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A faecal metabolite signature of impaired fasting glucose: results from two independent population-based cohorts

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posted on 2023-09-12, 22:32 authored by Ana Nogal, Francesca Tettamanzi, Qiuling Dong, Panayiotis Louca, Alessia Visconti, Colette Christiansen, Taylor Breuninger, Jakob Linseisen, Harald Grallert, Nina Wawro, Francesco Asnicar, Kari Wong, Andrei-Florin Baleanu, Gregory A. Michelotti, Nicola Segata, Mario Falchi, Annette Peters, Paul W. Franks, Vincenzo Bagnardi, Tim D Spector, Jordana T Bell, Christian Gieger, Ana M Valdes, Cristina Menni

Prediabetes is a metabolic condition associated with gut microbiome composition, though mechanisms remain elusive. We searched for faecal metabolites, a readout of gut microbiome function, associated with impaired fasting glucose (IFG) in 142 individuals with IFG and 1105 healthy individuals from TwinsUK. We used the KORA cohort (318 IFG individuals, 689 healthy individuals) to replicate our findings. We linearly combined 8 IFG-positively associated metabolites (1-methylxantine, nicotinate, glucuronate, uridine, cholesterol, serine, caffeine and protoporphyrin IX) into an IFG-metabolite score, which was significantly associated with higher odds ratios for IFG (TwinsUK: OR[95%CI]=3.9[3.02-5.02], p<0.0001, KORA: OR[95%CI]=1.3[1.16-1.52], p<0.0001) and incident type-2 diabetes (T2D) (TwinsUK: HR[95%CI]=4[1.97-8], p=0.0002). Although these are host-produced metabolites, we found that the gut microbiome is strongly associated with their faecal levels (AUC>70%). Abundances of Faecalibacillus intestinalis, Dorea formicigenerans, Ruminococcus torques and Dorea sp. AF24_7LB were positively associated with IFG, and such associations were partially mediated by 1-methylxanthine and nicotinate (VAF mean(SD)=14.4%(5.1), p<0.05). Our results suggest that gut microbiome is linked to prediabetes not only via the production of microbial metabolites but also by affecting intestinal absorption/excretion of host-produced metabolites and xenobiotics, which are correlated with the risk of IFG. Faecal metabolites enable modelling of another mechanism of gut microbiome effect on prediabetes and T2D onset.

Funding

This research was funded by the Chronic Disease Research Foundation, and in part by the Wellcome Trust (Grant number: 212904/Z/18/Z) and by DiabetesUK (19/0006053). For the purpose of open access, the authors have applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. TwinsUK receives funding from the Wellcome Trust, the European Commission H2020 grants SYSCID (contract #733100); the National Institute for Health Research (NIHR) Clinical Research Facility and the Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London, the Chronic Disease Research Foundation, the UKRI Medical Research Council (MRC)/British Heart Foundation Ancestry and Biological Informative Markers for Stratification of Hypertension (AIM-HY; MR/M016560/1), and Zoe Limited. This work was also supported by UKRI grant MR/W026813/1 to C.M. and A.M.V. The KORA study was initiated and financed by the Helmholtz Zentrum München – German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Stool sample collection and metabolomics analysis in KORA FF4 was supported by iMED, a research alliance within the Helmholtz Association, Germany. Data collection in the KORA study is done in cooperation with the University Hospital of Augsburg. C.M., L.P. and A.N. are funded by the Chronic Disease Research Foundation. A.M.V. is supported by the National Institute for Health Research Nottingham Biomedical Research Centre.

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