The role of gut microbiota metabolite trimethylamine N-oxide in functional impairment of bone marrow mesenchymal stem cells in osteoporosis disease

Background: Osteoporosis (OP) is a prevalent metabolic bone disease characterized by bone loss and structural deterioration, which increases the risk of fracture especially in older people. Recent research has shown that gut microbes play an important role in OP. Trimethylamine N-oxide (TMAO), a gut microbiota-derived metabolite, has been implicated in the pathogenesis of diseases, including Alzheimer's and cerebrovascular disease. This study aimed to examine the effect of TMAO in OP.

Methods: In this study, we firstly investigated the relationship between TMAO and OP. Serum samples were collected from patients with OP (n=10), and healthy participants (n=10), and the TMAO level in the serum was detected by ELISA assay. Then, bone marrow mesenchymal stem cells (BMSCs) were treated with TMAO, and we observed its effect on adipogenic and osteogenic differentiation, cell proliferation, reactive oxygen species (ROS) release, and inflammatory cytokine[interleukin (IL)-1β, IL-6 and tumor necrosis factor-alpha (TNF-α)] levels. Finally, we illustrated the underlying mechanism through which TMAO influenced BMSCs functions.

Results: Compared to the healthy group, highly significant TMAO levels were observed in the serum of the OP patients. When studied in vitro, TMAO treatment significantly promoted BMSCs adipogenesis and attenuated osteogenesis, increased ROS release and pro-inflammatory cytokine IL-1β, IL-6 and TNF-α production, and inhibited cell proliferation. Furthermore, we found that activation of the nuclear factor-κB (NF-κB) signaling pathway was necessary for TMAO to induce pro-inflammatory cytokine production, ROS release, and adipogenic and osteogenic differentiation in BMSCs.

Conclusions: Elevated TMAO levels have a strong negative correlation with the degree of bone mineral density (BMD) in OP. TMAO regulates BMSCs cell function by activating the NF-κB signaling pathway, which affects the balance of bone metabolism, leading to acceleration of bone loss and further progression of OP.

Keywords: NF‐κB signaling pathway; Osteoporosis (OP); bone marrow mesenchymal stem cells (BMSCs); trimethylamine N-oxide (TMAO).