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

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.