Tauroursodeoxycholic acid(TUDCA)improves intestinal barrier function associated with TGR5-MLCK pathway and the alteration of serum metabolites and gut bacteria in weaned piglets

Background:Tauroursodeoxycholic acid(TUDCA),a hydrophilic bile acid,is the main medicinal component of bear bile and is commonly used to treat a variety of hepatobiliary diseases.Meanwhile,TUDCA has been shown to modulate the intestinal barrier function and alleviate DSS-induced colitis in mice.However,the effect of TUDCA on the intestinal barrier of weaned piglets remains largely unclear.Methods:The weaned piglets and porcine IPEC-J2 intestinal epithelial cells were used to investigate the effects of TUDCA on intestinal barrier function in weaned piglets and explore the possible underlying mechanisms.In vivo,72 healthy weaned piglets were randomly allocated into 2 groups according to their gender and body weight,and piglets were fed the basal diet with 0(control,CON)and 200 mg/kg TUDCA for 30 d,respectively.Three female and three male piglets reflecting the average bodyweight were slaughtered in each group and samples were collected.In vitro,IPEC-J2 cells were subjected to 100μmol/L TUDCA to explore the possible underlying mechanisms.Results:Our results demonstrated that dietary TUDCA supplementation significantly reduced the diarrhea incidence of weaned piglets,possibly attributing to the TUDCA-enhanced intestinal barrier function and immunity.In addition,TUDCA supplementation altered serum metabolites and the relative abundance of certain gut bacteria,which might contribute to the improved intestinal barrier function.Furthermore,the in-vitro results showed that TUDCA improved the E.coli-induced epithelial barrier impairment of IPEC-J2 cells and increased Takeda G-coupled protein receptor 5(TGR5)protein expression.However,knockdown of TGR5 and inhibition of myosin light chain kinase(MLCK)pathway abolished the TUDCA-improved epithelial barrier impairment in E.coli-treated IPEC-J2 cells,indicating the involvement of TGR5-MLCK in this process.Conclusions:These findings showed that TUDCA improved intestinal barrier function associated with TGR5-MLCK pathway and the alteration of serum metabolites and gut bacteria in weaned piglets,suggesting the potential application of TUDCA in improving gut health in piglet production.

AKG/OXGR1 promotes skeletal muscle blood flow and metabolism by relaxing vascular smooth muscle

In response to contraction during exercise,skeletal muscle growth and metabolism are dynamically regulated by nerve action,blood flow,and metabolic feedback.α-Ketoglutarate(AKG),a bioactive intermediate in the tricarboxylic acid cycle released during exercise,has been shown to promote skeletal muscle hypertrophy.However,the underlying mechanism of AKG in regulating skeletal muscle development and metabolism is still less known.2-Oxoglutarate receptor 1(OXGR1),the endogenous AKG receptor,is found to be distributed in the vascular smooth muscle(VSM)of skeletal muscles.OXGR1 knockout results in skeletal muscle atrophy,accompanied by decreased expression of myosin heavy chain I(MyHC I),capillary density,and endurance exercise capacity.Furthermore,the study found that dietary AKG supplementation increased mice endurance exercise distance,MyHC I/MyHC IIb ratio,arteriole,and capillary densities in skeletal muscle.Meanwhile,acute AKG administration gradually increased the blood flow in the lower limbs.Further,by using OXGR1 global knockout and OXGR1 VSM-specific(MYH11-Cre×OXGR1-FloxP)knockdown models,we found that OXGR1 in VSM is essential for AKG-induced improvement of skeletal muscle performances.According to the in vitro study,AKG expanded the cell area in VSM with a decreased intracellular pH by OXGR1.Our results demonstrated a novel role of AKG/OXGR1 in VSM of skeletal muscle to regulate blood flow and then enhance slow muscle fiber conversion and capillarization.These findings provide a theoretical basis for the AKG/OXGR1 signaling pathway to maintain human muscle function and improve meat production and livestock and poultry meat quality.