Host cell and microbe interactions have evolved in practically every animal, with the cross-talk between microorganisms that inhabit the gut lumen with tissues of the gastrointestinal tract an example that is increasingly recognized as being critical to health and disease [1],[2],[3]. Microbial colonization of the gastrointestinal tract starts at birth, eventuating in a taxonomically diverse community by early adulthood [4]. Intestinal microbes flourish in an environment that is rich in nutrients, with specific taxa recognized as causative of conferring beneficial effects on the host, such as improved energy extraction from food, exclusion of pathogenic bacteria, and stimulation of tissue development [5],[6]. Gut luminal bacteria also beneficially influence tissue homeostasis in the intestine by enhancing epithelial cell proliferation and survival, and strengthening barrier function [7],[8],[9],[10],[11],[12]. Indeed, mice raised in germ-free conditions exhibit many functional weaknesses [13], and have impaired homeostasis [14]. These observations show that there is an active and dynamic association between microbes that reside within the gut and host cells.

Gut microbes have also been shown to modulate intestinal and systemic immune responses [15]. For instance, gut-resident microbes have a robust influence on the emergence and/or maintenance of CD4+ T cell subsets. Examples include the effects of specific bacteria on the emergence of Th17 cells [16] and the impact of Bacteroides fragilis in Th1 cells and Treg differentiation [17]. Indeed, abnormalities in gut microbial diversity (“dysbiosis”) have been suggested to be sufficient to aggravate intestinal pathologies related to the immune system such as in inflammatory bowel disease [18]. However, a more intriguing paradigm is emerging evidence that the commensal microbes also influence immune responses distant from mucosal surfaces, including, but not limited to, the CNS, joints and lungs [19],[20],[21],[22],[23]. Relevant to this review is the observation that gut microbes influence systemic immune responses critical for bone homeostasis. For example, investigations have revealed that germ-free mice display increased bone mass due to the lack of immune cell activation [24], that low-dose antibiotic treatment increases bone density in young mice [25], and that probiotic treatment prevents ovariectomy (ovx) induced bone loss [26],[27].