The gut-bone axis: how bacterial metabolites bridge the distance
Mario M. Zaiss, … , Georg Schett, Roberto Pacifici
Mario M. Zaiss, … , Georg Schett, Roberto Pacifici
Published July 15, 2019
Citation Information: J Clin Invest. 2019;129(8):3018-3028. https://doi.org/10.1172/JCI128521.
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Review

The gut-bone axis: how bacterial metabolites bridge the distance

Abstract

The gut microbiome is a key regulator of bone health that affects postnatal skeletal development and skeletal involution. Alterations in microbiota composition and host responses to the microbiota contribute to pathological bone loss, while changes in microbiota composition that prevent, or reverse, bone loss may be achieved by nutritional supplements with prebiotics and probiotics. One mechanism whereby microbes influence organs of the body is through the production of metabolites that diffuse from the gut into the systemic circulation. Recently, short-chain fatty acids (SCFAs), which are generated by fermentation of complex carbohydrates, have emerged as key regulatory metabolites produced by the gut microbiota. This Review will focus on the effects of SCFAs on the musculoskeletal system and discuss the mechanisms whereby SCFAs regulate bone cells.

Authors

Mario M. Zaiss, Rheinallt M. Jones, Georg Schett, Roberto Pacifici

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Figure 1

SCFAs bolster the gut epithelium and coerce a tolerogenic immune environment.

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SCFAs bolster the gut epithelium and coerce a tolerogenic immune environ...
(i) SCFAs act as a major and preferred energy source to the colonic epithelium. (ii) SCFAs signal via GPR43/109a to induce inflammasome activation, culminating in IL-18 secretion, which functions in gut barrier homeostasis. (iii) SCFAs dampen NF-κB signaling via HDAC inhibition, thereby inhibiting secretion of proinflammatory cytokines. (iv) SCFAs inhibit recruitment and activation of macrophages and neutrophils through a reduction in proinflammatory cytokine production. (v) SCFAs induce a tolerogenic dendritic cell phenotype by inducing the secretion of IL-10 and retinoic acid. IL-10 inhibits effector T cell function, while retinoic acid binds to the retinoic acid receptor in naive T cells to induce their differentiation into Tregs. (vi) SCFAs induce Treg differentiation through HDAC inhibition, which inhibits the activity of effector T cells, thus establishing a tolerogenic immune environment.