The Role of Gut Microbial Changes in Lysine Metabolism on Bone Mechanical Adaptation

Research Background

Osteoporosis, a severe global public health issue, affects over 200 million people, posing significant threats to health and life. Studies have shown that maintaining bone health and preventing osteoporosis are closely linked to mechanical load. However, clinical evidence indicates significant individual differences in skeletal responses to exercise load (bone mechanical adaptation). Over the past few decades, it has become increasingly clear that gut microbiota plays a crucial role in host health, and research has shown a connection between gut microbiota and bone homeostasis. Therefore, understanding the regulatory mechanisms of gut microbiota on bone mechanical adaptation and finding possible interventions has become a pressing scientific question that needs to be addressed.

Research Source

This study, titled “Gut microbial alterations in arginine metabolism determine bone mechanical adaptation,” was written by Dan Wang and her team. The paper reveals the key role of gut microbial alterations in lysine metabolism on bone mechanical adaptation. The study was published on June 4, 2024, in the journal Cell Metabolism. The research team primarily comes from the Department of Biomedical Engineering at the Fourth Military Medical University, the School of Life Sciences at Northwest University, the Basic Medical College of Shaanxi University of Chinese Medicine, and the Department of Orthopedics at Xijing Hospital.

Research Process

Experimental Subjects and Steps

The study first used an antibiotic-treated mouse model to investigate the effect of microbiota depletion on bone load adaptability. The mice received a broad-spectrum antibiotic cocktail treatment for two weeks, including ampicillin, metronidazole, neomycin, and vancomycin, which effectively depletes the native gut microbiota. After antibiotic treatment, the right tibia of the mice was subjected to uniaxial cyclic compression load, with the left leg serving as a control.

Treadmill Walking Experiment

Over six weeks, the mice were subjected to physical training on a treadmill. The researchers observed significant differences in the composition of the gut microbiota between the high-response group (HRs) and the low-response group (LRs) of mice in terms of bone mechanical adaptation. Compared to LRs mice, HRs mice had a higher abundance of Lachnospiraceae in the phylum Firmicutes.

Microbial Transfer and Metabolite Experiment

Through fecal transplantation experiments, it was found that gut microbiota isolated from HRs mice significantly improved the bone mechanical adaptability of recipient mice. Further experiments determined that specific lysine metabolites, such as L-citrulline and its conversion to L-arginine, significantly enhanced bone mechanical adaptation in normal, young, and ovariectomized mice.

Molecular Mechanism Analysis

The study demonstrated that L-arginine promotes the mechanical adaptability of osteocytes by activating a signal pathway centered on a nitric oxide-calcium ion (NO-Ca2+) positive feedback amplification loop. The continuous activation of this signaling pathway enhances the survival of osteocytes under mechanical load and the expression of related bone protein genes, thereby benefiting the maintenance of bone health.

Research Results

Inhibition of Bone Response

The results showed that in antibiotic-treated mice, mechanical loading no longer significantly affected the structure of cortical and trabecular bone, and there were no significant changes in bone mechanical properties. In contrast, untreated mice exhibited significant increases in bone mass and strength.

Differences Between High-Response and Low-Response Groups

Through treadmill training, the study distinguished high-response mice from low-response mice. In the HRs group, Lachnospiraceae in the phylum Firmicutes significantly increased after training, and their bone mechanical performance significantly improved. Additionally, the serum concentrations of L-citrulline and L-arginine in this group were significantly higher than those in the LRs group.

The Role of Microbial Transplantation and Lysine Metabolites

Fecal transplantation experiments showed that gut microbiota isolated from the HRs group significantly enhanced bone mechanical response in recipient mice. Specific bacterial strains, such as C. clostridioforme from Lachnospiraceae, were found to produce L-citrulline and its derivative L-arginine, which significantly improved bone structure and function under mechanical load in mice.

Exploration of Molecular Mechanisms

The exploration of molecular mechanisms revealed that L-arginine utilizes nitric oxide synthase (NOS) to produce nitric oxide (NO), a key mediator in osteocyte mechanical adaptation. L-arginine further increased NO concentration within osteocytes under fluid shear stress (FSS) and activated the NO-Ca2+ positive feedback loop, thereby enhancing osteocyte survival and gene expression regulation capacity, ultimately optimizing bone mechanical adaptation.

Research Significance and Value

Scientific Value

This study reveals the crucial role of gut microbiota and its metabolites in bone mechanical adaptation. This finding challenges the traditional belief that bone regulation relies solely on physical mechanical and biochemical signals, providing a new perspective for understanding bone loss and its prevention.

Application Value

The study results demonstrate the potential application of L-arginine as a therapeutic approach in the prevention and treatment of osteoporosis. Especially for the elderly and postmenopausal women with low mechanical adaptability, L-arginine offers new hope for improving their bone health.

Research Highlights

1. This study is the first to detail the regulatory mechanism of gut microbiota in bone mechanical adaptation.
2. The study confirms the critical role of L-citrulline and its derivative L-arginine in the response of osteocytes to mechanical load.
3. The discovery of a new mechanism by which L-arginine promotes bone health by activating the NO-Ca2+ positive feedback loop.

Conclusion

This study not only emphasizes the importance of gut microbiota and its metabolites in regulating bone mechanical adaptation but also proposes a new intervention strategy to optimize skeletal benefits from mechanical load through the microbiota-metabolite axis, providing important references for personalized osteoporosis prevention and treatment.