<strong>Gut flora-derived metabolites mediate protective effect of high fermentable fiber against placental inflammation in gestational diabetes mellitus.</strong>

Inflammation-associated insulin resistance is a key trigger of gestational diabetes mellitus (GDM), but the underlying mechanisms and effective interventions remain unclear. Here, we report the association of placental inflammation (tumor necrosis factor-α) and abnormal maternal glucose metabolism in GDM patients, and a high fermentable dietary fiber (HFDF, <em>Konjac</em>) could reduce GDM development through gut microbiota-short-chain fatty acids-placental inflammation axis in GDM mice model. Mechanistically, HFDF increases abundances of <em>Lachnospiraceae</em> and butyrate, reduces placental-derived inflammation by enhancing gut barrier and inhibiting the transfer of bacterial-derived lipopolysaccharide, and ultimately resists high fat diet-induced insulin resistance. Butyrate abundances in placentae of GDM patients and mice are negatively correlated with placental TNF-α. Moreover, <em>Lachnospiraceae</em> and butyrate have similar anti-GDM and anti-placental inflammation effects. These findings demonstrate the involvement of important placental inflammation-related mechanisms in the progression of GDM and the great potential of HFDFs to reduce susceptibility to GDM through gut-microbiota-placenta axis.