Microbial-Host Co-metabolites Are Prodromal Markers Predicting Phenotypic Heterogeneity in Behavior, Obesity, and Impaired Glucose Tolerance

Dumas, Marc; Rothwell, Alice; Hoyles, Lesley; Aranias, Thomas; Chilloux, Julien; Caldérari, Sophie; Noll, Elisa M.; Péan, Noémie; Boulangé, Claire; Blancher, Christine; Barton, Richard H.; Gu, Quan; Fearnside, Jane; Deshayes, Chloé; Hue, Christophe; Scott, James A.; Nicholson, Jeremy K.; Guyader, Dominique

doi:10.1016/j.celrep.2017.06.039

Cited by 85 publications

(81 citation statements)

References 69 publications

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“…Fig. 1h), consistent with our previous reports using this diet 12,26 . We used variance components analysis to decompose the contribution of diet and age to the excretion of these three metabolites, showing that the HFD contribution overwhelms the contribution of age (Suppl.…”

Section: Main Textsupporting

confidence: 93%

Inhibition of IRAK4 by microbial trimethylamine blunts metabolic inflammation and ameliorates glycemic control

Chilloux

Brial

Everard

et al. 2018

Preprint

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Referenced abstract The interaction between high-fat diet (HFD) feeding and the gut microbiome has a strong impact on the onset of insulin resistance (IR)1-3. In particular, bacterial lipopolysaccharides (LPS) and dietary fats trigger low-grade inflammation4 through activation of Toll-like receptor 4 (TLR4), a process called metabolic endotoxemia5. However, little is known about how the microbiome can mitigate this process. Here, we investigate longitudinal physiological and metabotypical responses of C57BL/6 mice to HFD feeding. A series of in vivo experiments with choline supplementation, then blocking trimethylamine (TMA) production and administering TMA, demonstrate that this microbiome-associated metabolite decouples inflammation and IR from obesity in HFD. Through in vitro kinome screens and in silico molecular dynamics studies, we reveal TMA specifically inhibits Interleukin-1 Receptor-associated Kinase 4 (IRAK-4), a central kinase integrating signals from various TLRs and cytokine receptors. Consistent with this, genetic ablation and chemical inhibition of IRAK-4 result in similar metabolic and immune improvements in HFD. In summary, TMA appears as a key microbial effector inhibiting IRAK-4 and mediating metabolic and immune effects with benefits upon HFD. Thereby we highlight the critical contribution of the microbial signalling metabolome in homeostatic regulation of host disease and the emerging role of the kinome6 in microbial–mammalian chemical crosstalk.

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Section: Main Textsupporting

confidence: 93%

Inhibition of IRAK4 by microbial trimethylamine blunts metabolic inflammation and ameliorates glycemic control

Chilloux

Brial

Everard

et al. 2018

Preprint

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“…TMAO concentrations decreased in mice fed an HFD (25), and the effect was exacerbated by p66Shc deletion. Interestingly, an early drop in TMAO levels during HFD was previously found to predict an obese and dysmetabolic phenotype in C57BL/6J mice (26). Thus, different gut microbial changes induced by p66Shc deletion could be responsible for elevation in BCAAs on an SD and for the modulation of TMAO during HFD.…”

Section: Discussionmentioning

confidence: 87%

Interplay between gut microbiota and p66Shc affects obesity‐associated insulin resistance

et al. 2018

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The 66 kDa isoform of the mammalian Shc gene promotes adipogenesis, and p66Shc mice accumulate less body weight than wild-type (WT) mice. As the metabolic consequences of the leaner phenotype of p66Shc mice is debated, we hypothesized that gut microbiota may be involved. We confirmed that p66Shc mice gained less weight than WT mice when on a high-fat diet (HFD), but they were not protected from insulin resistance and glucose intolerance. p66Shc deletion significantly modified the composition of gut microbiota and their modification after an HFD. This was associated with changes in gene expression of Il-1b and regenerating islet-derived protein 3 γ ( Reg3g) in the gut and in systemic trimethylamine N-oxide and branched chain amino acid levels, despite there being no difference in intestinal structure and permeability. Depleting gut microbiota at the end of HFD rendered both strains more glucose tolerant but improved insulin sensitivity only in p66Shc mice. Microbiota-depleted WT mice cohoused with microbiota-competent p66Shc mice became significantly more insulin resistant than WT mice cohoused with WT mice, despite no difference in weight gain. These findings reconcile previous inconsistent observations on the metabolic phenotype of p66Shc mice and illustrate the complex microbiome-host-genotype interplay under metabolic stress.-Ciciliot, S., Albiero, M., Campanaro, S., Poncina, N., Tedesco, S., Scattolini, V., Dalla Costa, F., Cignarella, A., Vettore, M., Di Gangi, I. M., Bogialli, S., Avogaro, A., Fadini, G. P. Interplay between gut microbiota and p66Shc affects obesity-associated insulin resistance.

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“…It worsens atherosclerosis in some mouse models of CVD, and is positively correlated with CVD severity in humans. Beneficial effects associated with TMAO include potential protection from hyperammonia and glutamate neurotoxicity, alleviation of endoplasmic reticulum stress and improved glucose homeostasis by stimulating insulin secretion by pancreatic cells [10,15,16].…”

Section: Discussionmentioning

confidence: 99%

“…Based on work done in mice [10,36], metabolic retroconversion of TMAO may be protective, and may even go some way to explaining why TMA and TMAO are detected at low levels in urine in the absence of dietary methylamines [17]. Chronic exposure of high-fat-fed mice to TMAO reduced diet-associated endoplasmic stress and adipogenesis, and improved glucose tolerance [10]. Exposure of high-fat-fed mice to TMA reduced low-grade inflammation and insulin resistance via inhibition of interleukin-1 receptor-associated kinase 4 (IRAK-4) [36].…”

Section: Discussionmentioning

confidence: 99%

Metabolic retroconversion of trimethylamine N-oxide and the gut microbiota

Hoyles

Jiménez-Pranteda

Chilloux

et al. 2017

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27Keywords: co-metabolic axis; gut-liver axis; metabolomics; Enterobacteriaceae; lactic acid bacteria. 28. CC-BY-NC-ND 4.0 International license not peer-reviewed) is the author/funder. It is made available under aThe copyright holder for this preprint (which was . http://dx.doi.org/10.1101/225581 doi: bioRxiv preprint first posted online Dec. 11, 2017; 2 ABSTRACT 29The dietary methylamines choline, carnitine and phosphatidylcholine are used by the gut microbiota 43TMA can be produced by the gut microbiota (predominantly Enterobacteriaceae) from TMAO. This 44TMA is then taken up by the host and converted back to TMAO. That is, metabolic retroconversion 45 occurs. In addition, TMAO influences microbial metabolism depending on isolation source and taxon 46 of gut bacterium.

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Microbial-Host Co-metabolites Are Prodromal Markers Predicting Phenotypic Heterogeneity in Behavior, Obesity, and Impaired Glucose Tolerance

Cited by 85 publications

References 69 publications

Inhibition of IRAK4 by microbial trimethylamine blunts metabolic inflammation and ameliorates glycemic control

Inhibition of IRAK4 by microbial trimethylamine blunts metabolic inflammation and ameliorates glycemic control

Interplay between gut microbiota and p66Shc affects obesity‐associated insulin resistance

Metabolic retroconversion of trimethylamine N-oxide and the gut microbiota

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