Fructus Ligustri Lucidi preserves bone quality through the regulation of gut microbiota diversity, oxidative stress, TMAO and Sirt6 levels in aging mice.

Lin Li,Yu Li,Dieter Brömme,Qiangqiang Jia,Yan Liu,Dongwei Zhang,Sihua Gao,Fangfang Mo,Lili Wang,Rui Li,Jinfa Tang,Yimiao Tian,Alexander N Orekhov,Chenyue Liu,Beibei Chen,Dandan Zhao,Ruyuan Zhu

doi:10.18632/aging.102376

Abstract

Gut dysbiosis and oxidative stress may trigger senile osteoporosis. Fructus Ligustri Lucidi (FLL) has bone-preserving properties and affects the intestinal microecology. However, the mechanism of the anti-osteoporotic effect of FLL and its link to the gut microbiota remains to be elucidated. Here, we demonstrated that sustained exposure of ICR mice to D-galactose / sodium nitrite for 90 days causes aging-related osteoporosis and reduced cognitive performance. The aging phenotype is also characterized by increased oxidative stress in serum. This is likely triggered by abnormal changes in the gut microbiota population of Bifidobacterium and the ratio of Firmicutes/ Bacteroidetes that resulted in increased levels of flavin-containing monooxygenase-3 and trimethylamine-N-oxide (TMAO). Moreover, the increased oxidative stress further accelerated aging by increasing tumor necrosis factor-α levels in serum and reducing Sirtuin 6 (Sirt6) expression in long bones, which prompted nuclear factor kappa-B acetylation as well as over-expression and activation of cathepsin K. FLL-treated aging mice revealed a non-osteoporotic bone phenotype and an improvement on the cognitive function. The mechanism underlying these effects may be linked to the regulation of gut microbiota diversity, antioxidant activity, and the levels of TMAO and Sirt6. FLL may represent a potential source for identifying anti-senile osteoporotic drug candidates.

Highlights

Osteoporosis is an age-associated skeletal disorder characterized by reduced bone quality and increased fracture risks
Aging mice demonstrated a deficit in memory and cognitive function which was improved by Fructus Ligustri Lucidi (FLL) treatment
To further characterize the specific gut microbiota compositional differences, we focused on the key community members derived from the Linear discriminant analysis effect size (LEfSe) analysis (Figure 4E and 4F)

Summary

Introduction

Osteoporosis is an age-associated skeletal disorder characterized by reduced bone quality and increased fracture risks. A growing body of evidence suggests that aging may play a central role in the induction of bone loss, regardless of estrogen deficiency [3, 4]. As bone loss primarily occurs in populations aged 30 years and above, the burden of osteoporosis is projected to increase dramatically due to the aging population [5]. Effective measures are needed for the early diagnosis and prevention of bone fractures. Plant-based therapies, including traditional Chinese medicine (TCM), have gained growing attention in the management of osteoporosis due to their cost effectiveness, multi-drug targets, and low risk of adverse reactions [8]

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