Defective NOD2 peptidoglycan sensing promotes diet-induced inflammation, dysbiosis, and insulin resistance

Emmanuel Denou, Karine Lolmède, Lucile Garidou, Celine Pomie, Chantal Chabo, Trevor C Lau, Morgan D Fullerton, Giulia Nigro, Alexia Zakaroff-Girard, Elodie Luche, Céline Garret, Matteo Serino, Jacques Amar, Michael Courtney, Joseph F Cavallari, Brandyn D Henriksbo, Nicole G Barra, Kevin P Foley, Joseph B McPhee, Brittany M Duggan & 10 others Hayley M O'Neill, Amanda J Lee, Philippe Sansonetti, Ali A Ashkar, Waliul I Khan, Michael G Surette, Anne Bouloumié, Gregory R Steinberg, Rémy Burcelin, Jonathan D Schertzer

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Abstract

Pattern recognition receptors link metabolite and bacteria-derived inflammation to insulin resistance during obesity. We demonstrate that NOD2 detection of bacterial cell wall peptidoglycan (PGN) regulates metabolic inflammation and insulin sensitivity. An obesity-promoting high-fat diet (HFD) increased NOD2 in hepatocytes and adipocytes, and NOD2(-/-) mice have increased adipose tissue and liver inflammation and exacerbated insulin resistance during a HFD. This effect is independent of altered adiposity or NOD2 in hematopoietic-derived immune cells. Instead, increased metabolic inflammation and insulin resistance in NOD2(-/-) mice is associated with increased commensal bacterial translocation from the gut into adipose tissue and liver. An intact PGN-NOD2 sensing system regulated gut mucosal bacterial colonization and a metabolic tissue dysbiosis that is a potential trigger for increased metabolic inflammation and insulin resistance. Gut dysbiosis in HFD-fed NOD2(-/-) mice is an independent and transmissible factor that contributes to metabolic inflammation and insulin resistance when transferred to WT, germ-free mice. These findings warrant scrutiny of bacterial component detection, dysbiosis, and protective immune responses in the links between inflammatory gut and metabolic diseases, including diabetes.

Original languageEnglish
Pages (from-to)259-274
Number of pages16
JournalEMBO Molecular Medicine
Volume7
Issue number3
DOIs
Publication statusPublished - 9 Feb 2015
Externally publishedYes

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Dysbiosis
Peptidoglycan
Insulin Resistance
Diet
Inflammation
High Fat Diet
Adipose Tissue
Obesity
Bacterial Translocation
Pattern Recognition Receptors
Liver
Metabolic Diseases
Adiposity
Adipocytes
Cell Wall
Hepatocytes
Bacteria

Cite this

Denou, E., Lolmède, K., Garidou, L., Pomie, C., Chabo, C., Lau, T. C., ... Schertzer, J. D. (2015). Defective NOD2 peptidoglycan sensing promotes diet-induced inflammation, dysbiosis, and insulin resistance. EMBO Molecular Medicine, 7(3), 259-274. https://doi.org/10.15252/emmm.201404169
Denou, Emmanuel ; Lolmède, Karine ; Garidou, Lucile ; Pomie, Celine ; Chabo, Chantal ; Lau, Trevor C ; Fullerton, Morgan D ; Nigro, Giulia ; Zakaroff-Girard, Alexia ; Luche, Elodie ; Garret, Céline ; Serino, Matteo ; Amar, Jacques ; Courtney, Michael ; Cavallari, Joseph F ; Henriksbo, Brandyn D ; Barra, Nicole G ; Foley, Kevin P ; McPhee, Joseph B ; Duggan, Brittany M ; O'Neill, Hayley M ; Lee, Amanda J ; Sansonetti, Philippe ; Ashkar, Ali A ; Khan, Waliul I ; Surette, Michael G ; Bouloumié, Anne ; Steinberg, Gregory R ; Burcelin, Rémy ; Schertzer, Jonathan D. / Defective NOD2 peptidoglycan sensing promotes diet-induced inflammation, dysbiosis, and insulin resistance. In: EMBO Molecular Medicine. 2015 ; Vol. 7, No. 3. pp. 259-274.
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abstract = "Pattern recognition receptors link metabolite and bacteria-derived inflammation to insulin resistance during obesity. We demonstrate that NOD2 detection of bacterial cell wall peptidoglycan (PGN) regulates metabolic inflammation and insulin sensitivity. An obesity-promoting high-fat diet (HFD) increased NOD2 in hepatocytes and adipocytes, and NOD2(-/-) mice have increased adipose tissue and liver inflammation and exacerbated insulin resistance during a HFD. This effect is independent of altered adiposity or NOD2 in hematopoietic-derived immune cells. Instead, increased metabolic inflammation and insulin resistance in NOD2(-/-) mice is associated with increased commensal bacterial translocation from the gut into adipose tissue and liver. An intact PGN-NOD2 sensing system regulated gut mucosal bacterial colonization and a metabolic tissue dysbiosis that is a potential trigger for increased metabolic inflammation and insulin resistance. Gut dysbiosis in HFD-fed NOD2(-/-) mice is an independent and transmissible factor that contributes to metabolic inflammation and insulin resistance when transferred to WT, germ-free mice. These findings warrant scrutiny of bacterial component detection, dysbiosis, and protective immune responses in the links between inflammatory gut and metabolic diseases, including diabetes.",
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Denou, E, Lolmède, K, Garidou, L, Pomie, C, Chabo, C, Lau, TC, Fullerton, MD, Nigro, G, Zakaroff-Girard, A, Luche, E, Garret, C, Serino, M, Amar, J, Courtney, M, Cavallari, JF, Henriksbo, BD, Barra, NG, Foley, KP, McPhee, JB, Duggan, BM, O'Neill, HM, Lee, AJ, Sansonetti, P, Ashkar, AA, Khan, WI, Surette, MG, Bouloumié, A, Steinberg, GR, Burcelin, R & Schertzer, JD 2015, 'Defective NOD2 peptidoglycan sensing promotes diet-induced inflammation, dysbiosis, and insulin resistance' EMBO Molecular Medicine, vol. 7, no. 3, pp. 259-274. https://doi.org/10.15252/emmm.201404169

Defective NOD2 peptidoglycan sensing promotes diet-induced inflammation, dysbiosis, and insulin resistance. / Denou, Emmanuel; Lolmède, Karine; Garidou, Lucile; Pomie, Celine; Chabo, Chantal; Lau, Trevor C; Fullerton, Morgan D; Nigro, Giulia; Zakaroff-Girard, Alexia; Luche, Elodie; Garret, Céline; Serino, Matteo; Amar, Jacques; Courtney, Michael; Cavallari, Joseph F; Henriksbo, Brandyn D; Barra, Nicole G; Foley, Kevin P; McPhee, Joseph B; Duggan, Brittany M; O'Neill, Hayley M; Lee, Amanda J; Sansonetti, Philippe; Ashkar, Ali A; Khan, Waliul I; Surette, Michael G; Bouloumié, Anne; Steinberg, Gregory R; Burcelin, Rémy; Schertzer, Jonathan D.

In: EMBO Molecular Medicine, Vol. 7, No. 3, 09.02.2015, p. 259-274.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Denou, Emmanuel

AU - Lolmède, Karine

AU - Garidou, Lucile

AU - Pomie, Celine

AU - Chabo, Chantal

AU - Lau, Trevor C

AU - Fullerton, Morgan D

AU - Nigro, Giulia

AU - Zakaroff-Girard, Alexia

AU - Luche, Elodie

AU - Garret, Céline

AU - Serino, Matteo

AU - Amar, Jacques

AU - Courtney, Michael

AU - Cavallari, Joseph F

AU - Henriksbo, Brandyn D

AU - Barra, Nicole G

AU - Foley, Kevin P

AU - McPhee, Joseph B

AU - Duggan, Brittany M

AU - O'Neill, Hayley M

AU - Lee, Amanda J

AU - Sansonetti, Philippe

AU - Ashkar, Ali A

AU - Khan, Waliul I

AU - Surette, Michael G

AU - Bouloumié, Anne

AU - Steinberg, Gregory R

AU - Burcelin, Rémy

AU - Schertzer, Jonathan D

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PY - 2015/2/9

Y1 - 2015/2/9

N2 - Pattern recognition receptors link metabolite and bacteria-derived inflammation to insulin resistance during obesity. We demonstrate that NOD2 detection of bacterial cell wall peptidoglycan (PGN) regulates metabolic inflammation and insulin sensitivity. An obesity-promoting high-fat diet (HFD) increased NOD2 in hepatocytes and adipocytes, and NOD2(-/-) mice have increased adipose tissue and liver inflammation and exacerbated insulin resistance during a HFD. This effect is independent of altered adiposity or NOD2 in hematopoietic-derived immune cells. Instead, increased metabolic inflammation and insulin resistance in NOD2(-/-) mice is associated with increased commensal bacterial translocation from the gut into adipose tissue and liver. An intact PGN-NOD2 sensing system regulated gut mucosal bacterial colonization and a metabolic tissue dysbiosis that is a potential trigger for increased metabolic inflammation and insulin resistance. Gut dysbiosis in HFD-fed NOD2(-/-) mice is an independent and transmissible factor that contributes to metabolic inflammation and insulin resistance when transferred to WT, germ-free mice. These findings warrant scrutiny of bacterial component detection, dysbiosis, and protective immune responses in the links between inflammatory gut and metabolic diseases, including diabetes.

AB - Pattern recognition receptors link metabolite and bacteria-derived inflammation to insulin resistance during obesity. We demonstrate that NOD2 detection of bacterial cell wall peptidoglycan (PGN) regulates metabolic inflammation and insulin sensitivity. An obesity-promoting high-fat diet (HFD) increased NOD2 in hepatocytes and adipocytes, and NOD2(-/-) mice have increased adipose tissue and liver inflammation and exacerbated insulin resistance during a HFD. This effect is independent of altered adiposity or NOD2 in hematopoietic-derived immune cells. Instead, increased metabolic inflammation and insulin resistance in NOD2(-/-) mice is associated with increased commensal bacterial translocation from the gut into adipose tissue and liver. An intact PGN-NOD2 sensing system regulated gut mucosal bacterial colonization and a metabolic tissue dysbiosis that is a potential trigger for increased metabolic inflammation and insulin resistance. Gut dysbiosis in HFD-fed NOD2(-/-) mice is an independent and transmissible factor that contributes to metabolic inflammation and insulin resistance when transferred to WT, germ-free mice. These findings warrant scrutiny of bacterial component detection, dysbiosis, and protective immune responses in the links between inflammatory gut and metabolic diseases, including diabetes.

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