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Drs. R. Burcelin & B. Lelouvier - Gut microbiota in chronic inflammatory disease

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Rémy Burcelin & Benjamin Lelouvier

Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), INSERM-Université Paul Sabatier & VAIOMER, Toulouse

Gut microbiota-impaired intestinal immune defense to establish a tissue microbiota in chronic inflammatory disease

The last decade demonstrated the crucial role of the gut microbiota on chronic low grade inflammatory diseases, such as obesity diabetes, liver and cardiovascular diseases. We demonstrated using germ free mice that a gut microbiota dysbiosis impairs the intestinal immune defense leading to gut microbiota translocation establishing a novel tissue microbiota responsible for inflammation.

By the mean of omics and hypothesis-driven strategies we identified molecular mechanisms responsible for an impaired antigen presenting cell to lymphocyte co-stimulatory process in the intestine. Microbiota-associated molecular patterns such as NOD2 and the corresponding signaling pathways have been causally identified to reduce the number of IL17-producing CD4 T cells in the lamina propria leading to an increased bacterial translocation from the gut to the adipose depots. This process sets the tone for adipose tissue inflammation leading to insulin resistance. Furthermore, state of the art methods suitable to quantify and sequence the bacterial DNA from tissues such as the blood allows the setting of novel biomarkers to predict, diagnose, and stratify disease.

Hence, a change in intestinal permeability and immune defense by gut microbiota dysbiosis demonstrates a potential therapeutic target of low grade inflammatory and metabolic disease.

Selected references

  • Amar J, Chabo C, Waget A, Klopp P, Vachoux C, Bermudez-Humaran LG, Smirnova N, Berge M, Sulpice T, Lahtinen S, Ouwehand A, Langella P, Rautonen N, Sansonetti PJ, Burcelin R: Intestinal mucosal adherence and translocation of commensal bacteria at the early onset of type 2 diabetes: molecular mechanisms and probiotic treatment. EMBO Mol Med 2011;3:559-572
  • Wu H, Esteve E, Tremaroli V, Khan MT, Caesar R, Manneras-Holm L, Stahlman M, Olsson LM, Serino M, Planas-Felix M, Xifra G, Mercader JM, Torrents D, Burcelin R, Ricart W, Perkins R, Fernandez-Real JM, Backhed F: Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. Nat Med 2017;23:850-858
  • Nicolas S, Blasco-Baque V, Fournel A, Gilleron J, Klopp P, Waget A, Ceppo F, Marlin A, Padmanabhan R, Iacovoni JS, Terce F, Cani PD, Tanti JF, Burcelin R, Knauf C, Cormont M, Serino M: Transfer of dysbiotic gut microbiota has beneficial effects on host liver metabolism. Mol Syst Biol 2017;13:921
  • Grasset E, Puel A, Charpentier J, Collet X, Christensen JE, Terce F, Burcelin R: A Specific Gut Microbiota Dysbiosis of Type 2 Diabetic Mice Induces GLP-1 Resistance through an Enteric NO-Dependent and Gut-Brain Axis Mechanism. Cell Metab 2017;25:1075-1090 e1075
  • Blasco-Baque V, Garidou L, Pomie C, Escoula Q, Loubieres P, Le Gall-David S, Lemaitre M, Nicolas S, Klopp P, Waget A, Azalbert V, Colom A, Bonnaure-Mallet M, Kemoun P, Serino M, Burcelin R: Periodontitis induced by Porphyromonas gingivalis drives periodontal microbiota dysbiosis and insulin resistance via an impaired adaptive immune response. Gut 2017;66:872-885
  • Pomie C, Blasco-Baque V, Klopp P, Nicolas S, Waget A, Loubieres P, Azalbert V, Puel A, Lopez F, Dray C, Valet P, Lelouvier B, Servant F, Courtney M, Amar J, Burcelin R, Garidou L: Triggering the adaptive immune system with commensal gut bacteria protects against insulin resistance and dysglycemia. Mol Metab 2016;5:392-403
  • Garidou L, Pomie C, Klopp P, Waget A, Charpentier J, Aloulou M, Giry A, Serino M, Stenman L, Lahtinen S, Dray C, Iacovoni JS, Courtney M, Collet X, Amar J, Servant F, Lelouvier B, Valet P, Eberl G, Fazilleau N, Douin-Echinard V, Heymes C, Burcelin R: The Gut Microbiota Regulates Intestinal CD4 T Cells Expressing RORgammat and Controls Metabolic Disease. Cell Metab 2015;22:100-112
  • Molecular Phenomics and Metagenomics of Hepatic Steatosis in Non-Diabetic Obese Women. Hoyles L, Fernández-Real JM, Federici M, Serino M, Abbott J, Charpentier J, Heymes C, Latorre Luque V, , Xifra G, Ricart W, Lopez F, Foufelle F, Butcher S, Holmes E, Nicholson JK, Postic C, Burcelin R*, Marc-Emmanuel Dumas*. Nat Med 2018 In press
  • Paisse S, Valle C, Servant F, Courtney M, Burcelin R, Amar J, Lelouvier B: Comprehensive description of blood microbiome from healthy donors assessed by 16S targeted metagenomic sequencing. Transfusion 2016;56:1138-47
  • Lelouvier B, Servant F, Paisse S, Brunet AC, Benyahya S, Serino M, Valle C, Rosa Ortiz M, Puig J, Courtney M, Federici M, Manuel Fernandez-Real J, Burcelin R, Amar J: Changes in blood microbiota profiles associated with liver fibrosis in obese patients: A pilot analysis. Hepatology 2016;64:2015-2027
  • Lluch J, Servant F, Paisse S, Valle C, Valiere S, Kuchly C, Vilchez G, Donnadieu C, Courtney M, Burcelin R, Amar J, Bouchez O, Lelouvier B: The characterization of novel tissue microbiota using an optimized 16S metagenomic sequencing pipeline. PLoS One 2015;10:e0142334

 

 

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15 May

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