Evidence of a genetically driven metabolomic signature in actively inflamed Crohn's disease.

Crohn's disease (CD) is characterised by chronic inflammation. We aimed to identify a relationship between plasma inflammatory metabolomic signature and genomic data in CD using blood plasma metabolic profiles. Proton NMR spectroscopy were achieved for 228 paediatric CD patients. Regression (OPLS) modelling and machine learning (ML) approaches were independently applied to establish the metabolic inflammatory signature, which was correlated against gene-level pathogenicity scores generated for all patients and functional enrichment was analysed. OPLS modelling of metabolomic spectra from unfasted patients revealed distinctive shifts in plasma metabolites corresponding to regions of the spectrum assigned to N-acetyl glycoprotein, glycerol and phenylalanine that were highly correlated (R2 = 0.62) with C-reactive protein levels. The same metabolomic signature was independently identified using ML to predict patient inflammation status. Correlation of the individual peaks comprising this metabolomic signature of inflammation with pathogenic burden across 15,854 unselected genes identified significant enrichment for genes functioning within 'intrinsic component of membrane' (p = 0.003) and 'inflammatory bowel disease (IBD)' (p = 0.003). The seven genes contributing IBD enrichment are critical regulators of pro-inflammatory signaling. Overall, a metabolomic signature of inflammation can be detected from blood plasma in CD. This signal is correlated with pathogenic mutation in pro-inflammatory immune response genes.

A new mechanism for cannabidiol in regulating the one-carbon cycle and methionine levels in Dictyostelium and in mammalian epilepsy models.

BACKGROUND AND PURPOSE: Epidiolex™, a form of highly purified cannabidiol (CBD) derived from Cannabis plants, has demonstrated seizure control activity in patients with Dravet syndrome, without a fully elucidated mechanism of action. We have employed an unbiased approach to investigate this mechanism at a cellular level. EXPERIMENTAL APPROACH: We use a tractable biomedical model organism, Dictyostelium, to identify a protein controlling the effect of CBD and characterize this mechanism. We then translate these results to a Dravet syndrome mouse model and an acute in vitro seizure model. KEY RESULTS: CBD activity is partially dependent upon the mitochondrial glycine cleavage system component, GcvH1 in Dictyostelium, orthologous to the human glycine cleavage system component H protein, which is functionally linked to folate one-carbon metabolism (FOCM). Analysis of FOCM components identified a mechanism for CBD in directly inhibiting methionine synthesis. Analysis of brain tissue from a Dravet syndrome mouse model also showed drastically altered levels of one-carbon components including methionine, and an in vitro rat seizure model showed an elevated level of methionine that is attenuated following CBD treatment. CONCLUSIONS AND IMPLICATIONS: Our results suggest a novel mechanism for CBD in the regulating methionine levels and identify altered one-carbon metabolism in Dravet syndrome and seizure activity.

Composition and content of phenolic acids and avenanthramides in commercial oat products: Are oats an important polyphenol source for consumers?

Oats contain a range of phenolic acids and avenanthramides which may have health benefits. Analysis of 22 commercial oat products (oat bran concentrate, oat bran, flaked oats, rolled oats and oatcakes) using HPLC-DAD detected eleven bound and thirteen free + conjugated phenolic acids and avenanthramides. The oat products (excluding concentrate) provided between 15.79 and 25.05 mg total phenolic acids (9.9-19.33 mg bound, 4.96-5.72 mg free + conjugated) and between 1.1 and 2 mg of avenanthramides in a 40 g portion while an 11 g portion of oat concentrate provided 16.7 mg of total phenolic acids (15.17 mg bound, 1.53 mg free + conjugated) and 1.2 mg of avenanthramides. The compositions and concentrations of the components in the different products were broadly similar, with the major component being ferulic acid (58-78.1%). The results show that commercial oat products are a source of phenolic acids and avenanthramides for consumers.

A Multi-omics Approach to Unraveling the Microbiome-Mediated Effects of Arabinoxylan Oligosaccharides in Overweight Humans.

Long-term consumption of dietary fiber is generally considered beneficial for weight management and metabolic health, but the results of interventions vary greatly depending on the type of dietary fibers involved. This study provides a comprehensive evaluation of the effects of a specific dietary fiber consisting of a wheat-bran extract enriched in arabinoxylan-oligosaccharides (AXOS) in a human intervention trial. An integrated multi-omics analysis has been carried out to evaluate the effects of an intervention trial with an AXOS-enriched diet in overweight individuals with indices of metabolic syndrome. Microbiome analyses were performed by shotgun DNA sequencing in feces; in-depth metabolomics using nuclear magnetic resonance in fecal, urine, and plasma samples; and massive lipid profiling using mass spectrometry in fecal and serum/plasma samples. In addition to their bifidogenic effect, we observed that AXOS boost the proportion of Prevotella species. Metagenome analysis showed increases in the presence of bacterial genes involved in vitamin/cofactor production, glycan metabolism, and neurotransmitter biosynthesis as a result of AXOS intake. Furthermore, lipidomics analysis revealed reductions in plasma ceramide levels. Finally, we observed associations between Prevotella abundance and short-chain fatty acids (SCFAs) and succinate concentration in feces and identified a potential protective role of Eubacterium rectale against metabolic disease given that its abundance was positively associated with plasma phosphatidylcholine levels, thus hypothetically reducing bioavailability of choline for methylamine biosynthesis. The metagenomics, lipidomics, and metabolomics data integration indicates that sustained consumption of AXOS orchestrates a wide variety of changes in the gut microbiome and the host metabolism that collectively would impact on glucose homeostasis. (This study has been registered at ClinicalTrials.gov under identifier NCT02215343)IMPORTANCE The use of dietary fiber food supplementation as a strategy to reduce the burden of diet-related diseases is a matter of study given its cost-effectiveness and the positive results demonstrated in clinical trials. This multi-omics assessment, on different biological samples of overweight subjects with signs of metabolic syndrome, sheds light on the early and less evident effects of short-term AXOS intake on intestinal microbiota and host metabolism. We observed a deep influence of AXOS on gut microbiota beyond their recognized bifidogenic effect by boosting concomitantly a wide diversity of butyrate producers and Prevotella copri, a microbial species abundant in non-Westernized populations with traditional lifestyle and diets enriched in fresh unprocessed foods. A comprehensive evaluation of hundreds of metabolites unveiled new benefits of the AXOS intake, such as reducing the plasma ceramide levels. Globally, we observed that multiple effects of AXOS consumption seem to converge in reversing the glucose homeostasis impairment.