Ovariectomy induces bone loss via microbial-dependent trafficking of intestinal TNF+ T cells and Th17 cells

Yu, Mingcan; Pal, Subhashis; Paterson, Cameron W; Li, Jau‐Yi; Tyagi, Abdul Malik; Adams, Jonathan; Coopersmith, Craig M.; Weitzmann, M. Neale; Pacifici, Roberto

doi:10.1172/jci143137

Cited by 69 publications

(82 citation statements)

References 83 publications

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“…Recent studies in osteomicrobiology have linked changes in bone phenotype to changes in gut flora. A balanced, "healthy" microbiome appears to be necessary to prevent sex hormone deficiency from inducing bone loss, a supposition supported by evidence that the supplementation of probiotics in the diets of ovariectomized mice led to the reversal of the pathogenic process of osteoporosis [8,47]. Furthermore, an examination of several studies that have evaluated the amount and diversity of bacterial populations in the gut of patients with osteoporosis has made it clear that osteoporotic adults appear to have reduced diversity of organisms, with increases in certain species such as Fusobacterium, Dialister, Faecalibacterium, and Tolumonas and decreases in Bacteroides and Roseburia spp.…”

Section: Human Gut Microbiota: Role In Osteoporosis and Osteoclastogenesismentioning

confidence: 99%

“…Many cell signaling cascades necessary for immune cell maturation and function, in part, depend on the gut microbiota for continued optimal function and homeostasis throughout life. Though incredibly complex, the leading hypothesis of recent literature regarding the connection between overall bone health and the gut microbiome centers around T and Th17 immune cells [7,8]. In a T-cell-dependent mechanism, the immune system's reaction to microbiota stimulation increases circulating osteoclastogenic cytokines [8].…”

Section: Human Gut Microbiota: Role In Osteoporosis and Osteoclastogenesismentioning

confidence: 99%

“…Though incredibly complex, the leading hypothesis of recent literature regarding the connection between overall bone health and the gut microbiome centers around T and Th17 immune cells [7,8]. In a T-cell-dependent mechanism, the immune system's reaction to microbiota stimulation increases circulating osteoclastogenic cytokines [8]. Furthermore, although the role is not entirely understood, it appears that Th17 immune cells are an integral member of the osteoclast population; thus, it can be postulated that any imbalance of the gut microbiome may, in turn, affect a critical immune mechanism necessary for bone homeostasis.…”

Section: Human Gut Microbiota: Role In Osteoporosis and Osteoclastogenesismentioning

confidence: 99%

“…Part of the impact of microbial dysbiosis on bone healing and ultimately bone health is mediated by the gut microbiota in the trafficking of TNF + T and Th17 inflammatory cells to the bone marrow as well as influencing the overall inflammatory state of the patient, in what is now being called the "brain-gut-bone" axis [7][8][9]. The inflammatory cells recruited to the wound site by a host of growth factors and chemokines begin laying Int.…”

Section: Introductionmentioning

confidence: 99%

“…In an abnormal state, the immune system's reaction to microbiota stimulation leads to an increase in circulating osteoclastogenic cytokines through the action of T-cells. This degradative process is not active in normal gut microbiota states [8].…”

mentioning

confidence: 98%

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The Human Gut Microbiota: A Key Mediator of Osteoporosis and Osteogenesis

Seely

Kotelko

Douglas

et al. 2021

IJMS

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An expanding body of research asserts that the gut microbiota has a role in bone metabolism and the pathogenesis of osteoporosis. This review considers the human gut microbiota composition and its role in osteoclastogenesis and the bone healing process, specifically in the case of osteoporosis. Although the natural physiologic processes of bone healing and the pathogenesis of osteoporosis and bone disease are now relatively well known, recent literature suggests that a healthy microbiome is tied to bone homeostasis. Nevertheless, the mechanism underlying this connection is still somewhat enigmatic. Based on the literature, a relationship between the microbiome, osteoblasts, osteoclasts, and receptor activator of nuclear factor-kappa-Β ligand (RANKL) is contemplated and explored in this review. Studies have proposed various mechanisms of gut microbiome interaction with osteoclastogenesis and bone health, including micro-RNA, insulin-like growth factor 1, and immune system mediation. However, alterations to the gut microbiome secondary to pharmaceutical and surgical interventions cannot be discounted and are discussed in the context of clinical therapeutic consideration. The literature on probiotics and their mechanisms of action is examined in the context of bone healing. The known and hypothesized interactions of common osteoporosis drugs and the human gut microbiome are examined. Since dysbiosis in the gut microbiota can function as a biomarker of bone metabolic activity, it may also be a pharmacological and nutraceutical (i.e., pre- and probiotics) therapeutic target to promote bone homeostasis.

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Section: Human Gut Microbiota: Role In Osteoporosis and Osteoclastogenesismentioning

confidence: 99%

Section: Human Gut Microbiota: Role In Osteoporosis and Osteoclastogenesismentioning

confidence: 99%

Section: Human Gut Microbiota: Role In Osteoporosis and Osteoclastogenesismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 98%

See 3 more Smart Citations

The Human Gut Microbiota: A Key Mediator of Osteoporosis and Osteogenesis

Seely

Kotelko

Douglas

et al. 2021

IJMS

View full text Add to dashboard Cite

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Deciphering Immune Landscape Remodeling Unravels the Underlying Mechanism for Synchronized Muscle and Bone Aging

Yin,

Chen,

Rao

et al. 2023

Advanced Science

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Evidence from numerous studies has revealed the synchronous progression of aging in bone and muscle; however, little is known about the underlying mechanisms. To this end, human muscles and bones are harvested and the aging‐associated transcriptional dynamics of two tissues in parallel using single‐cell RNA sequencing are surveyed. A subset of lipid‐associated macrophages (triggering receptor expressed on myeloid cells 2, TREM2+ Macs) is identified in both aged muscle and bone. Genes responsible for muscle dystrophy and bone loss, such as secreted phosphoprotein 1 (SPP1), are also highly expressed in TREM2+ Macs, suggesting its conserved role in aging‐related features. A common transition toward pro‐inflammatory phenotypes in aged CD4+ T cells across tissues is also observed, activated by the nuclear factor kappa B subunit 1 (NFKB1). CD4+ T cells in aged muscle experience Th1‐like differentiation, whereas, in bone, a skewing toward Th17 cells is observed. Furthermore, these results highlight that degenerated myocytes produce BAG6‐containing exosomes that can communicate with Th17 cells in the bone through its receptor natural cytotoxicity triggering receptor 3 (NCR3). This communication upregulates CD6 expression in Th17 cells, which then interact with TREM2+ Macs through CD6‐ALCAM signaling, ultimately stimulating the transcription of SPP1 in TREM2+ Macs. The negative correlation between serum exosomal BCL2‐associated athanogene 6 (BAG6) levels and bone mineral density further supports its role in mediating muscle and bone synchronization with aging.

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Microbial Tryptophan Metabolites Ameliorate Ovariectomy‐Induced Bone Loss by Repairing Intestinal AhR‐Mediated Gut‐Bone Signaling Pathway

Chen,

Cao,

Lei

et al. 2024

Advanced Science

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Microbial tryptophan (Trp) metabolites acting as aryl hydrocarbon receptor (AhR) ligands are shown to effectively improve metabolic diseases via regulating microbial community. However, the underlying mechanisms by which Trp metabolites ameliorate bone loss via gut‐bone crosstalk are largely unknown. In this study, supplementation with Trp metabolites, indole acetic acid (IAA), and indole‐3‐propionic acid (IPA), markedly ameliorate bone loss by repairing intestinal barrier integrity in ovariectomy (OVX)‐induced postmenopausal osteoporosis mice in an AhR‐dependent manner. Mechanistically, intestinal AhR activation by Trp metabolites, especially IAA, effectively repairs intestinal barrier function by stimulating Wnt/β‐catenin signaling pathway. Consequently, enhanced M2 macrophage by supplementation with IAA and IPA secrete large amount of IL‐10 that expands from intestinal lamina propria to bone marrow, thereby simultaneously promoting osteoblastogenesis and inhibiting osteoclastogenesis in vivo and in vitro. Interestingly, supplementation with Trp metabolites exhibit negligible ameliorative effects on both gut homeostasis and bone loss of OVX mice with intestinal AhR knockout (VillinCreAhrfl/fl). These findings suggest that microbial Trp metabolites may be potential therapeutic candidates against osteoporosis via regulating AhR‐mediated gut‐bone axis.

show abstract

Ovariectomy induces bone loss via microbial-dependent trafficking of intestinal TNF+ T cells and Th17 cells

Cited by 69 publications

References 83 publications

The Human Gut Microbiota: A Key Mediator of Osteoporosis and Osteogenesis

The Human Gut Microbiota: A Key Mediator of Osteoporosis and Osteogenesis

Deciphering Immune Landscape Remodeling Unravels the Underlying Mechanism for Synchronized Muscle and Bone Aging

Microbial Tryptophan Metabolites Ameliorate Ovariectomy‐Induced Bone Loss by Repairing Intestinal AhR‐Mediated Gut‐Bone Signaling Pathway

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