Anti-inflammatory and osteogenic effects of transcutaneous electrical nerve stimulation in knee osteoarthritis rats via the regulation of the intestinal microbiotaOA

Background:This study revealed the function and mechanism of the intestinal microbiota in knee osteoarthritis(KOA)rats treated using transcutaneous electrical nerve stimulation(TENS).Methods:KOA model rats were randomly divided into low−/medium−/high-intensity TENS groups,sodium hyaluronate(SH)-positive control group(SH),and model control group(KOA rat).After 1,2,and 3 weeks of treatment,the improvement in KOA severity was assessed,and the expression of interleukin-1β(IL-1β)/IL-6/IL-8/bone morphogenetic protein 2(BMP-2)/transforming growth factorβ(TGF-β)was analyzed.The diversity of the intestinal microbiota in KOA rats was analyzed via 16S ribosomal DNA(rDNA)sequencing.After fecal microbiota transplantation(FMT),which was induced by TENS,the improvement in the intestinal microbiota in KOA rats was analyzed.Results:After 3 weeks of treatment using TENS,compared to those in the model control group,the biomechanical parameters increased in the SH and TENS groups(p<0.05);the gait parameters improved in the SH and TENS groups;the bone mineral density(BMD)increased in the TENS group(p<0.05);the Mankin scores of the distal femur and proximal tibiofibular muscles decreased in the SH and TENS groups(p<0.05).IL-1β/6/8 expression levels decreased in the SH and TENS groups(p<0.05).BMP-2/TGF-βexpression in the distal femur increased in the TENS group(p<0.05).16S rDNA sequencing revealed that the intestinal microbiota of KOA rats was changed after TENS treatment,including increases in Escherichia-Shigella,Lachnospira,Eubacterium,Gastranaerophilales,and Rikenellaceae RC9 and decreases in Fusicatenibacter and Mycoplasma.After FMT,which is induced by TENS,similar improvements in KOA rats were obtained.Conclusions:TENS promoted anti-inflammatory and osteogenic effects by downregulating the Il-1β/6/8 expression levels and upregulating the BMP-2/TGF-βsignaling pathway.16S rDNA sequencing revealed that the intestinal microbiota of KOA rats was changed after TENS treatment via the gut–knee joint axis,and that these dominant genera of FMT elicited improvements in KOA rats.TENS caused improvements in KOA rats by regulating the intestinal microbiota;thus,TENS and induced FMT altered intestinal microbiota suggest a potential novel therapeutic avenue for KOA in clinical settings.