A Fecal Metabolite Signature of Impaired Fasting Glucose: results from two independent population-based cohorts

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 SpectorJordana T Bell, Christian Gieger, Ana M Valdes, Cristina Menni

Research output: Contribution to journalArticlepeer-review

Abstract

Prediabetes is a metabolic condition associated with gut mi-crobiome composition, although mechanisms remain elu-sive. We searched for fecal metabolites, a readout of gut microbiome function, associated with impaired fasting glucose (IFG) in 142 individuals with IFG and 1,105 healthy individuals from the UK Adult Twin Registry (TwinsUK). We used the Cooperative Health Research in the Region of Augsburg (KORA) cohort (318 IFG individuals, 689 healthy individuals) to replicate our findings. We linearly combined eight IFG-positively associated metabolites (1-methylxantine, nicoti-nate, glucuronate, uridine, cholesterol, serine, caffeine, and protoporphyrin IX) into an IFG-metabolite score, which was significantly associated with higher odds ratios (ORs) for IFG (TwinsUK: OR 3.9 [95% CI 3.02–5.02], P < 0.0001, KORA: OR 1.3 [95% CI 1.16–1.52], P < 0.0001) and incident type 2 diabetes (T2D; TwinsUK: hazard ratio 4 [95% CI 1.97–8], P = 0.0002). Although these are host-produced me-tabolites, we found that the gut microbiome is strongly associated with their fecal levels (area under the curve >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 (variance accounted for mean 14.4% [SD 5.1], P < 0.05). Our results suggest that the 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. Fecal metabolites enable modeling of another mechanism of gut microbiome effect on prediabetes and T2D onset.

Original languageEnglish
Pages (from-to)1870-1880
Number of pages11
JournalDiabetes
Volume72
Issue number12
Early online date12 Sept 2023
DOIs
Publication statusPublished - Dec 2023

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