lycopene Chemical compound CC(C)=CCC\C(C)=C\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C=C(/C)CCC=C(C)C OAIJSZIZWZSQBC-GYZMGTAESA-N 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 235000013336 milk Nutrition 0.000 description 4
- 239000008267 milk Substances 0.000 description 4
- 210000004080 milk Anatomy 0.000 description 4
- 235000010755 mineral Nutrition 0.000 description 4
- 239000011707 mineral Substances 0.000 description 4
- 235000021251 pulses Nutrition 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- ZCIHMQAPACOQHT-ZGMPDRQDSA-N trans-isorenieratene Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/c1c(C)ccc(C)c1C)C=CC=C(/C)C=Cc2c(C)ccc(C)c2C ZCIHMQAPACOQHT-ZGMPDRQDSA-N 0.000 description 4
- 239000003656 tris buffered saline Substances 0.000 description 4
- FJHBOVDFOQMZRV-XQIHNALSSA-N xanthophyll Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CC(O)CC1(C)C)C=CC=C(/C)C=CC2C=C(C)C(O)CC2(C)C FJHBOVDFOQMZRV-XQIHNALSSA-N 0.000 description 4
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 4
- OENHQHLEOONYIE-JLTXGRSLSA-N β-Carotene Chemical compound CC=1CCCC(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C OENHQHLEOONYIE-JLTXGRSLSA-N 0.000 description 4
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 3
- 244000215068 Acacia senegal Species 0.000 description 3
- 206010070545 Bacterial translocation Diseases 0.000 description 3
- 241000901050 Bifidobacterium animalis subsp. lactis Species 0.000 description 3
- 241001608472 Bifidobacterium longum Species 0.000 description 3
- 108010076119 Caseins Proteins 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 229920000084 Gum arabic Polymers 0.000 description 3
- SHZGCJCMOBCMKK-PQMKYFCFSA-N L-Fucose Natural products C[C@H]1O[C@H](O)[C@@H](O)[C@@H](O)[C@@H]1O SHZGCJCMOBCMKK-PQMKYFCFSA-N 0.000 description 3
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 3
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 3
- 241000186604 Lactobacillus reuteri Species 0.000 description 3
- 229920002774 Maltodextrin Polymers 0.000 description 3
- 102000014171 Milk Proteins Human genes 0.000 description 3
- 108010011756 Milk Proteins Proteins 0.000 description 3
- 102000003940 Occludin Human genes 0.000 description 3
- 108090000304 Occludin Proteins 0.000 description 3
- 240000007594 Oryza sativa Species 0.000 description 3
- 235000007164 Oryza sativa Nutrition 0.000 description 3
- 108010084695 Pea Proteins Proteins 0.000 description 3
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 3
- 108010009736 Protein Hydrolysates Proteins 0.000 description 3
- 235000019485 Safflower oil Nutrition 0.000 description 3
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 3
- 108010073771 Soybean Proteins Proteins 0.000 description 3
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 3
- 239000004473 Threonine Substances 0.000 description 3
- 240000008042 Zea mays Species 0.000 description 3
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 3
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 3
- 235000010489 acacia gum Nutrition 0.000 description 3
- 229940024606 amino acid Drugs 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 239000003963 antioxidant agent Substances 0.000 description 3
- 235000006708 antioxidants Nutrition 0.000 description 3
- 230000007375 bacterial translocation Effects 0.000 description 3
- PDWGIAAFQACISG-QZBWVFMZSA-N beta-D-Gal-(1->3)-beta-D-GlcNAc-(1->3)-[beta-D-Gal-(1->4)-beta-D-GlcNAc-(1->6)]-beta-D-Gal-(1->4)-D-Glc Chemical compound O([C@H]1[C@H](O)[C@H]([C@@H](O[C@@H]1CO)OC[C@@H]1[C@@H]([C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O3)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](O)[C@H](O[C@@H]2[C@H](OC(O)[C@H](O)[C@H]2O)CO)O1)O)NC(=O)C)[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O PDWGIAAFQACISG-QZBWVFMZSA-N 0.000 description 3
- NPPRJALWPIXIHO-PNCMPRLYSA-N beta-D-Gal-(1->4)-beta-D-GlcNAc-(1->3)-[beta-D-Gal-(1->4)-beta-D-GlcNAc-(1->6)]-beta-D-Gal-(1->4)-D-Glc Chemical compound O([C@H]1[C@H](O)[C@H]([C@@H](O[C@@H]1CO)OC[C@@H]1[C@@H]([C@H](O[C@H]2[C@@H]([C@@H](O)[C@H](O[C@H]3[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O3)O)[C@@H](CO)O2)NC(C)=O)[C@@H](O)[C@H](O[C@@H]2[C@H](OC(O)[C@H](O)[C@H]2O)CO)O1)O)NC(=O)C)[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O NPPRJALWPIXIHO-PNCMPRLYSA-N 0.000 description 3
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 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
- 239000003240 coconut oil Substances 0.000 description 3
- 235000019864 coconut oil Nutrition 0.000 description 3
- 239000003086 colorant Substances 0.000 description 3
- 235000005822 corn Nutrition 0.000 description 3
- 239000003398 denaturant Substances 0.000 description 3
- 238000003935 denaturing gradient gel electrophoresis Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 239000000796 flavoring agent Substances 0.000 description 3
- 235000019634 flavors Nutrition 0.000 description 3
- 235000012631 food intake Nutrition 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 230000002641 glycemic effect Effects 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 230000000813 microbial effect Effects 0.000 description 3
- 235000021239 milk protein Nutrition 0.000 description 3
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid group Chemical group C(CCCCCCC\C=C/CCCCCCCC)(=O)O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 229960002429 proline Drugs 0.000 description 3
- 239000003531 protein hydrolysate Substances 0.000 description 3
- 230000002294 pubertal effect Effects 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 235000009566 rice Nutrition 0.000 description 3
- 235000005713 safflower oil Nutrition 0.000 description 3
- 239000003813 safflower oil Substances 0.000 description 3
- 229960001153 serine Drugs 0.000 description 3
- 229940001941 soy protein Drugs 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- 229960002898 threonine Drugs 0.000 description 3
- 235000021119 whey protein Nutrition 0.000 description 3
- 229920001285 xanthan gum Polymers 0.000 description 3
- 235000010493 xanthan gum Nutrition 0.000 description 3
- 239000000230 xanthan gum Substances 0.000 description 3
- 229940082509 xanthan gum Drugs 0.000 description 3
- FYGDTMLNYKFZSV-URKRLVJHSA-N (2s,3r,4s,5s,6r)-2-[(2r,4r,5r,6s)-4,5-dihydroxy-2-(hydroxymethyl)-6-[(2r,4r,5r,6s)-4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxan-3-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1[C@@H](CO)O[C@@H](OC2[C@H](O[C@H](O)[C@H](O)[C@H]2O)CO)[C@H](O)[C@H]1O FYGDTMLNYKFZSV-URKRLVJHSA-N 0.000 description 2
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 2
- PHIQHXFUZVPYII-ZCFIWIBFSA-N (R)-carnitine Chemical compound C[N+](C)(C)C[C@H](O)CC([O-])=O PHIQHXFUZVPYII-ZCFIWIBFSA-N 0.000 description 2
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 2
- PYMYPHUHKUWMLA-UHFFFAOYSA-N 2,3,4,5-tetrahydroxypentanal Chemical compound OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 2
- PVXPPJIGRGXGCY-TZLCEDOOSA-N 6-O-alpha-D-glucopyranosyl-D-fructofuranose 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(O)(CO)O1 PVXPPJIGRGXGCY-TZLCEDOOSA-N 0.000 description 2
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 2
- 235000006491 Acacia senegal Nutrition 0.000 description 2
- 244000247812 Amorphophallus rivieri Species 0.000 description 2
- 235000001206 Amorphophallus rivieri Nutrition 0.000 description 2
- 229920000189 Arabinogalactan Polymers 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 102000011632 Caseins Human genes 0.000 description 2
- 229920001661 Chitosan Polymers 0.000 description 2
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 2
- 238000011891 EIA kit Methods 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- 229930091371 Fructose Natural products 0.000 description 2
- 239000005715 Fructose Substances 0.000 description 2
- PNNNRSAQSRJVSB-SLPGGIOYSA-N Fucose Natural products C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C=O PNNNRSAQSRJVSB-SLPGGIOYSA-N 0.000 description 2
- 108010024636 Glutathione Proteins 0.000 description 2
- 229920002907 Guar gum Polymers 0.000 description 2
- 229920000569 Gum karaya Polymers 0.000 description 2
- 101001039966 Homo sapiens Pro-glucagon Proteins 0.000 description 2
- 102000014150 Interferons Human genes 0.000 description 2
- 108010050904 Interferons Proteins 0.000 description 2
- 108090000174 Interleukin-10 Proteins 0.000 description 2
- 102000003814 Interleukin-10 Human genes 0.000 description 2
- 108090001005 Interleukin-6 Proteins 0.000 description 2
- 102000004889 Interleukin-6 Human genes 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 229920002752 Konjac Polymers 0.000 description 2
- TVVLIFCVJJSLBL-SEHWTJTBSA-N Lacto-N-fucopentaose V Chemical compound O[C@H]1C(O)C(O)[C@H](C)O[C@H]1OC([C@@H](O)C=O)[C@@H](C(O)CO)O[C@H]1[C@H](O)[C@@H](OC2[C@@H](C(OC3[C@@H](C(O)C(O)[C@@H](CO)O3)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](O)[C@@H](CO)O1 TVVLIFCVJJSLBL-SEHWTJTBSA-N 0.000 description 2
- 229920000161 Locust bean gum Polymers 0.000 description 2
- 102000009571 Macrophage Inflammatory Proteins Human genes 0.000 description 2
- 108010009474 Macrophage Inflammatory Proteins Proteins 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 239000005913 Maltodextrin Substances 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- 229920000881 Modified starch Polymers 0.000 description 2
- 102000014962 Monocyte Chemoattractant Proteins Human genes 0.000 description 2
- 108010064136 Monocyte Chemoattractant Proteins Proteins 0.000 description 2
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 208000007683 Pediatric Obesity Diseases 0.000 description 2
- 244000134552 Plantago ovata Species 0.000 description 2
- 235000003421 Plantago ovata Nutrition 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 239000009223 Psyllium Substances 0.000 description 2
- 229920000294 Resistant starch Polymers 0.000 description 2
- VYGQUTWHTHXGQB-FFHKNEKCSA-N Retinol Palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C VYGQUTWHTHXGQB-FFHKNEKCSA-N 0.000 description 2
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 description 2
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 241000934878 Sterculia Species 0.000 description 2
- 235000019486 Sunflower oil Nutrition 0.000 description 2
- 229920001615 Tragacanth Polymers 0.000 description 2
- 102000018594 Tumour necrosis factor Human genes 0.000 description 2
- 108050007852 Tumour necrosis factor Proteins 0.000 description 2
- 229930003268 Vitamin C Natural products 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 229940072056 alginate Drugs 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- CMQZRJBJDCVIEY-JEOLMMCMSA-N alpha-L-Fucp-(1->3)-[beta-D-Galp-(1->4)]-beta-D-GlcpNAc-(1->3)-beta-D-Galp-(1->4)-D-Glcp Chemical compound O[C@H]1[C@H](O)[C@H](O)[C@H](C)O[C@H]1O[C@H]1[C@H](O[C@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O2)O)[C@@H](CO)O[C@@H](O[C@@H]2[C@H]([C@H](O[C@@H]3[C@H](OC(O)[C@H](O)[C@H]3O)CO)O[C@H](CO)[C@@H]2O)O)[C@@H]1NC(C)=O CMQZRJBJDCVIEY-JEOLMMCMSA-N 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 235000019312 arabinogalactan Nutrition 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- DMYPRRDPOMGEAK-XWDFSUOISA-N beta-D-Galp-(1->3)-[alpha-L-Fucp-(1->4)]-beta-D-GlcpNAc-(1->3)-beta-D-Galp-(1->4)-[alpha-L-Fucp-(1->3)]-D-Glcp Chemical compound O[C@H]1[C@H](O)[C@H](O)[C@H](C)O[C@H]1O[C@H]1[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O[C@H]4[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O4)O)[C@H](O[C@H]4[C@H]([C@H](O)[C@H](O)[C@H](C)O4)O)[C@@H](CO)O3)NC(C)=O)[C@@H](O)[C@@H](CO)O2)O)[C@@H](CO)OC(O)[C@@H]1O DMYPRRDPOMGEAK-XWDFSUOISA-N 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 229960002685 biotin Drugs 0.000 description 2
- 235000020958 biotin Nutrition 0.000 description 2
- 239000011616 biotin Substances 0.000 description 2
- 229940098773 bovine serum albumin Drugs 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 239000000828 canola oil Substances 0.000 description 2
- 235000019519 canola oil Nutrition 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 2
- 235000021240 caseins Nutrition 0.000 description 2
- 235000013339 cereals Nutrition 0.000 description 2
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 2
- 235000020940 control diet Nutrition 0.000 description 2
- 239000008121 dextrose Substances 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 235000006694 eating habits Nutrition 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 230000002550 fecal effect Effects 0.000 description 2
- 235000013312 flour Nutrition 0.000 description 2
- 229960000304 folic acid Drugs 0.000 description 2
- 235000019152 folic acid Nutrition 0.000 description 2
- 239000011724 folic acid Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 125000002446 fucosyl group Chemical group C1([C@@H](O)[C@H](O)[C@H](O)[C@@H](O1)C)* 0.000 description 2
- 238000003304 gavage Methods 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- 229960003180 glutathione Drugs 0.000 description 2
- 235000003969 glutathione Nutrition 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 235000010417 guar gum Nutrition 0.000 description 2
- 239000000665 guar gum Substances 0.000 description 2
- 229960002154 guar gum Drugs 0.000 description 2
- 235000009200 high fat diet Nutrition 0.000 description 2
- 229940079322 interferon Drugs 0.000 description 2
- 210000001630 jejunum Anatomy 0.000 description 2
- 235000010494 karaya gum Nutrition 0.000 description 2
- 239000000231 karaya gum Substances 0.000 description 2
- 229940039371 karaya gum Drugs 0.000 description 2
- 239000000252 konjac Substances 0.000 description 2
- 235000010485 konjac Nutrition 0.000 description 2
- DMYPRRDPOMGEAK-UHFFFAOYSA-N lacto-N-difucohexaose II Natural products OC1C(O)C(O)C(C)OC1OC1C(OC2C(C(OC3C(C(OC4C(C(O)C(O)C(CO)O4)O)C(OC4C(C(O)C(O)C(C)O4)O)C(CO)O3)NC(C)=O)C(O)C(CO)O2)O)C(CO)OC(O)C1O DMYPRRDPOMGEAK-UHFFFAOYSA-N 0.000 description 2
- CMQZRJBJDCVIEY-UHFFFAOYSA-N lacto-N-fucopentaose III Natural products OC1C(O)C(O)C(C)OC1OC1C(OC2C(C(O)C(O)C(CO)O2)O)C(CO)OC(OC2C(C(OC3C(OC(O)C(O)C3O)CO)OC(CO)C2O)O)C1NC(C)=O CMQZRJBJDCVIEY-UHFFFAOYSA-N 0.000 description 2
- 150000002597 lactoses Chemical class 0.000 description 2
- 235000010420 locust bean gum Nutrition 0.000 description 2
- 239000000711 locust bean gum Substances 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 210000001165 lymph node Anatomy 0.000 description 2
- 235000021073 macronutrients Nutrition 0.000 description 2
- 229940057948 magnesium stearate Drugs 0.000 description 2
- 229940035034 maltodextrin Drugs 0.000 description 2
- 229940057917 medium chain triglycerides Drugs 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 238000010172 mouse model Methods 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- 230000035764 nutrition Effects 0.000 description 2
- 235000019895 oat fiber Nutrition 0.000 description 2
- 230000001717 pathogenic effect Effects 0.000 description 2
- 235000019702 pea protein Nutrition 0.000 description 2
- 229920001277 pectin Polymers 0.000 description 2
- 235000010987 pectin Nutrition 0.000 description 2
- 239000001814 pectin Substances 0.000 description 2
- 229960000292 pectin Drugs 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 229920002338 polyhydroxyethylmethacrylate Polymers 0.000 description 2
- 150000008442 polyphenolic compounds Chemical class 0.000 description 2
- 235000013824 polyphenols Nutrition 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229960003975 potassium Drugs 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 230000000529 probiotic effect Effects 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 229940070687 psyllium Drugs 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000011002 quantification Methods 0.000 description 2
- 235000021254 resistant starch Nutrition 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 239000011669 selenium Substances 0.000 description 2
- 229910052711 selenium Inorganic materials 0.000 description 2
- 235000011649 selenium Nutrition 0.000 description 2
- 229940091258 selenium supplement Drugs 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 125000005630 sialyl group Chemical group 0.000 description 2
- 235000010413 sodium alginate Nutrition 0.000 description 2
- 239000000661 sodium alginate Substances 0.000 description 2
- 229940005550 sodium alginate Drugs 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 150000005846 sugar alcohols Chemical class 0.000 description 2
- 239000002600 sunflower oil Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 229960003080 taurine Drugs 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 239000002562 thickening agent Substances 0.000 description 2
- 229910021642 ultra pure water Inorganic materials 0.000 description 2
- 239000012498 ultrapure water Substances 0.000 description 2
- 235000013311 vegetables Nutrition 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- 235000019155 vitamin A Nutrition 0.000 description 2
- 239000011719 vitamin A Substances 0.000 description 2
- 235000019154 vitamin C Nutrition 0.000 description 2
- 239000011718 vitamin C Substances 0.000 description 2
- 235000013618 yogurt Nutrition 0.000 description 2
- TYALNJQZQRNQNQ-UHFFFAOYSA-N #alpha;2,6-sialyllactose Natural products O1C(C(O)C(O)CO)C(NC(=O)C)C(O)CC1(C(O)=O)OCC1C(O)C(O)C(O)C(OC2C(C(O)C(O)OC2CO)O)O1 TYALNJQZQRNQNQ-UHFFFAOYSA-N 0.000 description 1
- LUEWUZLMQUOBSB-FSKGGBMCSA-N (2s,3s,4s,5s,6r)-2-[(2r,3s,4r,5r,6s)-6-[(2r,3s,4r,5s,6s)-4,5-dihydroxy-2-(hydroxymethyl)-6-[(2r,4r,5s,6r)-4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxan-3-yl]oxy-4,5-dihydroxy-2-(hydroxymethyl)oxan-3-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound O[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@@H](O[C@@H]2[C@H](O[C@@H](OC3[C@H](O[C@@H](O)[C@@H](O)[C@H]3O)CO)[C@@H](O)[C@H]2O)CO)[C@H](O)[C@H]1O LUEWUZLMQUOBSB-FSKGGBMCSA-N 0.000 description 1
- JKQXZKUSFCKOGQ-JLGXGRJMSA-N (3R,3'R)-beta,beta-carotene-3,3'-diol Chemical compound C([C@H](O)CC=1C)C(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(C)C=CC=C(C)C=CC1=C(C)C[C@@H](O)CC1(C)C JKQXZKUSFCKOGQ-JLGXGRJMSA-N 0.000 description 1
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 1
- PZNPLUBHRSSFHT-RRHRGVEJSA-N 1-hexadecanoyl-2-octadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[C@@H](COP([O-])(=O)OCC[N+](C)(C)C)COC(=O)CCCCCCCCCCCCCCC PZNPLUBHRSSFHT-RRHRGVEJSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- CILYIEBUXJIHCO-UHFFFAOYSA-N 102778-91-6 Natural products O1C(C(O)C(O)CO)C(NC(=O)C)C(O)CC1(C(O)=O)OC1C(O)C(OC2C(C(O)C(O)OC2CO)O)OC(CO)C1O CILYIEBUXJIHCO-UHFFFAOYSA-N 0.000 description 1
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 1
- 239000001763 2-hydroxyethyl(trimethyl)azanium Substances 0.000 description 1
- PMYDPQQPEAYXKD-UHFFFAOYSA-N 3-hydroxy-n-naphthalen-2-ylnaphthalene-2-carboxamide Chemical compound C1=CC=CC2=CC(NC(=O)C3=CC4=CC=CC=C4C=C3O)=CC=C21 PMYDPQQPEAYXKD-UHFFFAOYSA-N 0.000 description 1
- HFDKKNHCYWNNNQ-YOGANYHLSA-N 75976-10-2 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@@H](NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](C)N)C(C)C)[C@@H](C)O)C1=CC=C(O)C=C1 HFDKKNHCYWNNNQ-YOGANYHLSA-N 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- 206010048998 Acute phase reaction Diseases 0.000 description 1
- 108010076365 Adiponectin Proteins 0.000 description 1
- 102000011690 Adiponectin Human genes 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 108091093088 Amplicon Proteins 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 208000031729 Bacteremia Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 241000483634 Bifidobacterium animalis subsp. lactis BB-12 Species 0.000 description 1
- 241000186015 Bifidobacterium longum subsp. infantis Species 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 241000167854 Bourreria succulenta Species 0.000 description 1
- 108010074051 C-Reactive Protein Proteins 0.000 description 1
- 238000011740 C57BL/6 mouse Methods 0.000 description 1
- 238000011746 C57BL/6J (JAX™ mouse strain) Methods 0.000 description 1
- 241000252983 Caecum Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- GHOKWGTUZJEAQD-UHFFFAOYSA-N Chick antidermatitis factor Natural products OCC(C)(C)C(O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-UHFFFAOYSA-N 0.000 description 1
- 235000019743 Choline chloride Nutrition 0.000 description 1
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 1
- 229910021555 Chromium Chloride Inorganic materials 0.000 description 1
- ACTIUHUUMQJHFO-UHFFFAOYSA-N Coenzym Q10 Natural products COC1=C(OC)C(=O)C(CC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 244000241257 Cucumis melo Species 0.000 description 1
- 235000015510 Cucumis melo subsp melo Nutrition 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- AUNGANRZJHBGPY-UHFFFAOYSA-N D-Lyxoflavin Natural products OCC(O)C(O)C(O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-UHFFFAOYSA-N 0.000 description 1
- ZAKOWWREFLAJOT-CEFNRUSXSA-N D-alpha-tocopherylacetate Chemical compound CC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-CEFNRUSXSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 206010012689 Diabetic retinopathy Diseases 0.000 description 1
- 208000027244 Dysbiosis Diseases 0.000 description 1
- 239000004386 Erythritol Substances 0.000 description 1
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 235000016623 Fragaria vesca Nutrition 0.000 description 1
- 240000009088 Fragaria x ananassa Species 0.000 description 1
- 235000011363 Fragaria x ananassa Nutrition 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 229920002148 Gellan gum Polymers 0.000 description 1
- 101800000224 Glucagon-like peptide 1 Proteins 0.000 description 1
- 229920002581 Glucomannan Polymers 0.000 description 1
- 208000002705 Glucose Intolerance Diseases 0.000 description 1
- 101150026536 HDA2 gene Proteins 0.000 description 1
- 108010023302 HDL Cholesterol Proteins 0.000 description 1
- 238000013218 HFD mouse model Methods 0.000 description 1
- 102100025255 Haptoglobin Human genes 0.000 description 1
- 108091027305 Heteroduplex Proteins 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 240000005979 Hordeum vulgare Species 0.000 description 1
- 235000007340 Hordeum vulgare Nutrition 0.000 description 1
- 239000005905 Hydrolysed protein Substances 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 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
- 102000003812 Interleukin-15 Human genes 0.000 description 1
- 108090000172 Interleukin-15 Proteins 0.000 description 1
- 102000003810 Interleukin-18 Human genes 0.000 description 1
- 108090000171 Interleukin-18 Proteins 0.000 description 1
- 108090001007 Interleukin-8 Proteins 0.000 description 1
- 102000004890 Interleukin-8 Human genes 0.000 description 1
- 108010063738 Interleukins Proteins 0.000 description 1
- 102000015696 Interleukins Human genes 0.000 description 1
- 229920001202 Inulin Polymers 0.000 description 1
- 102000036770 Islet Amyloid Polypeptide Human genes 0.000 description 1
- 108010041872 Islet Amyloid Polypeptide Proteins 0.000 description 1
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 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
- QAQJMLQRFWZOBN-LAUBAEHRSA-N L-ascorbyl-6-palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O QAQJMLQRFWZOBN-LAUBAEHRSA-N 0.000 description 1
- 239000011786 L-ascorbyl-6-palmitate Substances 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- 240000001046 Lactobacillus acidophilus Species 0.000 description 1
- 244000116699 Lactobacillus acidophilus NCFM Species 0.000 description 1
- 240000001929 Lactobacillus brevis Species 0.000 description 1
- 241000093427 Lactobacillus fermentum CECT 5716 Species 0.000 description 1
- 241000218588 Lactobacillus rhamnosus Species 0.000 description 1
- 241000917009 Lactobacillus rhamnosus GG Species 0.000 description 1
- 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 description 1
- 241000239218 Limulus Species 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241000220225 Malus Species 0.000 description 1
- 235000011430 Malus pumila Nutrition 0.000 description 1
- 235000015103 Malus silvestris Nutrition 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 239000004368 Modified starch Substances 0.000 description 1
- ZOKXTWBITQBERF-UHFFFAOYSA-N Molybdenum Chemical compound [Mo] ZOKXTWBITQBERF-UHFFFAOYSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- OVRNDRQMDRJTHS-UHFFFAOYSA-N N-acelyl-D-glucosamine Natural products CC(=O)NC1C(O)OC(CO)C(O)C1O OVRNDRQMDRJTHS-UHFFFAOYSA-N 0.000 description 1
- OVRNDRQMDRJTHS-RTRLPJTCSA-N N-acetyl-D-glucosamine Chemical compound CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-RTRLPJTCSA-N 0.000 description 1
- CILYIEBUXJIHCO-UITFWXMXSA-N N-acetyl-alpha-neuraminyl-(2->3)-beta-D-galactosyl-(1->4)-beta-D-glucose Chemical compound O1[C@@H]([C@H](O)[C@H](O)CO)[C@H](NC(=O)C)[C@@H](O)C[C@@]1(C(O)=O)O[C@@H]1[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O)[C@H](O)O[C@@H]2CO)O)O[C@H](CO)[C@@H]1O CILYIEBUXJIHCO-UITFWXMXSA-N 0.000 description 1
- SQVRNKJHWKZAKO-PFQGKNLYSA-N N-acetyl-beta-neuraminic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@](O)(C(O)=O)O[C@H]1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-PFQGKNLYSA-N 0.000 description 1
- MBLBDJOUHNCFQT-LXGUWJNJSA-N N-acetylglucosamine Natural products CC(=O)N[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO MBLBDJOUHNCFQT-LXGUWJNJSA-N 0.000 description 1
- OIZGSVFYNBZVIK-UHFFFAOYSA-N N-acetylneuraminosyl-D-lactose Natural products O1C(C(O)C(O)CO)C(NC(=O)C)C(O)CC1(C(O)=O)OC1C(O)C(OC(C(O)CO)C(O)C(O)C=O)OC(CO)C1O OIZGSVFYNBZVIK-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 1
- 206010033307 Overweight Diseases 0.000 description 1
- 235000019482 Palm oil Nutrition 0.000 description 1
- 102000018886 Pancreatic Polypeptide Human genes 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 229920000148 Polycarbophil calcium Polymers 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 244000141353 Prunus domestica Species 0.000 description 1
- 239000004373 Pullulan Substances 0.000 description 1
- 229920001218 Pullulan Polymers 0.000 description 1
- 235000014443 Pyrus communis Nutrition 0.000 description 1
- 240000001987 Pyrus communis Species 0.000 description 1
- 238000011529 RT qPCR Methods 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- VYGQUTWHTHXGQB-UHFFFAOYSA-N Retinol hexadecanoate Natural products CCCCCCCCCCCCCCCC(=O)OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C VYGQUTWHTHXGQB-UHFFFAOYSA-N 0.000 description 1
- 240000007651 Rubus glaucus Species 0.000 description 1
- 235000011034 Rubus glaucus Nutrition 0.000 description 1
- 235000009122 Rubus idaeus Nutrition 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose 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)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 102000019197 Superoxide Dismutase Human genes 0.000 description 1
- 108010012715 Superoxide dismutase Proteins 0.000 description 1
- 101000983124 Sus scrofa Pancreatic prohormone precursor Proteins 0.000 description 1
- 235000009470 Theobroma cacao Nutrition 0.000 description 1
- 244000299461 Theobroma cacao Species 0.000 description 1
- 102000000591 Tight Junction Proteins Human genes 0.000 description 1
- 108010002321 Tight Junction Proteins Proteins 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 1
- 240000000851 Vaccinium corymbosum Species 0.000 description 1
- 235000003095 Vaccinium corymbosum Nutrition 0.000 description 1
- 235000017537 Vaccinium myrtillus Nutrition 0.000 description 1
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 description 1
- 229930003779 Vitamin B12 Natural products 0.000 description 1
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- 239000005862 Whey Substances 0.000 description 1
- JKQXZKUSFCKOGQ-LQFQNGICSA-N Z-zeaxanthin Natural products C([C@H](O)CC=1C)C(C)(C)C=1C=CC(C)=CC=CC(C)=CC=CC=C(C)C=CC=C(C)C=CC1=C(C)C[C@@H](O)CC1(C)C JKQXZKUSFCKOGQ-LQFQNGICSA-N 0.000 description 1
- QOPRSMDTRDMBNK-RNUUUQFGSA-N Zeaxanthin Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCC(O)C1(C)C)C=CC=C(/C)C=CC2=C(C)CC(O)CC2(C)C QOPRSMDTRDMBNK-RNUUUQFGSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- FJJCIZWZNKZHII-UHFFFAOYSA-N [4,6-bis(cyanoamino)-1,3,5-triazin-2-yl]cyanamide Chemical compound N#CNC1=NC(NC#N)=NC(NC#N)=N1 FJJCIZWZNKZHII-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004658 acute-phase response Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 238000000246 agarose gel electrophoresis Methods 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 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 1
- JKQXZKUSFCKOGQ-LOFNIBRQSA-N all-trans-Zeaxanthin Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CC(O)CC1(C)C)C=CC=C(/C)C=CC2=C(C)CC(O)CC2(C)C JKQXZKUSFCKOGQ-LOFNIBRQSA-N 0.000 description 1
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 238000000137 annealing Methods 0.000 description 1
- 229930014669 anthocyanidin Natural products 0.000 description 1
- 235000008758 anthocyanidins Nutrition 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 229960003121 arginine Drugs 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010385 ascorbyl palmitate Nutrition 0.000 description 1
- 239000000305 astragalus gummifer gum Substances 0.000 description 1
- 230000003190 augmentative effect Effects 0.000 description 1
- 230000007147 bacterial dysbiosis Effects 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000008033 biological extinction Effects 0.000 description 1
- 238000010352 biotechnological method Methods 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 235000021014 blueberries Nutrition 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 235000021152 breakfast Nutrition 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- FAPWYRCQGJNNSJ-UBKPKTQASA-L calcium D-pantothenic acid Chemical compound [Ca+2].OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O.OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O FAPWYRCQGJNNSJ-UBKPKTQASA-L 0.000 description 1
- FNAQSUUGMSOBHW-UHFFFAOYSA-H calcium citrate Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O FNAQSUUGMSOBHW-UHFFFAOYSA-H 0.000 description 1
- 239000001354 calcium citrate Substances 0.000 description 1
- 229960004256 calcium citrate Drugs 0.000 description 1
- 229960002079 calcium pantothenate Drugs 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 229960001714 calcium phosphate Drugs 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000007963 capsule composition Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 229960004203 carnitine Drugs 0.000 description 1
- 239000005018 casein Substances 0.000 description 1
- 229940021722 caseins Drugs 0.000 description 1
- 210000004534 cecum Anatomy 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 235000019693 cherries Nutrition 0.000 description 1
- SGMZJAMFUVOLNK-UHFFFAOYSA-M choline chloride Chemical compound [Cl-].C[N+](C)(C)CCO SGMZJAMFUVOLNK-UHFFFAOYSA-M 0.000 description 1
- 229960003178 choline chloride Drugs 0.000 description 1
- 229910052804 chromium Inorganic materials 0.000 description 1
- 239000011651 chromium Substances 0.000 description 1
- QSWDMMVNRMROPK-UHFFFAOYSA-K chromium(3+) trichloride Chemical compound [Cl-].[Cl-].[Cl-].[Cr+3] QSWDMMVNRMROPK-UHFFFAOYSA-K 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 230000006020 chronic inflammation Effects 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 230000008045 co-localization Effects 0.000 description 1
- AGVAZMGAQJOSFJ-WZHZPDAFSA-M cobalt(2+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2 Chemical compound [Co+2].N#[C-].[N-]([C@@H]1[C@H](CC(N)=O)[C@@]2(C)CCC(=O)NC[C@@H](C)OP(O)(=O)O[C@H]3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)\C2=C(C)/C([C@H](C\2(C)C)CCC(N)=O)=N/C/2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O AGVAZMGAQJOSFJ-WZHZPDAFSA-M 0.000 description 1
- 235000017471 coenzyme Q10 Nutrition 0.000 description 1
- 229940110767 coenzyme Q10 Drugs 0.000 description 1
- ACTIUHUUMQJHFO-UPTCCGCDSA-N coenzyme Q10 Chemical compound COC1=C(OC)C(=O)C(C\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UPTCCGCDSA-N 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229940124301 concurrent medication Drugs 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 229960002433 cysteine Drugs 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- ZAKOWWREFLAJOT-UHFFFAOYSA-N d-alpha-Tocopheryl acetate Natural products CC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-UHFFFAOYSA-N 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- 210000004443 dendritic cell Anatomy 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 235000013325 dietary fiber Nutrition 0.000 description 1
- 235000015872 dietary supplement Nutrition 0.000 description 1
- 208000010643 digestive system disease Diseases 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 230000007140 dysbiosis Effects 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 238000004146 energy storage Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 201000010063 epididymitis Diseases 0.000 description 1
- 229940009714 erythritol Drugs 0.000 description 1
- 235000019414 erythritol Nutrition 0.000 description 1
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 235000013861 fat-free Nutrition 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 239000011790 ferrous sulphate Substances 0.000 description 1
- 235000003891 ferrous sulphate Nutrition 0.000 description 1
- 208000030941 fetal growth restriction Diseases 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 235000021323 fish oil Nutrition 0.000 description 1
- 229930003935 flavonoid Natural products 0.000 description 1
- 235000017173 flavonoids Nutrition 0.000 description 1
- 150000002215 flavonoids Chemical class 0.000 description 1
- NWKFECICNXDNOQ-UHFFFAOYSA-N flavylium Chemical compound C1=CC=CC=C1C1=CC=C(C=CC=C2)C2=[O+]1 NWKFECICNXDNOQ-UHFFFAOYSA-N 0.000 description 1
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 235000021588 free fatty acids Nutrition 0.000 description 1
- 229940068517 fruit extracts Drugs 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 235000021255 galacto-oligosaccharides Nutrition 0.000 description 1
- 150000003271 galactooligosaccharides Chemical class 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 208000018685 gastrointestinal system disease Diseases 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000010492 gellan gum Nutrition 0.000 description 1
- 239000000216 gellan gum Substances 0.000 description 1
- 208000004104 gestational diabetes Diseases 0.000 description 1
- 229940046240 glucomannan Drugs 0.000 description 1
- 230000004153 glucose metabolism Effects 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 229960002743 glutamine Drugs 0.000 description 1
- 239000011544 gradient gel Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000000122 growth hormone Substances 0.000 description 1
- 229920000591 gum Polymers 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 235000019534 high fructose corn syrup Nutrition 0.000 description 1
- 238000012165 high-throughput sequencing Methods 0.000 description 1
- 235000012907 honey Nutrition 0.000 description 1
- 230000007412 host metabolism Effects 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 229940071826 hydroxyethyl cellulose Drugs 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 229960003943 hypromellose Drugs 0.000 description 1
- 230000005965 immune activity Effects 0.000 description 1
- 230000000899 immune system response Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000000266 injurious effect Effects 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 210000005027 intestinal barrier Anatomy 0.000 description 1
- 230000007358 intestinal barrier function Effects 0.000 description 1
- 210000005206 intestinal lamina propria Anatomy 0.000 description 1
- 210000004347 intestinal mucosa Anatomy 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 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 1
- 229940029339 inulin Drugs 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 229960003299 ketamine Drugs 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 229930013686 lignan Natural products 0.000 description 1
- 235000009408 lignans Nutrition 0.000 description 1
- 150000005692 lignans Chemical class 0.000 description 1
- 235000014666 liquid concentrate Nutrition 0.000 description 1
- 239000012263 liquid product Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 229960002337 magnesium chloride Drugs 0.000 description 1
- 235000011147 magnesium chloride Nutrition 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- 229960000869 magnesium oxide Drugs 0.000 description 1
- 235000012245 magnesium oxide Nutrition 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 235000010449 maltitol Nutrition 0.000 description 1
- 239000000845 maltitol Substances 0.000 description 1
- 229940035436 maltitol Drugs 0.000 description 1
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 description 1
- 239000011702 manganese sulphate Substances 0.000 description 1
- 235000007079 manganese sulphate Nutrition 0.000 description 1
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 description 1
- SQQMAOCOWKFBNP-UHFFFAOYSA-L manganese(II) sulfate Chemical compound [Mn+2].[O-]S([O-])(=O)=O SQQMAOCOWKFBNP-UHFFFAOYSA-L 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 229960004452 methionine Drugs 0.000 description 1
- 229960002900 methylcellulose Drugs 0.000 description 1
- 238000012543 microbiological analysis Methods 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 235000019426 modified starch Nutrition 0.000 description 1
- 229910052750 molybdenum Inorganic materials 0.000 description 1
- 239000011733 molybdenum Substances 0.000 description 1
- 239000012120 mounting media Substances 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 230000004682 mucosal barrier function Effects 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 229920001206 natural gum Polymers 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 229960003966 nicotinamide Drugs 0.000 description 1
- 235000005152 nicotinamide Nutrition 0.000 description 1
- 239000011570 nicotinamide Substances 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 235000006180 nutrition needs Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 235000020660 omega-3 fatty acid Nutrition 0.000 description 1
- 238000007410 oral glucose tolerance test Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 239000003346 palm kernel oil Substances 0.000 description 1
- 235000019865 palm kernel oil Nutrition 0.000 description 1
- 239000002540 palm oil Substances 0.000 description 1
- 229940055726 pantothenic acid Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 210000003200 peritoneal cavity Anatomy 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 235000019175 phylloquinone Nutrition 0.000 description 1
- 239000011772 phylloquinone Substances 0.000 description 1
- MBWXNTAXLNYFJB-NKFFZRIASA-N phylloquinone Chemical compound C1=CC=C2C(=O)C(C/C=C(C)/CCC[C@H](C)CCC[C@H](C)CCCC(C)C)=C(C)C(=O)C2=C1 MBWXNTAXLNYFJB-NKFFZRIASA-N 0.000 description 1
- 229960001898 phytomenadione Drugs 0.000 description 1
- 235000002378 plant sterols Nutrition 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- 229950005134 polycarbophil Drugs 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 235000020777 polyunsaturated fatty acids Nutrition 0.000 description 1
- 229920000915 polyvinyl chloride Polymers 0.000 description 1
- 239000004800 polyvinyl chloride Substances 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 229960002816 potassium chloride Drugs 0.000 description 1
- 239000001508 potassium citrate Substances 0.000 description 1
- 229960002635 potassium citrate Drugs 0.000 description 1
- QEEAPRPFLLJWCF-UHFFFAOYSA-K potassium citrate (anhydrous) Chemical compound [K+].[K+].[K+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O QEEAPRPFLLJWCF-UHFFFAOYSA-K 0.000 description 1
- 235000011082 potassium citrates Nutrition 0.000 description 1
- 229960004839 potassium iodide Drugs 0.000 description 1
- 235000007715 potassium iodide Nutrition 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 235000013406 prebiotics Nutrition 0.000 description 1
- GCYXWQUSHADNBF-AAEALURTSA-N preproglucagon 78-108 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 GCYXWQUSHADNBF-AAEALURTSA-N 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 235000019423 pullulan Nutrition 0.000 description 1
- ZUFQODAHGAHPFQ-UHFFFAOYSA-N pyridoxine hydrochloride Chemical compound Cl.CC1=NC=C(CO)C(CO)=C1O ZUFQODAHGAHPFQ-UHFFFAOYSA-N 0.000 description 1
- 239000011764 pyridoxine hydrochloride Substances 0.000 description 1
- 229960004172 pyridoxine hydrochloride Drugs 0.000 description 1
- 235000019171 pyridoxine hydrochloride Nutrition 0.000 description 1
- 210000003314 quadriceps muscle Anatomy 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 239000011769 retinyl palmitate Substances 0.000 description 1
- 229940108325 retinyl palmitate Drugs 0.000 description 1
- 235000019172 retinyl palmitate Nutrition 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 235000019192 riboflavin Nutrition 0.000 description 1
- 239000002151 riboflavin Substances 0.000 description 1
- 229960002477 riboflavin Drugs 0.000 description 1
- 210000003705 ribosome Anatomy 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- 235000010378 sodium ascorbate Nutrition 0.000 description 1
- 229960005055 sodium ascorbate Drugs 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 229960001790 sodium citrate Drugs 0.000 description 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- 239000011684 sodium molybdate Substances 0.000 description 1
- 235000015393 sodium molybdate Nutrition 0.000 description 1
- TVXXNOYZHKPKGW-UHFFFAOYSA-N sodium molybdate (anhydrous) Chemical compound [Na+].[Na+].[O-][Mo]([O-])(=O)=O TVXXNOYZHKPKGW-UHFFFAOYSA-N 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 229960003339 sodium phosphate Drugs 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- 239000011655 sodium selenate Substances 0.000 description 1
- 235000018716 sodium selenate Nutrition 0.000 description 1
- 229960001881 sodium selenate Drugs 0.000 description 1
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 229940071440 soy protein isolate Drugs 0.000 description 1
- 239000008347 soybean phospholipid Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 239000011885 synergistic combination Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 235000019191 thiamine mononitrate Nutrition 0.000 description 1
- 239000011748 thiamine mononitrate Substances 0.000 description 1
- UIERGBJEBXXIGO-UHFFFAOYSA-N thiamine mononitrate Chemical compound [O-][N+]([O-])=O.CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N UIERGBJEBXXIGO-UHFFFAOYSA-N 0.000 description 1
- 229960004860 thiamine mononitrate Drugs 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- 239000011135 tin Substances 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 125000002640 tocopherol group Chemical class 0.000 description 1
- 235000019149 tocopherols Nutrition 0.000 description 1
- 239000011573 trace mineral Substances 0.000 description 1
- 235000013619 trace mineral Nutrition 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 235000013337 tricalcium citrate Nutrition 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- PHYFQTYBJUILEZ-IUPFWZBJSA-N triolein Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CCCCCCCC)COC(=O)CCCCCCC\C=C/CCCCCCCC PHYFQTYBJUILEZ-IUPFWZBJSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229960004799 tryptophan Drugs 0.000 description 1
- 229960004441 tyrosine Drugs 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
- GPPXJZIENCGNKB-UHFFFAOYSA-N vanadium Chemical compound [V]#[V] GPPXJZIENCGNKB-UHFFFAOYSA-N 0.000 description 1
- 230000009278 visceral effect Effects 0.000 description 1
- 235000019163 vitamin B12 Nutrition 0.000 description 1
- 239000011715 vitamin B12 Substances 0.000 description 1
- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-YRZJJWOYSA-N 0.000 description 1
- 235000005282 vitamin D3 Nutrition 0.000 description 1
- 239000011647 vitamin D3 Substances 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
- 229940021056 vitamin d3 Drugs 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 230000010294 whole body metabolism Effects 0.000 description 1
- 235000020985 whole grains Nutrition 0.000 description 1
- BPICBUSOMSTKRF-UHFFFAOYSA-N xylazine Chemical compound CC1=CC=CC(C)=C1NC1=NCCCS1 BPICBUSOMSTKRF-UHFFFAOYSA-N 0.000 description 1
- 229960001600 xylazine Drugs 0.000 description 1
- 235000010930 zeaxanthin Nutrition 0.000 description 1
- 229940043269 zeaxanthin Drugs 0.000 description 1
- 239000001775 zeaxanthin Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 description 1
- 239000011686 zinc sulphate Substances 0.000 description 1
- 235000009529 zinc sulphate Nutrition 0.000 description 1
- 108010027843 zonulin Proteins 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7012—Compounds having a free or esterified carboxyl group attached, directly or through a carbon chain, to a carbon atom of the saccharide radical, e.g. glucuronic acid, neuraminic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Definitions
- This disclosure relates generally to compositions and methods for the treatment of metabolic disorders such as obesity and obesity induced pre-diabetes and type 2 diabetes.
- Diabetes type 2 is a metabolic disorder that is characterized by hyperglycaemia due to insulin resistance and relative lack of insulin and that is a rapidly growing global epidemic.
- the International Diabetes Federation (IDF) reports that as of 2013 there were more than 382 million people living with diabetes, and a further 316 million with impaired glucose tolerance who are at high risk from the disease (IDF Diabetes Atlas, 6 th edn.).
- the World Health Organization (WHO) furthermore estimates that 90 percent of people around the world who suffer from diabetes suffer from type 2 diabetes. Long-term complications from high blood sugar can include heart disease, strokes, diabetic retinopathy, kidney failure, and poor blood flow in the limbs.
- Gut microbiota may be a key factor with populations showing marked differences between healthy, obese, and type 2 diabetic patients.
- the dysbiosis of gut microbiota has the potential to affect host metabolism and energy storage and to affect gut permeability and, as a consequence, give rise to metabolic endotoxemia and higher plasma lipopolysaccharide (LPS).
- LPS plasma lipopolysaccharide
- gut peptides such as glucagon-like peptide 1 (GLP1) and GLP2 can play key roles in these processes.
- GLP1 and GLP2 can play key roles in these processes.
- GLP1 and GLP2 can play key roles in these processes.
- GLP2 which is secreted by intestine L cells, is a key regulator of intestinal permeability. Therapeutic regimes that target intestinal microbiota and intestinal barrier therefore show a broad prospect in treating diabetes.
- Gut microbiota does not only participate in whole-body metabolism by affecting energy balance and glucose metabolism, but is also involved in development of the low-grade inflammation, associated with obesity and related metabolic disorders such as diabetes.
- the association between inflammation and type 2 diabetes is seen in epidemiological studies indicating a rise in acute-phase response proteins in serum of type 2 diabetic patients compared with controls.
- a specific link between inflammatory and metabolic responses was made with the discovery that compared with lean tissue, obese adipose tissue secretes inflammatory cytokines and that these inflammatory cytokines themselves can inhibit insulin signalling.
- the definitive proof of a connection between inflammatory mediators and insulin resistance in obesity and type 2 diabetes came from genetic studies that interfered with inflammatory mediators and demonstrated beneficial effects of this interference on insulin action.
- gut microbiota derived LPS has been shown to be involved in the onset and progression of inflammation, and in pathological situations, such as obesity and type 2 diabetes, LPS play a major role in the onset of disease.
- LPS play a major role in the onset of disease.
- commensal intestinal bacteria are translocated from the intestine into adipose tissue and the blood where they can induce inflammation.
- This metabolic bacteraemia is characterized by an increased co-localization with dendritic cells from the intestinal lamina intestinal and by an augmented intestinal mucosal adherence of non-pathogenic Escherichia coli.
- the bacterial translocation process from intestine towards tissue with resulting inflammation was reversed by six weeks of treatment with the probiotic strain Bifidobacterium animalis subsp. lactis 420, suggesting an involvement of the microbiota.
- EP-A-1332759 discloses that oral doses of 2′-FL, 3′-SL, 6′-SL, LNnT and sialic acid promote insulin secretion in type 2 diabetes-model mice.
- EP-A-2143341 discloses that a mixture of GOS, sialylated oligosaccharides and N-acylated oligosaccharides reduces triglyceride concentration in liver in model mice.
- EP-A-2332552 discloses that 3′-SL and 6′-SL reduce/prevent fat accumulation in the liver and other organs in high-fat diet mice and rats.
- WO 2013/057061 discloses a composition for increasing insulin sensitivity and/or reducing insulin resistance.
- the composition contains long chain polyunsaturated fatty acids, probiotics and a mixture of oligosaccharides containing at least one of lacto-N-neotetraose (LNnT) and lacto-N-tetraose (LNT), at least one N-acetylated oligosaccharide different from LNnT and LNT, at least one sialylated oligosaccharide and at least one neutral oligosaccharide, for use in increasing insulin sensitivity and/or reducing insulin resistance.
- This composition can also contain 2′-O-fucosyllactose (2′-FL).
- the composition is particularly adapted for use in infants who were born preterm and/or who experienced IUGR, and in pregnant women suffering from gestational diabetes. It is also stated that the composition can be given to children, adolescents, and adults suffering from insulin resistance and/or type II diabetes. It is stated that the efficacy of the composition can be the result of the synergistic combination of immunity modulator effects triggered by the probiotics and the LC-PUFA through their stimulation with the specific oligosaccharide mixture.
- a method for treating metabolic disorders includes: determining a treatment group comprising obese non-infant humans, formulating a composition comprising an effective amount of one or more synthetic fucosylated human milk oligosaccharides (HMO) selected from 2′-fucosyllactose (2′-FL), 3-fucosyllactose (3-FL), difucosyllactose (DFL), and lacto-N-fucopentaose I (LNFP-I), that are effective for increasing in the gastrointestinal microbiota of the non-infant human during a treatment period, the relative abundance of Bifidobacterium adolescentis and reducing a precursor condition for a metabolic disorder associated with development of one or more of obesity-induced pre-diabetes and type 2 diabetes, the precursor condition selected from gut permeability, metabolic endotoxemia, low-grade metabolic inflammation, and body fat percentage.
- the method further includes reducing the precursor condition in at least one
- the method includes: determining a treatment group comprising obese non-infant humans, formulating a composition comprising an effective amount of one or more synthetic non-fucosylated human milk oligosaccharides (HMOs) selected from lacto-N-tetraose (LNT), lacto-N-neotetraose (LNnT), that are effective for: increasing in the gastrointestinal microbiota of the non-infant human during a treatment period, the relative abundance of Bifidobacterium adolescentis, and reducing a precursor condition for a metabolic disorder associated with development of one or more of obesity-induced pre-diabetes and type 2 diabetes, the precursor condition selected from gut permeability, metabolic endotoxemia, low-grade metabolic inflammation, and body fat percentage.
- the method further includes reducing the precursor condition in at least one non-infant human in the treatment group by providing the composition to the at least one non-infant human during the treatment period.
- the method includes: determining a treatment group comprising obese non-infant humans, f formulating a composition comprising an effective amount of two or more synthetic neutral human milk oligosaccharides (HMOs) selected from 2′-fucosyllactose (2′FL), 3-fucosyllactose (3-FL), difucosyllactose (DFL), lacto-N-fucopentaose I (LNFP-I), lacto-N-tetraose (LNT), and lacto-N-neotetraose (LNnT), wherein the selected HMOs are effective for: increasing in the gastrointestinal microbiota of the non-infant human during a treatment period, the relative abundance of Bifidobacterium adolescentis, and reducing a precursor condition for a metabolic disorder associated with development of one or more of obesity-induced pre-diabetes and type 2 diabetes, the precursor condition selected
- HMOs synthetic neutral human milk
- the precursor condition for the metabolic disorder associated with development of the one or more of obesity-induced pre-diabetes and type 2 diabetes is gut permeability.
- the reduced precursor condition is body fat percentage.
- the method includes increasing, in the gastrointestinal tract of the non-infant human, a level of glucagon-like peptide selected from GLP-1 and/or GLP-2 relative to the level of the selected glucagon-like peptide prior to the treatment period.
- the treatment period includes an initial treatment phase and a maintenance phase.
- the effective amount of the selected HMO is from about 2.5 g to about 7.5 g daily during the initial phase, and the effective amount of the selected HMO is from about 1 g to about 2.5 g daily during the maintenance phase.
- a single synthetic HMO of the selected HMOs is administered in a unit dosage form.
- the obese non-infant human is a prepubescent child.
- various embodiments of this invention provide a synthetic composition for use in one or more of the following: reducing intestinal permeability, reducing endotoxemia, reducing low-grade inflammation, reducing body fat percentage,
- the synthetic composition contains an effective amount of one or more human milk monosaccharides or one or more human milk oligosaccharides (“HMOs”) or both.
- the synthetic composition is preferably a nutritional composition.
- the composition can further comprise a source of threonine, serine and/or proline.
- the human milk oligosaccharides include both fucosylated and core HMOs such as LNT and LNnT HMOs.
- the human milk oligosaccharides can also include sialylated HMOs.
- the human milk oligosaccharides include both fucosylated and sialylated HMOs and the human milk oligosaccharides can also include backbone HMOs such as LNT and LNnT.
- the patient can be a paediatric or adult patient, preferably a prepubescent child.
- this disclosure provides a method for one or more of the following: reducing intestinal permeability, reducing endotoxemia, reducing low-grade inflammation, reducing body fat percentage, increasing the abundance of bifidobacteria, and/or increasing the levels of the gut hormones GLP-1 and GLP-2, in a patient having a metabolic disorder, for example obesity, obesity induced pre-diabetes and obesity induced type 2 diabetes, the method comprising orally administering to the patient an effective amount of one or human milk monosaccharides or one or more human milk oligosaccharides, or both, preferably in the form of a synthetic composition.
- the patient can be a paediatric or adult patient, preferably a prepubescent child.
- this disclosure relates to a use of one or more human milk monosaccharides or one or more human milk oligosaccharides or both, preferably in the form of a synthetic composition, for one or more of the following: reducing intestinal permeability, reducing endotoxemia in a patient, reducing low-grade inflammation, reducing body fat percentage, increasing the abundance of bifidobacteria, and/or increasing the levels of the gut hormones GLP-1 and GLP-2, in a patient having a metabolic disorder, for example obesity, obesity induced pre-diabetes and obesity induced type 2 diabetes.
- the patient can be a paediatric or adult patient, preferably a prepubescent child.
- human milk monosaccharides advantageously sialic acid and/or fucose
- human milk oligosaccharides advantageously 2′-FL, 3-FL, LNT, LNnT, 3′-SL, 6′-SL, DFL, DSLNT and/or LNFP-I
- body composition by reducing body fat percentage
- Bifidobacteria adolescentis is increased.
- Obese and pre-diabetic patients can be stabilized and the progression to diabetes slowed, stopped or reversed.
- Diabetic patients can be stabilized or at least the progression to diabetes with complications slowed.
- the synthetic composition preferably contains one or more core HMOs and/or one or more fucosylated HMOs, more preferably one or more core HMOs and one or more fucosylated HMOs.
- the core HMO is selected from the group consisting of LNT, LNnT, LNH, LNnH and pLNnH, particularly LNT and LNnT
- the fucosylated HMO is selected from the group consisting of 2′-FL, 3-FL, DFL and LNFP-I, particularly 2′-FL.
- the synthetic composition contains 2′-FL and LNT and/or LNnT.
- patient preferably means a human that can be a paediatric or adult patient. However, a “patient” can also be any other mammal.
- oral administration preferably means any conventional form for the oral delivery of a composition to a patient that causes the deposition of the composition in the gastrointestinal tract (including the stomach) of the patient. Accordingly, oral administration includes swallowing of composition by the patient, enteral feeding through a naso-gastric tube, and the like.
- an effective amount preferably means an amount of a composition that provides a human milk monosaccharide or human milk oligosaccharide in a sufficient amount to render a desired treatment outcome in a patient.
- An effective amount can be administered in one or more doses to the patient to achieve the desired treatment outcome.
- human milk monosaccharide or “HMS” preferably means a monosaccharide found in human breast milk.
- Examples include sialic acid and L-fucose.
- the sialic acid is N-acetylneuraminic acid.
- human milk oligosaccharide preferably means a complex carbohydrate found in human breast milk that can be in acidic or neutral form. More than about 200 different HMO structures are known to exist in human breast milk (Urashima et al.: Milk Oligosaccharides, Nova Biomedical Books, New York, 2011). HMOs can be core, fucosylated and sialylated oligosaccharides. Core HMOs consist of Glu, Gal and GlcNAc and are devoid of Fuc and sialic acid.
- core HMOs examples include lacto-N-tetraose (LNT), lacto-N-neotetraose (LNnT), lacto-N-neohexaose (LNnH), lacto-N-hexaose (LNH) and p-lacto-N-neohexaose (pLNnH).
- Fucosyl HMOs are fucosylated lactoses or fucosylated core HMOs such as 2′-fucosyllactose (2′-FL), lacto-N-fucopentaose I (LNFP-I), lacto-N-difucohexaose I (LNDFH-I), 3-fucosyllactose (3-FL), difucosyllactose (DFL), lacto-N-fucopentaose III (LNFP-III), fucosyl-para-lacto-N-neohexaose (F-pLNnH), lacto-N-difucohexaose I (LNDFH-I), fucosyl-lacto-N-hexaose II (FLNH-II), lacto-N-fucopentaose V (LNFP-V), lacto-N-difucohexaose II (LNDFH-I
- Sialyl HMOs are sialylated lactoses or sialylated core HMOs such as 3′,6-disialyllacto-N-tetraose (DSLNT), 6′-sialyllactose (6′-SL), 3′-sialyllactose (3′-SL), 6′-sialyllacto-N-neotetraose (LST c), 3′-sialyllacto-N-tetraose (LST a) and 6-sialyllacto-N-tetraose (LST b).
- DSLNT 3′,6-disialyllacto-N-tetraose
- 6′-SL 6′-sialyllactose
- 3′-SL 6′-sialyllactose
- LST c 6′-sialyllacto-N-neotetra
- HMOs containing both sialyl and fucosyl groups may be considered to belong to either of the latter two groups.
- sialylated and fucosylated HMOs include disialyl-fucosyl-lacto-N-hexaose II (DSFLNH-II), fucosyl-sialyl-lacto-N-neohexaose I (FSLNnH-I), fucosyl-sialyl-lacto-N-hexaose I (FSLNH-I) and 3-fucosyl-3′-sialyllactose (FSL).
- intestinal permeability preferably means the permeability of the intestinal mucosa of a patient, permitting the absorption of vital nutrients from the gut lumen while presenting a barrier against the passage of pathogenic substances into the patient's body.
- endotoxemia preferably means the presence of endotoxins, such as gut microbiota-derived lipopolysaccharides (LPS) in the blood of a patient.
- endotoxins such as gut microbiota-derived lipopolysaccharides (LPS)
- low-grade inflammation preferably means an immune system response of a patient characterized by altered levels of pro-inflammatory and anti-inflammatory cytokines as well as numerous other markers of immune system activity in response to an injurious stimuli.
- Body fat percentage preferably means total mass of body fat divided by total mass of the body.
- the HMOs can be isolated or enriched by well-known processes from milk(s) secreted by mammals including, but not limited to human, bovine, ovine, porcine, or caprine species.
- the HMOs can also be produced by well-known processes using microbial fermentation, enzymatic processes, chemical synthesis, or combinations of these technologies.
- LNnT can be made as described in WO 2011/100980 and WO 2013/044928
- LNT can be synthesized as described in WO 2012/155916 and WO 2013/044928
- a mixture of LNT and LNnT can be made as described in WO 2013/091660
- 2′-FL can be made as described in WO 2010/115934 and WO 2010/115935
- 3-FL can be made as described in WO 2013/13934
- 6′-SL and salts thereof can be made as described in WO 2010/100979
- sialylated oligosaccharides can be made as described in WO 2012/113404 and mixtures of human milk oligosaccharides can be made as described in WO 2012/113405.
- sialylated oligosaccharides can be made as described in WO 2012/007588
- fucosylated oligosaccharides can be made as described in WO 2012/127410
- advantageously diversified blends of human milk oligosaccharides can be made as described in WO 2012/156897 and WO 2012/156898.
- biotechnological methods WO 01/04341 and WO 2007/101862 describe how to make core human milk oligosaccharides optionally substituted by fucose or sialic acid using genetically modified E. coli.
- the human milk monosaccharides and/or oligosaccharides can be in the form of one or more core HMOs and one or more fucosylated HMOs.
- one or more core HMOs and one or more sialylated HMOs can be used.
- one or more fucosylated HMOs and one or more sialylated HMOs can be used.
- one or more core HMOs, one or more sialylated HMOs and one or more fucosylated HMOs are used.
- GI blood glucose response curve
- the synthetic composition can take any suitable form.
- the composition can be in the form of a nutritional composition which contains other macronutrients such as proteins, lipids or other carbohydrates.
- the synthetic composition can also be a pharmaceutical composition.
- a nutritional composition can contain sources of protein, lipids and/or digestible carbohydrates and can be in solid, powdered or liquid forms.
- the composition can be designed to be the sole source of nutrition or a nutritional supplement.
- Suitable protein sources include intact, hydrolysed, and partially hydrolysed protein, which can be derived from any suitable source such as milk (e.g., casein, whey), animal (e.g., meat, fish), cereal (e.g., rice, corn), and vegetable (e.g., soy, potato, pea), insect (e.g., locust) and combinations of these sources.
- milk e.g., casein, whey
- animal e.g., meat, fish
- cereal e.g., rice, corn
- vegetable e.g., soy, potato, pea
- insect e.g., locust
- Examples of the source of protein include whey protein concentrates, whey protein isolates, whey protein hydrolysates, acid caseins, sodium casemates, calcium casemates, potassium casemates, casein hydrolysates, milk protein concentrates, milk protein isolates, milk protein hydrolysates, non-fat dry milk, condensed skim milk, soy protein concentrates, soy protein isolates, soy protein hydrolysates, pea protein concentrates, pea protein isolates, pea protein hydrolysates, collagen proteins, and combinations of these sources.
- the amount of protein is preferably sufficient to provide about 5 to about 30% of the energy of the nutritional composition; for example about 10% to about 25% of the energy. Within these ranges, the amount of protein can vary depending upon the nutritional needs of the intended individual.
- the nutritional compositions can also include free amino acids such as tryptophan, glutamine, tyrosine, methionine, cysteine, taurine, arginine, carnitine, threonine, serine and proline and combinations of these amino acids.
- Threonine, serine and proline are important amino acids for the production of mucin which aids gut barrier function.
- Any suitable source of other carbohydrates can be used. Examples include maltodextrin, hydrolyzed or modified starch or corn starch, glucose polymers, corn syrup, corn syrup solids, rice-derived carbohydrates, sucrose, glucose, fructose, lactose, high fructose corn syrup, honey, sugar alcohols (e.g., maltitol, erythritol, sorbitol, etc.), isomaltulose, sucromalt, pullulan, potato starch, slowly-digested carbohydrates, dietary fibres such as oat fibre, soy fibre, gum arabic, sodium carboxymethylcellulose, methylcellulose, guar gum, gellan gum, locust bean gum, konjac flour, hydroxypropyl methylcellulose, tragacanth gum, karaya gum, gum acacia, chitosan, arabinogalactans, glucomannan, xanthan gum, alginate, pectin, low and high methoxy pectin,
- the carbohydrate source includes low glycaemic index carbohydrates having a GI score of 55 or below.
- low glycaemic index carbohydrates include sucromalt, FibersolTM (inulin), maltodextrins having a dextrose equivalence (DE) of less than 15, rice syrup having a dextrose equivalence of less than 15, fructooligosaccharides, resistant starches, starches, fruit sourced fibres, vegetable sourced fibres, whole grains, beta-glucans, soy fibres, oat fibres, locust bean gum, konjac flour, hydroxypropyl methylcellulose, gum acacia, chitosan, arabinogalactans, xanthan gum, alginate, low and high methoxy pectin, carrageenan, psyllium, isomaltulose, glycerine and sugar alcohols.
- the nutritional compositions can include carbohydrates in an amount sufficient to provide about 30 to about 70% of the energy of the composition, for example about 35 to about 65% of the energy. Within these parameters, the amount of carbohydrate can vary widely.
- Suitable lipid sources include coconut oil, fractionated coconut oil, soy oil, corn oil, olive oil, safflower oil, high oleic safflower oil, medium chain triglycerides, sunflower oil, high oleic sunflower oil, palm and palm kernel oils, palm olein, canola oil, marine oils, cottonseed oils and combinations of these oils.
- Fractionated coconut oils are a suitable source of medium chain triglycerides.
- the lipids can contain polyunsaturated fatty acids such as n-3 LC-PUFA.
- the n-3 LC-PUFA can be a C20 or a C22 n-3 fatty acid.
- n-3 LC-PUFA is docosahexanoic acid (DHA, C22:6, n-3).
- the source of LC-PUFA can be, for example, egg lipids, fungal oil, low EPA fish oil or algal oil.
- the nutritional compositions can include lipids in an amount sufficient to provide about 10 to about 50% of energy of the nutritional composition, for example about 15 to about 40% of the energy.
- the nutritional composition preferably also includes vitamins and minerals. If the nutritional composition is intended to be a sole source of nutrition, it preferably includes a complete vitamin and mineral profile.
- vitamins include vitamins A, B-complex (such as B1, B2, B6 and B12), C, D, E and K, niacin and acid vitamins such as pantothenic acid, folic acid and biotin.
- minerals include calcium, iron, zinc, magnesium, iodine, copper, phosphorus, manganese, potassium, chromium, molybdenum, selenium, nickel, tin, silicon, vanadium and boron.
- the nutritional composition can also include a carotenoid such as lutein, lycopene, zeaxanthin, and beta-carotene.
- a carotenoid such as lutein, lycopene, zeaxanthin, and beta-carotene.
- the total amount of carotenoid included can vary from about 0.001 ⁇ g/ml to about 10 ⁇ g/ml.
- Lutein can be included in an amount of from about 0.001 ⁇ g/ml to about 10 ⁇ g/ml, preferably from about 0.044 ⁇ g/ml to about 5 g/ml of lutein.
- Lycopene can be included in an amount from about 0.001 ⁇ g/ml to about 10 ⁇ g/ml, preferably about 0.0185 mg/ml to about 5 g/ml of lycopene.
- Beta-carotene can comprise from about 0.001 ⁇ g/ml to about 10 mg/ml, for example about 0.034 ⁇ g/ml to about 5 ⁇ g/ml of beta-carotene.
- the nutritional composition can also include a source of anthocyanidins. This can be in the form of a fruit or a fruit extract. Particularly useful fruits and fruit extracts include plum/prune, apple, pear, strawberry, blueberry, raspberry, cherry, and their combinations.
- the nutritional composition can also contain various other conventional ingredients such as preservatives, emulsifying agents, thickening agents, buffers, fibres and prebiotics (e.g. fructooligosaccharides, galactooligosaccharides), probiotics (e.g. B. animalis subsp. lactis BB-12, B. lactis HN019, B. lactis Bi07, B. infantis ATCC 15697, L. rhamnosus GG, L. rhamnosus HNOOI, L. acidophilus LA-5, L. acidophilus NCFM, L. fermentum CECT5716, B. longum BB536, B. longum AH1205, B. longum AH1206, B.
- prebiotics e.g. fructooligosaccharides, galactooligosaccharides
- probiotics e.g. B. animalis subsp. lactis BB-12, B. lactis HN019, B. lactis
- antioxidant/anti-inflammatory compounds including tocopherols, carotenoids, ascorbate/vitamin C, ascorbyl palmitate, polyphenols, glutathione, and superoxide dismutase (melon), other bioactive factors (e.g. growth hormones, cytokines, TFG ⁇ ), colorants, flavours, and stabilizers, lubricants, and so forth.
- the nutritional composition can be in the form of a food, soluble powder, a liquid concentrate, or a ready-to-use formulation.
- the composition can be eaten, drunk or can be fed via a nasogastric.
- Various flavours, fibres, and other additives can also be present.
- the nutritional compositions can be prepared by any commonly used manufacturing techniques for preparing nutritional compositions in solid or liquid form.
- the composition can be prepared by combining various feed solutions.
- a protein-in-fat feed solution can be prepared by heating and mixing the lipid source and then adding an emulsifier (e.g. lecithin), fat soluble vitamins, and at least a portion of the protein source while heating and stirring.
- a carbohydrate feed solution is then prepared by adding minerals, trace and ultra trace minerals, thickening or suspending agents to water while heating and stirring. The resulting solution is held for 10 minutes with continued heat and agitation before adding carbohydrates (e.g., the HMOs and digestible carbohydrate sources).
- the resulting feed solutions are then blended together while heating and agitating and the pH adjusted to 6.6-7.0, after which the composition is subjected to high-temperature short-time processing during which the composition is heat treated, emulsified and homogenized, and then allowed to cool.
- Water soluble vitamins and ascorbic acid are added, the pH is adjusted to the desired range if necessary, flavours are added, and water is added to achieve the desired total solid level.
- the resulting solution can then be aseptically packed to form an aseptically packaged nutritional composition.
- the nutritional composition can be in ready-to-feed or concentrated liquid form.
- the composition can be spray-dried and processed and packaged as a reconstitutable powder.
- the nutritional composition can also be in the form of a food such as a nutritional bar, a yoghurt, etc. These forms can be produced using standard technologies and processes.
- the total concentration of HMSs/HMOs in the liquid, by weight of the liquid is from about 0.0001% to about 2.0%, including from about 0.001% to about 1.5%, including from about 0.01% to about 1.0%.
- the total concentration of HMSs/HMOs in the liquid, by weight of the liquid is from about 0.0002% to about 4.0%, including from about 0.002% to about 3.0%, including from about 0.02% to about 2.0%.
- the synthetic composition of this disclosure can also be in a unit dosage form such as a capsule, tablet or sachet.
- the composition can be in a tablet form comprising the human milk monosaccharides and/or oligosaccharides, and one or more additional components to aid formulation and administration, such as diluents, excipients, antioxidants, lubricants, colorants, binders, disintegrants, and the like.
- Suitable diluents, excipients, lubricants, colorants, binders, and disintegrants include polyethylene, polyvinyl chloride, ethyl cellulose, acrylate polymers and their copolymers, hydroxyethyl-cellulose, hydroxypropylmethyl-cellulose (HPMC), sodium carboxymethylcellulose, polyhydroxyethyl methacrylate (PHEMA), polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), polyethylene oxide (PEO), or polyacrylamide (PA), carrageenan, sodium alginate, polycarbophil, polyacrylic acid, tragacanth, methyl cellulose, pectin, natural gums, xanthan gum, guar gum, karaya gum, hypromellose, magnesium stearate, microcrystalline cellulose, and colloidal silicon dioxide.
- Suitable antioxidants are vitamin A, carotenoids, vitamin C, vitamin E, selenium, flavonoids, polyphenols, lycopene, lutein, lignan, coenzyme Q10 (“CoQIO”) and glutathione.
- the unit dosage forms, especially those in sachet form, can also include various nutrients including macronutrients.
- the amount of human milk mono and/or oligosaccharide(s) required to be administered to the person will vary depending upon factors such as the risk and condition severity, the age of the person, the form of the composition, and other medications being administered to the person.
- the required amount can be readily set by a medical practitioner and would generally be in the range from about 10 mg to about 20 g per day, in certain embodiments from about 10 mg to about 15 g per day, from about 100 mg to about 10 g per day, in certain embodiments from about 500 mg to about 10 g per day, in certain embodiments from about 1 g to about 7.5 g per day.
- An appropriate dose can be determined based on several factors, including, for example, the body weight and/or condition of the patient being treated, the severity of the condition, being treated, other ailments and/or diseases of the person, the incidence and/or severity of side effects and the manner of administration. Appropriate dose ranges can be determined by methods known to those skilled in the art.
- the dosing can be higher (for example 200 mg to 20 g per day, preferably 500 mg to 15 g per day, more preferably 1 g to 10 g per day, in certain embodiments 2.5 g to 7.5 g per day).
- the dosing can be reduced (for example, 10 mg to 10 g per day, preferably 100 mg to 7.5 g per day, more preferably 500 mg to 5 g per day, in certain embodiments 1 g to 2.5 g per day).
- a synthetic composition of this disclosure can be co-administered to a patient who is also receiving a standard-of-care medication for obesity or diabetes.
- mice 10-week-old C57BL/6J mice (120 mice) are housed in groups of five mice per cage, with free access to food and water. The mice are divided into 12 groups of 10 mice, one control group and 11 treatment groups. All of the mice are fed a high-fat (HF) diet (60% fat and 20% carbohydrates [kcal/100 g], or an HF diet supplemented with HMS/HMO (20 g/kg of diet) for 8 weeks. Food and water intake are recorded twice a week.
- HF high-fat
- the 11 treatment groups are each administered one of the following: a) sialic acid, b) L-fucose, c) 2′-FL, d) 3-FL, e) 3′-SL, f) 6′-SL, g) LNT, h) LNnT, i) LNFP-I, j) DSLNT and k) a combination of these saccharides.
- the control group is administered the HF diet only. Fresh food is given daily.
- Intraperitoneal or oral glucose tolerance tests are performed as follows: 6-h-fasted mice are injected with glucose into the peritoneal cavity (1 g/kg glucose, 20% glucose solution) or by gavage (3 g/kg glucose, 66% glucose solution). Blood glucose is determined with a glucose meter (Roche Diagnostics) on 3.5 ⁇ l blood collected from the tip of the tail vein. A total of 20 ⁇ l blood is sampled 30 min before and 15 or 30 min after the glucose load to assess plasma insulin concentration.
- the intestinal permeability of 4000 Da fluorescent dextran-FITC (DX-4000-FITC) is measured. Mice are fasted for 6 h before given DX-44-FITC by gavage (500 mg/kg body weight, 125 mg/ml). After 1 h and 4 h, 120 ml of blood is collected from the tip of the tail vein. The blood is centrifuged at 4° C., 12 000 g for 3 min. Plasma is diluted in an equal volume of PBS (pH 7.4) and analysed for DX-4000-FITC concentration with a fluorescence spectrophotometer at an excitation wavelength of 485 nm and emission wavelength of 535 nm. Standard curves are obtained by diluting FITC-dextran in non-treated plasma diluted with PBS (1:3 v/v).
- Plasma LPS, cytokines and gut hormones are determined as follows. Plasma LPS concentration is measured using a kit based upon a Limulus amoebocyte extract (LAL kit endpoint-QCL1000). Samples are diluted 1/40 to 1/100 and heated for 20 cycles of 10 min at 68° C. and 10 min at 4° C. An internal control for LPS recovery is included in the calculation.
- LAL kit endpoint-QCL1000 Limulus amoebocyte extract
- Plasma cytokines interleukin (IL) 1 ⁇ , IL1 ⁇ , tumour necrosis factor (TNF) ⁇ , IL6, monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1 ⁇ , IL10, interferon (INF) c, IL15, IL18) and gut hormones (GLP-1 (active), GIP (total), amylin (active), pancreatic polypeptide) are respectively determined in duplicate by using a Bio-Plex Multiplex kit, or a mouse gut hormones panel (LincoPlex), and measured by using Luminex technology, an EIA kit (GLP-2 EIA kit) is used to quantify GLP-2.
- Mice are anaesthetised (ketamine/xylazine, intraperineally, 100 and 10 mg/kg, respectively) after a 5 h period of fasting, and blood samples and tissues are harvested for further analysis. Mice are killed by cervical dislocation. Liver, caecum (full and empty), muscles (vastus lateralis), and adipose tissues (mesenteric and corresponding lymph nodes, epididymal, subcutaneous and visceral) are precisely dissected and weighed. The intestinal segments (jejunum, colon) are immersed in liquid nitrogen, and stored at ⁇ 80° C., for further analysis.
- the caecal contents collected post mortem from mice are stored at ⁇ 80° C.
- DNA is isolated from the caecal content samples using QIAamp DNA Stool Mini Kit.
- the DNA concentration of extracts is measured using NanoDrop.
- Aliquots of 100 ng of extracted DNA are subjected to PCR using the 16S rDNA universal heteroduplex analysis (HDA) primers HDA1-GC and HDA2 which are disclosed in Walter et al. Appl. Environ. Microbiol. 66, 297 (2000)) at 56° C. for strand annealing.
- Initial denaturation at 94° C. for 4 min is followed by thirty cycles of 30 s at 94° C., 30 s at 56° C. and 1 min at 72° C.
- the quality of PCR products is verified by agarose gel electrophoresis.
- Amplified 16S rDNA fragments are separated by denaturing gradient gel electrophoresis (DGGE) using an INGENYphorU system equipped with 6% polyacrylamide gels with a denaturant in the range of 30-55%, where 100% denaturant is equivalent to 7M-urea and 40% formamide. Electrophoresis is carried out at 130 V for 4-5 hours at 60° C. Polyacrylamide gels are stained with GelRede nucleic acid stain for 45 min, destained in ultrapure water and viewed under UV light. Bands of interest are excised from gels and lysed in ultrapure water. Extracted DNA is re-amplified using the same primers and PCR conditions.
- DGGE denaturing gradient gel electrophoresis
- PCR products are reloaded on a denaturant gradient gel followed by excision and lysis of selected bands.
- DNA samples recovered from lysed bands of the second DGGE are re-amplified by PCR before purification using the QIAquick PCR Purification Kit and sequenced. Species identification is done using the Ribosomal Microbiome Database Project Classifier tool. Because of the limited sensitivity of DGGE to quantify microbial diversity, the microbial composition of DNA samples is also analysed using high-throughput sequencing.
- V5-V6 region of 16S rRNA from caecal content DNA samples is amplified using a forward primer and a reverse primer which are both disclosed in Andersson et al. PloS ONE 3, e2836 (2008)).
- Amplicons are pyrosequenced using a Roche 454 GS-FLX system. Sequences of at least 240 nucleotides and containing no more than two undetermined bases are retained for taxonomic assignment.
- the QIIME software is used for chimera check and the Greengenes database is used for classification. Bacterial diversity is determined at the phylum, family and genus levels.
- MAT mesenteric adipose tissue
- MN lymph nodes
- Quantification of bacterial DNA is performed by isolating genomic DNA from blood, MAT, MLN or intestine (contents and mucosa). All bacterial DNA is quantified by quantitative real-time PCR targeting conserved regions of the 16S rRNA gene, with bacterial DNA as standard template for absolute quantification.
- occludin and zonula occludens-1 (ZO-1) tight-junction proteins are assessed. Jejunum segments are immediately removed, washed with PBS, mounted in embedding medium, and stored at ⁇ 80° C. until use. Cryosections (5 mm) are fixed in acetone at ⁇ 20° C. for 5 min for occludin and in ethanol for 30 min at room temperature and in acetone at ⁇ 20° C. for 5 min for ZO-1. Non-specific background is blocked by incubation with 10% bovine serum albumin (BSA) in Tris-buffered saline (TBS) and 0.3% Triton X-100 (30 min at room temperature).
- BSA bovine serum albumin
- TBS Tris-buffered saline
- Sections are incubated with rabbit anti-occludin or rabbit anti-ZO-1 (1:400 for ZO-1 and 1:100 for occludin staining) for 2 h. Sections are washed three times for 10 min in TBS and probed with goat anti-rabbit fluorescein isothiocyante (FITC)-conjugated antibodies (1:50). Slides are washed three times for 10 min in TBS and mounted in mounting medium. Sections are visualized on a fluorescence microscope. As a control, slides are incubated with serial dilutions of the primary antibody to signal extinction. Two negative controls are used: slides incubated with irrelevant antibody or without primary antibody. All the stainings are performed in duplicate in non-serial distant sections, and analyzed in a double-blind manner by two different investigators.
- FITC goat anti-rabbit fluorescein isothiocyante
- HMS/HMO improve gut barrier function and reduce the metabolic inflammation and insulin resistance associated with obesity by increasing release of gut peptides, such as glucagon-like peptide-1 and -2 (GLP-1 and -2).
- mice Six-week-old ob/ob mice (120 mice) on C57BL/6 background are housed in a controlled environment (12 h daylight cycle) in groups of 2 mice/cage, and kept with free access to food and drinking water. The mice are separated into 12 groups of 10 mice, one control group and 11 treatment groups.
- One group is fed a control diet, and the 11 treatment groups each receive a control diets containing one of the following HMS/HMO (20 g/kg of diet) for five weeks: a) sialic acid, b) L-fucose, c) 2′-FL, d) 3-FL, e) 3′-SL, f) 6′-SL, g) LNT, h) LNnT, i) LNFP-I, j) DSLNT, and k) a combination of these saccharides. Fresh food is given daily.
- HMS/HMO 20 g/kg of diet
- the investigational products contain 4.5 grams of either 2′-FL alone or a combination of 2′-FL and LNnT while the placebo product contains 4.5 grams glucose. All products are in powder form in a unit dosage container.
- the patients are eligible to participate if: they are between 5 and 10 years of age, have a BMI SDS of ⁇ 2.0 and are enrolled in the childhood obesity treatment program at the Children's Obesity Clinic. All recruited patients and their representatives are able and willing to understand and comply with the study procedures.
- Patients are excluded if: they have participated in a clinical study one month prior to the screening visit and throughout the study; have any gastrointestinal disease(s) that may cause symptoms or may interfere with the trial outcome; have other severe disease(s) such as malignancy, kidney disease or neurological disease; have psychiatric disease; have used highly dosed probiotic supplements (yoghurt allowed) 3 months prior to screening and throughout the study; have consumed antibiotic drugs 3 months prior to screening and throughout the study; and consume on a regular basis medication that might interfere with symptom evaluation 2 weeks prior to screening and throughout the study.
- Eligibility criteria are checked and for children who are enrolled to the study, medical history and concomitant medication are registered. A physical examination is done and pubertal staging is determined. Blood pressure, pulse rate, height and bodyweight are measured, and body composition is determined by a DXA (dual energy x-ray absorptiometry)-scan and bioimpedance. BMI SDS is calculated, waist and hip circumferences are measured and food intake is registered. Fasting blood samples are collected for safety and biomarker studies and for biobanking.
- the serum from the blood samples is transferred to cryotubes and stored at ⁇ 80° C.
- the following biomarkers are measured; Lipopolysaccharides (LPS), hsCRP, free fatty acids, total cholesterol, HDL, LDL, HbA1c, glucose, insulin, triglycerides, TNF- ⁇ , IL-1 ⁇ , IL-6, IL-8, IL-10, GLP-1, GLP-2, Adiponectin, and Zonulin.
- faecal samples Equipment for collecting faecal samples is distributed.
- the faecal samples are stored at ⁇ 80° C. until analysis.
- Microbiological analysis is performed on the faecal samples using 16S rRNA gene sequencing.
- the Rome III Diagnostic Questionnaire for Paediatric Functional GI Disorders is completed on site by the participating child's representative(s), and the Bristol Stool Form Scales (BSFS) is distributed to the participant's representative(s) with instructions to assess the stool consistency at each faecal sampling point using the BSFS.
- QPFG Paediatric Functional GI Disorders
- BSFS Bristol Stool Form Scales
- faecal samples are collected and equipment for collection of new samples is distributed.
- BSFS is collected and new BSFS is distributed.
- Study products are distributed together with a compliance form (diary). Patients and their representatives are reminded to follow the healthy dietary habits.
- the study runs for 8 weeks with the patients consuming either a placebo or one of two investigational products daily. Patients are instructed to consume the products in the morning with breakfast. Compliance is monitored via a compliance form (diary) to be filled in daily.
- each patient has a visit with the medical team. Patients and their representatives are asked about adverse events and any changes in the patient's usual medication. Study products and compliance forms are collected to check compliance.
- BSFS and faecal samples are collected and equipment for collection of new samples is distributed. A physical examination is done and pubertal staging is determined. Blood pressure, pulse rate, height and bodyweight are measured, and body composition is determined by a DXA (dual energy x-ray absorptiometry)-scan and bioimpedance. BMI SDS is calculated, waist and hip circumferences measured and food intake registered. Fasting blood samples are collected for safety and biomarker studies and for biobanking, and equipment for collecting faecal samples is distributed. The QPFG questionnaire is completed on site by the participating child's representative(s).
- an un-blinded follow-up period follows with a visit 8 weeks after end of intervention.
- a physical examination is done and pubertal staging is determined.
- Blood pressure, pulse rate, height and bodyweight are measured, and body composition is determined by a DXA (dual energy x-ray absorptiometry)-scan and bioimpedance.
- BMI SDS is calculated, waist and hip circumferences measured and food intake registered.
- Fasting blood samples are collected for safety and biomarker studies and for biobanking. Fecal samples are collected.
- the intervention contributes to a normal body composition, and the patients given the investigational products show a greater reduction of body fat, body weight and BMI SDS as compared to the placebo group.
- the blood biomarker analysis indicates that the patients given the investigational products have increased levels of GLP-1 and GLP-2, reduced levels of metabolic endotoxemia and inflammatory markers and reduced gut permeability indicating an improved mucosal barrier compared to the placebo.
- the faecal analysis indicates that the patients given the investigational products have reduced bacterial dysbiosis and a higher level of bifidobacteria compared to the placebo, particularly Bifidobacteria adolescentis.
- a ready to feed nutritional composition is prepared from water, maltodextrin, milk protein concentrate, Sucromalt, glycerine, cocoa powder, soy protein isolate, fructose, high oleic safflower oil, soy oil, canola oil, plant sterol esters, HMSs/HMOs, soy lecithin, magnesium chloride, calcium phosphate, carrageenan, sodium ascorbate, potassium citrate, sodium phosphate, calcium citrate, choline chloride, potassium chloride, sodium citrate, magnesium oxide, taurine, L-carnitine, alpha-tocopheryl acetate, zinc sulphate, ferrous sulphate, niacinamide, calcium pantothenate, vitamin A palmitate, citric acid, manganese sulphate, pyridoxine hydrochloride, vitamin D3, copper sulphate, thiamine mononitrate, riboflavin, beta carotene, folic acid, biotin, potassium
- the composition has an energy density of 0.8 kcal/ml with an energy distribution (% of kcal) as follows: protein: 20%, carbohydrate: 48%, fat: 32%.
- a tablet is prepared from HMS/HMO, hydroxypropyl methylcellulose, sodium alginate, gum, microcrystalline cellulose, colloidal silicon dioxide, and magnesium stearate. All raw materials except the magnesium stearate are placed into a high shear granulator and premixed. Water is sprayed onto the premix while continuing to mix at 300 rpm. The granulate is transferred to a fluidized bed drier and dried at 75° C. The dried powder is sieved and sized using a mill. The resulting powder is then lubricated with magnesium stearate and pressed into tablets. The tablets each contain 325 mg of HMS/HMO. The tablets each have a weight of 750 mg.
- a capsule is prepared by filling about 1 g of HMS/HMO into a 000 gelatine capsule using a filing machine. The capsules are then closed. The HMS/HMO are in free flowing, powder form.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Obesity (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Child & Adolescent Psychology (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
A method for treating metabolic disorders includes determining a treatment group comprising obese non-infant humans; formulating a composition comprising one or more synthetic non-fucosylated human milk oligosaccharides (HMOs) selected from lacto-N-tetraose (LNT), lacto-N-neotetraose (LNnT) and/or 2′-fucosyllactose (2′-FL), 3-fucosyllactose (3-FL), difucosyllactose (DFL), and lacto-N-fucopentaose I (LNFP-I), that are effective for: increasing in the gastrointestinal microbiota of a non-infant human during a treatment period, the relative abundance of Bifidobacterium adolescentis and reducing a precursor condition for a metabolic disorder associated with development of one or more of obesity-induced pre-diabetes and type 2 diabetes, the precursor condition selected from gut permeability, metabolic endotoxemia, low-grade metabolic inflammation, and body fat percentage; and reducing the precursor condition in at least one non-infant human in the treatment group by providing the composition to the at least one non-infant human during the treatment period.
Description
- The present application is a Continuation of U.S. application Ser. No. 17/093,337 filed Nov. 9, 2020. U.S. application Ser. No. 17/093,337 is a Continuation of and claims priority to U.S. application Ser. No. 15/104,794 filed Jun. 15, 2016, now patented U.S. Pat. No. 10,828,313, which is the U.S. National Stage Entry of PCT/DK2015/050385 which claims priority to DK application PA 2014 70768, the entire contents of each of the aforementioned applications are incorporated herein by reference for all purposes permissible under relevant patent laws and rules.
- This disclosure relates generally to compositions and methods for the treatment of metabolic disorders such as obesity and obesity induced pre-diabetes and type 2 diabetes.
- Diabetes type 2 is a metabolic disorder that is characterized by hyperglycaemia due to insulin resistance and relative lack of insulin and that is a rapidly growing global epidemic. The International Diabetes Federation (IDF) reports that as of 2013 there were more than 382 million people living with diabetes, and a further 316 million with impaired glucose tolerance who are at high risk from the disease (IDF Diabetes Atlas, 6th edn.). The World Health Organization (WHO) furthermore estimates that 90 percent of people around the world who suffer from diabetes suffer from type 2 diabetes. Long-term complications from high blood sugar can include heart disease, strokes, diabetic retinopathy, kidney failure, and poor blood flow in the limbs.
- Since it is unlikely that there has been a dramatic alteration in genetic factors in the past decades, environmental factors must play a key role in the rapid rise in diabetes. Gut microbiota may be a key factor with populations showing marked differences between healthy, obese, and type 2 diabetic patients. The dysbiosis of gut microbiota has the potential to affect host metabolism and energy storage and to affect gut permeability and, as a consequence, give rise to metabolic endotoxemia and higher plasma lipopolysaccharide (LPS). In addition, gut peptides such as glucagon-like peptide 1 (GLP1) and GLP2 can play key roles in these processes. For example, GLP2, which is secreted by intestine L cells, is a key regulator of intestinal permeability. Therapeutic regimes that target intestinal microbiota and intestinal barrier therefore show a broad prospect in treating diabetes.
- Recent insights suggest that an altered composition and diversity of gut microbiota could play an important role in the development of metabolic disorders such as obesity and diabetes. Gut microbiota does not only participate in whole-body metabolism by affecting energy balance and glucose metabolism, but is also involved in development of the low-grade inflammation, associated with obesity and related metabolic disorders such as diabetes. The association between inflammation and type 2 diabetes is seen in epidemiological studies indicating a rise in acute-phase response proteins in serum of type 2 diabetic patients compared with controls. Later, a specific link between inflammatory and metabolic responses was made with the discovery that compared with lean tissue, obese adipose tissue secretes inflammatory cytokines and that these inflammatory cytokines themselves can inhibit insulin signalling. The definitive proof of a connection between inflammatory mediators and insulin resistance in obesity and type 2 diabetes came from genetic studies that interfered with inflammatory mediators and demonstrated beneficial effects of this interference on insulin action.
- In recent years, gut microbiota derived LPS has been shown to be involved in the onset and progression of inflammation, and in pathological situations, such as obesity and type 2 diabetes, LPS play a major role in the onset of disease. After only one week of a high-fat diet in mice, commensal intestinal bacteria are translocated from the intestine into adipose tissue and the blood where they can induce inflammation. This metabolic bacteraemia is characterized by an increased co-localization with dendritic cells from the intestinal lamina propria and by an augmented intestinal mucosal adherence of non-pathogenic Escherichia coli. The bacterial translocation process from intestine towards tissue with resulting inflammation was reversed by six weeks of treatment with the probiotic strain Bifidobacterium animalis subsp. lactis 420, suggesting an involvement of the microbiota.
- EP-A-1332759 discloses that oral doses of 2′-FL, 3′-SL, 6′-SL, LNnT and sialic acid promote insulin secretion in type 2 diabetes-model mice.
- EP-A-2143341 discloses that a mixture of GOS, sialylated oligosaccharides and N-acylated oligosaccharides reduces triglyceride concentration in liver in model mice.
- EP-A-2332552 discloses that 3′-SL and 6′-SL reduce/prevent fat accumulation in the liver and other organs in high-fat diet mice and rats.
- WO 2013/057061 discloses a composition for increasing insulin sensitivity and/or reducing insulin resistance. The composition contains long chain polyunsaturated fatty acids, probiotics and a mixture of oligosaccharides containing at least one of lacto-N-neotetraose (LNnT) and lacto-N-tetraose (LNT), at least one N-acetylated oligosaccharide different from LNnT and LNT, at least one sialylated oligosaccharide and at least one neutral oligosaccharide, for use in increasing insulin sensitivity and/or reducing insulin resistance. This composition can also contain 2′-O-fucosyllactose (2′-FL). The composition is particularly adapted for use in infants who were born preterm and/or who experienced IUGR, and in pregnant women suffering from gestational diabetes. It is also stated that the composition can be given to children, adolescents, and adults suffering from insulin resistance and/or type II diabetes. It is stated that the efficacy of the composition can be the result of the synergistic combination of immunity modulator effects triggered by the probiotics and the LC-PUFA through their stimulation with the specific oligosaccharide mixture.
- Most current therapeutic approaches aim at treating the consequences rather than causes of the impaired metabolism. This strategy is not efficient and therefore, there has remained a need for therapies that reduce intestinal permeability, endotoxemia and low-grade inflammation in patients with metabolic disorders to improve glucose and insulin sensitivity, and which are safe with little or no adverse side effects.
- A method is provided for treating metabolic disorders. In a first aspect, the method includes: determining a treatment group comprising obese non-infant humans, formulating a composition comprising an effective amount of one or more synthetic fucosylated human milk oligosaccharides (HMO) selected from 2′-fucosyllactose (2′-FL), 3-fucosyllactose (3-FL), difucosyllactose (DFL), and lacto-N-fucopentaose I (LNFP-I), that are effective for increasing in the gastrointestinal microbiota of the non-infant human during a treatment period, the relative abundance of Bifidobacterium adolescentis and reducing a precursor condition for a metabolic disorder associated with development of one or more of obesity-induced pre-diabetes and type 2 diabetes, the precursor condition selected from gut permeability, metabolic endotoxemia, low-grade metabolic inflammation, and body fat percentage. The method further includes reducing the precursor condition in at least one non-infant human in the treatment group by providing the composition to the at least one non-infant human during the treatment period.
- In a second aspect, the method includes: determining a treatment group comprising obese non-infant humans, formulating a composition comprising an effective amount of one or more synthetic non-fucosylated human milk oligosaccharides (HMOs) selected from lacto-N-tetraose (LNT), lacto-N-neotetraose (LNnT), that are effective for: increasing in the gastrointestinal microbiota of the non-infant human during a treatment period, the relative abundance of Bifidobacterium adolescentis, and reducing a precursor condition for a metabolic disorder associated with development of one or more of obesity-induced pre-diabetes and type 2 diabetes, the precursor condition selected from gut permeability, metabolic endotoxemia, low-grade metabolic inflammation, and body fat percentage. The method further includes reducing the precursor condition in at least one non-infant human in the treatment group by providing the composition to the at least one non-infant human during the treatment period.
- According to a third aspect of the disclosure, the method includes: determining a treatment group comprising obese non-infant humans, f formulating a composition comprising an effective amount of two or more synthetic neutral human milk oligosaccharides (HMOs) selected from 2′-fucosyllactose (2′FL), 3-fucosyllactose (3-FL), difucosyllactose (DFL), lacto-N-fucopentaose I (LNFP-I), lacto-N-tetraose (LNT), and lacto-N-neotetraose (LNnT), wherein the selected HMOs are effective for: increasing in the gastrointestinal microbiota of the non-infant human during a treatment period, the relative abundance of Bifidobacterium adolescentis, and reducing a precursor condition for a metabolic disorder associated with development of one or more of obesity-induced pre-diabetes and type 2 diabetes, the precursor condition selected from gut permeability, metabolic endotoxemia, low-grade metabolic inflammation, and body fat percentage. The method further includes reducing the precursor condition in at least one non-infant human in the treatment group by providing the composition to the at least one non-infant human during the treatment period.
- In some embodiments, the precursor condition for the metabolic disorder associated with development of the one or more of obesity-induced pre-diabetes and type 2 diabetes is gut permeability. In certain embodiments, the reduced precursor condition is body fat percentage.
- In various embodiments, the method includes increasing, in the gastrointestinal tract of the non-infant human, a level of glucagon-like peptide selected from GLP-1 and/or GLP-2 relative to the level of the selected glucagon-like peptide prior to the treatment period.
- In certain embodiments, the treatment period includes an initial treatment phase and a maintenance phase. The effective amount of the selected HMO is from about 2.5 g to about 7.5 g daily during the initial phase, and the effective amount of the selected HMO is from about 1 g to about 2.5 g daily during the maintenance phase.
- In some embodiments, a single synthetic HMO of the selected HMOs is administered in a unit dosage form. In certain embodiments, the obese non-infant human is a prepubescent child.
- In one aspect, various embodiments of this invention provide a synthetic composition for use in one or more of the following: reducing intestinal permeability, reducing endotoxemia, reducing low-grade inflammation, reducing body fat percentage,
- increasing the abundance of bifidobacteria, and/or increasing the levels of the gut hormones GLP-1 and GLP-2, in a patient having a metabolic disorder, for example obesity, obesity induced pre-diabetes and obesity induced type 2 diabetes, characterized in that the synthetic composition contains an effective amount of one or more human milk monosaccharides or one or more human milk oligosaccharides (“HMOs”) or both. The synthetic composition is preferably a nutritional composition. The composition can further comprise a source of threonine, serine and/or proline. Preferably the human milk oligosaccharides include both fucosylated and core HMOs such as LNT and LNnT HMOs. The human milk oligosaccharides can also include sialylated HMOs. Alternatively, the human milk oligosaccharides include both fucosylated and sialylated HMOs and the human milk oligosaccharides can also include backbone HMOs such as LNT and LNnT. The patient can be a paediatric or adult patient, preferably a prepubescent child.
- In another aspect, this disclosure provides a method for one or more of the following: reducing intestinal permeability, reducing endotoxemia, reducing low-grade inflammation, reducing body fat percentage, increasing the abundance of bifidobacteria, and/or increasing the levels of the gut hormones GLP-1 and GLP-2, in a patient having a metabolic disorder, for example obesity, obesity induced pre-diabetes and obesity induced type 2 diabetes, the method comprising orally administering to the patient an effective amount of one or human milk monosaccharides or one or more human milk oligosaccharides, or both, preferably in the form of a synthetic composition. The patient can be a paediatric or adult patient, preferably a prepubescent child.
- In a further aspect, this disclosure relates to a use of one or more human milk monosaccharides or one or more human milk oligosaccharides or both, preferably in the form of a synthetic composition, for one or more of the following: reducing intestinal permeability, reducing endotoxemia in a patient, reducing low-grade inflammation, reducing body fat percentage, increasing the abundance of bifidobacteria, and/or increasing the levels of the gut hormones GLP-1 and GLP-2, in a patient having a metabolic disorder, for example obesity, obesity induced pre-diabetes and obesity induced type 2 diabetes. The patient can be a paediatric or adult patient, preferably a prepubescent child.
- It has been surprisingly found that human milk monosaccharides, advantageously sialic acid and/or fucose, and human milk oligosaccharides, advantageously 2′-FL, 3-FL, LNT, LNnT, 3′-SL, 6′-SL, DFL, DSLNT and/or LNFP-I, not only modulate inflammation and microbiota in the GI tract, but also decrease gut permeability, reduce endotoxemia and low-grade inflammation, improve body composition (by reducing body fat percentage), increase the abundance of bifidobacteria, and increase the levels of the gut hormones GLP-1 and GLP-2 in human patients. Preferably the abundance of Bifidobacteria adolescentis is increased. This can result in lower chronic inflammation, improved insulin sensitivity and reduced insulin resistance. Obese and pre-diabetic patients can be stabilized and the progression to diabetes slowed, stopped or reversed. Diabetic patients can be stabilized or at least the progression to diabetes with complications slowed.
- In certain aspects, the synthetic composition preferably contains one or more core HMOs and/or one or more fucosylated HMOs, more preferably one or more core HMOs and one or more fucosylated HMOs. Even more preferably the core HMO is selected from the group consisting of LNT, LNnT, LNH, LNnH and pLNnH, particularly LNT and LNnT, and the fucosylated HMO is selected from the group consisting of 2′-FL, 3-FL, DFL and LNFP-I, particularly 2′-FL. Advantageously, the synthetic composition contains 2′-FL and LNT and/or LNnT.
- The term “patient” preferably means a human that can be a paediatric or adult patient. However, a “patient” can also be any other mammal.
- The term “oral administration” preferably means any conventional form for the oral delivery of a composition to a patient that causes the deposition of the composition in the gastrointestinal tract (including the stomach) of the patient. Accordingly, oral administration includes swallowing of composition by the patient, enteral feeding through a naso-gastric tube, and the like.
- The term “effective amount” preferably means an amount of a composition that provides a human milk monosaccharide or human milk oligosaccharide in a sufficient amount to render a desired treatment outcome in a patient. An effective amount can be administered in one or more doses to the patient to achieve the desired treatment outcome.
- The term “human milk monosaccharide” or “HMS” preferably means a monosaccharide found in human breast milk. Examples include sialic acid and L-fucose. In human milk, the sialic acid is N-acetylneuraminic acid.
- The term “human milk oligosaccharide” or “HMO” preferably means a complex carbohydrate found in human breast milk that can be in acidic or neutral form. More than about 200 different HMO structures are known to exist in human breast milk (Urashima et al.: Milk Oligosaccharides, Nova Biomedical Books, New York, 2011). HMOs can be core, fucosylated and sialylated oligosaccharides. Core HMOs consist of Glu, Gal and GlcNAc and are devoid of Fuc and sialic acid. Examples of core HMOs include lacto-N-tetraose (LNT), lacto-N-neotetraose (LNnT), lacto-N-neohexaose (LNnH), lacto-N-hexaose (LNH) and p-lacto-N-neohexaose (pLNnH). Fucosyl HMOs are fucosylated lactoses or fucosylated core HMOs such as 2′-fucosyllactose (2′-FL), lacto-N-fucopentaose I (LNFP-I), lacto-N-difucohexaose I (LNDFH-I), 3-fucosyllactose (3-FL), difucosyllactose (DFL), lacto-N-fucopentaose III (LNFP-III), fucosyl-para-lacto-N-neohexaose (F-pLNnH), lacto-N-difucohexaose I (LNDFH-I), fucosyl-lacto-N-hexaose II (FLNH-II), lacto-N-fucopentaose V (LNFP-V), lacto-N-difucohexaose II (LNDFH-II), fucosyl-lacto-N-hexaose I (FLNH-I), fucosyl-lacto-N-hexaose III (FLNH-III) and fucosyl-para-lacto-N-neohexaose (F-pLNnH). Sialyl HMOs are sialylated lactoses or sialylated core HMOs such as 3′,6-disialyllacto-N-tetraose (DSLNT), 6′-sialyllactose (6′-SL), 3′-sialyllactose (3′-SL), 6′-sialyllacto-N-neotetraose (LST c), 3′-sialyllacto-N-tetraose (LST a) and 6-sialyllacto-N-tetraose (LST b). HMOs containing both sialyl and fucosyl groups may be considered to belong to either of the latter two groups. Examples for sialylated and fucosylated HMOs include disialyl-fucosyl-lacto-N-hexaose II (DSFLNH-II), fucosyl-sialyl-lacto-N-neohexaose I (FSLNnH-I), fucosyl-sialyl-lacto-N-hexaose I (FSLNH-I) and 3-fucosyl-3′-sialyllactose (FSL).
- The term “intestinal permeability” preferably means the permeability of the intestinal mucosa of a patient, permitting the absorption of vital nutrients from the gut lumen while presenting a barrier against the passage of pathogenic substances into the patient's body.
- The term “endotoxemia” preferably means the presence of endotoxins, such as gut microbiota-derived lipopolysaccharides (LPS) in the blood of a patient.
- The term “low-grade inflammation” preferably means an immune system response of a patient characterized by altered levels of pro-inflammatory and anti-inflammatory cytokines as well as numerous other markers of immune system activity in response to an injurious stimuli.
- Body fat percentage preferably means total mass of body fat divided by total mass of the body.
- The HMOs can be isolated or enriched by well-known processes from milk(s) secreted by mammals including, but not limited to human, bovine, ovine, porcine, or caprine species. The HMOs can also be produced by well-known processes using microbial fermentation, enzymatic processes, chemical synthesis, or combinations of these technologies. As examples, using chemistry LNnT can be made as described in WO 2011/100980 and WO 2013/044928, LNT can be synthesized as described in WO 2012/155916 and WO 2013/044928, a mixture of LNT and LNnT can be made as described in WO 2013/091660, 2′-FL can be made as described in WO 2010/115934 and WO 2010/115935, 3-FL can be made as described in WO 2013/139344, 6′-SL and salts thereof can be made as described in WO 2010/100979, sialylated oligosaccharides can be made as described in WO 2012/113404 and mixtures of human milk oligosaccharides can be made as described in WO 2012/113405. As examples of enzymatic production, sialylated oligosaccharides can be made as described in WO 2012/007588, fucosylated oligosaccharides can be made as described in WO 2012/127410, and advantageously diversified blends of human milk oligosaccharides can be made as described in WO 2012/156897 and WO 2012/156898. With regard to biotechnological methods, WO 01/04341 and WO 2007/101862 describe how to make core human milk oligosaccharides optionally substituted by fucose or sialic acid using genetically modified E. coli.
- The human milk monosaccharides and/or oligosaccharides can be in the form of one or more core HMOs and one or more fucosylated HMOs. Alternatively, one or more core HMOs and one or more sialylated HMOs can be used. In a further alternative, one or more fucosylated HMOs and one or more sialylated HMOs can be used. In a preferred embodiment, one or more core HMOs, one or more sialylated HMOs and one or more fucosylated HMOs are used.
- The term “glycaemic index” or “GI” is defined as the incremental area under the two-hour blood glucose response curve (AUC) following a 12-hour fast and ingestion of a food with a certain quantity of available carbohydrate (usually 50 g). The AUC of the test food is divided by the AUC of the standard (glucose, the standard, has a GI of 100) and multiplied by 100. The average GI value is calculated from data collected in 10 human subjects. Both the standard and test food must contain an equal amount of available carbohydrate. The result gives a relative ranking for each tested food. Tables reporting commonly accepted GI values for a variety of foods are available including the international GI database maintained by the University of Sydney, and available on the internet at: www.glycemicindex.com.
- The synthetic composition can take any suitable form. For example, the composition can be in the form of a nutritional composition which contains other macronutrients such as proteins, lipids or other carbohydrates. The synthetic composition can also be a pharmaceutical composition.
- A nutritional composition can contain sources of protein, lipids and/or digestible carbohydrates and can be in solid, powdered or liquid forms. The composition can be designed to be the sole source of nutrition or a nutritional supplement.
- Suitable protein sources include intact, hydrolysed, and partially hydrolysed protein, which can be derived from any suitable source such as milk (e.g., casein, whey), animal (e.g., meat, fish), cereal (e.g., rice, corn), and vegetable (e.g., soy, potato, pea), insect (e.g., locust) and combinations of these sources. Examples of the source of protein include whey protein concentrates, whey protein isolates, whey protein hydrolysates, acid caseins, sodium casemates, calcium casemates, potassium casemates, casein hydrolysates, milk protein concentrates, milk protein isolates, milk protein hydrolysates, non-fat dry milk, condensed skim milk, soy protein concentrates, soy protein isolates, soy protein hydrolysates, pea protein concentrates, pea protein isolates, pea protein hydrolysates, collagen proteins, and combinations of these sources.
- The amount of protein is preferably sufficient to provide about 5 to about 30% of the energy of the nutritional composition; for example about 10% to about 25% of the energy. Within these ranges, the amount of protein can vary depending upon the nutritional needs of the intended individual.
- The nutritional compositions can also include free amino acids such as tryptophan, glutamine, tyrosine, methionine, cysteine, taurine, arginine, carnitine, threonine, serine and proline and combinations of these amino acids. Threonine, serine and proline are important amino acids for the production of mucin which aids gut barrier function.
- Any suitable source of other carbohydrates can be used. Examples include maltodextrin, hydrolyzed or modified starch or corn starch, glucose polymers, corn syrup, corn syrup solids, rice-derived carbohydrates, sucrose, glucose, fructose, lactose, high fructose corn syrup, honey, sugar alcohols (e.g., maltitol, erythritol, sorbitol, etc.), isomaltulose, sucromalt, pullulan, potato starch, slowly-digested carbohydrates, dietary fibres such as oat fibre, soy fibre, gum arabic, sodium carboxymethylcellulose, methylcellulose, guar gum, gellan gum, locust bean gum, konjac flour, hydroxypropyl methylcellulose, tragacanth gum, karaya gum, gum acacia, chitosan, arabinogalactans, glucomannan, xanthan gum, alginate, pectin, low and high methoxy pectin, cereal beta-glucans (i.e., oat beta-glucan, barley beta-glucan), carrageenan and psyllium, Fibersol™ other resistant starches, and combinations of these carbohydrate.
- Preferably the carbohydrate source includes low glycaemic index carbohydrates having a GI score of 55 or below. Examples of low glycaemic index carbohydrates include sucromalt, Fibersol™ (inulin), maltodextrins having a dextrose equivalence (DE) of less than 15, rice syrup having a dextrose equivalence of less than 15, fructooligosaccharides, resistant starches, starches, fruit sourced fibres, vegetable sourced fibres, whole grains, beta-glucans, soy fibres, oat fibres, locust bean gum, konjac flour, hydroxypropyl methylcellulose, gum acacia, chitosan, arabinogalactans, xanthan gum, alginate, low and high methoxy pectin, carrageenan, psyllium, isomaltulose, glycerine and sugar alcohols.
- The nutritional compositions can include carbohydrates in an amount sufficient to provide about 30 to about 70% of the energy of the composition, for example about 35 to about 65% of the energy. Within these parameters, the amount of carbohydrate can vary widely.
- Suitable lipid sources include coconut oil, fractionated coconut oil, soy oil, corn oil, olive oil, safflower oil, high oleic safflower oil, medium chain triglycerides, sunflower oil, high oleic sunflower oil, palm and palm kernel oils, palm olein, canola oil, marine oils, cottonseed oils and combinations of these oils. Fractionated coconut oils are a suitable source of medium chain triglycerides. The lipids can contain polyunsaturated fatty acids such as n-3 LC-PUFA. The n-3 LC-PUFA can be a C20 or a C22 n-3 fatty acid. Preferably the n-3 LC-PUFA is docosahexanoic acid (DHA, C22:6, n-3). The source of LC-PUFA can be, for example, egg lipids, fungal oil, low EPA fish oil or algal oil.
- The nutritional compositions can include lipids in an amount sufficient to provide about 10 to about 50% of energy of the nutritional composition, for example about 15 to about 40% of the energy.
- The nutritional composition preferably also includes vitamins and minerals. If the nutritional composition is intended to be a sole source of nutrition, it preferably includes a complete vitamin and mineral profile. Examples of vitamins include vitamins A, B-complex (such as B1, B2, B6 and B12), C, D, E and K, niacin and acid vitamins such as pantothenic acid, folic acid and biotin. Examples of minerals include calcium, iron, zinc, magnesium, iodine, copper, phosphorus, manganese, potassium, chromium, molybdenum, selenium, nickel, tin, silicon, vanadium and boron.
- The nutritional composition can also include a carotenoid such as lutein, lycopene, zeaxanthin, and beta-carotene. The total amount of carotenoid included can vary from about 0.001 μg/ml to about 10 μg/ml. Lutein can be included in an amount of from about 0.001 μg/ml to about 10 μg/ml, preferably from about 0.044 μg/ml to about 5 g/ml of lutein. Lycopene can be included in an amount from about 0.001 μg/ml to about 10 μg/ml, preferably about 0.0185 mg/ml to about 5 g/ml of lycopene. Beta-carotene can comprise from about 0.001 μg/ml to about 10 mg/ml, for example about 0.034 μg/ml to about 5 μg/ml of beta-carotene. The nutritional composition can also include a source of anthocyanidins. This can be in the form of a fruit or a fruit extract. Particularly useful fruits and fruit extracts include plum/prune, apple, pear, strawberry, blueberry, raspberry, cherry, and their combinations.
- The nutritional composition can also contain various other conventional ingredients such as preservatives, emulsifying agents, thickening agents, buffers, fibres and prebiotics (e.g. fructooligosaccharides, galactooligosaccharides), probiotics (e.g. B. animalis subsp. lactis BB-12, B. lactis HN019, B. lactis Bi07, B. infantis ATCC 15697, L. rhamnosus GG, L. rhamnosus HNOOI, L. acidophilus LA-5, L. acidophilus NCFM, L. fermentum CECT5716, B. longum BB536, B. longum AH1205, B. longum AH1206, B. breve M-16V, L. reuteri ATCC 55730, L. reuteri ATCC PTA-6485, L. reuteri DSM 17938), antioxidant/anti-inflammatory compounds including tocopherols, carotenoids, ascorbate/vitamin C, ascorbyl palmitate, polyphenols, glutathione, and superoxide dismutase (melon), other bioactive factors (e.g. growth hormones, cytokines, TFGβ), colorants, flavours, and stabilizers, lubricants, and so forth.
- The nutritional composition can be in the form of a food, soluble powder, a liquid concentrate, or a ready-to-use formulation. The composition can be eaten, drunk or can be fed via a nasogastric. Various flavours, fibres, and other additives can also be present.
- The nutritional compositions can be prepared by any commonly used manufacturing techniques for preparing nutritional compositions in solid or liquid form. For example, the composition can be prepared by combining various feed solutions. A protein-in-fat feed solution can be prepared by heating and mixing the lipid source and then adding an emulsifier (e.g. lecithin), fat soluble vitamins, and at least a portion of the protein source while heating and stirring. A carbohydrate feed solution is then prepared by adding minerals, trace and ultra trace minerals, thickening or suspending agents to water while heating and stirring. The resulting solution is held for 10 minutes with continued heat and agitation before adding carbohydrates (e.g., the HMOs and digestible carbohydrate sources). The resulting feed solutions are then blended together while heating and agitating and the pH adjusted to 6.6-7.0, after which the composition is subjected to high-temperature short-time processing during which the composition is heat treated, emulsified and homogenized, and then allowed to cool. Water soluble vitamins and ascorbic acid are added, the pH is adjusted to the desired range if necessary, flavours are added, and water is added to achieve the desired total solid level.
- For a liquid product, the resulting solution can then be aseptically packed to form an aseptically packaged nutritional composition. In this form, the nutritional composition can be in ready-to-feed or concentrated liquid form. Alternatively, the composition can be spray-dried and processed and packaged as a reconstitutable powder.
- The nutritional composition can also be in the form of a food such as a nutritional bar, a yoghurt, etc. These forms can be produced using standard technologies and processes.
- When the nutritional product is a ready-to-feed nutritional liquid, the total concentration of HMSs/HMOs in the liquid, by weight of the liquid, is from about 0.0001% to about 2.0%, including from about 0.001% to about 1.5%, including from about 0.01% to about 1.0%. When the nutritional product is a concentrated nutritional liquid, the total concentration of HMSs/HMOs in the liquid, by weight of the liquid, is from about 0.0002% to about 4.0%, including from about 0.002% to about 3.0%, including from about 0.02% to about 2.0%.
- The synthetic composition of this disclosure can also be in a unit dosage form such as a capsule, tablet or sachet. For example, the composition can be in a tablet form comprising the human milk monosaccharides and/or oligosaccharides, and one or more additional components to aid formulation and administration, such as diluents, excipients, antioxidants, lubricants, colorants, binders, disintegrants, and the like.
- Suitable diluents, excipients, lubricants, colorants, binders, and disintegrants include polyethylene, polyvinyl chloride, ethyl cellulose, acrylate polymers and their copolymers, hydroxyethyl-cellulose, hydroxypropylmethyl-cellulose (HPMC), sodium carboxymethylcellulose, polyhydroxyethyl methacrylate (PHEMA), polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), polyethylene oxide (PEO), or polyacrylamide (PA), carrageenan, sodium alginate, polycarbophil, polyacrylic acid, tragacanth, methyl cellulose, pectin, natural gums, xanthan gum, guar gum, karaya gum, hypromellose, magnesium stearate, microcrystalline cellulose, and colloidal silicon dioxide. Suitable antioxidants are vitamin A, carotenoids, vitamin C, vitamin E, selenium, flavonoids, polyphenols, lycopene, lutein, lignan, coenzyme Q10 (“CoQIO”) and glutathione. The unit dosage forms, especially those in sachet form, can also include various nutrients including macronutrients.
- For reducing intestinal permeability, endotoxemia, low-grade inflammation and/or body fat percentage, and/or increasing the abundance of bifidobacteria and/or the levels of the gut hormones GLP-1 and GLP-2 in a person, the amount of human milk mono and/or oligosaccharide(s) required to be administered to the person will vary depending upon factors such as the risk and condition severity, the age of the person, the form of the composition, and other medications being administered to the person. However, the required amount can be readily set by a medical practitioner and would generally be in the range from about 10 mg to about 20 g per day, in certain embodiments from about 10 mg to about 15 g per day, from about 100 mg to about 10 g per day, in certain embodiments from about 500 mg to about 10 g per day, in certain embodiments from about 1 g to about 7.5 g per day. An appropriate dose can be determined based on several factors, including, for example, the body weight and/or condition of the patient being treated, the severity of the condition, being treated, other ailments and/or diseases of the person, the incidence and/or severity of side effects and the manner of administration. Appropriate dose ranges can be determined by methods known to those skilled in the art. During an initial treatment phase, the dosing can be higher (for example 200 mg to 20 g per day, preferably 500 mg to 15 g per day, more preferably 1 g to 10 g per day, in certain embodiments 2.5 g to 7.5 g per day). During a maintenance phase, the dosing can be reduced (for example, 10 mg to 10 g per day, preferably 100 mg to 7.5 g per day, more preferably 500 mg to 5 g per day, in certain embodiments 1 g to 2.5 g per day).
- A synthetic composition of this disclosure can be co-administered to a patient who is also receiving a standard-of-care medication for obesity or diabetes.
- Examples are now described to further illustrate the features of the disclosed methods:
- 10-week-old C57BL/6J mice (120 mice) are housed in groups of five mice per cage, with free access to food and water. The mice are divided into 12 groups of 10 mice, one control group and 11 treatment groups. All of the mice are fed a high-fat (HF) diet (60% fat and 20% carbohydrates [kcal/100 g], or an HF diet supplemented with HMS/HMO (20 g/kg of diet) for 8 weeks. Food and water intake are recorded twice a week. The 11 treatment groups are each administered one of the following: a) sialic acid, b) L-fucose, c) 2′-FL, d) 3-FL, e) 3′-SL, f) 6′-SL, g) LNT, h) LNnT, i) LNFP-I, j) DSLNT and k) a combination of these saccharides. The control group is administered the HF diet only. Fresh food is given daily.
- Intraperitoneal or oral glucose tolerance tests are performed as follows: 6-h-fasted mice are injected with glucose into the peritoneal cavity (1 g/kg glucose, 20% glucose solution) or by gavage (3 g/kg glucose, 66% glucose solution). Blood glucose is determined with a glucose meter (Roche Diagnostics) on 3.5 μl blood collected from the tip of the tail vein. A total of 20 μl blood is sampled 30 min before and 15 or 30 min after the glucose load to assess plasma insulin concentration.
- To assess intestinal permeability in vivo, the intestinal permeability of 4000 Da fluorescent dextran-FITC (DX-4000-FITC) is measured. Mice are fasted for 6 h before given DX-44-FITC by gavage (500 mg/kg body weight, 125 mg/ml). After 1 h and 4 h, 120 ml of blood is collected from the tip of the tail vein. The blood is centrifuged at 4° C., 12 000 g for 3 min. Plasma is diluted in an equal volume of PBS (pH 7.4) and analysed for DX-4000-FITC concentration with a fluorescence spectrophotometer at an excitation wavelength of 485 nm and emission wavelength of 535 nm. Standard curves are obtained by diluting FITC-dextran in non-treated plasma diluted with PBS (1:3 v/v).
- Plasma LPS, cytokines and gut hormones are determined as follows. Plasma LPS concentration is measured using a kit based upon a Limulus amoebocyte extract (LAL kit endpoint-QCL1000). Samples are diluted 1/40 to 1/100 and heated for 20 cycles of 10 min at 68° C. and 10 min at 4° C. An internal control for LPS recovery is included in the calculation. Plasma cytokines (interleukin (IL) 1α, IL1β, tumour necrosis factor (TNF)α, IL6, monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1α, IL10, interferon (INF) c, IL15, IL18) and gut hormones (GLP-1 (active), GIP (total), amylin (active), pancreatic polypeptide) are respectively determined in duplicate by using a Bio-Plex Multiplex kit, or a mouse gut hormones panel (LincoPlex), and measured by using Luminex technology, an EIA kit (GLP-2 EIA kit) is used to quantify GLP-2.
- Mice are anaesthetised (ketamine/xylazine, intraperineally, 100 and 10 mg/kg, respectively) after a 5 h period of fasting, and blood samples and tissues are harvested for further analysis. Mice are killed by cervical dislocation. Liver, caecum (full and empty), muscles (vastus lateralis), and adipose tissues (mesenteric and corresponding lymph nodes, epididymal, subcutaneous and visceral) are precisely dissected and weighed. The intestinal segments (jejunum, colon) are immersed in liquid nitrogen, and stored at −80° C., for further analysis.
- To assess the microbiota profile, the caecal contents collected post mortem from mice are stored at −80° C. DNA is isolated from the caecal content samples using QIAamp DNA Stool Mini Kit. The DNA concentration of extracts is measured using NanoDrop. Aliquots of 100 ng of extracted DNA are subjected to PCR using the 16S rDNA universal heteroduplex analysis (HDA) primers HDA1-GC and HDA2 which are disclosed in Walter et al. Appl. Environ. Microbiol. 66, 297 (2000)) at 56° C. for strand annealing. Initial denaturation at 94° C. for 4 min is followed by thirty cycles of 30 s at 94° C., 30 s at 56° C. and 1 min at 72° C. The quality of PCR products is verified by agarose gel electrophoresis.
- Amplified 16S rDNA fragments are separated by denaturing gradient gel electrophoresis (DGGE) using an INGENYphorU system equipped with 6% polyacrylamide gels with a denaturant in the range of 30-55%, where 100% denaturant is equivalent to 7M-urea and 40% formamide. Electrophoresis is carried out at 130 V for 4-5 hours at 60° C. Polyacrylamide gels are stained with GelRede nucleic acid stain for 45 min, destained in ultrapure water and viewed under UV light. Bands of interest are excised from gels and lysed in ultrapure water. Extracted DNA is re-amplified using the same primers and PCR conditions.
- To purify the bacterial DNA, PCR products are reloaded on a denaturant gradient gel followed by excision and lysis of selected bands. DNA samples recovered from lysed bands of the second DGGE are re-amplified by PCR before purification using the QIAquick PCR Purification Kit and sequenced. Species identification is done using the Ribosomal Microbiome Database Project Classifier tool. Because of the limited sensitivity of DGGE to quantify microbial diversity, the microbial composition of DNA samples is also analysed using high-throughput sequencing.
- The V5-V6 region of 16S rRNA from caecal content DNA samples is amplified using a forward primer and a reverse primer which are both disclosed in Andersson et al. PloS ONE 3, e2836 (2008)). Amplicons are pyrosequenced using a Roche 454 GS-FLX system. Sequences of at least 240 nucleotides and containing no more than two undetermined bases are retained for taxonomic assignment. The QIIME software is used for chimera check and the Greengenes database is used for classification. Bacterial diversity is determined at the phylum, family and genus levels.
- To assess bacterial translocation from intestine into tissues, mesenteric adipose tissue (MAT) and corresponding lymph nodes (MLN) are harvested, and luminal and mucosal contents of each intestinal segment separated. Quantification of bacterial DNA is performed by isolating genomic DNA from blood, MAT, MLN or intestine (contents and mucosa). All bacterial DNA is quantified by quantitative real-time PCR targeting conserved regions of the 16S rRNA gene, with bacterial DNA as standard template for absolute quantification.
- In order to assess barrier permeability, the expression of occludin and zonula occludens-1 (ZO-1) tight-junction proteins are assessed. Jejunum segments are immediately removed, washed with PBS, mounted in embedding medium, and stored at −80° C. until use. Cryosections (5 mm) are fixed in acetone at −20° C. for 5 min for occludin and in ethanol for 30 min at room temperature and in acetone at −20° C. for 5 min for ZO-1. Non-specific background is blocked by incubation with 10% bovine serum albumin (BSA) in Tris-buffered saline (TBS) and 0.3% Triton X-100 (30 min at room temperature).
- Sections are incubated with rabbit anti-occludin or rabbit anti-ZO-1 (1:400 for ZO-1 and 1:100 for occludin staining) for 2 h. Sections are washed three times for 10 min in TBS and probed with goat anti-rabbit fluorescein isothiocyante (FITC)-conjugated antibodies (1:50). Slides are washed three times for 10 min in TBS and mounted in mounting medium. Sections are visualized on a fluorescence microscope. As a control, slides are incubated with serial dilutions of the primary antibody to signal extinction. Two negative controls are used: slides incubated with irrelevant antibody or without primary antibody. All the stainings are performed in duplicate in non-serial distant sections, and analyzed in a double-blind manner by two different investigators.
- The results show that HMS/HMO improve gut barrier function and reduce the metabolic inflammation and insulin resistance associated with obesity by increasing release of gut peptides, such as glucagon-like peptide-1 and -2 (GLP-1 and -2).
- Six-week-old ob/ob mice (120 mice) on C57BL/6 background are housed in a controlled environment (12 h daylight cycle) in groups of 2 mice/cage, and kept with free access to food and drinking water. The mice are separated into 12 groups of 10 mice, one control group and 11 treatment groups. One group is fed a control diet, and the 11 treatment groups each receive a control diets containing one of the following HMS/HMO (20 g/kg of diet) for five weeks: a) sialic acid, b) L-fucose, c) 2′-FL, d) 3-FL, e) 3′-SL, f) 6′-SL, g) LNT, h) LNnT, i) LNFP-I, j) DSLNT, and k) a combination of these saccharides. Fresh food is given daily.
- Experiments to show impact of HMS/HMO on glucose tolerance, intestinal permeability plasma LPS, cytokines and gut hormones, caecal microbiota profile and bacterial translocation are performed as described under Example 1.
- A total of 60 male and female patients, enrolled to a childhood obesity treatment program, are recruited to participate in the study. Patients are randomized into three groups, each of 20 patients, with 2 groups receiving different investigational products and one group receiving a placebo product for 8 weeks. The investigational products contain 4.5 grams of either 2′-FL alone or a combination of 2′-FL and LNnT while the placebo product contains 4.5 grams glucose. All products are in powder form in a unit dosage container.
- The patients are eligible to participate if: they are between 5 and 10 years of age, have a BMI SDS of ≥2.0 and are enrolled in the childhood obesity treatment program at the Children's Obesity Clinic. All recruited patients and their representatives are able and willing to understand and comply with the study procedures. Patients are excluded if: they have participated in a clinical study one month prior to the screening visit and throughout the study; have any gastrointestinal disease(s) that may cause symptoms or may interfere with the trial outcome; have other severe disease(s) such as malignancy, kidney disease or neurological disease; have psychiatric disease; have used highly dosed probiotic supplements (yoghurt allowed) 3 months prior to screening and throughout the study; have consumed antibiotic drugs 3 months prior to screening and throughout the study; and consume on a regular basis medication that might interfere with symptom evaluation 2 weeks prior to screening and throughout the study.
- At the initial visit (screening) patients and their representatives are given both oral and written information about the study; the children are asked for informed assent and their representatives to sign an informed consent form.
- Eligibility criteria are checked and for children who are enrolled to the study, medical history and concomitant medication are registered. A physical examination is done and pubertal staging is determined. Blood pressure, pulse rate, height and bodyweight are measured, and body composition is determined by a DXA (dual energy x-ray absorptiometry)-scan and bioimpedance. BMI SDS is calculated, waist and hip circumferences are measured and food intake is registered. Fasting blood samples are collected for safety and biomarker studies and for biobanking.
- The serum from the blood samples is transferred to cryotubes and stored at −80° C. The following biomarkers are measured; Lipopolysaccharides (LPS), hsCRP, free fatty acids, total cholesterol, HDL, LDL, HbA1c, glucose, insulin, triglycerides, TNF-α, IL-1β, IL-6, IL-8, IL-10, GLP-1, GLP-2, Adiponectin, and Zonulin.
- Equipment for collecting faecal samples is distributed. The faecal samples are stored at −80° C. until analysis. Microbiological analysis is performed on the faecal samples using 16S rRNA gene sequencing.
- The Rome III Diagnostic Questionnaire for Paediatric Functional GI Disorders (QPFG) is completed on site by the participating child's representative(s), and the Bristol Stool Form Scales (BSFS) is distributed to the participant's representative(s) with instructions to assess the stool consistency at each faecal sampling point using the BSFS.
- At the second visit (randomization), patients and their representatives are asked about adverse events, faecal samples are collected and equipment for collection of new samples is distributed. BSFS is collected and new BSFS is distributed. Study products are distributed together with a compliance form (diary). Patients and their representatives are reminded to follow the healthy dietary habits.
- The study runs for 8 weeks with the patients consuming either a placebo or one of two investigational products daily. Patients are instructed to consume the products in the morning with breakfast. Compliance is monitored via a compliance form (diary) to be filled in daily.
- Four weeks after commencement there is an intermediate check. Patients and their representatives are asked about adverse events and any changes in the patient's usual medication. Fecal samples are collected and equipment for collection of new samples is distributed. Blood pressure, pulse rate, waist and hip circumference, height and bodyweight are measured and BMI SDS calculated. The QPFG questionnaire is completed on site by the participating child's representative. The BSFS is collected and new BSFS is distributed to the participant's representative(s) with instructions to assess the stool consistency at each faecal sampling point using the BSFS. Patients and their representatives are reminded to follow the healthy dietary habits.
- At the end of intervention (8 weeks), each patient has a visit with the medical team. Patients and their representatives are asked about adverse events and any changes in the patient's usual medication. Study products and compliance forms are collected to check compliance. BSFS and faecal samples are collected and equipment for collection of new samples is distributed. A physical examination is done and pubertal staging is determined. Blood pressure, pulse rate, height and bodyweight are measured, and body composition is determined by a DXA (dual energy x-ray absorptiometry)-scan and bioimpedance. BMI SDS is calculated, waist and hip circumferences measured and food intake registered. Fasting blood samples are collected for safety and biomarker studies and for biobanking, and equipment for collecting faecal samples is distributed. The QPFG questionnaire is completed on site by the participating child's representative(s).
- To examine potential long term effects of the intervention, an un-blinded follow-up period follows with a visit 8 weeks after end of intervention. A physical examination is done and pubertal staging is determined. Blood pressure, pulse rate, height and bodyweight are measured, and body composition is determined by a DXA (dual energy x-ray absorptiometry)-scan and bioimpedance. BMI SDS is calculated, waist and hip circumferences measured and food intake registered. Fasting blood samples are collected for safety and biomarker studies and for biobanking. Fecal samples are collected. The intervention contributes to a normal body composition, and the patients given the investigational products show a greater reduction of body fat, body weight and BMI SDS as compared to the placebo group. The blood biomarker analysis indicates that the patients given the investigational products have increased levels of GLP-1 and GLP-2, reduced levels of metabolic endotoxemia and inflammatory markers and reduced gut permeability indicating an improved mucosal barrier compared to the placebo. The faecal analysis indicates that the patients given the investigational products have reduced bacterial dysbiosis and a higher level of bifidobacteria compared to the placebo, particularly Bifidobacteria adolescentis.
- A ready to feed nutritional composition is prepared from water, maltodextrin, milk protein concentrate, Sucromalt, glycerine, cocoa powder, soy protein isolate, fructose, high oleic safflower oil, soy oil, canola oil, plant sterol esters, HMSs/HMOs, soy lecithin, magnesium chloride, calcium phosphate, carrageenan, sodium ascorbate, potassium citrate, sodium phosphate, calcium citrate, choline chloride, potassium chloride, sodium citrate, magnesium oxide, taurine, L-carnitine, alpha-tocopheryl acetate, zinc sulphate, ferrous sulphate, niacinamide, calcium pantothenate, vitamin A palmitate, citric acid, manganese sulphate, pyridoxine hydrochloride, vitamin D3, copper sulphate, thiamine mononitrate, riboflavin, beta carotene, folic acid, biotin, potassium iodide, chromium chloride, sodium selenate, sodium molybdate, phytonadione, vitamin B12.
- The composition has an energy density of 0.8 kcal/ml with an energy distribution (% of kcal) as follows: protein: 20%, carbohydrate: 48%, fat: 32%.
- A tablet is prepared from HMS/HMO, hydroxypropyl methylcellulose, sodium alginate, gum, microcrystalline cellulose, colloidal silicon dioxide, and magnesium stearate. All raw materials except the magnesium stearate are placed into a high shear granulator and premixed. Water is sprayed onto the premix while continuing to mix at 300 rpm. The granulate is transferred to a fluidized bed drier and dried at 75° C. The dried powder is sieved and sized using a mill. The resulting powder is then lubricated with magnesium stearate and pressed into tablets. The tablets each contain 325 mg of HMS/HMO. The tablets each have a weight of 750 mg.
- A capsule is prepared by filling about 1 g of HMS/HMO into a 000 gelatine capsule using a filing machine. The capsules are then closed. The HMS/HMO are in free flowing, powder form.
Claims (20)
1. A method comprising:
determining a treatment group comprising obese non-infant humans,
formulating a composition comprising an effective amount of one or more synthetic fucosylated human milk oligosaccharides (HMO) selected from 2′-fucosyllactose (2′-FL), 3-fucosyllactose (3-FL), difucosyllactose (DFL), and lacto-N-fucopentaose I (LNFP-I), that are effective for:
increasing in the gastrointestinal microbiota of a non-infant human during a treatment period, the relative abundance of Bifidobacterium adolescentis; and
reducing a precursor condition for a metabolic disorder associated with development of one or more of obesity-induced pre-diabetes and type 2 diabetes, the precursor condition selected from gut permeability, metabolic endotoxemia, low-grade metabolic inflammation, and body fat percentage;
reducing the precursor condition in at least one non-infant human in the treatment group by providing the composition to the at least one non-infant human during the treatment period.
2. The method of claim 1 , wherein the reduced precursor condition for the metabolic disorder associated with development of the one or more of obesity-induced pre-diabetes and type 2 diabetes is gut permeability.
3. The method of claim 1 , wherein the reduced precursor condition for the metabolic disorder associated with development of the one or more of obesity-induced pre-diabetes and type 2 diabetes is body fat percentage.
4. The method of claim 1 , further comprising increasing, in the gastrointestinal tract of the non-infant human, a level of glucagon-like peptide selected from GLP-1 and/or GLP-2 relative to the level of the selected glucagon-like peptide prior to the treatment period.
5. The method of claim 1 , wherein:
the treatment period comprises an initial treatment phase and a maintenance phase;
the effective amount of the selected one or more HMOs is from about 2.5 g to about 7.5 g daily during the initial treatment phase; and
the effective amount of the selected one or more HMOs is from about 1 g to about 2.5 g daily during the maintenance phase.
6. The method of claim 1 , further comprising formulating the composition in a unit dosage form.
7. The method according to claim 1 , wherein the obese non-infant human is a prepubescent child.
8. A method comprising:
determining a treatment group comprising obese non-infant humans;
formulating a composition comprising one or more synthetic non-fucosylated human milk oligosaccharides (HMOs) selected from lacto-N-tetraose (LNT), lacto-N-neotetraose (LNnT), that are effective for:
increasing in the gastrointestinal microbiota of a non-infant human during a treatment period, the relative abundance of Bifidobacterium adolescentis and
reducing a precursor condition for a metabolic disorder associated with development of one or more of obesity-induced pre-diabetes and type 2 diabetes, the precursor condition selected from gut permeability, metabolic endotoxemia, low-grade metabolic inflammation, and body fat percentage; and
reducing the precursor condition in at least one non-infant human in the treatment group by providing the composition to the at least one non-infant human during the treatment period.
9. The method of claim 8 , wherein the reduced precursor condition for the metabolic disorder associated with development of the one or more of obesity-induced pre-diabetes and type 2 diabetes is gut permeability.
10. The method of claim 8 , wherein the reduced precursor condition for the metabolic disorder associated with development of the one or more of obesity-induced pre-diabetes and type 2 diabetes is body fat percentage.
11. The method of claim 8 , further comprising increasing, in the gastrointestinal tract of the non-infant human, a level of glucagon-like peptide selected from GLP-1 and/or GLP-2 relative to the level of the selected glucagon-like peptide prior to the treatment period.
12. The method of claim 8 , further comprising formulating the composition in a unit dosage form.
13. The method according to claim 8 , wherein the obese non-infant human is a prepubescent child.
14. The method of claim 8 , wherein:
the treatment period comprises an initial treatment phase and a maintenance phase;
the effective amount of the selected one or more HMOs is from about 2.5 g to about 7.5 g daily during the initial treatment phase; and
the effective amount of the selected one or more HMOs is from about 1 g to about 2.5 g daily during the maintenance phase.
15. A method comprising:
determining a treatment group comprising obese non-infant humans;
formulating a composition comprising an effective amount of two or more synthetic neutral human milk oligosaccharides (HMOs) selected from 2′-fucosyllactose (2′FL), 3-fucosyllactose (3-FL), difucosyllactose (DFL), lacto-N-fucopentaose I (LNFP-I), lacto-N-tetraose (LNT), and lacto-N-neotetraose (LNnT), wherein the selected HMOs are effective for:
increasing in the gastrointestinal microbiota of a non-infant human during a treatment period, the relative abundance of Bifidobacterium adolescentis, and
reducing in the non-infant human during the treatment period, a precursor condition for a metabolic disorder associated with development of one or more of obesity-induced pre-diabetes and type 2 diabetes, the precursor condition selected from gut permeability, metabolic endotoxemia, low-grade metabolic inflammation, and body fat percentage;
reducing the precursor condition in at least one non-infant human in the treatment group by providing the composition to the at least one non-infant human during the treatment period.
16. The method of claim 15 , wherein the reduced precursor condition for the metabolic disorder associated with development of the one or more of obesity-induced pre-diabetes and type 2 diabetes is gut permeability.
17. The method of claim 15 , wherein the reduced precursor condition for the metabolic disorder associated with development of the one or more of obesity-induced pre-diabetes and type 2 diabetes is body fat percentage.
18. The method of claim 15 , further comprising increasing, in the gastrointestinal tract of the non-infant human, a level of glucagon-like peptide selected from GLP-1 and/or GLP-2 relative to the level of the selected glucagon-like peptide prior to the treatment period.
19. The method of claim 15 , further comprising formulating the composition in a unit dosage form.
20. The method of claim 15 , wherein:
the treatment period comprises an initial treatment phase and a maintenance phase;
the effective amount of the selected HMO mixture is from about 2.5 g to about 7.5 g daily during the initial treatment phase; and
the effective amount of the selected HMO mixture is from about 1 g to about 2.5 g daily during the maintenance phase.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US18/082,793 US20230119720A1 (en) | 2014-12-08 | 2022-12-16 | Synthetic composition for treating metabolic disorders |
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DKPA201470768 | 2014-12-08 | ||
DKPA201470768 | 2014-12-08 | ||
PCT/DK2015/050385 WO2016091265A1 (en) | 2014-12-08 | 2015-12-08 | Synthetic composition for treating metabolic disorders |
US201615104794A | 2016-06-15 | 2016-06-15 | |
US17/093,337 US11529364B2 (en) | 2014-12-08 | 2020-11-09 | Synthetic composition for treating metabolic disorders |
US18/082,793 US20230119720A1 (en) | 2014-12-08 | 2022-12-16 | Synthetic composition for treating metabolic disorders |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US17/093,337 Continuation US11529364B2 (en) | 2014-12-08 | 2020-11-09 | Synthetic composition for treating metabolic disorders |
Publications (1)
Publication Number | Publication Date |
---|---|
US20230119720A1 true US20230119720A1 (en) | 2023-04-20 |
Family
ID=56106755
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/104,794 Active 2036-04-28 US10828313B2 (en) | 2014-12-08 | 2015-12-08 | Synthetic composition for treating metabolic disorders |
US17/093,337 Active 2036-01-17 US11529364B2 (en) | 2014-12-08 | 2020-11-09 | Synthetic composition for treating metabolic disorders |
US18/082,793 Pending US20230119720A1 (en) | 2014-12-08 | 2022-12-16 | Synthetic composition for treating metabolic disorders |
Family Applications Before (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/104,794 Active 2036-04-28 US10828313B2 (en) | 2014-12-08 | 2015-12-08 | Synthetic composition for treating metabolic disorders |
US17/093,337 Active 2036-01-17 US11529364B2 (en) | 2014-12-08 | 2020-11-09 | Synthetic composition for treating metabolic disorders |
Country Status (4)
Country | Link |
---|---|
US (3) | US10828313B2 (en) |
EP (1) | EP3229812A4 (en) |
CN (2) | CN107106584A (en) |
WO (1) | WO2016091265A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20210196735A1 (en) * | 2014-12-08 | 2021-07-01 | Glycom A/S | Synthetic composition for treating metabolic disorders |
Families Citing this family (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2016091265A1 (en) | 2014-12-08 | 2016-06-16 | Glycom A/S | Synthetic composition for treating metabolic disorders |
US10987368B2 (en) * | 2014-12-08 | 2021-04-27 | Glycom A/S | Synthetic composition for preventing or treating CVD |
US10835544B2 (en) | 2014-12-08 | 2020-11-17 | Glycom A/S | Synthetic composition for regulating satiety |
US20210205341A1 (en) * | 2016-01-26 | 2021-07-08 | Nestec S.A. | Compositions comprising human milk oligosaccharides for use in infants or young children to prevent or treat a health disorder by increasing glp-1 secretion |
WO2017144062A1 (en) * | 2016-02-24 | 2017-08-31 | Glycom A/S | Synthetic composition for microbiota modulation |
WO2017198276A1 (en) * | 2016-05-19 | 2017-11-23 | Glycom A/S | Synthetic composition |
EP3471562A4 (en) * | 2016-06-15 | 2020-07-29 | Glycom A/S | Synthetic compositions comprising human milk oligosaccharides for use the prevention and treatment of disorders |
US20190160082A1 (en) * | 2016-08-04 | 2019-05-30 | Nestec S.A. | Nutritional compositions with 2fl and lnnt for use in preventing and/or treating non-rotavirus diarrhea by acting on the gut microbiota dysbiosis |
US11278558B2 (en) | 2017-03-01 | 2022-03-22 | Glycom A/S | Synthetic composition for microbiota modulation |
WO2019087140A1 (en) * | 2017-11-02 | 2019-05-09 | Glycom A/S | One or more hmos for reducing or preventing fatigue and/or improving focus or concentration |
EP3486326A1 (en) | 2017-11-21 | 2019-05-22 | Jennewein Biotechnologie GmbH | Method for the purification of n-acetylneuraminic acid from a fermentation broth |
JP7327724B2 (en) * | 2017-11-30 | 2023-08-16 | グリコム・アクティーゼルスカブ | A mixture of HMOs to treat wheat sensitivity |
CN108813262A (en) * | 2018-07-02 | 2018-11-16 | 杭州相生相成科技有限公司 | A kind of compound probiotic solid beverage containing DHA algal oil |
WO2020126542A1 (en) | 2018-12-21 | 2020-06-25 | Societe Des Produits Nestle S.A. | A nutritional composition comprising 6'sl and lnt in combination to improve the gastrointestinal barrier function |
US20220079963A1 (en) * | 2018-12-21 | 2022-03-17 | Societe Des Produits Nestle S.A. | A nutritional composition comprising 2'-fucosyllactose (2' fl) to improve the gastrointestinal barrier |
AU2020281701A1 (en) | 2019-05-29 | 2021-11-25 | Frieslandcampina Nederland B.V. | Non-therapeutic methods for maintaining a healthy body weight or losing body weight |
CN113874024A (en) * | 2019-05-29 | 2021-12-31 | 菲仕兰坎皮纳荷兰公司 | Compositions comprising 2' -fucosyllactose and GOS |
ES1240969Y (en) * | 2019-09-18 | 2020-07-30 | Jennewein Biotechnologie Gmbh | CEREAL COMPOSITIONS CONTAINING OLIGOSACCHARIDS FROM HUMAN MILK |
WO2022117440A1 (en) * | 2020-12-04 | 2022-06-09 | Dsm Ip Assets B.V. | Compressed tablets comprising hmo |
CN114145354B (en) * | 2021-11-30 | 2023-08-22 | 内蒙古伊利实业集团股份有限公司 | Formula milk powder containing breast milk oligosaccharide and preparation method and application thereof |
WO2023215815A1 (en) * | 2022-05-05 | 2023-11-09 | Dabdoub Atif | Dietary macro/micronutritional compositions and applications thereof |
Family Cites Families (48)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4895838A (en) | 1988-03-09 | 1990-01-23 | Trustees Of Boston University | Method for provoking angiogenesis by administration of angiogenically active oligosaccharides |
US5470839A (en) | 1993-04-22 | 1995-11-28 | Clintec Nutrition Company | Enteral diet and method for providing nutrition to a diabetic |
US5906982A (en) | 1997-03-31 | 1999-05-25 | Abbott Laboratories | Nutritional formulations containing Lacto-N-neoTetraose |
FR2796082B1 (en) | 1999-07-07 | 2003-06-27 | Centre Nat Rech Scient | PROCESS FOR PRODUCING OLIGOSACCHARIDES |
US6946451B2 (en) | 2002-02-04 | 2005-09-20 | Kyowa Hakko Kogyo Co., Ltd. | Insulin secretion promoter |
ES2456292T3 (en) | 2006-03-09 | 2014-04-21 | Centre National De La Recherche Scientifique (Cnrs) | Sialylated oligosaccharide production process |
WO2009000803A1 (en) | 2007-06-25 | 2008-12-31 | Dsm Ip Assets B.V. | Novel prebiotics |
EP2143341A1 (en) | 2008-07-08 | 2010-01-13 | Nestec S.A. | Nutritional Composition Containing Oligosaccharide Mixture |
US20110189149A1 (en) | 2008-06-20 | 2011-08-04 | Remy Burcelin | New Uses of Lactic Acid Bacteria and Bifidobacteria |
KR101116864B1 (en) | 2008-08-01 | 2012-02-29 | 주식회사 베네비오 | Composition for Preventing or Treating of Hyperlipidemia, Fatty Liver or Obesity |
CA2745099C (en) * | 2008-12-02 | 2017-11-07 | Prolacta Bioscience, Inc. | Human milk permeate compositions and methods of making and using same |
EP2405524B1 (en) | 2009-03-05 | 2015-10-07 | Nissan Motor Co., Ltd. | Bipolar secondary cell and method for producing the same |
AU2010223965A1 (en) | 2009-03-13 | 2011-10-06 | Dsm Food Specialties Usa Inc. | Prebiotic oligosaccharides |
KR20120022875A (en) | 2009-04-07 | 2012-03-12 | 글리콤 에이/에스 | Synthesis of 2'-o-fucosyllactose |
NL2004200C2 (en) | 2010-02-05 | 2011-08-08 | Friesland Brands Bv | Use of sialyl oligosaccharides in weight management. |
US8993740B2 (en) | 2010-02-19 | 2015-03-31 | Glycom A/S | Method for preparation of the tetrasaccharide lacto-N-neotetraose (LNnt) containing N-acetyllactosamine |
CN102822186A (en) | 2010-02-19 | 2012-12-12 | 格礼卡姆股份公司 | Production of 6'-o-sialyllactose and intermediates |
WO2011119023A1 (en) | 2010-03-26 | 2011-09-29 | N.V. Nutricia | Low protein infant formula with increased essential amino acids |
CA2805499A1 (en) | 2010-07-16 | 2012-01-19 | Glycom A/S | Derivatization of oligosaccharides |
EP2465509A1 (en) * | 2010-11-23 | 2012-06-20 | Nestec S.A. | Oligosaccharide composition for treating acute respiratory tract infections |
US20120171166A1 (en) * | 2010-12-31 | 2012-07-05 | Abbott Laboratories | Synbiotic combination of probiotic and human milk oligosaccharides to promote growth of beneficial microbiota |
CN103402376A (en) * | 2010-12-31 | 2013-11-20 | 雅培制药有限公司 | Human milk oligosaccharides to promote growth of beneficial bacteria |
US9763970B2 (en) * | 2010-12-31 | 2017-09-19 | Abbott Laboratories | Nutritional compositions comprising human milk oligosaccharides and nucleotides and uses thereof for treating and/or preventing enteric viral infection |
WO2012107865A2 (en) | 2011-02-10 | 2012-08-16 | Wyeth Llc | Modulation of growth of bifidobacteria using a combination of oligosaccharides found in human milk |
US20140057868A1 (en) | 2011-02-21 | 2014-02-27 | Glycom A/S | Catalytic hydrogenolysis of a composition of a mixture of oligosaccharide precursors and uses thereof |
WO2012127410A1 (en) | 2011-03-18 | 2012-09-27 | Glycom A/S | Synthesis of new fucose-containing carbohydrate derivatives |
WO2012155916A1 (en) | 2011-05-13 | 2012-11-22 | Glycom A/S | Manufacture of lacto-n-tetraose |
BR112013029208A2 (en) | 2011-05-13 | 2017-02-14 | Glycom As | method for preparing one or more human milk oligosaccharides or derivatives or precursors therefor, use of oligosaccharides, and, compound |
JP6106160B2 (en) | 2011-05-13 | 2017-03-29 | グリコム アー/エスGlycom A/S | Diversification of human milk oligosaccharide (HMO) or its precursor |
WO2012158517A1 (en) | 2011-05-13 | 2012-11-22 | Glycosyn LLC | The use of purified 2'-fucosyllactose, 3-fucosyllactose and lactodifucotetraose as prebiotics |
NL2007268C2 (en) * | 2011-08-16 | 2013-02-19 | Friesland Brands Bv | Nutritional compositions comprising human milk oligosaccharides and uses thereof. |
CN113662199A (en) * | 2011-08-29 | 2021-11-19 | 雅培制药有限公司 | Human milk oligosaccharides for preventing gastrointestinal damage and/or promoting gastrointestinal healing |
WO2013036104A1 (en) | 2011-09-08 | 2013-03-14 | N.V. Nutricia | Infant nutrition for regulating food intake later in life |
CN103958537A (en) | 2011-09-30 | 2014-07-30 | 格礼卡姆股份公司 | Synthesis of HMO core structures |
TW201316983A (en) * | 2011-10-18 | 2013-05-01 | Nestec Sa | Composition for use in the promotion of intestinal angiogenesis and of nutrient absorption and of enteral feeding tolerance and/or in the prevention and/or treatment of intestinal inflammation and/or in the recovery after intestinal injury and surgery |
AU2012325072B2 (en) * | 2011-10-18 | 2015-12-03 | Société des Produits Nestlé S.A. | Composition for use in increasing insulin sensitivity and/or reducing insulin resistance |
WO2013091660A1 (en) | 2011-12-23 | 2013-06-27 | Glycom A/S | A method for obtaining crystalline lacto-n-tetraose and lacto-n-neotetraose precursors and mixtures thereof |
EP2828275B1 (en) | 2012-03-20 | 2017-03-01 | Glycom A/S | Synthesis of the trisaccharide 3-o-fucosyllactose and intermediates thereof |
CN104507483A (en) | 2012-04-13 | 2015-04-08 | 波士顿学院理事会 | Prebiotic compositions and methods of use |
ES2572831T3 (en) | 2012-09-14 | 2016-06-02 | Abbott Laboratories | Nutritional compositions for use in methods to modulate corticosterone levels in individuals with psychological stress |
EP3469912A1 (en) | 2012-12-20 | 2019-04-17 | Abbott Laboratories | Nutritional formulations using human milk oligosaccharides for modulating inflammation |
BR112015022820A8 (en) | 2013-03-12 | 2019-11-26 | Nestec Sa | trial to select a treatment regimen for an individual with depression, use of a compound comprising folate, composition and kit |
WO2014187464A1 (en) | 2013-05-22 | 2014-11-27 | Glycom As | Synthetic mixture of oligosaccharides for t treating a microbiota of a mammal |
US10165788B2 (en) | 2013-06-17 | 2019-01-01 | The Regents Of The University Of California | Methods and compositions for improved digestion of milk oligosaccharides |
EP3074020B1 (en) | 2013-11-15 | 2022-03-30 | Société des Produits Nestlé S.A. | Compositions for use in the prevention or treatment of necrotizing enterocolitis in infants and young children |
AU2014350157A1 (en) * | 2013-11-15 | 2016-04-14 | Nestec S.A. | Compositions for use in the prevention or treatment of necrotizing enterocolitis in infants and young children |
AU2014350156A1 (en) * | 2013-11-15 | 2016-04-14 | Nestec S.A. | Compositions for use in the prevention or treatment of necrotizing enterocolitis in infants or young children born by C-section |
WO2016091265A1 (en) | 2014-12-08 | 2016-06-16 | Glycom A/S | Synthetic composition for treating metabolic disorders |
-
2015
- 2015-12-08 WO PCT/DK2015/050385 patent/WO2016091265A1/en active Application Filing
- 2015-12-08 CN CN201580071696.XA patent/CN107106584A/en active Pending
- 2015-12-08 US US15/104,794 patent/US10828313B2/en active Active
- 2015-12-08 EP EP15866518.2A patent/EP3229812A4/en active Pending
- 2015-12-08 CN CN202211007289.0A patent/CN115350200A/en active Pending
-
2020
- 2020-11-09 US US17/093,337 patent/US11529364B2/en active Active
-
2022
- 2022-12-16 US US18/082,793 patent/US20230119720A1/en active Pending
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20210196735A1 (en) * | 2014-12-08 | 2021-07-01 | Glycom A/S | Synthetic composition for treating metabolic disorders |
US11890293B2 (en) * | 2014-12-08 | 2024-02-06 | Glycom A/S | Synthetic composition for treating metabolic disorders |
Also Published As
Publication number | Publication date |
---|---|
WO2016091265A1 (en) | 2016-06-16 |
US11529364B2 (en) | 2022-12-20 |
CN107106584A (en) | 2017-08-29 |
EP3229812A1 (en) | 2017-10-18 |
CN115350200A (en) | 2022-11-18 |
US20210052615A1 (en) | 2021-02-25 |
US10828313B2 (en) | 2020-11-10 |
EP3229812A4 (en) | 2018-10-03 |
US20160310514A1 (en) | 2016-10-27 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11529364B2 (en) | Synthetic composition for treating metabolic disorders | |
JP7301093B2 (en) | Synthetic compositions and methods for treatment of irritable bowel syndrome | |
US11432578B2 (en) | Mixture of HMOs | |
US10751354B2 (en) | Synthetic composition for microbiota modulation | |
US11890293B2 (en) | Synthetic composition for treating metabolic disorders | |
CN108348535B (en) | Synthetic compositions and methods for modulating brain function and behavior | |
US10987368B2 (en) | Synthetic composition for preventing or treating CVD | |
JP2021504420A (en) | Human milk oligosaccharides for microbial flora regulation and their synthetic compositions | |
EP3452050A1 (en) | Composition comprising hmos for the treatment of non-infectious diarrhoea | |
WO2017215721A1 (en) | Synthetic compositions comprising human milk oligosaccharides for use γν the prevention and treatment of disorders | |
US20160243138A1 (en) | Composition comprising HMSs/HMOs and use thereof | |
US10835544B2 (en) | Synthetic composition for regulating satiety | |
US11452736B2 (en) | Mixture of HMOs for treating wheat sensitivity | |
US20220233561A1 (en) | Human milk oligosaccharides for use in the treatment of symptoms in a patient suffering from non-coeliac wheat and / or gluten sensitivity |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STPP | Information on status: patent application and granting procedure in general |
Free format text: DOCKETED NEW CASE - READY FOR EXAMINATION |
|
AS | Assignment |
Owner name: GLYCOM A/S, DENMARK Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:ELISON, EMMA;MCCONNELL, BRUCE;HENNET, THIERRY;AND OTHERS;SIGNING DATES FROM 20151208 TO 20210702;REEL/FRAME:066038/0042 |