Prophylactic oral diosgenin attenuates acute sleep deprivation-induced liver injury in mice via modulation of the gut microbiota and vascular barrier.

Acute sleep deprivation (SD) is an increasingly prevalent health risk, yet the early inflammatory processes associated with acute hepatic injury following SD remain largely elusive. Following a two-step screening of 265 natural products and bioactive small molecules, diosgenin (DG), a sapogenin found in Dioscorea species, was prioritized for subsequent in vivo evaluation. Under the rotating-platform paradigm in mice, 24-hour SD (SD24h) was associated with acute hepatic inflammation, increased overall intestinal permeability, gut vascular barrier (GVB)-associated alterations, gut microbiota dysbiosis, and elevated intestinal and hepatic lipopolysaccharide (LPS) levels. Prophylactic oral DG pretreatment attenuated hepatic and intestinal inflammatory responses, intestinal permeability changes, and GVB-associated alterations, while partially ameliorating SD-associated changes in the gut microbiota and intestinal and hepatic LPS levels. Fecal microbiota transplantation further showed that microbiota from SD24h donors transferred part of the hepato-intestinal inflammatory and barrier-associated phenotypes to antibiotic-pretreated recipients, whereas microbiota from DG-pretreated SD24h donors transferred an attenuated phenotype. Collectively, these findings support the involvement of the gut microbiota and intestinal barrier in acute SD-associated liver injury and indicate that prophylactic oral DG pretreatment attenuates these hepato-intestinal responses.