Abstract
Aims/hypothesisIndividuals with type 2 diabetes have aberrant intestinal microbiota. However, recent studies suggest that metformin alters the composition and functional potential of gut microbiota, thereby interfering with the diabetes-related microbial signatures. We tested whether specific gut microbiota profiles are associated with prediabetes (defined as fasting plasma glucose of 6.1–7.0 mmol/l or HbA1c of 42–48 mmol/mol [6.0–6.5%]) and a range of clinical biomarkers of poor metabolic health.MethodsIn the present case–control study, we analysed the gut microbiota of 134 Danish adults with prediabetes, overweight, insulin resistance, dyslipidaemia and low-grade inflammation and 134 age- and sex-matched individuals with normal glucose regulation.ResultsWe found that five bacterial genera and 36 operational taxonomic units (OTUs) were differentially abundant between individuals with prediabetes and those with normal glucose regulation. At the genus level, the abundance of Clostridium was decreased (mean log2 fold change −0.64 (SEM 0.23), padj = 0.0497), whereas the abundances of Dorea, [Ruminococcus], Sutterella and Streptococcus were increased (mean log2 fold change 0.51 (SEM 0.12), padj = 5 × 10−4; 0.51 (SEM 0.11), padj = 1 × 10−4; 0.60 (SEM 0.21), padj = 0.0497; and 0.92 (SEM 0.21), padj = 4 × 10−4, respectively). The two OTUs that differed the most were a member of the order Clostridiales (OTU 146564) and Akkermansia muciniphila, which both displayed lower abundance among individuals with prediabetes (mean log2 fold change −1.74 (SEM 0.41), padj = 2 × 10−3 and −1.65 (SEM 0.34), padj = 4 × 10−4, respectively). Faecal transfer from donors with prediabetes or screen-detected, drug-naive type 2 diabetes to germfree Swiss Webster or conventional C57BL/6 J mice did not induce impaired glucose regulation in recipient mice.Conclusions/interpretationCollectively, our data show that individuals with prediabetes have aberrant intestinal microbiota characterised by a decreased abundance of the genus Clostridium and the mucin-degrading bacterium A. muciniphila. Our findings are comparable to observations in overt chronic diseases characterised by low-grade inflammation.
Highlights
The pathogenesis of type 2 diabetes is a continuous process, during which blood glucose levels gradually rise due to increasing insulin resistance and decreasing beta cell function [1]
Individuals with prediabetes recruited from IMI-DIRECT and Danish study of Functional Disorders (DanFunD) were similar with respect to clinical biomarkers (ESM Table 1)
Among 142 individuals from DanFunD where dietary habits could be reliably compared, intake of meat, poultry, fish and vegetables did not differ between individuals with prediabetes (n = 71) and normal glucose regulation (n = 71), whereas the intake of fruit was slightly higher among individuals with normal glucose regulation (ESM Table 2)
Summary
The pathogenesis of type 2 diabetes is a continuous process, during which blood glucose levels gradually rise due to increasing insulin resistance and decreasing beta cell function [1]. Individuals with prediabetes often present with overweight, insulin resistance and low-grade inflammation, and they have an increased risk of type 2 diabetes and ischaemic cardiovascular disease [2]. Several studies have suggested that altered gut microbiota composition and function are associated with overt type 2 diabetes [3,4,5,6,7] and atherosclerosis [8]. In a recent study, we called into question previously reported associations between aberrant gut microbiota and type 2 diabetes by demonstrating that metformin, the first choice drug for treatment of hyperglycaemia in type 2 diabetes, confounds this relationship [9]. An alternative approach to post hoc stratification to circumvent confounding by drug treatment is to study individuals with prediabetes who are not currently treated with glucoselowering drugs
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