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.
Many studies have suggested a role for gut-resident microbes (the “gut microbiome”) in modulating host health; however, the mechanisms by which they impact systemic physiology remain largely unknown. ...In this study, metabolomic and transcriptional profiling of germ-free and conventionalized mouse liver revealed an upregulation of the Nrf2 antioxidant and xenobiotic response in microbiome-replete animals. Using a Drosophila-based screening assay, we identified members of the genus Lactobacillus capable of stimulating Nrf2. Indeed, the human commensal Lactobacillus rhamnosus GG (LGG) potently activated Nrf2 in the Drosophila liver analog and the murine liver. This activation was sufficient to protect against two models of oxidative liver injury, acetaminophen overdose and acute ethanol toxicity. Characterization of the portal circulation of LGG-treated mice by tandem mass spectrometry identified a small molecule activator of Nrf2, 5-methoxyindoleacetic acid, produced by LGG. Taken together, these data demonstrate a mechanism by which intestinal microbes modulate hepatic susceptibility to oxidative injury.
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•The gut microbiome induces the Nrf2 antioxidant response pathway in the liver•Gut-resident Lactobacilli induce hepatic Nrf2 in both Drosophila and mice•Oral delivery of Lactobacillus rhamnosus GG protects against oxidative liver injury•Lactobacilli-derived 5-methoxyindoleacetic acid activates Nrf2
Saeedi et al. demonstrate that the gut microbiome acts at a distance to activate host antioxidant responses in the liver. These responses can be amplified by exogenous administration of Lactobacilli and protect against oxidative liver injury. Finally, they identify a Lactobacilli-derived small molecule that mediates, in part, these effects.
A eubiotic microbiota influences many physiological processes in the metazoan host, including development and intestinal homeostasis. Here, we have shown that the intestinal microbiota modulates ...inflammatory responses caused by sex steroid deficiency, leading to trabecular bone loss. In murine models, sex steroid deficiency increased gut permeability, expanded Th17 cells, and upregulated the osteoclastogenic cytokines TNFα (TNF), RANKL, and IL-17 in the small intestine and the BM. In germ-free (GF) mice, sex steroid deficiency failed to increase osteoclastogenic cytokine production, stimulate bone resorption, and cause trabecular bone loss, demonstrating that the gut microbiota is central in sex steroid deficiency-induced trabecular bone loss. Furthermore, we demonstrated that twice-weekly treatment of sex steroid-deficient mice with the probiotics Lactobacillus rhamnosus GG (LGG) or the commercially available probiotic supplement VSL#3 reduces gut permeability, dampens intestinal and BM inflammation, and completely protects against bone loss. In contrast, supplementation with a nonprobiotic strain of E. coli or a mutant LGG was not protective. Together, these data highlight the role that the gut luminal microbiota and increased gut permeability play in triggering inflammatory pathways that are critical for inducing bone loss in sex steroid-deficient mice. Our data further suggest that probiotics that decrease gut permeability have potential as a therapeutic strategy for postmenopausal osteoporosis.
The microbiota that inhabits the mammalian intestine can influence a range of physiological functions, including the modulation of immune responses, enhancement epithelial barrier function, and the ...stimulation of cell proliferation. While the mechanisms by which commensal prokaryotes stimulate immune signaling networks are well-characterized, less is known about the mechanistic control over homeostatic pathways within tissues. Recent reports by our research group have demonstrated that contact between the gut epithelia and some groups of enteric commensal bacteria prompts the rapid generation of reactive oxygen species (ROS) within host cells. Whereas the bacterial-induced production of ROS in phagocytes in response to ligand binding to Formyl Peptide Receptors (FPRs) and ensuing activation of NADPH oxidase 2 (Nox2) is a well-defined mechanism, ROS generated by other cell types such as intestinal epithelia in response to microbial signals via FPRs and the NADPH oxidase 1 (Nox1) is less appreciated. Importantly, enzymatically generated ROS have been shown to function as second messengers in many signal transduction pathways via the transient oxidative activity on sensor proteins bearing oxidant-sensitive thiol groups. Examples of redox sensitive proteins include tyrosine phosphatases that serve as regulators of MAPK pathways, focal adhesion kinase, as well as components involved NF-kB activation. Here, we review the leading edge discoveries gleaned from investigations that focus on microbial-induced generation of ROS and their functional effects on host physiology. These studies identify the functional molecular elements and mechanistic events that mediate the established effects of the normal microbiota on intestinal physiology.
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•Bacterial contact with host epithelial cells can result in redox signaling.•ROS is produced by mechanisms involving formyl peptide receptors and NAPDH oxidases.•Distinct bacterial taxa have different abilities to stimulate redox signaling.•Redox signaling is involved in cytoprotection, cellular motility and proliferation.
It is known that the gut microbiota, the numerically vast and taxonomically diverse microbial communities that thrive in a symbiotic fashion within our alimentary tract, can affect the normal ...physiology of the gastrointestinal tract and liver. Further, disturbances of the microbiota community structure from both endogenous and exogenous influences as well as the failure of host responsive mechanisms have been implicated in a variety of disease processes. Mechanistically, alterations in intestinal permeability and dysbiosis of the microbiota can result in inflammation, immune activation, and exposure to xenobiotic influences. Additionally, the gut and liver are continually exposed to small molecule products of the microbiota with proinflammatory, gene regulatory, and oxidative properties. Long-term coevolution has led to tolerance and incorporation of these influences into normal physiology and homeostasis; conversely, changes in this equilibrium from either the host or the microbial side can result in a wide variety of immune, inflammatory, metabolic, and neoplastic intestinal and hepatic disorders.
The intestinal epithelium is a highly dynamic structure that rejuvenates in response to acute stressors and can undergo alterations in cellular composition as animals age. The microbiota, acting via ...secreted factors related to indole, appear to regulate the sensitivity of the epithelium to stressors and promote epithelial repair via IL-22 and type I IFN signaling. As animals age, the cellular composition of the intestinal epithelium changes, resulting in a decreased proportion of goblet cells in the colon. We show that colonization of young or geriatric mice with bacteria that secrete indoles and various derivatives or administration of the indole derivative indole-3 aldehyde increases proliferation of epithelial cells and promotes goblet cell differentiation, reversing an effect of aging. To induce goblet cell differentiation, indole acts via the xenobiotic aryl hydrocarbon receptor to increase expression of the cytokine IL-10. However, the effects of indoles on goblet cells do not depend on type I IFN or on IL-22 signaling, pathways responsible for protection against acute stressors. Thus, indoles derived from the commensal microbiota regulate intestinal homeostasis, especially during aging, via mechanisms distinct from those used during responses to acute stressors. Indoles may have utility as an intervention to limit the decline of barrier integrity and the resulting systemic inflammation that occurs with aging.
An optimal gut microbiota influences many beneficial processes in the metazoan host. However, the molecular mechanisms that mediate and function in symbiont-induced host responses have not yet been ...fully characterized. Here, we report that cellular ROS enzymatically generated in response to contact with lactobacilli in both mice and Drosophila has salutary effects against exogenous insults to the intestinal epithelium via the activation of Nrf2 responsive cytoprotective genes. These data show that the xenobiotic-inducible Nrf2 pathway participates as a signaling conduit between the prokaryotic symbiont and the eukaryotic host. Indeed, our data imply that the capacity of lactobacilli to induce redox signaling in epithelial cells is a highly conserved hormetic adaptation to impel cellular conditioning to exogenous biotic stimuli. These data also highlight the role the microbiota plays in eukaryotic cytoprotective pathways and may have significant implications in the characterization of a eubiotic microbiota.
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•Commensal lactobacilli activate the xenobiotic responsive Nrf2 pathway•Nrf2 pathway activation upregulates cytoprotective genes in both Drosophila and mice•Nrf2 target genes protect against environmental stresses•Lactobacilli transduce cytoprotective effects via Nrf2 pathway activation
Jones et al. report that the commensal gut bacterial taxa lactobacilli are able to mediate beneficial cytoprotective effects in the gut of both flies and mice. These highly conserved events are mediated by ROS-dependent activation of the Nrf2 xenobiotic pathway and conserved effector genes.
Bone loss is a frequent but not universal complication of hyperparathyroidism. Using antibiotic-treated or germ-free mice, we show that parathyroid hormone (PTH) only caused bone loss in mice whose ...microbiota was enriched by the Th17 cell-inducing taxa segmented filamentous bacteria (SFB). SFB
microbiota enabled PTH to expand intestinal TNF
T and Th17 cells and increase their S1P-receptor-1 mediated egress from the intestine and recruitment to the bone marrow (BM) that causes bone loss. CXCR3-mediated TNF
T cell homing to the BM upregulated the Th17 chemoattractant CCL20, which recruited Th17 cells to the BM. This study reveals mechanisms for microbiota-mediated gut-bone crosstalk in mice models of hyperparathyroidism that may help predict its clinical course. Targeting the gut microbiota or T cell migration may represent therapeutic strategies for hyperparathyroidism.
The results generated from the NIH funded Human Microbiome Project (HMP) are necessarily tied to the overall mission of the agency, which is to foster scientific discoveries as a basis for protecting ...and improving health. The investment in the HMP phase 1 accomplished many of its goals including the preliminary characterization of the human microbiome and the identification of links between microbiome diversity and disease states. Going forward, the next step in these studies must involve the identification of the functional molecular elements that mediate the positive influence of a eubiotic microbiome on health and disease. This review will focus on recent advances describing mechanistic events in the intestine elicited by the microbiome. These include symbiotic bacteria-induced activation of redox-dependent cell signaling, the bacterial production of short chain fatty acids and ensuing cellular responses, and the secretion of bacteriocins by bacteria that have anti-microbial activities against potential pathogens.
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