Home LiteratureArticle Details
PMID: 19240062 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability.

Gut ·Vol. 58 ·No. 8 ·2009-08-00 ·Pages 1091-103

Cani PD, Possemiers S, Van de Wiele T, Guiot Y, Everard A, Rottier O, Geurts L, Naslain D, Neyrinck A, Lambert DM, Muccioli GG, Delzenne NM

Abstract

Obese and diabetic mice display enhanced intestinal permeability and metabolic endotoxaemia that participate in the occurrence of metabolic disorders. Our recent data support the idea that a selective increase of Bifidobacterium spp. reduces the impact of high-fat diet-induced metabolic endotoxaemia and inflammatory disorders. Here, we hypothesised that prebiotic modulation of gut microbiota lowers intestinal permeability, by a mechanism involving glucagon-like peptide-2 (GLP-2) thereby improving inflammation and metabolic disorders during obesity and diabetes. Study 1: ob/ob mice (Ob-CT) were treated with either prebiotic (Ob-Pre) or non-prebiotic carbohydrates as control (Ob-Cell). Study 2: Ob-CT and Ob-Pre mice were treated with GLP-2 antagonist or saline. Study 3: Ob-CT mice were treated with a GLP-2 agonist or saline. We assessed changes in the gut microbiota, intestinal permeability, gut peptides, intestinal epithelial tight-junction proteins ZO-1 and occludin (qPCR and immunohistochemistry), hepatic and systemic inflammation. Prebiotic-treated mice exhibited a lower plasma lipopolysaccharide (LPS) and cytokines, and a decreased hepatic expression of inflammatory and oxidative stress markers. This decreased inflammatory tone was associated with a lower intestinal permeability and improved tight-junction integrity compared to controls. Prebiotic increased the endogenous intestinotrophic proglucagon-derived peptide (GLP-2) production whereas the GLP-2 antagonist abolished most of the prebiotic effects. Finally, pharmacological GLP-2 treatment decreased gut permeability, systemic and hepatic inflammatory phenotype associated with obesity to a similar extent as that observed following prebiotic-induced changes in gut microbiota. We found that a selective gut microbiota change controls and increases endogenous GLP-2 production, and consequently improves gut barrier functions by a GLP-2-dependent mechanism, contributing to the improvement of gut barrier functions during obesity and diabetes.

MeSH Terms
Adiposity/drug effects,physiology Animals Bacteria/isolation & purification Cecum/microbiology,physiopathology Endotoxemia/etiology,prevention & control Glucagon-Like Peptide 2/agonists,antagonists & inhibitors,physiology Hepatitis/etiology,prevention & control Inflammation/etiology,microbiology,prevention & control Intestinal Absorption/drug effects,physiology Membrane Proteins/metabolism Mice Mice, Obese Obesity/complications,microbiology,physiopathology Occludin Oxidative Stress/drug effects,physiology Permeability Phosphoproteins/metabolism Probiotics/therapeutic use Proglucagon/genetics RNA, Messenger/genetics Tight Junctions/metabolism Zonula Occludens-1 Protein
Chemicals
Glucagon-Like Peptide 2 Membrane Proteins Occludin Ocln protein, mouse Phosphoproteins RNA, Messenger Tjp1 protein, mouse Zonula Occludens-1 Protein Proglucagon
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Cani P D
Unit of Pharmacokinetics, Metabolism, Nutrition and Toxicology, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium. [email protected]
Possemiers S
Van de Wiele T
Guiot Y
Everard A
Rottier O
Geurts L
Naslain D
Neyrinck A
Lambert D M
Muccioli G G
Delzenne N M
References (84)
84 references, click to expand
  1. Ethanol exacerbates hepatic microvascular dysfunction, endotoxemia, and lethality in septic mice.
    Shock. 1994 Jun;1(6):413-8 PMID: 7735970
  2. Insulin-like growth factor I and glucagon-like peptide-2 responses to fasting followed by controlled or ad libitum refeeding in rats.
    Am J Physiol Regul Integr Comp Physiol. 2008 Apr;294(4):R1175-84 PMID: 18256135
  3. IL-6 is essential for development of gut barrier dysfunction after hemorrhagic shock and resuscitation in mice.
    Am J Physiol Gastrointest Liver Physiol. 2003 Sep;285(3):G621-9 PMID: 12773301
  4. Obesity alters gut microbial ecology.
    Proc Natl Acad Sci U S A. 2005 Aug 2;102(31):11070-5 PMID: 16033867
  5. Dietary non-digestible carbohydrates promote L-cell differentiation in the proximal colon of rats.
    Br J Nutr. 2007 Jul;98(1):32-7 PMID: 17367575
  6. Selective increases of bifidobacteria in gut microflora improve high-fat-diet-induced diabetes in mice through a mechanism associated with endotoxaemia.
    Diabetologia. 2007 Nov;50(11):2374-83 PMID: 17823788
  7. Encapsulated Bifidobacteria reduced bacterial translocation in rats following hemorrhagic shock and resuscitation.
    Nutrition. 2007 Oct;23(10):754-61 PMID: 17706400
  8. Lactobacillus rhamnosus strain GG prevents enterohemorrhagic Escherichia coli O157:H7-induced changes in epithelial barrier function.
    Infect Immun. 2008 Apr;76(4):1340-8 PMID: 18227169
  9. The truncated metabolite GLP-2 (3-33) interacts with the GLP-2 receptor as a partial agonist.
    Regul Pept. 2002 Jan 15;103(1):9-15 PMID: 11738243
  10. Risk factors of development of gut-derived bacterial translocation in thermally injured rats.
    World J Gastroenterol. 2004 Jun 1;10(11):1619-24 PMID: 15162536
  11. Role of endotoxin in the hypermetabolic state after acute ethanol exposure.
    Am J Physiol. 1998 Dec;275(6):G1252-8 PMID: 9843760
  12. Intestinal growth adaptation and glucagon-like peptide 2 in rats with ileal--jejunal transposition or small bowel resection.
    Dig Dis Sci. 2001 Feb;46(2):379-88 PMID: 11281189
  13. Glucagon-like peptide-2 enhances intestinal epithelial barrier function of both transcellular and paracellular pathways in the mouse.
    Gut. 2000 Jul;47(1):112-9 PMID: 10861272
  14. Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB.
    Nat Med. 2005 Feb;11(2):183-90 PMID: 15685173
  15. Inability of Lactobacillus casei strain GG, L. acidophilus, and Bifidobacterium bifidum to degrade intestinal mucus glycoproteins.
    Scand J Gastroenterol. 1995 Jul;30(7):675-80 PMID: 7481531
  16. Physiological effects of dietary fructans extracted from Agave tequilana Gto. and Dasylirion spp.
    Br J Nutr. 2008 Feb;99(2):254-61 PMID: 17711612
  17. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice.
    Diabetes. 2008 Jun;57(6):1470-81 PMID: 18305141
  18. Lactobacillus casei DN-114 001 inhibits the increase in paracellular permeability of enteropathogenic Escherichia coli-infected T84 cells.
    Res Microbiol. 2005 Mar;156(2):256-62 PMID: 15748992
  19. Effects of fermentation products of pro- and prebiotics on trans-epithelial electrical resistance in an in vitro model of the colon.
    Nutr Cancer. 2005;51(1):102-9 PMID: 15749636
  20. Relation between colonic proglucagon expression and metabolic response to oligofructose in high fat diet-fed mice.
    Life Sci. 2006 Aug 1;79(10):1007-13 PMID: 16757002
  21. Short-chain fatty acid-supplemented total parenteral nutrition alters intestinal structure, glucose transporter 2 (GLUT2) mRNA and protein, and proglucagon mRNA abundance in normal rats.
    Am J Clin Nutr. 1998 Jul;68(1):118-25 PMID: 9665105
  22. Mechanisms underlying the resistance to diet-induced obesity in germ-free mice.
    Proc Natl Acad Sci U S A. 2007 Jan 16;104(3):979-84 PMID: 17210919
  23. GIP receptor antagonism reverses obesity, insulin resistance, and associated metabolic disturbances induced in mice by prolonged consumption of high-fat diet.
    Am J Physiol Endocrinol Metab. 2007 Dec;293(6):E1746-55 PMID: 17848629
  24. Increased intestinal permeability in obese mice: new evidence in the pathogenesis of nonalcoholic steatohepatitis.
    Am J Physiol Gastrointest Liver Physiol. 2007 Feb;292(2):G518-25 PMID: 17023554
  25. The gut microbiota as an environmental factor that regulates fat storage.
    Proc Natl Acad Sci U S A. 2004 Nov 2;101(44):15718-23 PMID: 15505215
  26. Intestinal permeability is reduced and IL-10 levels are increased in septic IL-6 knockout mice.
    Am J Physiol Regul Integr Comp Physiol. 2001 Sep;281(3):R1013-23 PMID: 11507020
  27. Prebiotic effects of chicory inulin in the simulator of the human intestinal microbial ecosystem.
    FEMS Microbiol Ecol. 2004 Dec 27;51(1):143-53 PMID: 16329863
  28. The metabolic syndrome--a new worldwide definition.
    Lancet. 2005 Sep 24-30;366(9491):1059-62 PMID: 16182882
  29. Targeted ablation of glucose-dependent insulinotropic polypeptide-producing cells in transgenic mice reduces obesity and insulin resistance induced by a high fat diet.
    J Biol Chem. 2008 Jun 27;283(26):18365-76 PMID: 18420580
  30. Oxidative stress and septic shock: metabolic aspects of oxygen-derived free radicals generated in the liver during endotoxemia.
    FEMS Immunol Med Microbiol. 2006 Jul;47(2):167-77 PMID: 16831203
  31. Loss-of-function mutation in Toll-like receptor 4 prevents diet-induced obesity and insulin resistance.
    Diabetes. 2007 Aug;56(8):1986-98 PMID: 17519423
  32. Evaluation of nested PCR-DGGE (denaturing gradient gel electrophoresis) with group-specific 16S rRNA primers for the analysis of bacterial communities from different wastewater treatment plants.
    FEMS Microbiol Ecol. 2002 Feb 1;39(2):101-12 PMID: 19709189
  33. Glucagon-like peptide-2 increases sucrase-isomaltase but not caudal-related homeobox protein-2 gene expression.
    Am J Physiol Gastrointest Liver Physiol. 2000 Mar;278(3):G425-8 PMID: 10712262
  34. In vivo effects of bifidobacteria and lactoferrin on gut endotoxin concentration and mucosal immunity in Balb/c mice.
    Dig Dis Sci. 2004 Apr;49(4):579-89 PMID: 15185861
  35. Oligofructose promotes satiety in rats fed a high-fat diet: involvement of glucagon-like Peptide-1.
    Obes Res. 2005 Jun;13(6):1000-7 PMID: 15976142
  36. Glucagon-like peptide 2 (GLP-2) accelerates the growth of colonic neoplasms in mice.
    Gut. 2004 Aug;53(8):1145-50 PMID: 15247183
  37. TLR4 links innate immunity and fatty acid-induced insulin resistance.
    J Clin Invest. 2006 Nov;116(11):3015-25 PMID: 17053832
  38. Leptin and adipocytokines: bridging the gap between immunity and atherosclerosis.
    Curr Pharm Des. 2007;13(36):3676-80 PMID: 18220805
  39. C3H/HeJ mice carrying a toll-like receptor 4 mutation are protected against the development of insulin resistance in white adipose tissue in response to a high-fat diet.
    Diabetologia. 2007 Jun;50(6):1267-76 PMID: 17426960
  40. Antibiotics prevent liver injury in rats following long-term exposure to ethanol.
    Gastroenterology. 1995 Jan;108(1):218-24 PMID: 7806045
  41. Gut microflora as a target for energy and metabolic homeostasis.
    Curr Opin Clin Nutr Metab Care. 2007 Nov;10(6):729-34 PMID: 18089955
  42. Nutrient-stimulated GLP-2 release and crypt cell proliferation in experimental short bowel syndrome.
    Am J Physiol Gastrointest Liver Physiol. 2005 Mar;288(3):G431-8 PMID: 15388486
  43. Insulin, glucagon-like peptide 1, glucose-dependent insulinotropic polypeptide and insulin-like growth factor I as putative mediators of the hypolipidemic effect of oligofructose in rats.
    J Nutr. 1998 Jul;128(7):1099-103 PMID: 9649591
  44. Frontiers in glucagon-like peptide-2: multiple actions, multiple mediators.
    Am J Physiol Endocrinol Metab. 2007 Aug;293(2):E460-5 PMID: 17652153
  45. Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome.
    Cell Host Microbe. 2008 Apr 17;3(4):213-23 PMID: 18407065
  46. Improvement of glucose tolerance and hepatic insulin sensitivity by oligofructose requires a functional glucagon-like peptide 1 receptor.
    Diabetes. 2006 May;55(5):1484-90 PMID: 16644709
  47. Microbial translocation augments the function of adoptively transferred self/tumor-specific CD8+ T cells via TLR4 signaling.
    J Clin Invest. 2007 Aug;117(8):2197-204 PMID: 17657310
  48. Glicentin inhibits internalization of enteric bacteria by cultured INT-407 enterocytes.
    Pediatr Surg Int. 2007 Jun;23(6):551-4 PMID: 17333210
  49. Induction of intestinal epithelial proliferation by glucagon-like peptide 2.
    Proc Natl Acad Sci U S A. 1996 Jul 23;93(15):7911-6 PMID: 8755576
  50. Chemical gastric inhibitory polypeptide receptor antagonism protects against obesity, insulin resistance, glucose intolerance and associated disturbances in mice fed high-fat and cafeteria diets.
    Diabetologia. 2007 Aug;50(8):1752-62 PMID: 17558485
  51. Inulin-type fructans modulate gastrointestinal peptides involved in appetite regulation (glucagon-like peptide-1 and ghrelin) in rats.
    Br J Nutr. 2004 Sep;92(3):521-6 PMID: 15469657
  52. Kupffer cell sensitization by alcohol involves increased permeability to gut-derived endotoxin.
    Alcohol Clin Exp Res. 2001 Jun;25(6 Suppl):51S-4S PMID: 11410742
  53. Supplementation of total parenteral nutrition with butyrate acutely increases structural aspects of intestinal adaptation after an 80% jejunoileal resection in neonatal piglets.
    JPEN J Parenter Enteral Nutr. 2004 Jul-Aug;28(4):210-22; discussion 222-3 PMID: 15291402
  54. Protective effects of glucagon-like peptide 2 on intestinal ischemia-reperfusion rats.
    Microsurgery. 2008;28(4):285-90 PMID: 18383347
  55. Glucagon-like peptide 2 improves nutrient absorption and nutritional status in short-bowel patients with no colon.
    Gastroenterology. 2001 Mar;120(4):806-15 PMID: 11231933
  56. Endotoxemia and hepatic injury in a rodent model of hindlimb unloading.
    J Appl Physiol (1985). 2003 Oct;95(4):1656-63 PMID: 12794033
  57. Modulation of glucagon-like peptide 1 and energy metabolism by inulin and oligofructose: experimental data.
    J Nutr. 2007 Nov;137(11 Suppl):2547S-2551S PMID: 17951500
  58. Stress impairs murine intestinal barrier function: improvement by glucagon-like peptide-2.
    J Pharmacol Exp Ther. 2005 Jul;314(1):214-20 PMID: 15798004
  59. Glucagon-like peptide 2 stimulates intestinal epithelial proliferation in vitro.
    Dig Dis Sci. 2002 May;47(5):1135-40 PMID: 12018913
  60. Metabolic endotoxemia initiates obesity and insulin resistance.
    Diabetes. 2007 Jul;56(7):1761-72 PMID: 17456850
  61. Hepatic inflammation in rats with experimental small intestinal bacterial overgrowth.
    Gastroenterology. 1990 Feb;98(2):414-23 PMID: 2295397
  62. Regulation of airway tight junctions by proinflammatory cytokines.
    Mol Biol Cell. 2002 Sep;13(9):3218-34 PMID: 12221127
  63. Hepatic injury associated with small bowel bacterial overgrowth in rats is prevented by metronidazole and tetracycline.
    Gastroenterology. 1991 Feb;100(2):513-9 PMID: 1985047
  64. Fructans in the diet cause alterations of intestinal mucosal architecture, released mucins and mucosa-associated bifidobacteria in gnotobiotic rats.
    Br J Nutr. 2003 May;89(5):597-606 PMID: 12720580
  65. Activation of Toll-like receptor 4 is associated with insulin resistance in adipocytes.
    Biochem Biophys Res Commun. 2006 Aug 4;346(3):739-45 PMID: 16781673
  66. Glucagon-like peptide-2 activates beta-catenin signaling in the mouse intestinal crypt: role of insulin-like growth factor-I.
    Endocrinology. 2008 Jan;149(1):291-301 PMID: 17884945
  67. Involvement of endogenous glucagon-like peptide-1(7-36) amide on glycaemia-lowering effect of oligofructose in streptozotocin-treated rats.
    J Endocrinol. 2005 Jun;185(3):457-65 PMID: 15930172
  68. Alcohol causes both tolerance and sensitization of rat Kupffer cells via mechanisms dependent on endotoxin.
    Gastroenterology. 1998 Aug;115(2):443-51 PMID: 9679050
  69. Role of TNF-alpha in ileum tight junction alteration in mouse model of restraint stress.
    Am J Physiol Gastrointest Liver Physiol. 2008 May;294(5):G1268-80 PMID: 18308862
  70. Attenuation of obesity-induced adipose tissue inflammation in C3H/HeJ mice carrying a Toll-like receptor 4 mutation.
    Biochem Biophys Res Commun. 2007 Mar 2;354(1):45-9 PMID: 17210129
  71. The essential role of insulin-like growth factor-1 in the intestinal tropic effects of glucagon-like peptide-2 in mice.
    Gastroenterology. 2006 Aug;131(2):589-605 PMID: 16890611
  72. Obesity-induced lymphocyte hyperresponsiveness to chemokines: a new mechanism of Fatty liver inflammation in obese mice.
    Gastroenterology. 2008 May;134(5):1459-69 PMID: 18471520
  73. Dietary fructans modulate polyamine concentration in the cecum of rats.
    J Nutr. 2000 Oct;130(10):2456-60 PMID: 11015472
  74. Bifidobacterial supplementation reduces the incidence of necrotizing enterocolitis in a neonatal rat model.
    Gastroenterology. 1999 Sep;117(3):577-83 PMID: 10464133
  75. Gut microbiota modulation with norfloxacin and ampicillin enhances glucose tolerance in mice.
    FASEB J. 2008 Jul;22(7):2416-26 PMID: 18326786
  76. Dietary fiber modulates intestinal proglucagon messenger ribonucleic acid and postprandial secretion of glucagon-like peptide-1 and insulin in rats.
    Endocrinology. 1996 Sep;137(9):3948-56 PMID: 8756571
  77. Glucagon-like peptide-2-enhanced barrier function reduces pathophysiology in a model of food allergy.
    Am J Physiol Gastrointest Liver Physiol. 2003 Jun;284(6):G905-12 PMID: 12736145
  78. Severity of liver injury in experimental alcoholic liver disease. Correlation with plasma endotoxin, prostaglandin E2, leukotriene B4, and thromboxane B2.
    Am J Pathol. 1993 Feb;142(2):367-73 PMID: 8382006
  79. The prenylflavonoid isoxanthohumol from hops (Humulus lupulus L.) is activated into the potent phytoestrogen 8-prenylnaringenin in vitro and in the human intestine.
    J Nutr. 2006 Jul;136(7):1862-7 PMID: 16772450
  80. Intestinal growth-promoting properties of glucagon-like peptide-2 in mice.
    Am J Physiol. 1997 Jul;273(1 Pt 1):E77-84 PMID: 9252482
  81. The role of bifidobacteria in gut barrier function after thermal injury in rats.
    J Trauma. 2006 Sep;61(3):650-7 PMID: 16967002
  82. IFN-gamma modulation of epithelial barrier function. Time course, reversibility, and site of cytokine binding.
    J Immunol. 1993 Mar 15;150(6):2356-63 PMID: 8450217
  83. Mucosal adaptation to enteral nutrients is dependent on the physiologic actions of glucagon-like peptide-2 in mice.
    Gastroenterology. 2005 May;128(5):1340-53 PMID: 15887116
  84. Molecular physiology and pathophysiology of tight junctions. IV. Regulation of tight junctions by extracellular stimuli: nutrients, cytokines, and immune cells.
    Am J Physiol Gastrointest Liver Physiol. 2000 Nov;279(5):G851-7 PMID: 11052980
Article Info
Journal
Gut
Abbr.
Gut
ISSN
1468-3288
DOI
10.1136/gut.2008.165886
Email
[email protected]
Published
2009-08-00
Epub
2009-00-24
Pages
1091-103
Language
English
Region
England
NLM ID
2985108R
PMCID
PMC2702831
Subset
IM
Corrections
CommentIn
PMID: 19592687
CommentIn
PMID: 20026034
External Links
PubMed source DOI: 10.1136/gut.2008.165886 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2