Abstract
Microbial metabolites are known to modulate immune responses of the host. The main metabolites derived from microbial fermentation of dietary fibers in the intestine, short-chain fatty acids (SCFA), affect local and systemic immune functions. Here we show that SCFA are regulators of osteoclast metabolism and bone mass in vivo. Treatment of mice with SCFA as well as feeding with a high-fiber diet significantly increases bone mass and prevents postmenopausal and inflammation-induced bone loss. The protective effects of SCFA on bone mass are associated with inhibition of osteoclast differentiation and bone resorption in vitro and in vivo, while bone formation is not affected. Mechanistically, propionate (C3) and butyrate (C4) induce metabolic reprogramming of osteoclasts resulting in enhanced glycolysis at the expense of oxidative phosphorylation, thereby downregulating essential osteoclast genes such as TRAF6 and NFATc1. In summary, these data identify SCFA as potent regulators of osteoclast metabolism and bone homeostasis.
Highlights
Microbial metabolites are known to modulate immune responses of the host
Micro-computed tomography analysis of tibial bone showed that short-chain fatty acids (SCFA) treatment significantly increased bone mass as shown by increased bone volume per tissue volume (BV/TV) and decreased trabecular separation (Tb.Sp) (Fig. 1a–c)
Osteoclast differentiation assays showed that concentrations from 0.03 mM of C2 and 0.015 mM of C3/C4 suppressed osteoclast differentiation (Fig. 2a, b), and this range of concentration was found in pooled bone marrow fluids from two individual experiments after SCFA feeding, namely, around 0.4 mM for C3 and 0.15 mM for C4 after adjusting measured concentrations in flushed bone marrow samples to what we experimentally found in the bone marrow fluid volume from repeated measurements of 5.5 ± 1.34 μl (n = 5) (Supplementary Fig. 2a, b)
Summary
Microbial metabolites are known to modulate immune responses of the host. The main metabolites derived from microbial fermentation of dietary fibers in the intestine, short-chain fatty acids (SCFA), affect local and systemic immune functions. Propionate (C3) and butyrate (C4) induce metabolic reprogramming of osteoclasts resulting in enhanced glycolysis at the expense of oxidative phosphorylation, thereby downregulating essential osteoclast genes such as TRAF6 and NFATc1 These data identify SCFA as potent regulators of osteoclast metabolism and bone homeostasis. Studies addressing the role of the gut microbiota on bone homeostasis by using germ-free (GF), antibiotictreated or mono-colonized mice reported contradicting findings[10,11,12,13,14,15] These discrepancies may be explained by different microbial exposure of the mice used for the experiments. Our findings indicate a crucial role of SCFA in bone metabolism and immune responses attenuating the severity of arthritis
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