Getting Warmer: Following One's Gut to Build Bone

Abstract

In this issue of the Cell Metabolism, Chevalier et al. show that a warm environment produces changes in the composition of intestinal microbiota and that these changes can prevent bone loss due to hypogonadism. Dovetailing with prior studies on the ability of probiotics to reverse hypogonadism-induced osteopenia, the findings reaffirm a central role for the microbiome in regulating bone mass in response to both environmental and hormonal cues.

Figure 1.. The Gut Microbiota-Bone Metabolism Circuitry in Hypogonadism and in Warm Environments

In normal physiology, the gut flora do not produce detrimental immunological activation, nor are there excessive levels of sex steroids and gonadotropins that regulate the inflammatory signaling response. As a result, bone remodeling is precisely controlled to the extent that osteoclastic bone resorption is matched with equal quanta of newly formed bone, with no net bone loss (upper panel). In a hypogonadal state, when sex steroids decline and gonadotropins, such as follicle-stimulating hormone (FSH), rise, there is a change in the gut microbiota favoring the proliferation of proteobacteria and a resultant increase in lipopolysaccharide (LPS). This, in turn, leads to increased inflammation and effector T cell activation (middle panel). A warm (34°C) environment can induce changes in the composition of normal gut flora (lower panel). Colonization by strains such as Akkermansiaceae increases, while that by others, including Ruminiclostridium, decreases. Certain strains, such as Muribaculaceae, show reduced biodiversity. These compositional changes lead to an increase in the intestinal production of polyamines. One of these, spermidine is produced from putrescine by spermidine synthase. Amino acids, such as arginine and methionine, contribute to the generation of putrescine. Spermidine, in turn, can decrease inflammation and bone resorption while simultaneously increasing osteoblastic bone formation. Together, these actions will prevent the bone loss seen during times of pathophysiologic stress, such as in hypogonadal states.