Aberrant intestinal microbiota in individuals with prediabetes

Abstract

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 HbA_1c 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.

Keywords: Akkermansia muciniphila; Clostridium; Faecal transfer; Gut microbiota; Hyperglycaemia; Intestinal microbiota; Low-grade inflammation; Prediabetes.

Fig. 1

Genera and OTUs that display differential abundance among 134 individuals with prediabetes and 134 individuals with normal glucose regulation (p_adj < 0.05). Genera are depicted by white circles and OTUs by black circles. Circles indicate mean log₂ fold difference and horizontal bars indicate SEM. Positive values imply higher abundance among individuals with prediabetes and negative values imply lower abundance among individuals with prediabetes. The taxa names indicate the lowest taxonomic affiliation available for the OTUs in the Greengenes database. To obtain a more specific affiliation we blasted the OTUs against the NCBI bacterial database, the best match with the per cent identity is provided in ESM Table 3

Fig. 2

Association between differentially abundant genera and clinical biomarkers relevant for diabetes in the total group of 268 individuals. The genera names are from the Greengenes database. The colour key indicates Spearman’s ρ and the numbers in the cells represent p values <0.05. Spearman’s ρ and associated p values are listed in ESM Table 4

Fig. 3

Association between differentially abundant OTUs and clinical biomarkers relevant for diabetes in the total group of 268 individuals. The taxa names indicate the lowest taxonomic affiliation available for the OTUs in the Greengenes database. To obtain a more specific affiliation we blasted the OTUs against the NCBI bacterial database, the best match with the per cent identity are provided in ESM Table 3. The colour key indicates Spearman’s ρ and the numbers in the cells represent p values <0.05. Spearman’s ρ and associated p values are listed in ESM Table 4

Fig. 4

Association between clinical biomarkers and α-diversity estimated as phylogenetic diversity in the total group of 268 individuals. The black line represents the fitted regression line and the grey shaded areas represent the 95% CIs. r² is the proportion of variance in the clinical biomarkers that can be predicted from the phylogenetic diversity