First trimester gut microbiome induces Inflammation-dependent gestational diabetes phenotype in mice

Gestational diabetes mellitus (GDM) is a condition in which non-diabetic women are diagnosed with glucose intolerance during pregnancy, typically in the second trimester. GDM can lead to a wide range of obstetrical and metabolic complications for both mother and neonate. Early identification of GDM risk, along with a better understanding of its pathophysiology during the first trimester of pregnancy, may be effective in reducing GDM incidence, as well as its associated short and long term morbidities. Here, we comprehensively profiled the gut microbiome, metabolome, inflammatory cytokines, nutrition and clinical records of 394 women during the first trimester of pregnancy. We found elevated levels of proinflammatory serum cytokines in those who later developed GDM. The women stool samples were also characterized by decreased levels of several fecal short-chain fatty acids and altered microbiome. We next tested the hypothesis that differences in GDM-associated microbial composition during the first trimester drove inflammation and insulin-resistance. Stool samples collected early in pregnancy from women from three populations who did and did not later develop GDM were transplanted to germ-free mice and confirmed that both inflammation and insulin-resistance are induced by the microbiome of pregnant women more than 10 weeks prior to GDM diagnosis. Following these observations, we used a machine-learning approach to predict GDM based on first trimester clinical, microbial and inflammatory markers. Our model showed high predictive accuracy. Overall, our results suggest that the gut microbiome of women in the first trimester plays a remarkable role in inflammation-induced GDM pathogenesis and point to dozens of GDM markers during the first trimester of pregnancy, some of which may be targets for therapeutic intervention.