Defective <scp>NOD</scp>2 peptidoglycan sensing promotes diet‐induced inflammation, dysbiosis, and insulin resistance

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

doi:10.15252/emmm.201404169

Cited by 163 publications

(167 citation statements)

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“…Correlations between microbiota composition and host lipid levels have been obtained previously for mouse mutants (Toll-like receptor 5 [TLR5], MyD88, and NOD2), with the microbiota identified as a causal factor by reproducing the deleterious metabolic phenotype via transplantation of gut microbiota from mutant to wild-type mice (46)(47)(48). Our study of Drosophila shows that the interactive effects of host genotype and microbiota on nutritional phenotype are not unique to mice (or mammals), and may be general to animals.…”

Section: Discussionmentioning

confidence: 99%

Host Genetic Control of the Microbiota Mediates the Drosophila Nutritional Phenotype

Chaston

Dobson

Newell

et al. 2016

Appl Environ Microbiol

121

130

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A wealth of studies has demonstrated that resident microorganisms (microbiota) influence the pattern of nutrient allocation to animal protein and energy stores, but it is unclear how the effects of the microbiota interact with other determinants of animal nutrition, including animal genetic factors and diet. Here, we demonstrate that members of the gut microbiota in Drosophila melanogaster mediate the effect of certain animal genetic determinants on an important nutritional trait, triglyceride (lipid) content. Parallel analysis of the taxonomic composition of the associated bacterial community and host nutritional indices (glucose, glycogen, triglyceride, and protein contents) in multiple Drosophila genotypes revealed significant associations between the abundance of certain microbial taxa, especially Acetobacteraceae and Xanthamonadaceae, and host nutritional phenotype. By a genome-wide association study of Drosophila lines colonized with a defined microbiota, multiple host genes were statistically associated with the abundance of one bacterium, Acetobacter tropicalis. Experiments using mutant Drosophila validated the genetic association evidence and reveal that host genetic control of microbiota abundance affects the nutritional status of the flies. These data indicate that the abundance of the resident microbiota is influenced by host genotype, with consequent effects on nutrient allocation patterns, demonstrating that host genetic control of the microbiome contributes to the genotype-phenotype relationship of the animal host.T he recognition that animals are routinely colonized by dense and often diverse communities of microorganisms is driving a major reassessment of fundamental aspects of animal biology (1). Notably, there is accumulating evidence that resident microorganisms influence the nutritional status of animals in multiple ways, including competition for ingested nutrients, providing supplementary nutrients (e.g., vitamins, short-chain fatty acids, essential amino acids), and by modulating the nutrient signaling circuits that regulate nutrient allocation (2-5). These discoveries demonstrate the inadequacy of traditional explanations of animal nutrition in terms of nutritional inputs (amount and composition of food ingested) and outputs (animal nutritional demand for activity, growth, reproduction, etc.) and highlight our ignorance of how microbial effects on animal nutrition interact with other factors, especially animal genotype (6-10).The focus of this study is the impact of interactions between the gut microbiota and host genotype on animal nutrition. The nutritional consequence of the microbiota is known to vary with the abundance and composition of the microorganisms (7, 10-13). For example, comparison of nutritional phenotypes in Drosophila melanogaster raised with or without gut bacteria revealed that the microbiome can influence penetrance of host mutations (12). To the extent that the abundance and composition of the microbiota are determined by host genotype, the impact of animal genetic ...

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Section: Discussionmentioning

confidence: 99%

Host Genetic Control of the Microbiota Mediates the Drosophila Nutritional Phenotype

Chaston

Dobson

Newell

et al. 2016

Appl Environ Microbiol

121

130

View full text Add to dashboard Cite

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“…Nod2 -/-mice show increased inflammation of adipose tissue and the liver and exacerbated insulin resistance under an HFD that is associated with bacterial translocation from the gut to adipose tissue and the liver 96 .…”

Section: [H3] Nod2mentioning

confidence: 99%

Innate immunity in diabetes and diabetic nephropathy

2015

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Abstract:The innate immune system consists of several classes of pattern recognition receptors (PRRs), including membrane-bound Toll-like receptors (TLRs) and nucleotide-binding domain leucine-rich oligomerization domain (NOD)-like receptors (NLRs).These receptors detect pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) in the extracellular and intracellular space. Intracellular NLRs constitute inflammasomes, which activate and release caspase-1, IL1β, and IL18 and thus initiate an inflammatory response. Systemic and local low-grade inflammation and release of proinflammatory cytokines are implicated in the development and progression of diabetes mellitus and diabetic nephropathy. TLR2, TLR4, and the NLRP3 inflammasome are critically involved in the inflammatory responses in pancreatic islets, adipose, liver and kidney tissues. This Review discusses how innate immune system-driven inflammatory processes can lead to apoptosis, tissue fibrosis, and organ dysfunction to cause insulin resistance, impaired insulin secretion, and renal failure. We propose that careful targeting of TLR2, TLR4, and NLRP3 signalling pathways may be beneficial for the treatment of diabetes mellitus and diabetic nephropathy. 2 Key points The innate immune system consists of several classes of pattern recognition receptors, including TLRs and NLRs, which detect pathogen-associated and danger-associated molecular patterns and initiate an inflammatory response  TLR2 and TLR4 are the predominant toll-like receptors expressed on pancreatic β cells that trigger an inflammatory response in insulitis during type 1 diabetes mellitus  TLR2 and TLR4 signaling, and activation of NLRP3 inflammasomes results in production of various proinflammatory cytokines that can induce insulin resistance in type 2 diabetes mellitus (T2DM) and obesity  Innate immune responses in T2DM and obesity are modulated by the status of the gut microbiota, autophagy, and adipokines  TLR2, TLR4, NOD2, and NLRP3 inflammasome-mediated inflammation are involved in the perpetuation of inflammation in diabetic nephropathy  The activation of TLRs and NLRs stimulates the expression of MCP-1, which is associated with the progression of diabetic nephropathy [H1] IntroductionThe prevalence of diabetes mellitus is estimated to be 8.3%, affecting ~387 million people as of 2014. The number of patients living with diabetes mellitus is expected to increase to ~592 million by 2035, as reported by the International Diabetes Federation 1 . The incidence of end-stage renal disease (ESRD) is also rapidly increasing worldwide but varies up to 15-fold by country. In 2012, the number of new diagnoses of ESRD worldwide ranged from 25 to 467 patients per million. The proportion of new cases of ESRD with diabetes mellitus as the primary cause also differs by country, with 66% cases reported in Singapore and 12-16% cases reported in Ukraine, Romania, and the Netherlands 2 . Although intensified multifactorial intervention in patients with type 2 diabete...

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“…Indeed, multiple studies have now linked HFD-related obesity to changes in intestinal PRRs, cytokines, and immune cell populations within the intestine (summarized in Figure 1 and Table 1). Using genetically engineered mouse models, changes in expression of PRRs for flagellin (TLR5), lipoproteins (TLR2), LPS (TLR4), and peptidoglycan (NOD1/2) have linked dysbiosis to the low-grade inflammatory changes of metabolic syndrome (65)(66)(67). Other PRRs, including the NLRP3 inflammasome, which is expressed by IECs, also link nutrient sensing, including saturated fatty acids, ceramide, or cholesterol crystals, to intracellular metabolic disease (68)(69)(70).…”

Section: Diet-induced Obesity Alters the Intestinal Immune Systemmentioning

confidence: 99%