(665d) Short Chain Fatty Acid Influence on Normal and Estrogen Deficient Bone Remodeling

Introduction: Osteoporosis is a costly and debilitating disease in which bone resorption chronically exceeds bone formation. Estrogen deficiency, a major contributor to osteoporosis, influences the cytokines involved in bone health through T cell populations such as anti-inflammatory T regulatory cells (Tregs) and inflammatory T helper (Th)17 cells [1]. A promising area of research to treat osteoporosis involves the use of prebiotics or probiotics to increase the amount of short chain fatty acids (SCFAs) produced by gut metabolites. These SCFAs have been shown to positively influence bone health indirectly, by increasing Tregs. The Tregs then modulate osteoblast production (bone forming cells) via Wnt signaling [2]. However, in a previous model developed in our lab we determined that Wnt signaling alone could not reproduce the result of SCFAs on bone health pointing to other influences [3, 4]. We hypothesize that dietary induced increases of SCFAs could prevent or reverse bone loss caused by estrogen deficiency.

Methods: In this work we will explore other SCFA influences, model estrogen deficiency via T cell populations and cytokines, and apply the SCFA action to an estrogen deficient case. We will utilize newly acquired data to inform and expand our multicompartment ordinary differential equations (ODEs) model of SCFA influence on bone. Our initial model includes compartments for the gut, blood, and bone with ODEs corresponding to SCFA production, naïve CD4+ T cells, and Treg cells. TGF-β and Wnt signaling are also considered in the bone compartment along with equations corresponding to bone cell populations such as Osteoblasts, Osteoclasts, and Osteocytes.

Because our initial model is unable to replicate the total effect of increase SCFAs with Wnt signaling alone, we will consider the possibility of SCFAs having a direct action on bone health as well as other indirect actions caused by the increase in Tregs. We previously explored possible direct actions of SCFA on bone health and determined that they could influence osteoblasts proliferation, osteoclasts differentiation, and osteoclasts death. Here we will apply a new data set to the model to better understand the possible direct actions of SCFAs. Our initial model also only considers the indirect impact of Tregs via Wnt signaling. The new data will allow us to determine other cytokine changes in the bone compartment that could be related to the change in Tregs. These cytokine changes would add new terms to the bone cell population ODEs that are proportional to the Treg population.

Knowing that estrogen influence T cell populations, we will then alter the bone compartment of the model to include and ODE equation for Th17 cells. Here, we will focus on capturing the proportional relationship between Tregs and Th17 cells as well as the inflammatory action of Th17 cells. For the inflammatory action of Th17 cells we will fit new parameters to the existing equations that allow Th17 cells to influence osteoclast production and survival. Using the newly altered model we will simulate an estrogen deficient case by altering parameters related to estrogen in bone health such as increasing osteocyte death, reducing the ratio of Treg to Th 17 cells, and increasing inflammatory cytokines. Lastly, we will artificially dose this case with SCFAs to explore the action of SCFAs on estrogen deficient bone loss.

Results: Using the model, we will identify other potential actions of SCFAs on bone health. We will also be able to see the effect of estrogen deficiency on the ratio of Treg and Th17 cells within the bone compartment. Lastly, we will be able to predict if and at what amounts increased SCFAs could counteract estrogen deficient bone loss. These insights on bone health could lead to improved treatment and prevention protocols for those at risk for osteoporosis.

Acknowledgment: This work was supported by the National Institutes of Health grants R35GM133763 and R15AT010725 and the University at Buffalo.

References:

1. Pacifici, et al., Role of T cells in ovariectomy induced bone loss—revisited, J Bone Miner Res (2012).

2. Tyagi, et al., The microbial metabolite butyrate stimulates bone formation via T regulatory cell-mediated regulation of WNT10B expression. Immunity (2018).

3. Islam, et al., Mathematical modeling of the gut-bone axis and implications of butyrate treatment on osteoimmunology, Ind Eng Chem Res (2021).

4. Cook, et al., Mathematical modeling of the effects of Wnt-10b on bone metabolism, bioRxiv (2022).