Nearly half of orthopaedic trauma patients are intoxicated at the time of injury, and excess alcohol consumption increases the risk for fracture nonunion. Previous studies show alcohol disrupts fracture associated Wnt...Nearly half of orthopaedic trauma patients are intoxicated at the time of injury, and excess alcohol consumption increases the risk for fracture nonunion. Previous studies show alcohol disrupts fracture associated Wnt signaling required for normal bone fracture repair. Intermittent parathyroid hormone(PTH) promotes bone growth through canonical Wnt signaling, however, no studies have investigated the effect of PTH on alcohol-inhibited bone fracture repair. Male C57 BL/6 mice received two-3 day alcohol binges separated by 4 days before receiving a mid-shaft tibia fracture. Postoperatively, mice received PTH daily until euthanasia. Wnt/β-catenin signaling was analyzed at 9 days post-fracture. As previously observed, acute alcohol exposure resulted in a >2-fold decrease in total and the active form of β-catenin and a 2-fold increase in inactive β-catenin within the fracture callus. Intermittent PTH abrogated the effect of alcohol on β-catenin within the fracture callus. Upstream of β-catenin, alcohol-treated animals had a 2-fold decrease in total LRP6, the Wnt co-receptor, which was restored with PTH treatment. Alcohol nor PTH had any significant effect on GSK-3β. These data show that intermittent PTH following a tibia fracture restores normal expression of Wnt signaling proteins within the fracture callus of alcohol-treated mice.展开更多
Background Patients intoxicated at the time of burn experience increased rates of sepsis and death compared with that observed in similarly sized burns alone.We sought to characterise changes in the intestinal microbi...Background Patients intoxicated at the time of burn experience increased rates of sepsis and death compared with that observed in similarly sized burns alone.We sought to characterise changes in the intestinal microbiome and short-chain fatty acids(SCFAs)following alcohol intoxication and burn injury and to determine whether these changes are associated with intestinal inflammation.Methods 10–12-week-old C57BL/6 male and female mice were subjected to ethanol intoxication and a 12.5%total body surface area scald burn injury.The following day,mice were euthanised and faecal contents from the caecum and small intestine(SI)were harvested for 16S sequencing for microbial analysis and caecum contents underwent high-performance liquid chromatography mass spectroscopy to assess SCFAs.Results The intestinal microbiome of ethanol burn(EB)mice exhibited decreased alpha diversity and distinct beta diversity compared with sham vehicle(SV).EB faeces were marked by increased Proteobacteria and many pathobionts.EB caecum faeces exhibited a significant decrease in butyrate and a downward trend in acetate and total SCFAs.SCFA changes correlated with microbial changes particularly in the SI.Treatment of murine duodenal cell clone-K(MODE-K)cells with faecal slurries led to upregulation of interleukin-6(IL-6)from EB faeces compared with SV faeces which correlated with levels of Enterobacteriaceae.However,supplementation of butyrate reduced faecal slurry-induced MODE-K cells IL-6 release.Conclusion Together,these findings suggest that alcohol and burn injury induce bacterial dysbiosis and a decrease in SCFAs,which together can promote intestinal inflammation and barrier disruption,predisposing to postinjury pathology.展开更多
基金AO North AmericaNational Institute on Alcohol Abuse and Alcoholism,Grant/Award Number R21AA025551 and T32AA013527。
文摘Nearly half of orthopaedic trauma patients are intoxicated at the time of injury, and excess alcohol consumption increases the risk for fracture nonunion. Previous studies show alcohol disrupts fracture associated Wnt signaling required for normal bone fracture repair. Intermittent parathyroid hormone(PTH) promotes bone growth through canonical Wnt signaling, however, no studies have investigated the effect of PTH on alcohol-inhibited bone fracture repair. Male C57 BL/6 mice received two-3 day alcohol binges separated by 4 days before receiving a mid-shaft tibia fracture. Postoperatively, mice received PTH daily until euthanasia. Wnt/β-catenin signaling was analyzed at 9 days post-fracture. As previously observed, acute alcohol exposure resulted in a >2-fold decrease in total and the active form of β-catenin and a 2-fold increase in inactive β-catenin within the fracture callus. Intermittent PTH abrogated the effect of alcohol on β-catenin within the fracture callus. Upstream of β-catenin, alcohol-treated animals had a 2-fold decrease in total LRP6, the Wnt co-receptor, which was restored with PTH treatment. Alcohol nor PTH had any significant effect on GSK-3β. These data show that intermittent PTH following a tibia fracture restores normal expression of Wnt signaling proteins within the fracture callus of alcohol-treated mice.
基金National Institutes of Health grants,T32AA013527,R01GM128242,and F30DK123929 supported this work.
文摘Background Patients intoxicated at the time of burn experience increased rates of sepsis and death compared with that observed in similarly sized burns alone.We sought to characterise changes in the intestinal microbiome and short-chain fatty acids(SCFAs)following alcohol intoxication and burn injury and to determine whether these changes are associated with intestinal inflammation.Methods 10–12-week-old C57BL/6 male and female mice were subjected to ethanol intoxication and a 12.5%total body surface area scald burn injury.The following day,mice were euthanised and faecal contents from the caecum and small intestine(SI)were harvested for 16S sequencing for microbial analysis and caecum contents underwent high-performance liquid chromatography mass spectroscopy to assess SCFAs.Results The intestinal microbiome of ethanol burn(EB)mice exhibited decreased alpha diversity and distinct beta diversity compared with sham vehicle(SV).EB faeces were marked by increased Proteobacteria and many pathobionts.EB caecum faeces exhibited a significant decrease in butyrate and a downward trend in acetate and total SCFAs.SCFA changes correlated with microbial changes particularly in the SI.Treatment of murine duodenal cell clone-K(MODE-K)cells with faecal slurries led to upregulation of interleukin-6(IL-6)from EB faeces compared with SV faeces which correlated with levels of Enterobacteriaceae.However,supplementation of butyrate reduced faecal slurry-induced MODE-K cells IL-6 release.Conclusion Together,these findings suggest that alcohol and burn injury induce bacterial dysbiosis and a decrease in SCFAs,which together can promote intestinal inflammation and barrier disruption,predisposing to postinjury pathology.
