Abstract
BACKGROUND: Previous case-control studies have reported aberrations of the gut microbiota in individuals with prediabetes. The primary objective of the present study was to explore the dynamics of the gut microbiota of individuals with prediabetes over 4 years with a secondary aim of relating microbiota dynamics to temporal changes of metabolic phenotypes. METHODS: The study included 486 European patients with prediabetes. Gut microbiota profiling was conducted using shotgun metagenomic sequencing and the same bioinformatics pipelines at study baseline and after 4 years. The same phenotyping protocols and core laboratory analyses were applied at the two timepoints. Phenotyping included anthropometrics and measurement of fasting plasma glucose and insulin levels, mean plasma glucose and insulin under an oral glucose tolerance test (OGTT), 2-h plasma glucose after an OGTT, oral glucose insulin sensitivity index, Matsuda insulin sensitivity index, body mass index, waist circumference, and systolic and diastolic blood pressure. Measures of the dynamics of bacterial microbiota were related to concomitant changes in markers of host metabolism. RESULTS: Over 4 years, significant declines in richness were observed in gut bacterial and viral species and microbial pathways accompanied by significant changes in the relative abundance and the genetic composition of multiple bacterial species. Additionally, bacterial-viral interactions diminished over time. Despite the overall reduction in bacterial richness and microbial pathway richness, 80 dominant core bacterial species and 78 core microbial pathways were identified at both timepoints in 99% of the individuals, representing a resilient component of the gut microbiota. Over the same period, individuals with prediabetes exhibited a significant increase in glycemia and insulinemia alongside a significant decline in insulin sensitivity. Estimates of the gut bacterial microbiota dynamics were significantly correlated with temporal impairments in host metabolic health. CONCLUSIONS: In this 4-year prospective study of European patients with prediabetes, the gut microbiota exhibited major changes in taxonomic composition, bacterial species genetics, and microbial functional potentials, many of which paralleled an aggravation of host metabolism. Whether the temporal gut microbiota changes represent an adaptation to the progression of metabolic abnormalities or actively contribute to these in prediabetes cases remains unsettled. TRIAL REGISTRATION: The Diabetes Research on Patient Stratification (DIRECT) study, an exploratory observational study initiated on October 15, 2012, was registered on ClinicalTrials.gov under the number NCT03814915.