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Background  Recent studies have indicated an association of gut microbiota and microbial metabolites with type 2 diabetes mellitus (T2D). However, large-scale investigation of the gut microbiota of “prediabetic” (PD) subjects has not been reported. Identifying robust gut microbiome signatures of prediabetes and characterizing early prediabetic stages is important for the understanding of disease development and could be crucial in early diagnosis and prevention.    Methods  The current study performed amplification and sequencing on the variable regions (V1–V5) of the 16S rRNA genes to profile and compare gut microbiota of prediabetic individuals ( N  = 262) with normoglycemic individuals ( N  = 275) from two cohorts in India and Denmark. Similarly, fasting serum inflammatory biomarkers were profiled from the study participants.    Results  After correcting for strong country-specific cohort effect, 16 operational taxonomic units (OTUs) including members from the genera  Prevotella9 ,  Phascolarctobacterium ,  Barnesiella ,  Flavonifractor ,  Tyzzerella_4 ,  Bacteroides ,  Faecalibacterium , and  Agathobacter  were identified as enriched in normoglycaemic subjects with respect to the subjects with prediabetes using a negative binomial Wald test. We also identified 144 OTUs enriched in the prediabetic subjects, which included members from the genera  Megasphaera ,  Streptococcus ,  Prevotella9 ,  Alistipes ,  Mitsuokella ,  Escherichia/Shigella ,  Prevotella2 ,  Vibrio ,  Lactobacillus ,  Alloprevotella ,  Rhodococcus , and  Klebsiella . Comparative analyses of relative abundance of bacterial taxa revealed that the  Streptococcus ,  Escherichia/Shigella ,  Prevotella2 ,  Vibrio , and  Alloprevotella  OTUs exhibited more than fourfold enrichment in the gut microbiota of prediabetic subjects. When considering subjects from the two geographies separately, we were able to identify additional gut microbiome signatures of prediabetes. The study reports a probable association of  Megasphaera  OTU(s) with impaired glucose tolerance, which is significantly pronounced in Indian subjects. While the overall results confirm a state of proinflammation as early as in prediabetes, the Indian cohort exhibited a characteristic pattern of abundance of inflammatory markers indicating low-grade intestinal inflammation at an overall population level, irrespective of glycemic status.    Conclusions  The results present trans-ethnic gut microbiome and inflammation signatures associated with prediabetes, in Indian and Danish populations. The identified associations may be explored further as potential early indicators for individuals at risk of dysglycemia.    Supplementary Information  The online version contains supplementary material available at 10.1186/s13073-021-00851-9.

Trans-ethnic gut microbial signatures of prediabetic subjects from India and Denmark