Microbial Signatures in High- and Low-Blood-Glucose Participants of the Generation 100 Study

Introduction: Type 2 diabetes mellitus (T2DM) is an age-related metabolic disease that is often considered inflammatory, as various cytokine profiles are associated with its progression. T2DM typically follows a prediabetic stage, during which insulin resistance develops. This stage can often be corrected early in life, potentially preventing or delaying the onset of T2D. Intestinal dysbiosis has been linked to metabolic disorders, including insulin resistance and T2D. A healthy, diverse gut microbiome, composed primarily of four phyla—Bacteroidetes, Firmicutes, Actinobacteria, and Proteobacteria—is essential for maintaining the gut epithelial barrier. Phylogenetically related bacterial groups, such as Proteobacteria and Enterobacteriaceae, have been linked to poor glycaemic control and negative metabolic outcomes, including obesity, insulin resistance, and an impaired lipid profile. Methods: This study involved 73 older adults (ages 76–83) from the randomized controlled trial entitled the Generation 100 Study. We performed high-throughput sequencing of the bacterial 16S rRNA gene to obtain metagenomic microbial profiles for all participants. These profiles were then correlated with clinical measures. Results: We observed distinct patterns of microbial beta diversity between the high- and normal-glucose groups. Overall, the microbial diversity was significantly reduced in the high-glucose group. At the highest taxonomic level (Phylum), we found that Synergistes, Elusimicobia, Euryarchaeota, Verrucomicrobia, and Proteobacteria were all significantly decreased in participants with high blood glucose. Additionally, P. copri was significantly elevated in the high-glucose (10-fold increase) and high-CRP (777-fold increase) groups, suggesting that it may serve as an early inflammatory and diabetic marker. These findings are consistent with previous research identifying P. copri as a pro-inflammatory pathogen. We also found that the Fusobacterium genus was significantly increased in the normal glucose group, with a 151-fold increase compared to the high-glucose group (p < 0.005). Conclusions: Our results indicate significant changes in the microbiome that may provide valuable insights for early intervention in pre-diabetic states.