SCFA: a new hope for the treatment of bone loss?

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Bone loss is one of the main causes of morbidity in the elderly. Current treatments are increasingly effective but they are not without side effects. The intestinal microbiota and its metabolites offer unique opportunities to better understand the mechanisms at play and develop new potential treatments, according to studies conducted by a German team.

 

Osteoporosis and rheumatic diseases are real public health issues and are the subject of many studies, some of which have recently demonstrated the influence of certain bacteria in inflammatory diseases such as rheumatoid arthritis and ankylosing spondylitis. To show that the metabolites —rather than the bacteria themselves—may have a beneficial effect on the bones, the researchers focused their analyses on short-chain fatty acids (SCFA). They followed three approaches in mice: direct supplementation with SCFA, high-fiber diet and bacterial transfer.

Reduction in bone remodeling

The main SCFAs involved in mammalian physiology, i.e. acetic (C2), propionic (C3) and butyric (C4) acids, were administered to mice. The treatment led to a significant increase in bone mass and an improvement in trabecular microarchitecture. CTX*, used clinically as a marker of bone resorption, significantly decreased, as was osteoclast-mediated bone destruction. The high-fiber diet generated similar effects, since it increased intestinal and serum levels of SCFA. Finally, changing the microbiota by inoculating a specific bacterial species seems to have an impact on bone homeostasis: transfer of Prevotella spp. not only increased the number of osteoclasts, but also reduced SCFA levels and total bone mass.

Osteoclast downregulation

The protective effect of SCFA on bones is due to the in vitro and in vivo inhibition of osteoclast differentiation and bone resorption, while bone formation is not affected. This study shows that SCFAs act at a very early stage in osteoclast regulation. Propionate (C3) and butyrate (C4) induce metabolic reprogramming. This results in an increased glycolysis at the expense of oxidative phosphorylation, triggering a downregulation of osteoclast-essential genes such as TRAF6 and NFATc1. These results are in good agreement with those of other studies, which have already shown that glycolysis is associated with a downregulation of TRAF6 in other cells. The authors took their investigation of the effects of SCFA further. The clinical approach was tested in ovariectomized mice, showing that treatment with C3 and C4 could prevent bone loss after menopause. These data make it possible to foresee effective therapies that target the microbiota and its metabolites.

 

*CTX: C-terminal telopeptide of type I collagen

 

Sources:

Lucas, S. et al. Short-chain fatty acids regulate systemic bone mass and protect from pathological bone loss. Nature Communications 9, 55 (2018).