Nogal, A.* ; Tettamanzi, F.* ; Dong, Q. ; Louca, P.* ; Visconti, A.* ; Christiansen, C.* ; Breuninger, T.A.* ; Linseisen, J.* ; Grallert, H. ; Wawro, N. ; Asnicar, F.* ; Wong, K.* ; Baleanu, A.F.* ; Michelotti, G.A.* ; Segata, N.* ; Falchi, M.* ; Peters, A. ; Franks, P.W.* ; Bagnardi, V.* ; Spector, T.D.* ; Bell, J.T.* ; Gieger, C. ; Valdes, A.M.* ; Menni, C.*
     
    
        
A faecal metabolite signature of impaired fasting glucose: Results from twoindependent population-based cohorts.
    
    
        
    
    
        
        Diabetes 72, 1870-1880 (2023)
    
    
    
      
      
	
	    UNLABELLED: Prediabetes is a metabolic condition associated with gut microbiome composition, although mechanisms remain elusive. 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, nicotinate, 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 metabolites, 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. ARTICLE HIGHLIGHTS: Prediabetes is a metabolic condition associated with gut microbiome composition, although mechanisms remain elusive. We investigated whether there is a fecal metabolite signature of impaired fasting glucose (IFG) and the possible underlying mechanisms of action. We identified a fecal metabolite signature of IFG associated with prevalent IFG in two independent cohorts and incident type 2 diabetes in a subanalysis. Although the signature consists of metabolites of nonmicrobial origin, it is strongly correlated with gut microbiome composition. Fecal metabolites enable modeling of another mechanism of gut microbiome effect on prediabetes by affecting intestinal absorption or excretion of host compounds and xenobiotics.
	
	
	    
	
       
      
	
	    
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        Publication type
        Article: Journal article
    
 
    
        Document type
        Scientific Article
    
 
    
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        Keywords
        Gut Microbiota
    
 
    
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        Language
        english
    
 
    
        Publication Year
        2023
    
 
    
        Prepublished in Year
        0
    
 
    
        HGF-reported in Year
        2023
    
 
    
    
        ISSN (print) / ISBN
        0012-1797
    
 
    
        e-ISSN
        1939-327X
    
 
    
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        Quellenangaben
        
	    Volume: 72,  
	    Issue: 12,  
	    Pages: 1870-1880 
	    Article Number: ,  
	    Supplement: ,  
	
    
 
    
        
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            American Diabetes Association
        
 
        
            Publishing Place
            Alexandria, VA.
        
 
	
        
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        Reviewing status
        Peer reviewed
    
 
    
        Institute(s)
        Institute of Epidemiology (EPI)
    
 
    
        POF-Topic(s)
        30202 - Environmental Health
    
 
    
        Research field(s)
        Genetics and Epidemiology
    
 
    
        PSP Element(s)
        G-504090-001
G-504091-002
G-504000-010
G-504091-004
    
 
    
        Grants
        Wellcome Trust
    
 
    
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        Erfassungsdatum
        2023-11-28