Abstract
ABSTRACTOsteoporosis and its associated fractures are highly prevalent in older women. Recent studies have shown that gut microbiota play important roles in regulating bone metabolism. A previous randomized controlled trial (RCT) found that supplementation with Lactobacillus reuteri ATCC PTA 6475 (L.reuteri) led to substantially reduced bone loss in older women with low BMD. However, the total metabolic effects of L. reuteri supplementation on older women are still not clear. In this study, a post hoc analysis (not predefined) of serum metabolomic profiles of older women from the previous RCT was performed to investigate the metabolic dynamics over 1 year and to evaluate the effects of L. reuteri supplementation on human metabolism. Distinct segregation of the L. reuteri and placebo groups in response to the treatment was revealed by partial least squares‐discriminant analysis. Although no individual metabolite was differentially and significantly associated with treatment after correction for multiple testing, 97 metabolites responded differentially at any one time point between L. reuteri and placebo groups (variable importance in projection score >1 and p value <0.05). These metabolites were involved in multiple processes, including amino acid, peptide, and lipid metabolism. Butyrylcarnitine was particularly increased at all investigated time points in the L. reuteri group compared with placebo, indicating that the effects of L. reuteri on bone loss are mediated through butyrate signaling. Furthermore, the metabolomic profiles in a case (low BMD) and control population (high BMD) of elderly women were analyzed to confirm the associations between BMD and the identified metabolites regulated by L. reuteri supplementation. The amino acids, especially branched‐chain amino acids, showed association with L. reuteri treatment and with low BMD in older women, and may serve as potential therapeutic targets. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
Highlights
IntroductionOsteoporosis is a disease characterized by reduced BMD, deteriorated bone microarchitecture, and reduced bone strength, which increases the susceptibility to low energy or fragility fractures primarily affecting the older population.[1,2] Accumulating evidence has revealed that the gut microbiota is a key regulator of bone metabolism and could affect bone health.[3,4,5,6] Previous studies in mice have revealed that gut microbiota influences bone health by the regulation of the immune system and balance.[7]
Osteoporosis is a disease characterized by reduced BMD, deteriorated bone microarchitecture, and reduced bone strength, which increases the susceptibility to low energy or fragility fractures primarily affecting the older population.[1,2] Accumulating evidence has revealed that the gut microbiota is a key regulator of bone metabolism and could affect bone health.[3,4,5,6] Previous studies in mice have revealed that gut microbiota influences bone health by the regulation of the immune system and balance.[7]. The supplementation of probiotic strain Lactobacillus reuteri ATCC PTA 6475 (L. reuteri) has been shown to reduce bone loss and increase bone density in mice with estrogen deficiency or increased inflammation.[8,9] These data suggest that L. reuteri may be a potential therapeutic strategy to prevent postmenopausal bone loss
We first analyzed time-series metabolomic profiles of elderly women with bone loss to evaluate if metabolic changes were caused by the supplementation of L. reuteri
Summary
Osteoporosis is a disease characterized by reduced BMD, deteriorated bone microarchitecture, and reduced bone strength, which increases the susceptibility to low energy or fragility fractures primarily affecting the older population.[1,2] Accumulating evidence has revealed that the gut microbiota is a key regulator of bone metabolism and could affect bone health.[3,4,5,6] Previous studies in mice have revealed that gut microbiota influences bone health by the regulation of the immune system and balance.[7]. Untargeted metabolomics have provided an opportunity to investigate the global metabolic changes in human populations.[11,12] the existing metabolomic studies related to osteoporosis have been performed in rats and humans,(13-16) the effects of probiotic supplementation on human bone metabolism have not been explored. We investigated the effect of daily supplementation with L. reuteri or placebo on serum metabolomic profiles in older women who had been included in a 1-year randomized controlled trial (RCT) in a nonpredefined post hoc analysis.[10] We further examined differences in metabolic profiles between older women with severe osteoporosis (case group) and high bone density (control group). We identified the key serum metabolic makers that were regulated by L. reuteri treatment and discriminated subjects with severe osteoporosis from controls. The present study’s results suggest that the affected metabolic pathways by L. reuteri contribute to the regulation of bone loss in older women
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