Aberrant intestinal microbiota in individuals with prediabetes.

AIMS/HYPOTHESIS: Individuals 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. METHODS: In 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. RESULTS: We 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), p adj = 0.0497), whereas the abundances of Dorea, [Ruminococcus], Sutterella and Streptococcus were increased (mean log2 fold change 0.51 (SEM 0.12), p adj = 5 × 10-4; 0.51 (SEM 0.11), p adj = 1 × 10-4; 0.60 (SEM 0.21), p adj = 0.0497; and 0.92 (SEM 0.21), p adj = 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), p adj = 2 × 10-3 and -1.65 (SEM 0.34), p adj = 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/INTERPRETATION: Collectively, 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.

Age-dependent alterations of glucose clearance and homeostasis are temporally separated and modulated by dietary fat.

Diet- and age-dependent changes in glucose regulation in mice occur, but the temporal development, mechanisms and influence of dietary fat source remain to be defined. We followed metabolic changes in three groups of mice including a low-fat diet (LFD) reference group and two high-fat, high-sucrose diets based on either fish oil (FOD) or soybean oil (SOD), rich in ω3- and ω6-polyunsaturated fatty acids, respectively, to closely monitor the age-dependent development in glucose regulation in both obese (SOD-fed) and lean (LFD- and FOD-fed) mice. We assessed glucose homeostasis and glucose clearance at week 8, 12, 16, 24, 31, and 39 and performed an insulin tolerance test at week 40. We further analyzed correlations between the gut microbiota and key metabolic parameters. Interestingly, alterations in glucose homeostasis and glucose clearance were temporally separated, while 16S ribosomal gene amplicon sequencing revealed that gut microbial alterations formed correlation clusters with fat mass and either glucose homeostasis or glucose clearance, but rarely both. Importantly, effective glucose clearance was maintained in FOD- and even increased in LFD-fed mice, whereas SOD-fed mice rapidly developed impaired glucose clearance followed by a gradual improvement from week 8 to week 39. All groups had similar responses to insulin 40 weeks post diet initiation despite severe nonalcoholic steatohepatitis in SOD-fed mice. We conclude that age-related alterations in glucose regulation may occur in both lean and obese mice and are modulated by dietary fat as indicated by the sustained metabolic homeostasis observed in mice fed ω3-polyunsaturated fatty acids.