激素补充治疗对围绝经期女性肠道微生态的影响及其与骨代谢的相关性OA

Objective:To investigate the effects of hormone replacement therapy(HRT)on the structure,di-versity,and fecal metabolites of gut microbiota in perimenopausal women,and to analyze their correlations with bone metabolism indicators.Methods:A total of 48 perimenopausal patients who visited the hospital from April 2021 to May 2022 were enrolled.According to whether they received HRT and the treatment duration,they were di-vided into three groups:the control group(without HRT,n=24),the short-term supplementation group(treatment duration:10～12 months,n=12),and the long-term supplementation group(treatment duration:20～26 months,n=12).Fecal samples were collected from patients,and 16S rDNA sequencing was performed to analyze the composition and diversity of gut microbiota(including Ace,Chao,Sobs,and Shannon indices).Meanwhile,untar-geted metabolomics detection was conducted using liquid chromatography-mass spectrometry(LC-MS).Mean-while,bone mineral density(BMD)of the lumbar spine(L1～L4)and bilateral femoral necks,as well as the levels of procollagen type I N-terminal peptide(PINP,a bone formation marker)and C-terminal telopeptide of type I col-lagen(CTX,a bone resorption marker),were measured in patients before and after treatment.Pearson correlation coefficients were calculated to analyze the correlation between differential metabolites and gut microbiota,while Spearman correlation analysis was performed to explore the relationship between differential metabolites and bone metabolism indicators.Results:①Comparisons of bone metabolism indicators showed that after treatment,the BMD of the lumbar spine(L1～L4)(0.91±0.19 g/cm2),BMD of the bilateral femoral necks(0.94±0.14 g/cm2),and PINP levels(38.52±6.72 ng/ml)in the long-term supplementation group were significantly higher than those in the short-term supplementation group and the control group(P<0.05),while the CTX levels(535.19±21.59 pg/mL)were significantly lower.②Sequentially analyzing the differential microbiota among the three groups at the phylum,class,order,family,genus,and species levels revealed the following:there were no statistically significant differences in the average relative abundances of Firmicutes,Bacteroidetes,or the Firmi-cutes/Bacteroidetes ratio among the three groups(P>0.05);the average relative abundances of Lachnospirace-ae,Butyricicoccaceae,and Christensenellaceae were significantly different among the three groups(P<0.05);the average relative abundance of Faecalibacterium prausnitzii in the long-term supplementation group was higher than that in the short-term supplementation group,but the difference was not statistically significant(P>0.05).Compared with the control group and the short-term supplementation group,the gut microbiota α-diversity indices(Ace,Chao,Sobs,and Shannon indices)in the long-term supplementation group were significantly increased(P<0.05).③ Metabolomic analysis showed that the levels of indole-3-acetic acid,arachidonic acid,and L-proline in the long-term supplementation group were significantly higher than those in the other two groups(P<0.05).④Correlation analysis showed that indole-3-acetic acid,arachidonic acid(AA),and L-proline were all positively cor-related with Faecalibacterium prausnitzii(r>0,P<0.05);after merging the short-term supplementation group and the long-term supplementation group into a treatment group(regardless of the duration of HRT),it was found that the content of indole-3-acetic acid was positively correlated with procollagen type I N-terminal peptide(PINP),lumbar spine(L1～L4)BMD,and bilateral femoral neck BMD(r>0,P<0.05).Conclusions:Long-term HRT can significantly increase the gut microbiota diversity of perimenopausal women,alter the relative abundances of spe-cific bacterial families(e.g.,Lachnospiraceae,Christensenellaceae,and Butyricicoccaceae),and upregulate the fecal metabolite levels of indole-3-acetic acid,arachidonic acid,and L-proline.Among these metabolites,in-dole-3-acetic acid is positively correlated with bone formation markers and BMD,suggesting that HRT may im-prove bone metabolism in perimenopausal women by regulating the gut microecology and its metabolites(espe-cially indole-3-acetic acid).Modulating the gut microbiota composition or metabolite pathways may serve as a po-tential strategy for perimenopausal management.