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The dynamics of the gut microbiota in prediabetes during a four-year follow-up among European patients-an IMI-DIRECT prospective study

Lyu, Liwei ; Fan, Yong ; Vogt, Josef Korbinian ; Clos-Garcia, Marc ; Bonnefond, Amelie ; Pedersen, Helle Krogh ; Dutta, Avirup ; Koivula, Robert LU ; Sharma, Sapna and Allin, Kristine Højgaard , et al. (2025) In Genome Medicine 17(1).
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... (More)

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.

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publishing date
type
Contribution to journal
publication status
published
subject
keywords
Adult, Aged, Female, Humans, Male, Middle Aged, Bacteria/classification, Blood Glucose, Europe, Follow-Up Studies, Gastrointestinal Microbiome, Glucose Tolerance Test, Metagenomics, Prediabetic State/microbiology, Prospective Studies
in
Genome Medicine
volume
17
issue
1
article number
78
publisher
BioMed Central (BMC)
external identifiers
  • pmid:40665409
ISSN
1756-994X
DOI
10.1186/s13073-025-01508-7
language
English
LU publication?
yes
additional info
© 2025. The Author(s).
id
1bea868d-c98d-4c21-9739-282d10f5eb1b
date added to LUP
2025-08-14 13:12:53
date last changed
2025-08-14 13:21:09
@article{1bea868d-c98d-4c21-9739-282d10f5eb1b,
  abstract     = {{<p>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.</p><p>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.</p><p>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.</p><p>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.</p><p>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.</p>}},
  author       = {{Lyu, Liwei and Fan, Yong and Vogt, Josef Korbinian and Clos-Garcia, Marc and Bonnefond, Amelie and Pedersen, Helle Krogh and Dutta, Avirup and Koivula, Robert and Sharma, Sapna and Allin, Kristine Højgaard and Brorsson, Caroline and Cederberg, Henna and Chabanova, Elizaveta and De Masi, Federico and Dermitzakis, Emmanouil and Elders, Petra J and Blom, Marieke T and Hollander, Monika and Eriksen, Rebeca and Forgie, Ian and Frost, Gary and Giordano, Giuseppe N and Grallert, Harald and Haid, Mark and Hansen, Tue Haldor and Jablonka, Bernd and Kokkola, Tarja and Mahajan, Anubha and Mari, Andrea and McDonald, Timothy J and Musholt, Petra B and Pavo, Imre and Prehn, Cornelia and Ridderstråle, Martin and Ruetten, Hartmut and Hart, Leen M 't and Schwenk, Jochen M and Stankevic, Evelina and Thomsen, Henrik S and Vangipurapu, Jagadish and Vestergaard, Henrik and Viñuela, Ana and Walker, Mark and Hansen, Torben and Linneberg, Allan and Nielsen, Henrik Bjørn and Brunak, Søren and McCarthy, Mark I and Franks, Paul W and Pearson, Ewan and Pedersen, Oluf}},
  issn         = {{1756-994X}},
  keywords     = {{Adult; Aged; Female; Humans; Male; Middle Aged; Bacteria/classification; Blood Glucose; Europe; Follow-Up Studies; Gastrointestinal Microbiome; Glucose Tolerance Test; Metagenomics; Prediabetic State/microbiology; Prospective Studies}},
  language     = {{eng}},
  month        = {{07}},
  number       = {{1}},
  publisher    = {{BioMed Central (BMC)}},
  series       = {{Genome Medicine}},
  title        = {{The dynamics of the gut microbiota in prediabetes during a four-year follow-up among European patients-an IMI-DIRECT prospective study}},
  url          = {{http://dx.doi.org/10.1186/s13073-025-01508-7}},
  doi          = {{10.1186/s13073-025-01508-7}},
  volume       = {{17}},
  year         = {{2025}},
}