Dataset Information

Elevated faecal 12,13-diHOME concentration in neonates at high risk for asthma is produced by gut bacteria and impedes immune tolerance.

ABSTRACT: Neonates at risk of childhood atopy and asthma exhibit perturbation of the gut microbiome, metabolic dysfunction and increased concentrations of 12,13-diHOME in their faeces. However, the mechanism, source and contribution of this lipid to allergic inflammation remain unknown. Here, we show that intra-abdominal treatment of mice with 12,13-diHOME increased pulmonary inflammation and decreased the number of regulatory T (Treg) cells in the lungs. Treatment of human dendritic cells with 12,13-diHOME altered expression of PPAR?-regulated genes and reduced anti-inflammatory cytokine secretion and the number of Treg cells in vitro. Shotgun metagenomic sequencing of neonatal faeces indicated that bacterial epoxide hydrolase (EH) genes are more abundant in the gut microbiome of neonates who develop atopy and/or asthma during childhood. Three of these bacterial EH genes (3EH) specifically produce 12,13-diHOME, and treatment of mice with bacterial strains expressing 3EH caused a decrease in the number of lung Treg cells in an allergen challenge model. In two small birth cohorts, an increase in the copy number of 3EH or the concentration of 12,13-diHOME in the faeces of neonates was found to be associated with an increased probability of developing atopy, eczema or asthma during childhood. Our data indicate that elevated 12,13-diHOME concentrations impede immune tolerance and may be produced by bacterial EHs in the neonatal gut, offering a mechanistic link between perturbation of the gut microbiome during early life and atopy and asthma during childhood.

SUBMITTER: Levan SR

PROVIDER: S-EPMC6830510 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Elevated faecal 12,13-diHOME concentration in neonates at high risk for asthma is produced by gut bacteria and impedes immune tolerance.

Levan Sophia R SR Stamnes Kelsey A KA Lin Din L DL Panzer Ariane R AR Fukui Elle E McCauley Kathryn K Fujimura Kei E KE McKean Michelle M Ownby Dennis R DR Zoratti Edward M EM Boushey Homer A HA Cabana Michael D MD Johnson Christine C CC Lynch Susan V SV

Nature microbiology 20190722 11

Neonates at risk of childhood atopy and asthma exhibit perturbation of the gut microbiome, metabolic dysfunction and increased concentrations of 12,13-diHOME in their faeces. However, the mechanism, source and contribution of this lipid to allergic inflammation remain unknown. Here, we show that intra-abdominal treatment of mice with 12,13-diHOME increased pulmonary inflammation and decreased the number of regulatory T (T<sub>reg</sub>) cells in the lungs. Treatment of human dendritic cells with ...[more]

PMID: 31332384

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Project description:AIMS/HYPOTHESIS:Circulating succinate and 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME) were recently shown to promote brown adipocyte thermogenesis and protect against metabolic disorders in rodents. This study aimed to evaluate the associations between plasma levels of these metabolites and adiposity and metabolic profile in humans. METHODS:Fasting plasma succinate and 12,13-diHOME levels were quantified using ultra HPLC-tandem MS in 2248 individuals (50% female, mean age 41.3?±?5.9 years, mean BMI 26.1?±?4.6 kg/m2) in addition to fasting plasma biochemistry. Total and regional adiposity were assessed with dual-energy x-ray absorptiometry. An age- and sex-adjusted linear regression model was used to determine the associations between succinate and 12,13-diHOME levels and body composition and metabolic profile. Two-sample Mendelian randomisation was used to assess the associations between genetically determined BMI and metabolic traits with circulating plasma succinate and 12,13-diHOME. RESULTS:A one-SD higher plasma succinate and 12,13-diHOME concentration was associated with a 0.15 SD (95% CI 0.28, 0.03) and 0.08 SD (0.15, 0.01) lower total fat mass respectively. Additionally, a one-SD higher plasma 12,13-diHOME level was associated with a 0.09 SD (0.16, 0.02) lower fasting plasma insulin and 0.10 SD (0.17, 0.04) lower plasma triacylglycerol. In Mendelian randomisation analyses, genetically determined higher BMI, fasting hyperinsulinaemia and elevated lipid levels were not associated with changes in either plasma succinate or plasma 12,13-diHOME concentrations. No indications of bias due to directional pleiotropy were detected in the Mendelian randomisation analyses. CONCLUSIONS/INTERPRETATION:Our findings tentatively suggest that plasma succinate and 12,13-diHOME may play a role in the regulation of energy metabolism and brown adipose tissue activation in humans. Further studies encompassing direct assessment of brown adipose tissue activity and dietary supplementation are necessary to investigate the potential beneficial effects of these metabolites on systemic metabolism.

Dataset Information

Elevated faecal 12,13-diHOME concentration in neonates at high risk for asthma is produced by gut bacteria and impedes immune tolerance.

Publications

Elevated faecal 12,13-diHOME concentration in neonates at high risk for asthma is produced by gut bacteria and impedes immune tolerance.

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