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Zhang Y, Zhu Y, Li M, Zhang M, Shou D, Tong P. A promising approach to diabetic osteoporosis: oxymatrine's effects on gut microbiota and osteoblasts. Nutr Diabetes 2025; 15:19. [PMID: 40328755 PMCID: PMC12055986 DOI: 10.1038/s41387-025-00374-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 04/25/2025] [Accepted: 04/28/2025] [Indexed: 05/08/2025] Open
Abstract
OBJECTIVES Oxymatrine (OMT), a quinolizidine alkaloid derived from Sophora flavescens Ait., has demonstrated therapeutic potential in type 2 diabetes mellitus (T2DM). This study aimed to investigate its effects on diabetic osteoporosis (DOP) and explore the underlying mechanisms involving gut microbiota and osteogenic regulation. METHODS In a rat model of T2DM, intragastric Oxymatrine was used to study trabecular bone repair through bone microstructure and histopathology analyses. Changes in gut microbiota, especially Gram-negative bacteria releasing lipopolysaccharides (LPS), were assessed via 16S rRNA sequencing. miRNA sequencing on LPS-induced rat osteoblasts, with and without Oxymatrine, explored osteoblast proliferation, mineralization, and the miR-539-5p/OGN/Runx2 pathway. RESULTS The administration of OMT resulted in an enhancement of diabetic osteopathy by reversing trabecular bone loss and modifying the composition of gut microbiota, specifically affecting Gram-negative bacteria that release LPS into the bloodstream. miRNA sequencing revealed that miR-539-5p, which was upregulated in LPS-induced ROBs, was downregulated following OMT treatment. Furthermore, OMT was found to promote osteoblast proliferation and mineralization under conditions of LPS exposure and modulate the miR-539-5p/OGN/Runx2 signaling pathway. CONCLUSIONS OMT improves diabetic osteoporosis by altering gut microbiota, decreasing LPS release, and enhancing osteoblast growth and differentiation through the miR-539-5p/OGN/Runx2 pathway, suggesting its potential as a treatment.
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Affiliation(s)
- Yang Zhang
- Institute of Orthopaedics and Traumatology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Yiwen Zhu
- The First Clinical School, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Mengying Li
- College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Minjie Zhang
- College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Dan Shou
- College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
| | - Peijian Tong
- Institute of Orthopaedics and Traumatology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310053, China.
- The First Clinical School, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
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2
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Di Rienzi SC, Danhof HA, Forshee MD, Roberts A, Britton RA. Limosilactobacillus reuteri promotes the expression and secretion of enteroendocrine- and enterocyte-derived hormones. FASEB J 2025; 39:e70408. [PMID: 40098558 PMCID: PMC11914943 DOI: 10.1096/fj.202401669r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2024] [Revised: 01/20/2025] [Accepted: 02/10/2025] [Indexed: 03/19/2025]
Abstract
Intestinal microbes can beneficially impact host physiology, prompting investigations into the therapeutic usage of such microbes in a range of diseases. For example, human intestinal microbe Limosilactobacillus reuteri strains ATCC PTA 6475 and DSM 17938 are being considered for use for intestinal ailments, including colic, infection, and inflammation, as well as for non-intestinal ailments, including osteoporosis, wound healing, and autism spectrum disorder. While many of their beneficial properties are attributed to suppressing inflammatory responses, we postulated that L. reuteri may also regulate intestinal hormones to affect physiology within and outside of the gut. To determine if L. reuteri secreted factors impact the secretion of enteric hormones, we treated an engineered jejunal organoid line, NGN3-HIO, which can be induced to be enriched in enteroendocrine cells, with L. reuteri 6475 or 17938 conditioned medium and performed transcriptomics. Our data suggest that these L. reuteri strains affect the transcription of many gut hormones, including vasopressin and luteinizing hormone subunit beta, which have not been previously recognized as produced in the gut epithelium. Moreover, we find that these hormones appear to be produced in enterocytes, in contrast to canonical gut hormones produced in enteroendocrine cells. Finally, we show that L. reuteri conditioned media promote the secretion of enteric hormones, including serotonin, GIP, PYY, vasopressin, and luteinizing hormone subunit beta, and identify by metabolomics metabolites potentially mediating these effects on hormones. These results support L. reuteri affecting host physiology through intestinal hormone secretion, thereby expanding our understanding of the mechanistic actions of this microbe.
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Affiliation(s)
- Sara C. Di Rienzi
- Department of Molecular Virology and MicrobiologyBaylor College of MedicineHoustonTexasUSA
- Alkek Center for Metagenomics and Microbiome ResearchBaylor College of MedicineHoustonTexasUSA
| | - Heather A. Danhof
- Department of Molecular Virology and MicrobiologyBaylor College of MedicineHoustonTexasUSA
- Alkek Center for Metagenomics and Microbiome ResearchBaylor College of MedicineHoustonTexasUSA
| | - Micah D. Forshee
- Department of Molecular Virology and MicrobiologyBaylor College of MedicineHoustonTexasUSA
- Alkek Center for Metagenomics and Microbiome ResearchBaylor College of MedicineHoustonTexasUSA
| | - Ari Roberts
- Department of Molecular Virology and MicrobiologyBaylor College of MedicineHoustonTexasUSA
- Alkek Center for Metagenomics and Microbiome ResearchBaylor College of MedicineHoustonTexasUSA
| | - Robert A. Britton
- Department of Molecular Virology and MicrobiologyBaylor College of MedicineHoustonTexasUSA
- Alkek Center for Metagenomics and Microbiome ResearchBaylor College of MedicineHoustonTexasUSA
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3
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Jha SS, Jeyaraman N, Jeyaraman M, Ramasubramanian S, Muthu S, Santos GS, da Fonseca LF, Lana JF. Cross-talks between osteoporosis and gut microbiome. World J Orthop 2025; 16:102274. [PMID: 40124724 PMCID: PMC11924030 DOI: 10.5312/wjo.v16.i3.102274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2024] [Revised: 01/06/2025] [Accepted: 02/06/2025] [Indexed: 03/12/2025] Open
Abstract
The gut microbiome comprises a vast community of microbes inhabiting the human alimentary canal, playing a crucial role in various physiological functions. These microbes generally live in harmony with the host; however, when dysbiosis occurs, it can contribute to the pathogenesis of diseases, including osteoporosis. Osteoporosis, a systemic skeletal disease characterized by reduced bone mass and increased fracture risk, has attracted significant research attention concerning the role of gut microbes in its development. Advances in molecular biology have highlighted the influence of gut microbiota on osteoporosis through mechanisms involving immunoregulation, modulation of the gut-brain axis, and regulation of the intestinal barrier and nutrient absorption. These microbes can enhance bone mass by inhibiting osteoclast differentiation, inducing apoptosis, reducing bone resorption, and promoting osteoblast proliferation and maturation. Despite these promising findings, the therapeutic effectiveness of targeting gut microbes in osteoporosis requires further investigation. Notably, gut microbiota has been increasingly studied for their potential in early diagnosis, intervention, and as an adjunct therapy for osteoporosis, suggesting a growing utility in improving bone health. Further research is essential to fully elucidate the therapeutic potential and clinical application of gut microbiome modulation in the management of osteoporosis.
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Affiliation(s)
- Shiva Shankar Jha
- Department of Orthopaedics, Harishchandra Orthopaedic Research Institute, Patna 880023, Bihar, India
| | - Naveen Jeyaraman
- Department of Orthopaedics, ACS Medical College and Hospital, Dr MGR Educational and Research Institute, Chennai 600077, Tamil Nadu, India
- Department of Orthopaedics, Orthopaedic Research Group, Coimbatore 641045, Tamil Nadu, India
| | - Madhan Jeyaraman
- Department of Orthopaedics, ACS Medical College and Hospital, Dr MGR Educational and Research Institute, Chennai 600077, Tamil Nadu, India
- Department of Orthopaedics, Orthopaedic Research Group, Coimbatore 641045, Tamil Nadu, India
- Department of Orthopaedics, Brazilian Institute of Regenerative Medicine (BIRM), Indaiatuba 13334-170, São Paulo, Brazil
| | - Swaminathan Ramasubramanian
- Department of Orthopaedics, Government Medical College, Omandurar Government Estate, Chennai 600002, Tamil Nadu, India
| | - Sathish Muthu
- Department of Orthopaedics, Government Medical College and Hospital, Karur 639004, Tamil Nadu, India
- Department of Orthopaedics, Orthopaedic Research Group, Coimbatore 641045, Tamil Nadu, India
- Department of Biotechnology, Faculty of Engineering, Karpagam Academy of Higher Education, Coimbatore 641021, Tamil Nadu, India
| | - Gabriel Silva Santos
- Department of Orthopaedics, Brazilian Institute of Regenerative Medicine (BIRM), Indaiatuba 13334-170, São Paulo, Brazil
| | - Lucas Furtado da Fonseca
- Department of Orthopaedics, Brazilian Institute of Regenerative Medicine (BIRM), Indaiatuba 13334-170, São Paulo, Brazil
| | - José Fábio Lana
- Department of Orthopaedics, Brazilian Institute of Regenerative Medicine (BIRM), Indaiatuba 13334-170, São Paulo, Brazil
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4
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Fan K, Hua X, Wang S, Efferth T, Tan S, Wang Z. A promising fusion: Traditional Chinese medicine and probiotics in the quest to overcome osteoporosis. FASEB J 2025; 39:e70428. [PMID: 40047492 DOI: 10.1096/fj.202403209r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 01/23/2025] [Accepted: 02/19/2025] [Indexed: 05/13/2025]
Abstract
Botanical drugs and probiotic supplements present safer alternative options for the prevention and treatment of osteoporosis (OP). However, pathological disorders of the gut microbiota and the specific properties of probiotics and traditional Chinese medicine (TCM) significantly limit their therapeutic efficacy. Given the favorable synergistic and complementary effects between probiotics and herbal medicines, a creative combination of these approaches may address the issue of their current limited efficacy. A comprehensive analysis is necessary to provide a detailed review of their potential for combination, the mechanisms behind their synergy, scientific applications, and future developments. There exists a complex relationship between gut microbiota and OP, and the underlying regulatory mechanisms are multidimensional, involving the production of pro-inflammatory metabolites, immune system disruption, and the impairment of the intestinal mucosal barrier. Furthermore, we analyzed the complex mechanisms and potential connections between probiotics, TCM, and their combined applications. We highlighted the principle of complementary gain and the substantial therapeutic potential of their organic combination, which facilitates the release of active substances in TCM, increases the bioavailability of TCM, enhances probiotic delivery efficiency, and exerts synergistic effects. The combined use of probiotics and TCM offers a safe and effective strategy for managing OP and presents an innovative and promising direction for the future development of modern phytomedicine.
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Affiliation(s)
- Kangcheng Fan
- College of Exercise and Health, Shenyang Sport University, Shenyang, China
| | - Xin Hua
- Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou, China
| | - Shuwan Wang
- College of Exercise and Health, Shenyang Sport University, Shenyang, China
| | - Thomas Efferth
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany
| | - Shengnan Tan
- Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou, China
| | - Zhuo Wang
- College of Exercise and Health, Shenyang Sport University, Shenyang, China
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5
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Sharan K, Brandt C, Yusuf MA, Singh P, Halder N, Edwards ME, Mangu SVVSR, Das A, Mishra A, Kumar SS, Sharma A, Gupta A, Liu XS, Guo EX, Monani UR, Ponnalagu D, Ivanov II, Lal G, Clare S, Dougan G, Yadav VK. Rapid and relaying deleterious effects of a gastrointestinal pathogen, Citrobacter rodentium, on bone, an extra-intestinal organ. iScience 2025; 28:111802. [PMID: 39967874 PMCID: PMC11834125 DOI: 10.1016/j.isci.2025.111802] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 08/04/2024] [Accepted: 01/10/2025] [Indexed: 02/20/2025] Open
Abstract
Enteropathogenic infections cause pathophysiological changes in the host but their effects beyond the gastrointestinal tract are undefined. Here, using Citrobacter rodentium infection in mouse, which mimics human diarrheal enteropathogenic Escherichia coli, we show that gastrointestinal infection negatively affects bone remodeling, leading to compromised bone architecture. Transmission of infection through fecal-oral route from Citrobacter rodentium-infected to non-infected mice caused bone loss in non-infected cage mates. Mice with B cell deficiency (Igh6-/- mice) failed to clear C. rodentium infection and exhibited more severe and long-term bone loss compared to WT mice. Unbiased cytokine profiling showed an increase in circulating tumor necrosis factor α (TNFα) levels following Citrobacter rodentium infection, and immunoneutralization of TNFα prevented infection-induced bone loss completely in WT and immunocompromised mice. These findings reveal rapid, relaying, and modifiable effects of enteropathogenic infections on an extraintestinal organ-bone, and provide insights into the mechanism(s) through which these infections affect extraintestinal organ homeostasis.
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Affiliation(s)
- Kunal Sharan
- Mouse Genetics Project, Wellcome Sanger Institute, Hinxton, Saffron Walden, UK
- Department of Molecular Nutrition, CSIR-CFTRI, Mysore, Karnataka, India
| | - Cordelia Brandt
- Host-Pathogen Interaction Group, Wellcome Sanger Institute, Hinxton, Saffron Walden, UK
| | - Mohd Aslam Yusuf
- Department of Bioengineering, Integral University, Lucknow, Uttar Pradesh, India
| | - Parminder Singh
- National Institute of Immunology, New Delhi, New Delhi, India
| | - Namrita Halder
- National Centre for Cell Science, Pune, Maharastra, India
| | - Madeline E. Edwards
- Department of Microbiology and Immunology, Columbia University, New York, NY, USA
| | - SVVS Ravi Mangu
- Department of Molecular Nutrition, CSIR-CFTRI, Mysore, Karnataka, India
| | - Abhilipsa Das
- Department of Molecular Nutrition, CSIR-CFTRI, Mysore, Karnataka, India
| | - Amrita Mishra
- National Centre for Cell Science, Pune, Maharastra, India
| | - Shashi S. Kumar
- Center for Motor Neuron Biology & Disease, Columbia University, New York, NY, USA
- Department of Neurology, Columbia University, New York, NY, USA
| | - Amita Sharma
- Pediatric Kidney Foundation, New Delhi, New Delhi, India
| | - Alka Gupta
- Reproductive Biology Laboratory, National Institute of Immunology, New Delhi, New Delhi, India
| | - Xiaowei S. Liu
- Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, PA, USA
| | - Edward X. Guo
- Bone Biomechanics Laboratory, Columbia University, New York, NY, USA
| | - Umrao R. Monani
- Center for Motor Neuron Biology & Disease, Columbia University, New York, NY, USA
- Department of Neurology, Columbia University, New York, NY, USA
- Department of Pathology & Cell Biology, Columbia University, New York, NY, USA
| | | | - Ivaylo I. Ivanov
- Department of Microbiology and Immunology, Columbia University, New York, NY, USA
| | - Girdhari Lal
- National Centre for Cell Science, Pune, Maharastra, India
| | - Simon Clare
- Host-Pathogen Interaction Group, Wellcome Sanger Institute, Hinxton, Saffron Walden, UK
| | - Gordon Dougan
- Host-Pathogen Interaction Group, Wellcome Sanger Institute, Hinxton, Saffron Walden, UK
- Department of Medicine, University of Cambridge, Cambridge, Cambridgeshire, UK
- Centre for Translational Stem Cell Biology, Hong Kong, China
| | - Vijay K. Yadav
- Mouse Genetics Project, Wellcome Sanger Institute, Hinxton, Saffron Walden, UK
- National Institute of Immunology, New Delhi, New Delhi, India
- Department of Genetics and Development, Columbia University, New York, NY, USA
- Healthy Longevity Program, Department of Pathology, Immunology and Laboratory Medicine, Rutgers University, Newark, NJ, USA
- Center for Cell Signaling, Rutgers University, Newark, NJ, USA
- Center for Immunity and Inflammation, Rutgers University, Newark, NJ, USA
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6
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Indrio F, Salatto A. Gut Microbiota-Bone Axis. ANNALS OF NUTRITION & METABOLISM 2025:1-10. [PMID: 39848230 DOI: 10.1159/000541999] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Accepted: 10/11/2024] [Indexed: 01/25/2025]
Abstract
BACKGROUND Knowledge of the complex interplay between gut microbiota and human health is gradually increasing as it has just recently been a field of such great interest. SUMMARY Recent studies have reported that communities of microorganisms inhabiting the gut influence the immune system through cellular responses and shape many physiological and pathophysiological aspects of the body, including muscle and bone metabolism (formation and resorption). Specifically, the gut microbiota affects skeletal homeostasis through changes in host metabolism, the immune system, hormone secretion, and the gut-brain axis. The major role on gut-bone axis is due to short-chain fatty acids (SCFAs). They have the ability to influence regulatory T-cell (Tregs) development and activate bone metabolism through the action of Wnt10. SCFA production may be a mechanism by which the microbial community, by increasing the serum level of insulin-like growth factor 1 (IGF-1), leads to the growth and regulation of bone homeostasis. A specific SCFA, butyrate, diffuses into the bone marrow where it expands Tregs. The Tregs induce production of the Wnt ligand Wnt10b by CD8+ T cells, leading to activation of Wnt signaling and stimulation of bone formation. At the hormonal level, the effect of the gut microbiota on bone homeostasis is expressed through the biphasic action of serotonin. Some microbiota, such as spore-forming microbes, regulate the level of serotonin in the gut, serum, and feces. Another group of bacterial species (Lactococcus, Mucispirillum, Lactobacillus, and Bifidobacterium) can increase the level of peripheral/vascular leptin, which in turn manages bone homeostasis through the action of brain serotonin.
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Affiliation(s)
- Flavia Indrio
- Department of Experimental Medicine, University of Salento, Lecce, Italy
| | - Alessia Salatto
- Department of Translational Medical Science, University of Naples Federico II, Napoli, Italy
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Yumol JL, Gittings W, de Souza RJ, Ward WE. A systematic review and meta-analysis of the effects of probiotics on bone outcomes in rodent models. J Bone Miner Res 2024; 40:100-113. [PMID: 39545776 DOI: 10.1093/jbmr/zjae187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 10/18/2024] [Accepted: 11/14/2024] [Indexed: 11/17/2024]
Abstract
Emerging evidence demonstrates an opportunity for using probiotics to support bone health, but findings in humans are limited. This systematic review investigated if probiotic supplementation improves bone mineral density (BMD) and bone structure in rodent models compared to no supplementation. Studies (n = 71) examining the effect of oral consumption of any probiotic strain on BMD or bone structure in rodents were included. Meta-analyses were conducted separately by study model (intact, ovariectomized) and bone site (femur, tibia, spine) to determine the probiotic effect (standardized mean difference, SMD) on volumetric BMD (vBMD), bone volume fraction (BV/TV), and cortical thickness (Ct.Th). Reasons for heterogeneity were explored (probiotic genus, sex, type of rodent). In intact rodents, probiotics resulted in greater vBMD (SMD = 0.43, 95% CI [0.13, 0.74], I2 = 3%, p < 0.05) and higher BV/TV (SMD = 0.63, 95% CI [0.25, 1.02], I2 = 57%, p < 0.05) at the femur without changes in cortical bone structure. In ovariectomized models, probiotic supplementation resulted in greater vBMD (femur: SMD = 1.28, 95% CI [1.01, 1.55], I2 = 3%, p < 0.05; tibia: SMD = 1.29, 95% CI [0.52, 2.05], I2 = 67%, p < 0.05; and spine: SMD = 1.47, 95% CI [0.97, 1.97], I2 = 26%, p < 0.05) as well as higher BV/TV (femur: SMD = 1.16, 95% CI [0.80, 1.52], I2 = 56%, p < 0.05; tibia: SMD = 2.13, 95% CI [1.09, 3.17], I2 = 79%, p < 0.05; spine: SMD = 2.04, 95% CI [1.17, 2.90], I2 = 76%, p < 0.05) and Ct.Th at the tibia (SMD = 2.35; 95% CI [0.72, 3.97], I2 = 82%, p < .0.05) but not at the femur versus control. The syntheses support probiotics as a strategy to improve bone outcomes in rodent models.
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Affiliation(s)
- Jenalyn L Yumol
- Department of Kinesiology, Brock University, St. Catharines, ON L2S 3A1, Canada
- Centre for Bone and Muscle Health, Brock University, St. Catharines, ON L2S 3A1, Canada
| | - William Gittings
- Department of Kinesiology, Brock University, St. Catharines, ON L2S 3A1, Canada
- Centre for Bone and Muscle Health, Brock University, St. Catharines, ON L2S 3A1, Canada
| | - Russell J de Souza
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON L8R 2K3, Canada
| | - Wendy E Ward
- Department of Kinesiology, Brock University, St. Catharines, ON L2S 3A1, Canada
- Centre for Bone and Muscle Health, Brock University, St. Catharines, ON L2S 3A1, Canada
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8
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Panchal L, Arora S, Pramanik J, Batta K, Kumar A, Prajapati B. Probiotics: a promising intervention for osteoporosis prevention and management. Z NATURFORSCH C 2024; 79:405-411. [PMID: 38965037 DOI: 10.1515/znc-2024-0063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Accepted: 06/20/2024] [Indexed: 07/06/2024]
Abstract
Osteoporosis (OP) is a systemic skeletal disease that is characterized by low bone mass and increased fracture risk. This article explores the potential of probiotics as an adjunctive approach for the prevention and management of OP. It has been well established that the gut microbiota (GM), a complex community of microbes, plays an important role in bone health. The gut dysbiosis is linked with a higher risk of OP. However, the consumption of probiotics in adequate amounts restores gut health thus improving bone health. Probiotics may influence bone metabolism through enhanced calcium absorption, reduced inflammation, and increased bone formation. The animal and human studies demonstrate the positive effects of probiotics on bone health parameters like reduced osteoclastogenesis, bone resorption markers, osteoblast, osteocyte apoptosis, and increased bone mineral density and expression of osteoprotegerin. The current evidence suggests that probiotics can be used as an adjunctive approach along with the existing therapies for the prevention and management of OP.
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Affiliation(s)
- Lakshay Panchal
- M.M Institute of Physiotherapy and Rehabilitation, Maharishi Markandeshwar University, Mullana, India
| | - Shivam Arora
- M.M Institute of Physiotherapy and Rehabilitation, Maharishi Markandeshwar University, Mullana, India
| | - Jhilam Pramanik
- Department of Food Technology, William Carrey University, Shillong, India
| | - Kajol Batta
- Department of Food Technology, ITM University, Gwalior, India
| | - Akash Kumar
- Department of Food Technology, SRM University, Delhi-NCR, Sonepat, India
- MMICT&BM (HM), Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala, India
| | - Bhupendra Prajapati
- 79233 Shree S.K. Patel College of Pharmaceutical Education and Research, Ganpat University , Mehsana, India
- Faculty of Pharmacy, Silpakorn University, Nakhon Pathom 73000, Thailand
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9
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You X, Yan J, Herzog J, Nobakhti S, Campbell R, Hoke A, Hammamieh R, Sartor RB, Shefelbine S, Kacena MA, Chakraborty N, Charles JF. Bone loss with aging is independent of gut microbiome in mice. Bone Res 2024; 12:65. [PMID: 39523344 PMCID: PMC11551211 DOI: 10.1038/s41413-024-00366-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 08/19/2024] [Accepted: 08/27/2024] [Indexed: 11/16/2024] Open
Abstract
Emerging evidence suggests a significant role of gut microbiome in bone health. Aging is well recognized as a crucial factor influencing the gut microbiome. In this study, we investigated whether age-dependent microbial change contributes to age-related bone loss in CB6F1 mice. The bone phenotype of 24-month-old germ-free (GF) mice was indistinguishable compared to their littermates colonized by fecal transplant at 1-month-old. Moreover, bone loss from 3 to 24-month-old was comparable between GF and specific pathogen-free (SPF) mice. Thus, GF mice were not protected from age-related bone loss. 16S rRNA gene sequencing of fecal samples from 3-month and 24-month-old SPF males indicated an age-dependent microbial shift with an alteration in energy and nutrient metabolism potential. An integrative analysis of 16S predicted metagenome function and LC-MS fecal metabolome revealed an enrichment of protein and amino acid biosynthesis pathways in aged mice. Microbial S-adenosyl methionine metabolism was increased in the aged mice, which has previously been associated with the host aging process. Collectively, aging caused microbial taxonomic and functional alteration in mice. To demonstrate the functional importance of young and old microbiome to bone, we colonized GF mice with fecal microbiome from 3-month or 24-month-old SPF donor mice for 1 and 8 months. The effect of microbial colonization on bone phenotypes was independent of the microbiome donors' age. In conclusion, our study indicates age-related bone loss occurs independent of gut microbiome.
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Affiliation(s)
- Xiaomeng You
- Department of Orthopaedic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
| | - Jing Yan
- Department of Orthopaedic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA
| | - Jeremy Herzog
- National Gnotobiotic Rodent Resource Center, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Sabah Nobakhti
- Department of Mechanical and Industrial Engineering, Northeastern University, Boston, MA, 02115, USA
| | - Ross Campbell
- The Geneva Foundation, Walter Reed Army Institute of Research, Silver Spring, MD, 20910, USA
- Medical Readiness Systems Biology, Walter Reed Army Institute of Research, Silver Spring, MD, 20910, USA
| | - Allison Hoke
- Medical Readiness Systems Biology, Walter Reed Army Institute of Research, Silver Spring, MD, 20910, USA
- ORISE, Walter Reed Army Institute of Research, Silver Spring, MD, 20910, USA
| | - Rasha Hammamieh
- Medical Readiness Systems Biology, Walter Reed Army Institute of Research, Silver Spring, MD, 20910, USA
| | - R Balfour Sartor
- National Gnotobiotic Rodent Resource Center, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Sandra Shefelbine
- Department of Mechanical and Industrial Engineering, Northeastern University, Boston, MA, 02115, USA
| | - Melissa A Kacena
- Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
- Richard L. Roudebush VA Medical Center, Indianapolis, IN, 46202, USA
| | - Nabarun Chakraborty
- Medical Readiness Systems Biology, Walter Reed Army Institute of Research, Silver Spring, MD, 20910, USA
| | - Julia F Charles
- Department of Orthopaedic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
- Division of Rheumatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
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10
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Ma Z, Liu Y, Shen W, Yang J, Wang T, Li Y, Ma J, Zhang X, Wang H. Osteoporosis in postmenopausal women is associated with disturbances in gut microbiota and migration of peripheral immune cells. BMC Musculoskelet Disord 2024; 25:791. [PMID: 39375626 PMCID: PMC11460084 DOI: 10.1186/s12891-024-07904-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Accepted: 09/23/2024] [Indexed: 10/09/2024] Open
Abstract
BACKGROUND Postmenopausal osteoporosis (PMO) results from a reduction in bone mass and microarchitectural deterioration in bone tissue due to estrogen deficiency, which may increase the incidence of fragility fractures. In recent years, the "gut-immune response-bone" axis has been proposed as a novel potential approach in the prevention and treatment of PMO. Studies on ovariectomized murine model indicated the reciprocal role of Th17 cells and Treg cells in the aetiology of osteoporosis. However, the relationship among gut microbiota, immune cells and bone metabolic indexes remains unknown in PMO. METHODS A total of 77 postmenopausal women were recruited for the study and divided into control (n = 30), osteopenia (n = 19), and osteoporosis (n = 28) groups based on their T score. The frequency of Treg and Th17 cells in lymphocytes were analyzed by flow cytometry. The serum levels of interleukin (IL)-10, 17 A, 1β, 6, tumor necrosis factor (TNF)-α, and lipopolysaccharide (LPS) were determined via enzyme-linked immunosorbent assay. Additionally, 16S rRNA gene V3-V4 region sequencing analysis was performed to investigate the gut microbiota of the participants. RESULTS The results demonstrated decreased bacterial richness and diversed intestinal composition in PMO. In addition, significant differences of relative abundance of the gut microbial community in phylum and genus levels were found, mainly including increased Bacteroidota, Proteobacteria, and Campylobacterota, as well as reduced Firmicutes, Butyricicoccus, and Faecalibacterium. Intriugingly, in the osteoporosis group, the concentration of Treg cells and associated IL-10 in peripheral circulation was negatively regulated, while other chronic systemic proinflammatory cytokines and Th17 cells showed opposite trends. Moreover, significantly elevated plasma lipopolysaccharide (LPS) in patients with osteoporosis indicated that disrupted intestinal integrity and permeability. A correlation analysis showed close relationships between gut bacteria and inflammation. CONCLUSIONS Collectively, these observations will lead to a better understanding of the relationship among bone homeostasis, the microbiota, and circulating immune cells in PMO. The elevated LPS levels of osteoporosis patients which not only indicate a breach in intestinal integrity but also suggest a novel biomarker for assessing osteoporosis risk linked to gut health.
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Affiliation(s)
- Zongjun Ma
- General Hospital of Ningxia Medical University, Yinchuan, 750004, Ningxia, China
| | - Yuanyuan Liu
- School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, 750004, Ningxia, China
| | - Wenke Shen
- School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, 750004, Ningxia, China
| | - Jiaxiao Yang
- School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, 750004, Ningxia, China
| | - Ting Wang
- School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, 750004, Ningxia, China
| | - Yiwei Li
- School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, 750004, Ningxia, China
| | - Junbai Ma
- School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, 750004, Ningxia, China
| | - Xiaoxia Zhang
- College of Traditional Chinese Medicine, Ningxia Medical University, Yinchuan, 750004, Ningxia, China.
| | - Hao Wang
- School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, 750004, Ningxia, China.
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Yue W, Sun N, Zhang J, Zhang W, Wu Y, Qu X, Zong J, Xu G. Alleviated diabetic osteoporosis and peripheral neuropathic pain by Rehmannia glutinosa Libosch polysaccharide via increasing regulatory T cells. Int J Biol Macromol 2024; 277:134241. [PMID: 39084449 DOI: 10.1016/j.ijbiomac.2024.134241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Revised: 07/02/2024] [Accepted: 07/26/2024] [Indexed: 08/02/2024]
Abstract
Diabetic peripheral neuropathy (DPN) and diabetic osteoporosis (DOP) are conditions that significantly impact the quality of life of patients worldwide. Rehmanniae Radix Preparata, a component of traditional Chinese medicine with a history spanning thousands of years, has been utilized in the treatment of osteoporosis and diabetes. Specifically, Rehmannia glutinosa Libosch polysaccharide (RGP), a key bioactive compound of Rehmanniae Radix Preparata, has demonstrated immune-modulating properties and beneficial effects on hyperglycemia, hyperlipidemia, and vascular inflammation in diabetic mice. Despite these known actions, the precise mechanisms of RGP in addressing DOP and DPN remain unclear. Our study aimed to explore the impact of RGP on osteoporosis and peripheral neuropathic pain in diabetic mice induced by streptozotocin (STZ). The findings revealed that RGP not only improved hyperglycemia and osteoporosis in STZ-induced diabetic mice but also enhanced osteogenesis, insulin production, and nerve health. Specifically, RGP alleviated distal pain, improved nerve conduction velocity, nerve fiber integrity, and immune cell balance in the spleen. Mechanistically, RGP was found to upregulate HDAC6 mRNA expression in regulatory T cells, potentially shedding light on novel pathways for preventing DOP and DPN. These results offer promising insights for the development of new therapeutic approaches for diabetic complications.
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Affiliation(s)
- Wenjie Yue
- Department of Orthopaedics, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
| | - Na Sun
- Department of Pharmacy, The Third People's Hospital of Dalian, Dalian 116091, China
| | - Jing Zhang
- Department of Orthopaedics, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
| | - Wanhao Zhang
- Department of Orthopaedics, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
| | - Yueshu Wu
- Department of Orthopaedics, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
| | - Xiaochen Qu
- Department of Orthopaedics, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China; Key Laboratory of Molecular Mechanism for Repair and Remodeling of Orthopaedic Diseases, Dalian 116011, Liaoning Province, China
| | - Junwei Zong
- Department of Orthopaedics, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China; Key Laboratory of Molecular Mechanism for Repair and Remodeling of Orthopaedic Diseases, Dalian 116011, Liaoning Province, China
| | - Gang Xu
- Department of Orthopaedics, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China; Key Laboratory of Molecular Mechanism for Repair and Remodeling of Orthopaedic Diseases, Dalian 116011, Liaoning Province, China.
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12
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Ge Y, Jia Z, Zhao S, Zhang W, Shi X, Xie R, Gong Y, Sheng J, van 't Hof RJ, Yang J, Han C, Hu X, Wang Y, Wu Y, Li C, Wang M. Mitigating lead-induced osteoporosis: The role of butyrate in gut-bone axis restoration. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2024; 283:116943. [PMID: 39216219 DOI: 10.1016/j.ecoenv.2024.116943] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/24/2024] [Revised: 08/22/2024] [Accepted: 08/23/2024] [Indexed: 09/04/2024]
Abstract
Lead (Pb) is an environmentally widespread bone toxic pollutant, contributes to the development of osteoporosis. Butyric acid, mainly produced by the fermentation of indigestible dietary fiber by gut microbiota, plays a pivotal role in the maintenance of bone homeostasis. However, the effects of butyric acids on the Pb induced osteoporosis have not yet been elucidated. In this study, our results showed that Pb exposure was negatively related to the abundance of butyric acid, in the Pb-exposed population and Pb-exposed mice. Pb exposure caused gut microbiota disorders, resulting in the decline of butyric acid-producing bacteria, such as Butyrivibrio_crossotus, Clostridium_sp._JN9, and the butyrate-producing enzymes through the acetyl-CoA pathway. Moreover, results from the NHANES data suggested that dietary intake of butyrate was associated with a reduced risk of osteoporosis in lead-burdened populations, particularly among men or participants aged 18-60 years. In addition, butyrate supplementation in mice with chronic Pb exposure improved the bone microarchitectures, repaired intestinal damage, upregulated the proportion of Treg cells. Taken together, these results demonstrated that chronic Pb exposure disturbs the gut-bone axis, which can be restored by butyric acid supplement. Our results suggest that butyrate supplementation is a possible therapeutic strategy for lead-induced bone toxicity.
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Affiliation(s)
- Yuqiu Ge
- MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, Wuxi School of medicine, Jiangnan University, China; Lab of Modern Environmental Toxicology, School of Public Health Research, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China; Public Health Research Center, Jiangnan University, Wuxi, Jiangsu, China
| | - Zhongtang Jia
- Lab of Modern Environmental Toxicology, School of Public Health Research, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - Shiting Zhao
- Lab of Modern Environmental Toxicology, School of Public Health Research, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - WenChao Zhang
- Lab of Modern Environmental Toxicology, School of Public Health Research, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - Xian Shi
- Lab of Modern Environmental Toxicology, School of Public Health Research, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - Ruijin Xie
- Affiliated Hospital of Jiangnan University, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - Yan Gong
- Department of Occupational Medicine, Wuxi Center for Disease Control and Prevention, Wuxi, Jiangsu, China
| | - Jixiang Sheng
- Lab of Modern Environmental Toxicology, School of Public Health Research, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - Rob J van 't Hof
- Institute of Ageing and Chronic Disease, University of Liverpool, United Kingdom
| | - Jiatao Yang
- Lab of Modern Environmental Toxicology, School of Public Health Research, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - Chunqing Han
- Lab of Modern Environmental Toxicology, School of Public Health Research, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - Xiping Hu
- Lab of Modern Environmental Toxicology, School of Public Health Research, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - Yafeng Wang
- Lab of Modern Environmental Toxicology, School of Public Health Research, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - Yu Wu
- MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, Wuxi School of medicine, Jiangnan University, China; Lab of Modern Environmental Toxicology, School of Public Health Research, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China; Public Health Research Center, Jiangnan University, Wuxi, Jiangsu, China.
| | - Chunping Li
- Department of Occupational Medicine, Wuxi Center for Disease Control and Prevention, Wuxi, Jiangsu, China.
| | - Miaomiao Wang
- Department of Occupational Medicine, Wuxi Center for Disease Control and Prevention, Wuxi, Jiangsu, China.
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Rienzi SCD, Danhof HA, Forshee MD, Roberts A, Britton RA. Limosilactobacillus reuteri promotes the expression and secretion of enteroendocrine- and enterocyte-derived hormones. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.08.30.610555. [PMID: 39257733 PMCID: PMC11384013 DOI: 10.1101/2024.08.30.610555] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 09/12/2024]
Abstract
Observations that intestinal microbes can beneficially impact host physiology have prompted investigations into the therapeutic usage of such microbes in a range of diseases. For example, the human intestinal microbe Limosilactobacillus reuteri strains ATCC PTA 6475 and DSM 17938 are being considered for use for intestinal ailments including colic, infection, and inflammation as well as non-intestinal ailments including osteoporosis, wound healing, and autism spectrum disorder. While many of their beneficial properties are attributed to suppressing inflammatory responses in the gut, we postulated that L. reuteri may also regulate hormones of the gastrointestinal tract to affect physiology within and outside of the gut. To determine if L. reuteri secreted factors impact the secretion of enteric hormones, we treated an engineered jejunal organoid line, NGN3-HIO, which can be induced to be enriched in enteroendocrine cells, with L. reuteri 6475 or 17938 conditioned medium and performed transcriptomics. Our data suggest that these L. reuteri strains affect the transcription of many gut hormones, including vasopressin and luteinizing hormone subunit beta, which have not been previously recognized as being produced in the gut epithelium. Moreover, we find that these hormones appear to be produced in enterocytes, in contrast to canonical gut hormones which are produced in enteroendocrine cells. Finally, we show that L. reuteri conditioned media promotes the secretion of several enteric hormones including serotonin, GIP, PYY, vasopressin, and luteinizing hormone subunit beta. These results support L. reuteri affecting host physiology through intestinal hormone secretion, thereby expanding our understanding of the mechanistic actions of this microbe.
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Affiliation(s)
- Sara C. Di Rienzi
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA
- Alkek Center for Metagenomics and Microbiome Research, Baylor College of Medicine, Houston, TX, USA
| | - Heather A. Danhof
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA
- Alkek Center for Metagenomics and Microbiome Research, Baylor College of Medicine, Houston, TX, USA
| | - Micah D. Forshee
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA
- Alkek Center for Metagenomics and Microbiome Research, Baylor College of Medicine, Houston, TX, USA
| | - Ari Roberts
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA
- Alkek Center for Metagenomics and Microbiome Research, Baylor College of Medicine, Houston, TX, USA
| | - Robert A. Britton
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA
- Alkek Center for Metagenomics and Microbiome Research, Baylor College of Medicine, Houston, TX, USA
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He W, Bertram HC, Yin JY, Nie SP. Lactobacilli and Their Fermented Foods as a Promising Strategy for Enhancing Bone Mineral Density: A Review. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:17730-17745. [PMID: 39078823 DOI: 10.1021/acs.jafc.4c03218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/15/2024]
Abstract
Lactobacilli fermentation possesses special nutritional and health values to food, especially in improving diseases related to the gut microbiota such as osteoporosis risk. Previous research indicates that lactobacilli-fermented foods have the potential to enhance the bone mineral density (BMD), as suggested by some clinical studies. Nonetheless, there is currently a lack of comprehensive summaries of the effects and potential mechanisms of lactobacilli-fermented foods on BMD. This review summarizes findings from preclinical and clinical studies, revealing that lactobacilli possess the potential to mitigate age-related and secondary factor-induced bone loss. Furthermore, these findings imply that lactobacilli are likely mediated through the modulation of bone remodeling via gut inflammation-related pathways. Additionally, lactobacilli fermentation may augment calcium accessibility through directly promoting calcium absorption or modifying food constituents. Considering the escalating global health challenge of bone-related issues among the elderly population, this review may offer a valuable reference for the development of food strategies aimed at preventing osteoporosis.
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Affiliation(s)
- Weiwei He
- State Key Laboratory of Food Science and Resources, China-Canada Joint Lab of Food Science and Technology (Nanchang), Nanchang University, 235 Nanjing East Road, Nanchang 330047, Jiangxi, China
| | | | - Jun-Yi Yin
- State Key Laboratory of Food Science and Resources, China-Canada Joint Lab of Food Science and Technology (Nanchang), Nanchang University, 235 Nanjing East Road, Nanchang 330047, Jiangxi, China
| | - Shao-Ping Nie
- State Key Laboratory of Food Science and Resources, China-Canada Joint Lab of Food Science and Technology (Nanchang), Nanchang University, 235 Nanjing East Road, Nanchang 330047, Jiangxi, China
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15
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Gregori G, Pivodic A, Magnusson P, Johansson L, Hjertonsson U, Brättemark E, Lorentzon M. Limosilactobacillus reuteri 6475 and Prevention of Early Postmenopausal Bone Loss: A Randomized Clinical Trial. JAMA Netw Open 2024; 7:e2415455. [PMID: 38865129 PMCID: PMC11170297 DOI: 10.1001/jamanetworkopen.2024.15455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Accepted: 04/05/2024] [Indexed: 06/13/2024] Open
Abstract
Importance Daily supplementation with the probiotic Limosilactobacillus reuteri ATCC PTA 6475 (L reuteri) vs placebo has previously been demonstrated to reduce bone loss in an estrogen deficiency mice model and older women, although the magnitude of the effect was small. We hypothesized that long-term treatment with L reuteri could result in clinically relevant skeletal benefits in postmenopausal osteoporosis. Objective To evaluate whether daily supplementation with L reuteri vs placebo could reduce early postmenopausal bone loss and whether the effects remained or increased over time during 2 years of treatment. Design, Setting, and Participants A double-blind, randomized, placebo-controlled clinical trial was conducted between December 4, 2019, and October 6, 2022, at a single center in Gothenburg, southwestern Sweden. Participants were recruited by online advertisements, and letters were sent to 10 062 women aged 50 to 60 years. Responding women (n = 752) underwent telephone screening, resulting in 292 women being invited to a screening visit. Of those who were screened, 239 women met all inclusion criteria and had no exclusion criteria. Interventions Capsules with L reuteri in 2 doses, 5 × 108 (low dose) or 5 × 109 (high dose) colony-forming units, taken twice daily or placebo were administered. All capsules also included cholecalciferol, 200 IU. Main Outcomes and Measures The primary outcome was the relative change in tibia total volumetric bone mineral density (vBMD) over 2 years. Secondary outcomes included relative change in areal BMD of the lumbar spine and total hip, bone turnover markers C-terminal telopeptide cross-links of collagen type I and type I procollagen intact N-terminal propeptide, as well as tibia trabecular bone volume fraction and cortical vBMD. Both intention-to-treat and per-protocol analyses were conducted. Results A total of 239 postmenopausal women (median age, 55 [IQR, 53-56] years) were included. Tibia vBMD (primary outcome), hip and spine vBMD, and tibia cortical area and BMD decreased significantly in all groups, with no group-to-group differences (percent change tibia vBMD high dose vs placebo least-squares means, -0.08 [95 CI, -0.85 to 0.69] and low dose vs placebo least-squares means, -0.22 [95% CI, -0.99 to 0.55]). There were no significant treatment effects on any other predefined outcomes. A prespecified sensitivity analysis found a significant interaction between body mass index (BMI) and treatment effect at 2 years. No significant adverse effects were observed. Conclusions and Relevance In this randomized clinical trial of 239 early postmenopausal women, supplementation with L reuteri had no effect on bone loss or bone turnover over 2 years. The observed interaction between BMI and treatment effect warrants further investigation. Trial Registration ClinicalTrials.gov Identifier: NCT04169789.
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Affiliation(s)
- Giulia Gregori
- Sahlgrenska Osteoporosis Centre, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Aldina Pivodic
- APNC, Gothenburg, Sweden
- Department of Ophthalmology, Sahlgrenska University Hospital, the Västra Götaland Region, Mölndal, Sweden
| | - Per Magnusson
- Department of Clinical Chemistry, and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Lisa Johansson
- Sahlgrenska Osteoporosis Centre, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
- The Västra Götaland Region, Department of Orthopedics, Sahlgrenska University Hospital, Mölndal, Sweden
| | - Ulrika Hjertonsson
- Sahlgrenska Osteoporosis Centre, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Emma Brättemark
- Sahlgrenska Osteoporosis Centre, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Mattias Lorentzon
- Sahlgrenska Osteoporosis Centre, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
- Geriatric Medicine, Sahlgrenska University Hospital, the Västra Götaland Region, Mölndal, Sweden
- Mary McKillop Institute for Health Research, Australian Catholic University, Melbourne, Australia
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16
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Wang T, Xiong K, He Y, Feng B, Guo L, Gu J, Zhang M, Wang H, Wu X. Chronic pancreatitis-associated metabolic bone diseases: epidemiology, mechanisms, and clinical advances. Am J Physiol Endocrinol Metab 2024; 326:E856-E868. [PMID: 38656128 DOI: 10.1152/ajpendo.00113.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 04/11/2024] [Accepted: 04/17/2024] [Indexed: 04/26/2024]
Abstract
Chronic pancreatitis (CP) is a progressive inflammatory disease with an increasing global prevalence. In recent years, a strong association between CP and metabolic bone diseases (MBDs), especially osteoporosis, has been identified, attracting significant attention in the research field. Epidemiological data suggest a rising trend in the incidence of MBDs among CP patients. Notably, recent studies have highlighted a profound interplay between CP and altered nutritional and immune profiles, offering insights into its linkage with MBDs. At the molecular level, CP introduces a series of biochemical disturbances that compromise bone homeostasis. One critical observation is the disrupted metabolism of vitamin D and vitamin K, both essential micronutrients for maintaining bone integrity, in CP patients. In this review, we provide physio-pathological perspectives on the development and mechanisms of CP-related MBDs. We also outline some of the latest therapeutic strategies for treating patients with CP-associated MBDs, including stem cell transplantation, monoclonal antibodies, and probiotic therapy. In summary, CP-associated MBDs represent a rising medical challenge, involving multiple tissues and organs, complex disease mechanisms, and diverse treatment approaches. More in-depth studies are required to understand the complex interplay between CP and MBDs to facilitate the development of more specific and effective therapeutic approaches.
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Affiliation(s)
- Tianlin Wang
- Department of Emergency, The Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Ke Xiong
- Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yanli He
- Department of General Surgery, The Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Binbin Feng
- Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - LinBin Guo
- Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Jingliang Gu
- Department of Orthopedics, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Mengrui Zhang
- Quantitative Sciences Unit, Department of Medicine, Stanford University, Stanford, California, United States
- Division of Immunology and Rheumatology, Stanford University, Stanford, California, United States
- Veterans Affairs Palo Alto Health Care System, Palo Alto, California, United States
| | - Hong Wang
- Department of General Surgery, The Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Xiaohao Wu
- Division of Immunology and Rheumatology, Stanford University, Stanford, California, United States
- Veterans Affairs Palo Alto Health Care System, Palo Alto, California, United States
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17
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Jang YJ, Choi HS, Oh I, Chung JH, Moon JS. Effects of Limosilactobacillus reuteri ID-D01 Probiotic Supplementation on Exercise Performance and Gut Microbiota in Sprague-Dawley Rats. Probiotics Antimicrob Proteins 2024:10.1007/s12602-024-10257-9. [PMID: 38635106 DOI: 10.1007/s12602-024-10257-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/07/2024] [Indexed: 04/19/2024]
Abstract
The gut microbiota composition in animals and humans has recently been found to be influenced by exercise. Although Limosilactobacillus reuteri strains have notable probiotic properties that promote human health, understanding of its effects in combination with exercise and physical activity is limited. Therefore, this study examined the effects of L. reuteri ID-D01, a human-derived probiotic, on exercise performance and fatigue in Sprague-Dawley rats. Organ weight, maximal running distance, serum biochemistry, muscle performance, microbial community composition, and short-chain fatty acid (SCFA) levels were assessed. Results indicated that ID-D01 supplementation significantly improved endurance performance. Rats in the probiotic group demonstrated a significant increase in maximal running distance compared with that in the control group (p < 0.05). Additionally, levels of fatigue markers, such as lactate and creatine phosphokinase, were significantly reduced in the ID-D01-administered groups, suggesting its potential to alleviate exercise-induced fatigue. Microbiome analysis revealed a distinct shift in gut microbiota composition in response to ID-D01 administration. The group that received ID-D01 probiotics exhibited a significant increase in the abundance of SCFA-producing bacteria, particularly Akkermansia spp., compared with that in the control groups. Furthermore, they showed elevated production of SCFAs, such as acetate and butyrate. In conclusion, this study demonstrated that ID-D01 can enhance exercise performance and reduce fatigue. Herein, we highlighted that human-derived probiotics could improve physical performance, as observed by changes in gut microbiota composition and SCFA production.
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Affiliation(s)
- Ye-Ji Jang
- YUNOVIA Co., Ltd, Hwaseong, 18449, Republic of Korea
| | - Han Sol Choi
- YUNOVIA Co., Ltd, Hwaseong, 18449, Republic of Korea
| | - Ikhoon Oh
- YUNOVIA Co., Ltd, Hwaseong, 18449, Republic of Korea
| | | | - Jin Seok Moon
- YUNOVIA Co., Ltd, Hwaseong, 18449, Republic of Korea.
- Ildong Pharmaceutical Co., Ltd, Seoul, 06752, Republic of Korea.
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18
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Han D, Wang W, Gong J, Ma Y, Li Y. Microbiota metabolites in bone: Shaping health and Confronting disease. Heliyon 2024; 10:e28435. [PMID: 38560225 PMCID: PMC10979239 DOI: 10.1016/j.heliyon.2024.e28435] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2023] [Revised: 02/16/2024] [Accepted: 03/19/2024] [Indexed: 04/04/2024] Open
Abstract
The intricate interplay between the gut microbiota and bone health has become increasingly recognized as a fundamental determinant of skeletal well-being. Microbiota-derived metabolites play a crucial role in dynamic interaction, specifically in bone homeostasis. In this sense, short-chain fatty acids (SCFAs), including acetate, propionate, and butyrate, indirectly promote bone formation by regulating insulin-like growth factor-1 (IGF-1). Trimethylamine N-oxide (TMAO) has been found to increase the expression of osteoblast genes, such as Runt-related transcription factor 2 (RUNX2) and bone morphogenetic protein-2 (BMP2), thus enhancing osteogenic differentiation and bone quality through BMP/SMADs and Wnt signaling pathways. Remarkably, in the context of bone infections, the role of microbiota metabolites in immune modulation and host defense mechanisms potentially affects susceptibility to infections such as osteomyelitis. Furthermore, ongoing research elucidates the precise mechanisms through which microbiota-derived metabolites influence bone cells, such as osteoblasts and osteoclasts. Understanding the multifaceted influence of microbiota metabolites on bone, from regulating homeostasis to modulating susceptibility to infections, has the potential to revolutionize our approach to bone health and disease management. This review offers a comprehensive exploration of this evolving field, providing a holistic perspective on the impact of microbiota metabolites on bone health and diseases.
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Affiliation(s)
- Dong Han
- Department of Trauma Orthopedics, Yantaishan Hospital, Yantai 264000, China
| | - Weijiao Wang
- Department of Otolaryngology, Yantaishan Hospital, Yantai 264000, China
| | - Jinpeng Gong
- Department of Trauma Orthopedics, Yantaishan Hospital, Yantai 264000, China
| | - Yupeng Ma
- Department of Trauma Orthopedics, Yantaishan Hospital, Yantai 264000, China
| | - Yu Li
- Department of Trauma Orthopedics, Yantaishan Hospital, Yantai 264000, China
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Leanza G, Cannata F, Faraj M, Pedone C, Viola V, Tramontana F, Pellegrini N, Vadalà G, Piccoli A, Strollo R, Zalfa F, Beeve AT, Scheller EL, Tang SY, Civitelli R, Maccarrone M, Papalia R, Napoli N. Bone canonical Wnt signaling is downregulated in type 2 diabetes and associates with higher advanced glycation end-products (AGEs) content and reduced bone strength. eLife 2024; 12:RP90437. [PMID: 38598270 PMCID: PMC11006415 DOI: 10.7554/elife.90437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/11/2024] Open
Abstract
Type 2 diabetes (T2D) is associated with higher fracture risk, despite normal or high bone mineral density. We reported that bone formation genes (SOST and RUNX2) and advanced glycation end-products (AGEs) were impaired in T2D. We investigated Wnt signaling regulation and its association with AGEs accumulation and bone strength in T2D from bone tissue of 15 T2D and 21 non-diabetic postmenopausal women undergoing hip arthroplasty. Bone histomorphometry revealed a trend of low mineralized volume in T2D (T2D 0.249% [0.156-0.366]) vs non-diabetic subjects 0.352% [0.269-0.454]; p=0.053, as well as reduced bone strength (T2D 21.60 MPa [13.46-30.10] vs non-diabetic subjects 76.24 MPa [26.81-132.9]; p=0.002). We also showed that gene expression of Wnt agonists LEF-1 (p=0.0136) and WNT10B (p=0.0302) were lower in T2D. Conversely, gene expression of WNT5A (p=0.0232), SOST (p<0.0001), and GSK3B (p=0.0456) were higher, while collagen (COL1A1) was lower in T2D (p=0.0482). AGEs content was associated with SOST and WNT5A (r=0.9231, p<0.0001; r=0.6751, p=0.0322), but inversely correlated with LEF-1 and COL1A1 (r=-0.7500, p=0.0255; r=-0.9762, p=0.0004). SOST was associated with glycemic control and disease duration (r=0.4846, p=0.0043; r=0.7107, p=0.00174), whereas WNT5A and GSK3B were only correlated with glycemic control (r=0.5589, p=0.0037; r=0.4901, p=0.0051). Finally, Young's modulus was negatively correlated with SOST (r=-0.5675, p=0.0011), AXIN2 (r=-0.5523, p=0.0042), and SFRP5 (r=-0.4442, p=0.0437), while positively correlated with LEF-1 (r=0.4116, p=0.0295) and WNT10B (r=0.6697, p=0.0001). These findings suggest that Wnt signaling and AGEs could be the main determinants of bone fragility in T2D.
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Affiliation(s)
- Giulia Leanza
- Department of Medicine and Surgery, Research Unit of Endocrinology and Diabetes, Università Campus Bio-Medico di Roma, Via Alvaro del PortilloRomaItaly
- Operative Research Unit of Osteometabolic and Thyroid Diseases, Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del PortilloRomaItaly
| | - Francesca Cannata
- Department of Medicine and Surgery, Research Unit of Endocrinology and Diabetes, Università Campus Bio-Medico di Roma, Via Alvaro del PortilloRomaItaly
| | - Malak Faraj
- Department of Medicine and Surgery, Research Unit of Endocrinology and Diabetes, Università Campus Bio-Medico di Roma, Via Alvaro del PortilloRomaItaly
| | - Claudio Pedone
- Operative Research Unit of Geriatrics, Fondazione Policlinico Universitario Campus Bio Medico, Via Alvaro del PortilloRomaItaly
| | - Viola Viola
- Department of Medicine and Surgery, Research Unit of Endocrinology and Diabetes, Università Campus Bio-Medico di Roma, Via Alvaro del PortilloRomaItaly
| | - Flavia Tramontana
- Department of Medicine and Surgery, Research Unit of Endocrinology and Diabetes, Università Campus Bio-Medico di Roma, Via Alvaro del PortilloRomaItaly
- Operative Research Unit of Osteometabolic and Thyroid Diseases, Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del PortilloRomaItaly
| | - Niccolò Pellegrini
- Department of Medicine and Surgery, Research Unit of Endocrinology and Diabetes, Università Campus Bio-Medico di Roma, Via Alvaro del PortilloRomaItaly
| | - Gianluca Vadalà
- Operative Research Unit of Orthopedic and Trauma Surgery, Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del PortilloRomaItaly
| | - Alessandra Piccoli
- Department of Medicine and Surgery, Research Unit of Endocrinology and Diabetes, Università Campus Bio-Medico di Roma, Via Alvaro del PortilloRomaItaly
| | - Rocky Strollo
- Department of Human Sciences and Promotion of the Quality of Life San Raffaele Roma Open University Via di Val CannutaRomaItaly
| | - Francesca Zalfa
- Predictive Molecular Diagnostic Unit, Pathology Department, Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del PortilloRomaItaly
- Microscopic and Ultrastructural Anatomy Unit, Università Campus Bio-Medico di Roma, Via Alvaro del PortilloRomaItaly
| | - Alec T Beeve
- Department of Medicine, Division of Bone and Mineral Diseases, Musculoskeletal Research Center, Washington University School of MedicineSt. LouisUnited States
| | - Erica L Scheller
- Department of Medicine, Division of Bone and Mineral Diseases, Musculoskeletal Research Center, Washington University School of MedicineSt. LouisUnited States
| | - Simon Y Tang
- Department of Orthopaedic Surgery, Washington University in St. LouisSt LouisUnited States
| | - Roberto Civitelli
- Department of Medicine, Division of Bone and Mineral Diseases, Musculoskeletal Research Center, Washington University School of MedicineSt. LouisUnited States
| | - Mauro Maccarrone
- Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, Via Vetoio sncAquilaItaly
- European Center for Brain Research, Santa Lucia Foundation IRCCSRomaItaly
| | - Rocco Papalia
- Operative Research Unit of Orthopedic and Trauma Surgery, Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del PortilloRomaItaly
| | - Nicola Napoli
- Department of Medicine and Surgery, Research Unit of Endocrinology and Diabetes, Università Campus Bio-Medico di Roma, Via Alvaro del PortilloRomaItaly
- Operative Research Unit of Osteometabolic and Thyroid Diseases, Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del PortilloRomaItaly
- Department of Medicine, Division of Bone and Mineral Diseases, Musculoskeletal Research Center, Washington University School of MedicineSt. LouisUnited States
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20
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Cook CV, Lighty AM, Smith BJ, Ford Versypt AN. A review of mathematical modeling of bone remodeling from a systems biology perspective. FRONTIERS IN SYSTEMS BIOLOGY 2024; 4:1368555. [PMID: 40012834 PMCID: PMC11864782 DOI: 10.3389/fsysb.2024.1368555] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/28/2025]
Abstract
Bone remodeling is an essential, delicately balanced physiological process of coordinated activity of bone cells that remove and deposit new bone tissue in the adult skeleton. Due to the complex nature of this process, many mathematical models of bone remodeling have been developed. Each of these models has unique features, but they have underlying patterns. In this review, the authors highlight the important aspects frequently found in mathematical models for bone remodeling and discuss how and why these aspects are included when considering the physiology of the bone basic multicellular unit, which is the term used for the collection of cells responsible for bone remodeling. The review also emphasizes the view of bone remodeling from a systems biology perspective. Understanding the systemic mechanisms involved in remodeling will help provide information on bone pathology associated with aging, endocrine disorders, cancers, and inflammatory conditions and enhance systems pharmacology. Furthermore, some features of the bone remodeling cycle and interactions with other organ systems that have not yet been modeled mathematically are discussed as promising future directions in the field.
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Affiliation(s)
- Carley V. Cook
- Department of Chemical and Biological Engineering, University at Buffalo, The State University of New York, Buffalo, NY, United States
| | - Ariel M. Lighty
- Department of Chemical and Biological Engineering, University at Buffalo, The State University of New York, Buffalo, NY, United States
| | - Brenda J. Smith
- Indiana Center for Musculoskeletal Health, School of Medicine, Indiana University, Indianapolis, IN, United States
- Department of Obstetrics and Gynecology, School of Medicine, Indiana University, Indianapolis, IN, United States
| | - Ashlee N. Ford Versypt
- Department of Chemical and Biological Engineering, University at Buffalo, The State University of New York, Buffalo, NY, United States
- Department of Biomedical Engineering, University at Buffalo, The State University of New York, Buffalo, NY, United States
- Institute for Artificial Intelligence and Data Science, University at Buffalo, The State University of New York, Buffalo, NY, United States
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21
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Chargo NJ, Kang HJ, Das S, Jin Y, Rockwell C, Cho JY, McCabe LR, Parameswaran N. Korean red ginseng extract prevents bone loss in an oral model of glucocorticoid induced osteoporosis in mice. Front Pharmacol 2024; 15:1268134. [PMID: 38533264 PMCID: PMC10963623 DOI: 10.3389/fphar.2024.1268134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 02/20/2024] [Indexed: 03/28/2024] Open
Abstract
The gut microbiota and barrier function play important roles in bone health. We previously demonstrated that chronic glucocorticoid (GC)-induced bone loss in mice is associated with significant shifts in gut microbiota composition and impaired gut barrier function. Korean Red Ginseng (KRG, Panax Ginseng Meyer, Araliaceae) extract has been shown to prevent glucocorticoid-induced osteoporosis (GIO) in a subcutaneous pellet model in mice, but its effect on gut microbiota and barrier function in this context is not known. The overall goal of this study was to test the effect of KRG extract in a clinically relevant, oral model of GIO and further investigate its role in modulating the gut-bone axis. Growing male mice (CD-1, 8 weeks) were treated with 75 μg/mL corticosterone (∼9 mg/kg/day) or 0.4% ethanol vehicle in the drinking water for 4 weeks. During this 4-week period, mice were treated daily with 500 mg/kg/day KRG extract dissolved in sterile water or an equal amount of sterile water via oral gastric gavage. After 4 weeks of treatment, we assessed bone volume, microbiota composition, gut barrier integrity, and immune cells in the bone marrow (BM) and mesenteric lymph nodes (MLNs). 4 weeks of oral GC treatment caused significant distal femur trabecular bone loss, and this was associated with changes in gut microbiota composition, impaired gut barrier function and altered immune cell composition. Importantly, KRG extract prevented distal femur trabecular bone loss and caused significant alterations in gut microbiota composition but had only modest effects on gut barrier function and immune cell populations. Taken together, these results demonstrate that KRG extract significantly modulates the gut microbiota-bone axis and prevents glucocorticoid-induced bone loss in mice.
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Affiliation(s)
- Nicholas J. Chargo
- Department of Physiology, Michigan State University, East Lansing, MI, United States
- College of Osteopathic Medicine, Michigan State University, East Lansing, MI, United States
| | - Ho Jun Kang
- Department of Physiology, Michigan State University, East Lansing, MI, United States
| | - Subhashari Das
- Department of Physiology, Michigan State University, East Lansing, MI, United States
| | - Yining Jin
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, United States
| | - Cheryl Rockwell
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, United States
| | - Jae Youl Cho
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, Republic of Korea
| | - Laura R. McCabe
- Department of Physiology, Michigan State University, East Lansing, MI, United States
- College of Osteopathic Medicine, Michigan State University, East Lansing, MI, United States
| | - Narayanan Parameswaran
- Department of Physiology, Michigan State University, East Lansing, MI, United States
- College of Human Medicine, Michigan State University, East Lansing, MI, United States
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22
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Mirmohammadali SN, Hill Gallant KM, Biruete A. Oh, My Gut! New insights on the role of the gastrointestinal tract and the gut microbiome in chronic kidney disease-mineral and bone disorder. Curr Opin Nephrol Hypertens 2024; 33:226-230. [PMID: 38088374 PMCID: PMC11957419 DOI: 10.1097/mnh.0000000000000961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2024]
Abstract
PURPOSE OF REVIEW The aim of this review is to highlight recent evidence on the role of the gastrointestinal tract and gut microbiome on chronic kidney disease-mineral bone disorder (CKD-MBD) outcomes, including intestinal phosphorus absorption and sensing, and the effect of gut-oriented therapies. RECENT FINDINGS Recent evidence has revealed a complex interplay among mineral metabolism and novel gut-related factors, including paracellular intestinal phosphate absorption, the gut microbiome, and the immune system, prompting a reevaluation of treatment approaches for CKD-MBD. The inhibition of NHE3 limits phosphate transport in the intestine and may lead to changes in the gut microbiome. A study in rats with CKD showed that the supplementation of the fermentable dietary inulin delayed CKD-MBD, lowering circulating phosphorus and parathyroid hormone, reducing bone remodeling and improving cortical parameters, and lowering cardiovascular calcifications. In non-CKD preclinical studies, probiotics and prebiotics improved bone formation mediated through the effect of butyrate facilitating the differentiation of T cells into Tregs, and Tregs stimulating the osteogenic Wnt10b, and butyrate was also necessary for the parathyroid hormone (PTH) bone effects. SUMMARY Recent findings support multiple possible roles for gut-oriented therapies in addressing CKD-MBD prevention and management that should be further explored through clinical and translational studies.
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Affiliation(s)
| | - Kathleen M. Hill Gallant
- Department of Food Science and Nutrition, University of Minnesota, St. Paul, Minnesota, USA
- Department of Medicine, Division of Nephrology, Indiana University School of Medicine, Indianapolis, USA
| | - Annabel Biruete
- Department of Nutrition Science, Purdue University, West Lafayette, Indiana, USA
- Department of Medicine, Division of Nephrology, Indiana University School of Medicine, Indianapolis, USA
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23
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Virk MS, Virk MA, He Y, Tufail T, Gul M, Qayum A, Rehman A, Rashid A, Ekumah JN, Han X, Wang J, Ren X. The Anti-Inflammatory and Curative Exponent of Probiotics: A Comprehensive and Authentic Ingredient for the Sustained Functioning of Major Human Organs. Nutrients 2024; 16:546. [PMID: 38398870 PMCID: PMC10893534 DOI: 10.3390/nu16040546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2024] [Revised: 02/10/2024] [Accepted: 02/14/2024] [Indexed: 02/25/2024] Open
Abstract
Several billion microorganisms reside in the gastrointestinal lumen, including viruses, bacteria, fungi, and yeast. Among them, probiotics were primarily used to cure digestive disorders such as intestinal infections and diarrhea; however, with a paradigm shift towards alleviating health through food, their importance is large. Moreover, recent studies have changed the perspective that probiotics prevent numerous ailments in the major organs. Probiotics primarily produce biologically active compounds targeting discommodious pathogens. This review demonstrates the implications of using probiotics from different genres to prevent and alleviate ailments in the primary human organs. The findings reveal that probiotics immediately activate anti-inflammatory mechanisms by producing anti-inflammatory cytokines such as interleukin (IL)-4, IL-10, IL-11, and IL-13, and hindering pro-inflammatory cytokines such as IL-1, IL-6, and TNF-α by involving regulatory T cells (Tregs) and T helper cells (Th cells). Several strains of Lactobacillus plantarum, Lactobacillus rhamnosus, Lactobacillus casei, Lactobacillus reuteri, Bifidobacterium longum, and Bifidobacterium breve have been listed among the probiotics that are excellent in alleviating various simple to complex ailments. Therefore, the importance of probiotics necessitates robust research to unveil the implications of probiotics, including the potency of strains, the optimal dosages, the combination of probiotics, their habitat in the host, the host response, and other pertinent factors.
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Affiliation(s)
- Muhammad Safiullah Virk
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang 212013, China; (M.S.V.)
| | | | - Yufeng He
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang 212013, China; (M.S.V.)
| | - Tabussam Tufail
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang 212013, China; (M.S.V.)
- University Institute of Diet and Nutritional Sciences, The University of Lahore, Lahore 54000, Pakistan
| | - Mehak Gul
- Department of Internal Medicine, Sheikh Zayed Hospital, Lahore 54000, Pakistan
| | - Abdul Qayum
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang 212013, China; (M.S.V.)
| | - Abdur Rehman
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang 212013, China; (M.S.V.)
| | - Arif Rashid
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang 212013, China; (M.S.V.)
| | - John-Nelson Ekumah
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang 212013, China; (M.S.V.)
| | - Xu Han
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang 212013, China; (M.S.V.)
| | - Junxia Wang
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang 212013, China; (M.S.V.)
| | - Xiaofeng Ren
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang 212013, China; (M.S.V.)
- Institute of Food Physical Processing, Jiangsu University, Zhenjiang 212013, China
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24
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Chargo NJ, Neugebauer K, Guzior DV, Quinn RA, Parameswaran N, McCabe LR. Glucocorticoid-induced osteoporosis is prevented by dietary prune in female mice. Front Cell Dev Biol 2024; 11:1324649. [PMID: 38375074 PMCID: PMC10875082 DOI: 10.3389/fcell.2023.1324649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Accepted: 12/11/2023] [Indexed: 02/21/2024] Open
Abstract
Glucocorticoid-induced osteoporosis (GIO) is a significant side effect of prolonged glucocorticoid (GC) treatment. Chronic GC treatment also leads to trabecular bone loss and gut microbiota dysbiosis in mice. The gut dysbiosis is mechanistically linked to GIO, which indicates that the microbiota can be targeted to prevent GIO. Prunes, a dried fruit and prebiotic, have emerged in the literature as an effective treatment for sex-steroid deficiency induced osteoporosis (primary osteoporosis). Prunes also significantly alter the composition of the gut microbiota in both rodent models and human studies. Therefore, we tested if dietary prune (DP) supplementation could prevent GC-induced bone loss and affect microbiota composition in an established model of GIO. Sixteen-week-old, skeletally mature, female C57BL/6J mice were treated with a subcutaneous 5 mg placebo or prednisolone pellet for 8 weeks and fed an AIN-93M control diet or a diet modified to include 5, 15, or 25% (w/w) dried California prune powder. As expected, GC treated mice developed significant trabecular bone loss in the distal femur. More importantly, as little as 5% DP supplementation effectively prevented trabecular bone loss. Further, dose dependent increases in trabecular bone volume fraction were observed in GC + 15% and GC + 25% DP mice. Amazingly, in the placebo (non-GC treated) groups, 25% DP supplementation caused a ∼3-fold increase in distal femur trabecular bone volume fraction; this sizable bone response has not been previously observed in healthy mice with gut targeted natural treatments. Along with the striking effect on bone health, GC treatment and 25% DP supplementation led to drastic shifts in gut microbiota composition and several specific changes are strongly associated with bone health. Taken together, these results are the first to demonstrate that DP supplementation effectively prevents the negative effects of prolonged GC therapy on trabecular bone health and strongly associates with shifts in the composition of the gut microbiota.
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Affiliation(s)
- Nicholas J. Chargo
- Department of Physiology, Michigan State University, East Lansing, MI, United States
- College of Osteopathic Medicine, Michigan State University, East Lansing, MI, United States
| | - Kerri Neugebauer
- Department of Plant Soil and Microbiology, Michigan State University, East Lansing, MI, United States
| | - Douglas V. Guzior
- Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI, United States
- Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, United States
| | - Robert A. Quinn
- Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, United States
| | - Narayanan Parameswaran
- Department of Physiology, Michigan State University, East Lansing, MI, United States
- College of Human Medicine, Michigan State University, East Lansing, MI, United States
| | - Laura R. McCabe
- Department of Physiology, Michigan State University, East Lansing, MI, United States
- College of Osteopathic Medicine, Michigan State University, East Lansing, MI, United States
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25
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Umar S, Cronin O, Tyagi AM. Editorial: The role of the gut microbiota on bone mass in health and disease. Front Endocrinol (Lausanne) 2024; 14:1346156. [PMID: 38250740 PMCID: PMC10797037 DOI: 10.3389/fendo.2023.1346156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Accepted: 12/13/2023] [Indexed: 01/23/2024] Open
Affiliation(s)
- Sadiq Umar
- Department of Oral Biology, College of Dentistry, University of Illinois, Chicago, IL, United States
| | - Owen Cronin
- School of Medicine, University College Cork, College, Road, Ireland
- Department of Rheumatology, Bon Secours Hospital, Cork, Ireland
| | - Abdul Malik Tyagi
- Division of Orthopedic Surgery, Washington University, Saint Louis, MO, United States
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26
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Tyagi AM. Mechanism of action of gut microbiota and probiotic Lactobacillus rhamnosus GG on skeletal remodeling in mice. Endocrinol Diabetes Metab 2024; 7:e440. [PMID: 37505196 PMCID: PMC10782069 DOI: 10.1002/edm2.440] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 06/28/2023] [Accepted: 07/01/2023] [Indexed: 07/29/2023] Open
Abstract
INTRODUCTION Gut microbiota (GM) is the collection of small organisms such as bacteria, fungi, bacteriophages and protozoans living in the intestine in symbiotics relation within their host. GM regulates host metabolism by various mechanisms. METHODS This review aims to consolidate current information for physicians on the effect of GM on bone health. For this, an online search of the literature was conducted using the keywords gut microbiota, bone mass, osteoporosis, Lactobacillus and sex steroid. RESULTS AND CONCLUSIONS There is a considerable degree of variation in bone mineral density (BMD) within populations, and it is estimated that a significant component of BMD variability is due to genetics. However, the remaining causes of bone mass variance within populations remain largely unknown. A well-recognized cause of phenotypic variation in bone mass is the composition of the microbiome. Studies have shown that germ-free (GF) mice have higher bone mass compared to conventionally raised (CR) mice. Furthermore, GM dysbiosis, also called dysbacteriosis, is defined as any alteration in the composition of the microbial community that has been colonized in the host intestine and associated with the development of bone diseases. For instance, postmenopausal osteoporosis (PMO) and diabetes. GM can be modulated by several factors such as genetics, age, drugs, food habits and probiotics. Probiotics are defined as viable bacteria that confer health benefits by modulating GM when administered in adequate quantity. Lactobacillus rhamnosus GG (LGG) is a great example of such a probiotic. LGG has been shown to regulate bone mass in healthy mice as well as ovariectomized (OVX) mice via two different mechanisms. This review will focus on the literature regarding the mechanism by which GM and probiotic LGG regulate bone mass in healthy mice as well as in OVX mice, a model of PMO.
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27
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Danhof HA, Lee J, Thapa A, Britton RA, Di Rienzi SC. Microbial stimulation of oxytocin release from the intestinal epithelium via secretin signaling. Gut Microbes 2023; 15:2256043. [PMID: 37698879 PMCID: PMC10498800 DOI: 10.1080/19490976.2023.2256043] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 08/11/2023] [Accepted: 09/01/2023] [Indexed: 09/13/2023] Open
Abstract
Intestinal microbes impact the health of the intestine and organs distal to the gut. Limosilactobacillus reuteri is a human intestinal microbe that promotes normal gut transit, the anti-inflammatory immune system, wound healing, normal social behavior in mice, and prevents bone reabsorption. Oxytocin impacts these functions and oxytocin signaling is required for L. reuteri-mediated wound healing and social behavior; however, the events in the gut leading to oxytocin stimulation and beneficial effects are unknown. Here we report evolutionarily conserved oxytocin production in the intestinal epithelium through analysis of single-cell RNA-Seq datasets and imaging of human and mouse intestinal tissues. Moreover, human intestinal organoids produce oxytocin, demonstrating that the intestinal epithelium is sufficient to produce oxytocin. We find that L. reuteri facilitates oxytocin secretion from human intestinal tissue and human intestinal organoids. Finally, we demonstrate that stimulation of oxytocin secretion by L. reuteri is dependent on the gut hormone secretin, which is produced in enteroendocrine cells, while oxytocin itself is produced in enterocytes. Altogether, this work demonstrates that oxytocin is produced and secreted from enterocytes in the intestinal epithelium in response to secretin stimulated by L. reuteri. This work thereby identifies oxytocin as an intestinal hormone and provides mechanistic insight into avenues by which gut microbes promote host health.
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Affiliation(s)
- Heather A. Danhof
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA
- Alkek Center for Metagenomics and Microbiome Research, Baylor College of Medicine, Houston, TX, USA
| | - Jihwan Lee
- Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA
| | - Aanchal Thapa
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA
| | - Robert A. Britton
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA
- Alkek Center for Metagenomics and Microbiome Research, Baylor College of Medicine, Houston, TX, USA
| | - Sara C. Di Rienzi
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA
- Alkek Center for Metagenomics and Microbiome Research, Baylor College of Medicine, Houston, TX, USA
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28
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Chargo NJ, Schepper JD, Rios‐Arce N, Kang HJ, Gardinier JD, Parameswaran N, McCabe LR. Lactobacillus Reuteri 6475 Prevents Bone Loss in a Clinically Relevant Oral Model of Glucocorticoid-Induced Osteoporosis in Male CD-1 Mice. JBMR Plus 2023; 7:e10805. [PMID: 38130770 PMCID: PMC10731127 DOI: 10.1002/jbm4.10805] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 07/06/2023] [Accepted: 07/28/2023] [Indexed: 12/23/2023] Open
Abstract
Glucocorticoids (GCs) are commonly used anti-inflammatory medications with significant side effects, including glucocorticoid-induced osteoporosis (GIO). We have previously demonstrated that chronic subcutaneous GC treatment in mice leads to gut barrier dysfunction and trabecular bone loss. We further showed that treating with probiotics or barrier enhancers improves gut barrier function and prevents GIO. The overall goal of this study was to test if probiotics could prevent GC-induced gut barrier dysfunction and bone loss in a clinically relevant oral-GC model of GIO. Eight-week-old male CD-1 mice were treated with vehicle or corticosterone in the drinking water for 4 weeks and administered probiotics Lactobacillus reuteri ATCC 6475 (LR 6475) or VSL#3 thrice weekly via oral gavage. As expected, GC treatment led to significant gut barrier dysfunction (assessed by measuring serum endotoxin levels) and bone loss after 4 weeks. Serum endotoxin levels significantly and negatively correlated with bone volume. Importantly, LR 6475 treatment effectively prevented both GC-induced increase in serum endotoxin and trabecular bone loss. VSL#3 had intermediate results, not differing from either control or GC-treated animals. GC-induced reductions in femur length, cortical thickness, and cortical area were not affected by probiotic treatment. Taken together, these results are the first to demonstrate that LR 6475 effectively prevents the detrimental effects of GC treatment on gut barrier, which correlates with enhanced trabecular bone health in an oral mouse model of GIO. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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Affiliation(s)
- Nicholas J Chargo
- Department of PhysiologyMichigan State UniversityEast LansingMIUSA
- College of Osteopathic MedicineMichigan State UniversityEast LansingMIUSA
| | | | - Naoimy Rios‐Arce
- Department of PhysiologyMichigan State UniversityEast LansingMIUSA
| | - Ho Jun Kang
- Department of PhysiologyMichigan State UniversityEast LansingMIUSA
| | | | - Narayanan Parameswaran
- Department of PhysiologyMichigan State UniversityEast LansingMIUSA
- College of Human MedicineMichigan State UniversityEast LansingMIUSA
| | - Laura R McCabe
- Department of PhysiologyMichigan State UniversityEast LansingMIUSA
- College of Osteopathic MedicineMichigan State UniversityEast LansingMIUSA
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Wang Y, Li Y, Bo L, Zhou E, Chen Y, Naranmandakh S, Xie W, Ru Q, Chen L, Zhu Z, Ding C, Wu Y. Progress of linking gut microbiota and musculoskeletal health: casualty, mechanisms, and translational values. Gut Microbes 2023; 15:2263207. [PMID: 37800576 PMCID: PMC10561578 DOI: 10.1080/19490976.2023.2263207] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2023] [Accepted: 09/21/2023] [Indexed: 10/07/2023] Open
Abstract
The musculoskeletal system is important for balancing metabolic activity and maintaining health. Recent studies have shown that distortions in homeostasis of the intestinal microbiota are correlated with or may even contribute to abnormalities in musculoskeletal system function. Research has also shown that the intestinal flora and its secondary metabolites can impact the musculoskeletal system by regulating various phenomena, such as inflammation and immune and metabolic activities. Most of the existing literature supports that reasonable nutritional intervention helps to improve and maintain the homeostasis of intestinal microbiota, and may have a positive impact on musculoskeletal health. The purpose of organizing, summarizing and discussing the existing literature is to explore whether the intervention methods, including nutritional supplement and moderate exercise, can affect the muscle and bone health by regulating the microecology of the intestinal flora. More in-depth efficacy verification experiments will be helpful for clinical applications.
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Affiliation(s)
- Yu Wang
- Department of Health and Kinesiology, School of Physical Education, Jianghan University, Wuhan, China
| | - Yusheng Li
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Lin Bo
- Department of Rheumatology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Enyuan Zhou
- Department of Health and Kinesiology, School of Physical Education, Jianghan University, Wuhan, China
| | - Yanyan Chen
- Department of Health and Kinesiology, School of Physical Education, Jianghan University, Wuhan, China
| | - Shinen Naranmandakh
- School of Arts and Sciences, National University of Mongolia, Ulaanbaatar, Mongolia
| | - Wenqing Xie
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Qin Ru
- Department of Health and Kinesiology, School of Physical Education, Jianghan University, Wuhan, China
| | - Lin Chen
- Department of Health and Kinesiology, School of Physical Education, Jianghan University, Wuhan, China
| | - Zhaohua Zhu
- Clinical Research Centre, Orthopedic Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Changhai Ding
- Clinical Research Centre, Orthopedic Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, China
- Department of Rheumatology, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, China
- Department of Orthopaedics, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China
- Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia
| | - Yuxiang Wu
- Department of Health and Kinesiology, School of Physical Education, Jianghan University, Wuhan, China
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Xu J, Chen C, Gan S, Liao Y, Fu R, Hou C, Yang S, Zheng Z, Chen W. The Potential Value of Probiotics after Dental Implant Placement. Microorganisms 2023; 11:1845. [PMID: 37513016 PMCID: PMC10383117 DOI: 10.3390/microorganisms11071845] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 07/15/2023] [Accepted: 07/18/2023] [Indexed: 07/30/2023] Open
Abstract
Dental implantation is currently the optimal solution for tooth loss. However, the health and stability of dental implants have emerged as global public health concerns. Dental implant placement, healing of the surgical site, osseointegration, stability of bone tissues, and prevention of peri-implant diseases are challenges faced in achieving the long-term health and stability of implants. These have been ongoing concerns in the field of oral implantation. Probiotics, as beneficial microorganisms, play a significant role in the body by inhibiting pathogens, promoting bone tissue homeostasis, and facilitating tissue regeneration, modulating immune-inflammatory levels. This review explores the potential of probiotics in addressing post-implantation challenges. We summarize the existing research regarding the importance of probiotics in managing dental implant health and advocate for further research into their potential applications.
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Affiliation(s)
- Jia Xu
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
- Department of Oral Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Chenfeng Chen
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
- Department of General Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Shuaiqi Gan
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
- Department of Oral Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Yihan Liao
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
- Department of Oral Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Ruijie Fu
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
- Department of Oral Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Chuping Hou
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
- Department of Oral Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Shuhan Yang
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
- Department of Oral Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Zheng Zheng
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
- Department of Oral Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Wenchuan Chen
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
- Department of Oral Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
- Jinjiang Out-Patient Section, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
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Lyu Z, Hu Y, Guo Y, Liu D. Modulation of bone remodeling by the gut microbiota: a new therapy for osteoporosis. Bone Res 2023; 11:31. [PMID: 37296111 PMCID: PMC10256815 DOI: 10.1038/s41413-023-00264-x] [Citation(s) in RCA: 41] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 04/01/2023] [Accepted: 04/18/2023] [Indexed: 06/12/2023] Open
Abstract
The gut microbiota (GM) plays a crucial role in maintaining the overall health and well-being of the host. Recent studies have demonstrated that the GM may significantly influence bone metabolism and degenerative skeletal diseases, such as osteoporosis (OP). Interventions targeting GM modification, including probiotics or antibiotics, have been found to affect bone remodeling. This review provides a comprehensive summary of recent research on the role of GM in regulating bone remodeling and seeks to elucidate the regulatory mechanism from various perspectives, such as the interaction with the immune system, interplay with estrogen or parathyroid hormone (PTH), the impact of GM metabolites, and the effect of extracellular vesicles (EVs). Moreover, this review explores the potential of probiotics as a therapeutic approach for OP. The insights presented may contribute to the development of innovative GM-targeted therapies for OP.
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Affiliation(s)
- Zhengtian Lyu
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Yongfei Hu
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Yuming Guo
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Dan Liu
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China.
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Danhof HA, Lee J, Thapa A, Britton RA, Di Rienzi SC. Microbial stimulation of oxytocin release from the intestinal epithelium via secretin signaling. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.03.09.531917. [PMID: 36945649 PMCID: PMC10028957 DOI: 10.1101/2023.03.09.531917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/12/2023]
Abstract
Intestinal microbes impact the health of the intestine and organs distal to the gut. Limosilactobacillus reuteri is a human intestinal microbe that promotes normal gut transit 1 , the anti-inflammatory immune system 2-4 , wound healing 5-7 , normal social behavior in mice 8-10 , and prevents bone reabsorption 11-17 . Each of these functions is impacted by oxytocin 18-22 , and oxytocin signaling is required for L. reuteri- mediated wound healing 5 and social behavior 9 ; however, the initiating events in the gut that lead to oxytocin stimulation and related beneficial functions remain unknown. Here we found evolutionarily conserved oxytocin production in the intestinal epithelium through analysis of single-cell RNA-Seq datasets and imaging of human and mouse intestinal tissues. Moreover, human intestinal organoids produce oxytocin, demonstrating that the intestinal epithelium is sufficient to produce oxytocin. We subsequently found that L. reuteri facilitates oxytocin secretion directly from human intestinal tissue and human intestinal organoids. Finally, we demonstrate that stimulation of oxytocin secretion by L. reuteri is dependent on the gut hormone secretin, which is produced in enteroendocrine cells 23 , while oxytocin itself is produced in enterocytes. Altogether, this work demonstrates that oxytocin is produced and secreted from enterocytes in the intestinal epithelium in response to secretin stimulated by L. reuteri . This work thereby identifies oxytocin as an intestinal hormone and provides mechanistic insight into avenues by which gut microbes promote host health.
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Affiliation(s)
- Heather A. Danhof
- Department of Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA
- Alkek Center for Metagenomics and Microbiome Research, Baylor College of Medicine, Houston, Texas, USA
| | - Jihwan Lee
- Department of Neuroscience, Baylor College of Medicine, Houston, Texas, USA
| | - Aanchal Thapa
- Department of Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA
- Rice University, Houston, Texas, USA
| | - Robert A. Britton
- Department of Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA
- Alkek Center for Metagenomics and Microbiome Research, Baylor College of Medicine, Houston, Texas, USA
| | - Sara C. Di Rienzi
- Department of Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA
- Alkek Center for Metagenomics and Microbiome Research, Baylor College of Medicine, Houston, Texas, USA
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Perkins RS, Singh R, Abell AN, Krum SA, Miranda-Carboni GA. The role of WNT10B in physiology and disease: A 10-year update. Front Cell Dev Biol 2023; 11:1120365. [PMID: 36814601 PMCID: PMC9939717 DOI: 10.3389/fcell.2023.1120365] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Accepted: 01/16/2023] [Indexed: 02/09/2023] Open
Abstract
WNT10B, a member of the WNT family of secreted glycoproteins, activates the WNT/β-catenin signaling cascade to control proliferation, stemness, pluripotency, and cell fate decisions. WNT10B plays roles in many tissues, including bone, adipocytes, skin, hair, muscle, placenta, and the immune system. Aberrant WNT10B signaling leads to several diseases, such as osteoporosis, obesity, split-hand/foot malformation (SHFM), fibrosis, dental anomalies, and cancer. We reviewed WNT10B a decade ago, and here we provide a comprehensive update to the field. Novel research on WNT10B has expanded to many more tissues and diseases. WNT10B polymorphisms and mutations correlate with many phenotypes, including bone mineral density, obesity, pig litter size, dog elbow dysplasia, and cow body size. In addition, the field has focused on the regulation of WNT10B using upstream mediators, such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). We also discussed the therapeutic implications of WNT10B regulation. In summary, research conducted during 2012-2022 revealed several new, diverse functions in the role of WNT10B in physiology and disease.
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Affiliation(s)
- Rachel S. Perkins
- Department of Orthopaedic Surgery and Biomedical Engineering, University of Tennessee Health Science Center, Memphis, TN, United States
| | - Rishika Singh
- College of Medicine, University of Tennessee Health Science Center, Memphis, TN, United States
| | - Amy N. Abell
- Department of Biological Sciences, University of Memphis, Memphis, TN, United States
| | - Susan A. Krum
- Department of Orthopaedic Surgery and Biomedical Engineering, University of Tennessee Health Science Center, Memphis, TN, United States,Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, United States
| | - Gustavo A. Miranda-Carboni
- Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, United States,Department of Medicine, Division of Hematology and Oncology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, United States,*Correspondence: Gustavo A. Miranda-Carboni,
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Tornatore S. [Osteomicrobiology - Literature Review]. PRAXIS 2023; 112:83-86. [PMID: 36722108 DOI: 10.1024/1661-8157/a003981] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/18/2023]
Abstract
Osteomicrobiology - Literature Review Abstract. Abtract: Several in vivo studies show interesting correlations between microbiota and bone remodeling. The microbiota model and stimulate the immune system, which exerts a direct effect on the bone. The first clinical studies confirm these results and open new perspectives for the prevention of osteoporosis.
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Artoni de Carvalho JA, Magalhães LR, Polastri LM, Batista IET, de Castro Bremer S, Caetano HRDS, Rufino MN, Bremer-Neto H. Prebiotics improve osteoporosis indicators in a preclinical model: systematic review with meta-analysis. Nutr Rev 2022; 81:nuac097. [PMID: 36474436 DOI: 10.1093/nutrit/nuac097] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/17/2024] Open
Abstract
CONTEXT Studies using experimental models have demonstrated that prebiotics are involved in antiosteoporotic mechanisms. OBJECTIVE This study was conducted to determine the impact of supplementation with prebiotics in the basal diet of ovariectomized rats with induced osteoporosis as a preclinical model. METHODS A comprehensive systematic search was carried out in the electronic databases PubMed, Science Direct, Web of Science, Scielo, and Google through March 2022 for studies that investigated the impact of prebiotics on bone mineral density (BMD), bone mineral content (BMC), and bone biomechanics. RESULTS The search returned 844 complete articles, abstracts, or book chapters. After detailed screening, 8 studies met the inclusion criteria. Rats (n = 206), were randomly divided between control and treatment groups. Weighted mean differences (WMDs) with the 95%CIs were used to estimate the combined effect size. Compared with the control group, dietary intake of prebiotics significantly increased bone density in the BMD subgroups, with WMDs as follows: 0.03 g/cm3, 95%CI, 0.01-0.05, P < 0.00001, n = 46; and 0.00 g/cm2, 95%CI, 0.00-0.02, P < 0.00001, n = 81; total BMD: WMD, 0.01, 95%CI, 0.01-0.02, P < 0.00001, n = 127; bone content in BMC: WMD, 0.02 g, 95%CI, 0.00-0.04, P = 0.05, n = 107; and the 3-point-bend test: WMD, 15.20 N, 95%CI, 5.92-24.47, P = 0.00001, n = 120. CONCLUSION Prebiotics improve indicators of osteoporosis, BMD, BMC, and bone biomechanics in ovariectomized rats. More studies are needed to increase the level of evidence. SYSTEMIC REVIEW REGISTRATION Systematic Review Protocol for Animal Intervention Studies.
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Affiliation(s)
- João Alberto Artoni de Carvalho
- Department of Orthopedics and Traumatology, Medicine School of Presidente Prudente, Western Sao Paulo University, Presidente Prudente, São Paulo, Brazil
| | - Leticia Rocha Magalhães
- Department of Orthopedics and Traumatology, Medicine School of Presidente Prudente, Western Sao Paulo University, Presidente Prudente, São Paulo, Brazil
| | - Laryssa Mayara Polastri
- Department of Orthopedics and Traumatology, Medicine School of Presidente Prudente, Western Sao Paulo University, Presidente Prudente, São Paulo, Brazil
| | - Ingrid Eloise Trombine Batista
- Department of Orthopedics and Traumatology, Medicine School of Presidente Prudente, Western Sao Paulo University, Presidente Prudente, São Paulo, Brazil
| | | | - Heliard Rodrigues Dos Santos Caetano
- Department of Functional Sciences, Health Technology Assessment Nucleus of the Medical School of Presidente Prudente, Western Sao Paulo University, Presidente Prudente, São Paulo, Brazil
| | - Marcos Natal Rufino
- Department of Functional Sciences, Health Technology Assessment Nucleus of the Medical School of Presidente Prudente, Western Sao Paulo University, Presidente Prudente, São Paulo, Brazil
| | - Hermann Bremer-Neto
- Department of Functional Sciences, Health Technology Assessment Nucleus of the Medical School of Presidente Prudente, Western Sao Paulo University, Presidente Prudente, São Paulo, Brazil
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Xie H, Hua Z, Guo M, Lin S, Zhou Y, Weng Z, Wu L, Chen Z, Xu Z, Li W. Gut microbiota and metabonomics used to explore the mechanism of Qing'e Pills in alleviating osteoporosis. PHARMACEUTICAL BIOLOGY 2022; 60:785-800. [PMID: 35387559 PMCID: PMC9004512 DOI: 10.1080/13880209.2022.2056208] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 01/20/2022] [Accepted: 03/16/2022] [Indexed: 06/14/2023]
Abstract
CONTEXT The traditional Chinese medicine Qing'e Pills (QEP) has been used to treat postmenopausal osteoporosis (PMO). OBJECTIVE We evaluated the regulatory effects of QEP on gut microbiota in osteoporosis. MATERIALS AND METHODS Eighteen female SD rats were divided into three groups: sham surgery (SHAM), ovariectomized (OVX) and ovariectomized treated with QEP (OVX + QEP). Six weeks after ovariectomy, QEP was administered to OVX + QEP rats for eight weeks (4.5 g/kg/day, i.g.). After 14 weeks, the bone microstructure was evaluated. Differences in gut microbiota were analysed via 16S rRNA gene sequencing. Changes in endogenous metabolites were studied using UHPLC-Q-TOF/MS technology. GC-MS was used to detect short-chain fatty acids. Furthermore, we measured serum inflammatory factors, such as IL-6, TNF-α and IFN-γ, which may be related to gut microbiota. RESULTS OVX + QEP exhibited increased bone mineral density (0.11 ± 0.03 vs. 0.21 ± 0.02, p< 0.001) compared to that of OVX. QEP altered the composition of gut microbiota. We identified 19 potential biomarkers related to osteoporosis. QEP inhibited the elevation of TNF-α (38.86 ± 3.19 vs. 29.43 ± 3.65, p< 0.05) and IL-6 (83.38 ± 16.92 vs. 45.26 ± 3.94, p< 0.05) levels, while it increased the concentrations of acetic acid (271.95 ± 52.41 vs. 447.73 ± 46.54, p< 0.001), propionic acid (28.96 ± 5.73 vs. 53.41 ± 14.26, p< 0.01) and butyric acid (24.92 ± 18.97 vs. 67.78 ± 35.68, p< 0.05). CONCLUSIONS These results indicate that QEP has potential of regulating intestinal flora and improving osteoporosis. The combination of anti-osteoporosis drugs and intestinal flora could become a new treatment for osteoporosis.
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Affiliation(s)
- Hui Xie
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Key Laboratory of Chinese Medicine Processing, Engineering Center of State Ministry of Education for Standardization of Chinese Medicine Processing, Nanjing University of Chinese Medicine, Nanjing, China
| | - Zhengying Hua
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Key Laboratory of Chinese Medicine Processing, Engineering Center of State Ministry of Education for Standardization of Chinese Medicine Processing, Nanjing University of Chinese Medicine, Nanjing, China
| | - Mengyu Guo
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Key Laboratory of Chinese Medicine Processing, Engineering Center of State Ministry of Education for Standardization of Chinese Medicine Processing, Nanjing University of Chinese Medicine, Nanjing, China
| | - Shangyang Lin
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Key Laboratory of Chinese Medicine Processing, Engineering Center of State Ministry of Education for Standardization of Chinese Medicine Processing, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yaqian Zhou
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Key Laboratory of Chinese Medicine Processing, Engineering Center of State Ministry of Education for Standardization of Chinese Medicine Processing, Nanjing University of Chinese Medicine, Nanjing, China
| | - Zebin Weng
- School of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Li Wu
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Zhipeng Chen
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Key Laboratory of Chinese Medicine Processing, Engineering Center of State Ministry of Education for Standardization of Chinese Medicine Processing, Nanjing University of Chinese Medicine, Nanjing, China
| | - Zisheng Xu
- Wuhu Pure Sunshine Natural Medicine Company Limited, Wuhu, China
| | - Weidong Li
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Key Laboratory of Chinese Medicine Processing, Engineering Center of State Ministry of Education for Standardization of Chinese Medicine Processing, Nanjing University of Chinese Medicine, Nanjing, China
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Rastogi S, Singh A. Gut microbiome and human health: Exploring how the probiotic genus Lactobacillus modulate immune responses. Front Pharmacol 2022; 13:1042189. [PMID: 36353491 PMCID: PMC9638459 DOI: 10.3389/fphar.2022.1042189] [Citation(s) in RCA: 108] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Accepted: 10/12/2022] [Indexed: 12/15/2022] Open
Abstract
The highest density of microbes resides in human gastrointestinal tract, known as “Gut microbiome”. Of note, the members of the genus Lactobacillus that belong to phyla Firmicutes are the most important probiotic bacteria of the gut microbiome. These gut-residing Lactobacillus species not only communicate with each other but also with the gut epithelial lining to balance the gut barrier integrity, mucosal barrier defence and ameliorate the host immune responses. The human body suffers from several inflammatory diseases affecting the gut, lungs, heart, bone or neural tissues. Mounting evidence supports the significant role of Lactobacillus spp. and their components (such as metabolites, peptidoglycans, and/or surface proteins) in modulatingimmune responses, primarily through exchange of immunological signals between gastrointestinal tract and distant organs. This bidirectional crosstalk which is mediated by Lactobacillus spp. promotes anti-inflammatory response, thereby supporting the improvement of symptoms pertaining to asthma, chronic obstructive pulmonary disease (COPD), neuroinflammatory diseases (such as multiple sclerosis, alzheimer’s disease, parkinson’s disease), cardiovascular diseases, inflammatory bowel disease (IBD) and chronic infections in patients. The metabolic disorders, obesity and diabetes are characterized by a low-grade inflammation. Genus Lactobacillus alleviates metabolic disorders by regulating the oxidative stress response and inflammatory pathways. Osteoporosis is also associated with bone inflammation and resorption. The Lactobacillus spp. and their metabolites act as powerful immune cell controllers and exhibit a regulatory role in bone resorption and formation, supporting bone health. Thus, this review demonstrated the mechanisms and summarized the evidence of the benefit of Lactobacillus spp. in alleviating inflammatory diseases pertaining to different organs from animal and clinical trials. The present narrative review explores in detail the complex interactions between the gut-dwelling Lactobacillus spp. and the immune components in distant organs to promote host’s health.
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Guo X, Zhong K, Zhang J, Hui L, Zou L, Xue H, Guo J, Zheng S, Huang D, Tan M. Gut microbiota can affect bone quality by regulating serum estrogen levels. Am J Transl Res 2022; 14:6043-6055. [PMID: 36247294 PMCID: PMC9556462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Accepted: 07/25/2022] [Indexed: 06/16/2023]
Abstract
Germ-free (GF) animals and animal models of the antibiotic disruption of gut microbiota are widely used to explore studies of gut microbiota-host interactions. The role of gut microbiota in bone growth and development has been well explained in studies on GF mice, indicating that changes in the gut microbiota may affect normal bone developmental processes. The mechanisms, however, are yet unclear. This study aims to clarify the effect of antibiotic treatment disrupting the gut microbiota on bone development in mice and investigate the possible causes of this effect. Our results show that long-term antibiotic feeding significantly alters gut microbiota composition in mice, reduces the bone mineral density of the spinal region, and leads to changes in trabecular microstructure. Interestingly, we found a significant decrease in the serum estrogen levels in mice treated with antibiotics, suggesting that gut microbiota may affect bone quality by regulating serum estrogen levels. These results may help understand how gut ecological dysregulation affects sex hormones and provide a new conception for the clinical treatments of osteoporosis.
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Affiliation(s)
- Xing Guo
- Department of Orthopedic Surgery, The Affiliated Hospital of Southwest Medical University No. 25 Taiping Road, Luzhou 646000, Sichuan, People's Republic of China
| | - Kai Zhong
- Department of Orthopedic Surgery, The Affiliated Hospital of Southwest Medical University No. 25 Taiping Road, Luzhou 646000, Sichuan, People's Republic of China
| | - Jianhua Zhang
- Department of Orthopedic Surgery, The Affiliated Hospital of Southwest Medical University No. 25 Taiping Road, Luzhou 646000, Sichuan, People's Republic of China
| | - Lv Hui
- Department of Orthopedic Surgery, The Affiliated Hospital of Southwest Medical University No. 25 Taiping Road, Luzhou 646000, Sichuan, People's Republic of China
| | - Longfei Zou
- Department of Orthopedic Surgery, The Affiliated Hospital of Southwest Medical University No. 25 Taiping Road, Luzhou 646000, Sichuan, People's Republic of China
| | - Hao Xue
- Department of Orthopedic Surgery, The Affiliated Hospital of Southwest Medical University No. 25 Taiping Road, Luzhou 646000, Sichuan, People's Republic of China
| | - Jiang Guo
- Department of Orthopedic Surgery, The Affiliated Hospital of Southwest Medical University No. 25 Taiping Road, Luzhou 646000, Sichuan, People's Republic of China
| | - Shuling Zheng
- Department of Orthopedic Surgery, The Affiliated Hospital of Southwest Medical University No. 25 Taiping Road, Luzhou 646000, Sichuan, People's Republic of China
| | - Denghua Huang
- Department of Orthopedic Surgery, The Affiliated Hospital of Southwest Medical University No. 25 Taiping Road, Luzhou 646000, Sichuan, People's Republic of China
| | - Meiyun Tan
- Department of Orthopedic Surgery, The Affiliated Hospital of Southwest Medical University No. 25 Taiping Road, Luzhou 646000, Sichuan, People's Republic of China
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Zhou J, Wang R, Zhao R, Guo X, Gou P, Bai H, Lei P, Xue Y. Intermittent Parathyroid Hormone Alters Gut Microbiota in Ovariectomized Osteoporotic Rats. Orthop Surg 2022; 14:2330-2338. [PMID: 35946436 PMCID: PMC9483047 DOI: 10.1111/os.13419] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 06/20/2022] [Accepted: 06/26/2022] [Indexed: 11/29/2022] Open
Abstract
Objective To investigate the effect of intermittent parathyroid hormone (PTH) on gut microbiota (GM) in ovariectomized (OVX) osteoporotic rats. Methods Thirty female Sprague–Dawley rats were divided into three groups: sham‐operation (SHAM) group, OVX group and PTH treatment group. After 3 months of treatment, the femurs, serum and feces were acquired for micro‐CT, biochemical analysis and 16S rRNA sequencing, respectively. For 16S rRNA sequencing, after raw reads filtrated and chimera sequences removed, the clean reads were obtained. According to these clean reads, the operational taxonomic units (OTUs) were clustered. Venn diagram analysis was conducted to explore common and unique GM among the three groups. The α‐diversity analysis including Shannon and Simpson indexes were used to evaluate the richness and diversity of the GM. The β‐diversity analysis was performed to estimate the structure of GM. The metabolic function was predicted by Tax4Fun analysis. Results With micro‐CT and biochemical analysis, significant improvements were found in the PTH group compared with the OVX group. In Venn diagram analysis, more unique OTUs were found in the SHAM and PTH groups than the OVX group. According to the rank abundance curve, the SHAM and PTH groups had similar richness and evenness, which were higher than the OVX group. Simpson and Shannon indexes were higher in the SHAM and PTH groups compared with the OVX group, indicating that the SHAM and PTH groups had higher microbiota complexity than the OVX group. In β‐diversity analysis, apparent separation was found in the OVX group from the PTH and SHAM groups, which suggested that osteoporosis is the critical factor influencing the GM composition and PTH treatment and can restore the structure of GM. Compared with the OVX group, treatment with PTH increased the abundances of GM which were reported to increase bone mass, such as Lactobacillus_reuteri, Muribaculaceae, Ruminococcaceae, and Clostridia, and inhibited the relative abundance of Rikenellaceae, which was reported to be potentially related to osteoporosis. GM function analysis showed that PTH could promote butyrate synthesis. In Tax4Fun analysis, the function of butanoate metabolism is more vital in the PTH group than the OVX and SHAM groups, suggesting PTH treatment could regulate microbial metabolic function, including butanoate metabolism. Conclusion Intermittent PTH can interact with GM through increasing the abundance of probiotics and reducing the abundance of the pathogenic bacteria to enhance the bone mass.
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Affiliation(s)
- Jiaming Zhou
- Department of Orthopaedic Surgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Rui Wang
- Department of Orthopaedic Surgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Rui Zhao
- Department of Orthopaedic Surgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Xing Guo
- Department of Orthopaedic Surgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Pengguo Gou
- Department of Orthopaedic Surgery, The Affiliated People's Hospital of Shanxi Medical University, Taiyuan, China
| | - He Bai
- Department of Orthopaedic Surgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Ping Lei
- Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Yuan Xue
- Department of Orthopaedic Surgery, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin Key Laboratory of Spine and Spinal Cord, Tianjin Medical University General Hospital, Tianjin, China
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Lawenius L, Colldén H, Horkeby K, Wu J, Grahnemo L, Vandenput L, Ohlsson C, Sjögren K. A probiotic mix partially protects against castration-induced bone loss in male mice. J Endocrinol 2022; 254:91-101. [PMID: 35661635 PMCID: PMC9254303 DOI: 10.1530/joe-21-0408] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 05/30/2022] [Indexed: 11/19/2022]
Abstract
Studies in postmenopausal women and ovariectomized mice show that the probiotic mix Lacticaseibacillus paracasei DSM13434, Lactiplantibacillus plantarum DSM 15312 and DSM 15313 (L. Mix) can protect from bone loss caused by sex steroid deficiency. Whether probiotic bacteria can protect bone also in sex steroid-deficient males is less studied. We used the orchiectomized mouse as a model for age-dependent bone loss caused by decreasing sex hormone levels in males. We treated 10-week-old male mice with either vehicle (veh) or L. Mix for 6 weeks, starting 2 weeks before orchiectomy (orx) or sham surgery. Importantly, mice treated with L. Mix had a general increase in total body bone mineral density (BMD) and lean mass (P ≤ 0.05) compared with veh-treated mice. Detailed computer tomography analysis of dissected bones showed increased trabecular BMD of the distal metaphyseal region of the femur in L. Mix compared to veh-treated orx mice (+8.0%, P ≤ 0.05). In the vertebra, L. Mix treatment increased trabecular bone volume fraction BV/TV (+11.5%, P ≤ 0.05) compared to veh in orx mice. Also, L. Mix increased the levels of short-chain fatty acids (SCFAs) such as propionate and acetate and important intermediates in SCFA synthesis such as succinate and lactate in the cecal content of male mice. In conclusion, L. Mix treatment resulted in a general increase in BMD in adult male mice and prevented trabecular bone loss in femur and vertebra of orx mice. These bone protective effects of L. Mix were associated with increased levels of SCFAs in the cecal content of male mice.
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Affiliation(s)
- Lina Lawenius
- Sahlgrenska Osteoporosis Centre and Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Hannah Colldén
- Sahlgrenska Osteoporosis Centre and Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Karin Horkeby
- Sahlgrenska Osteoporosis Centre and Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Jianyao Wu
- Sahlgrenska Osteoporosis Centre and Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Louise Grahnemo
- Sahlgrenska Osteoporosis Centre and Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Liesbeth Vandenput
- Sahlgrenska Osteoporosis Centre and Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
- Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, Australia
| | - Claes Ohlsson
- Sahlgrenska Osteoporosis Centre and Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Klara Sjögren
- Sahlgrenska Osteoporosis Centre and Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
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Zhang YW, Cao MM, Li YJ, Dai GC, Lu PP, Zhang M, Bai LY, Chen XX, Zhang C, Shi L, Rui YF. The regulative effect and repercussion of probiotics and prebiotics on osteoporosis: involvement of brain-gut-bone axis. Crit Rev Food Sci Nutr 2022; 63:7510-7528. [PMID: 35234534 DOI: 10.1080/10408398.2022.2047005] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Osteoporosis (OP) is a systemic disease characterized by decreased bone mass and degeneration of bone microstructure. In recent years, more and more researches have focused on the close relationship between gut microbiota (GM) and the occurrence and progression of OP, and the regulation of probiotics and prebiotics on bone metabolism has gradually become a research hotspot. Based on the influence of brain-gut-bone axis on bone metabolism, this review expounds the potential mechanisms of probiotics and prebiotics on OP from next perspectives: regulation of intestinal metabolites, regulation of intestinal epithelial barrier function, involvement of neuromodulation, involvement of immune regulation and involvement of endocrine regulation, so as to provide a novel and promising idea for the prevention and treatment of OP in the future.
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Affiliation(s)
- Yuan-Wei Zhang
- Department of Orthopaedics, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, P.R. China
- Multidisciplinary Team (MDT) for Geriatric Hip Fracture Management, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, P.R. China
- School of Medicine, Southeast University, Nanjing, Jiangsu, P.R. China
- Orthopaedic Trauma Institute (OTI), Southeast University, Nanjing, Jiangsu, P.R. China
- Trauma Center, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, P.R. China
| | - Mu-Min Cao
- Department of Orthopaedics, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, P.R. China
- Multidisciplinary Team (MDT) for Geriatric Hip Fracture Management, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, P.R. China
- School of Medicine, Southeast University, Nanjing, Jiangsu, P.R. China
- Orthopaedic Trauma Institute (OTI), Southeast University, Nanjing, Jiangsu, P.R. China
- Trauma Center, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, P.R. China
| | - Ying-Juan Li
- Multidisciplinary Team (MDT) for Geriatric Hip Fracture Management, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, P.R. China
- Department of Geriatrics, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, P.R. China
| | - Guang-Chun Dai
- Department of Orthopaedics, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, P.R. China
- Multidisciplinary Team (MDT) for Geriatric Hip Fracture Management, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, P.R. China
- School of Medicine, Southeast University, Nanjing, Jiangsu, P.R. China
- Orthopaedic Trauma Institute (OTI), Southeast University, Nanjing, Jiangsu, P.R. China
- Trauma Center, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, P.R. China
| | - Pan-Pan Lu
- Department of Orthopaedics, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, P.R. China
- Multidisciplinary Team (MDT) for Geriatric Hip Fracture Management, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, P.R. China
- School of Medicine, Southeast University, Nanjing, Jiangsu, P.R. China
- Orthopaedic Trauma Institute (OTI), Southeast University, Nanjing, Jiangsu, P.R. China
- Trauma Center, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, P.R. China
| | - Ming Zhang
- Department of Orthopaedics, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, P.R. China
- Multidisciplinary Team (MDT) for Geriatric Hip Fracture Management, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, P.R. China
- School of Medicine, Southeast University, Nanjing, Jiangsu, P.R. China
- Orthopaedic Trauma Institute (OTI), Southeast University, Nanjing, Jiangsu, P.R. China
- Trauma Center, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, P.R. China
| | - Li-Yong Bai
- Department of Orthopaedics, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, P.R. China
- Multidisciplinary Team (MDT) for Geriatric Hip Fracture Management, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, P.R. China
- School of Medicine, Southeast University, Nanjing, Jiangsu, P.R. China
- Orthopaedic Trauma Institute (OTI), Southeast University, Nanjing, Jiangsu, P.R. China
- Trauma Center, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, P.R. China
| | - Xiang-Xu Chen
- Department of Orthopaedics, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, P.R. China
- Multidisciplinary Team (MDT) for Geriatric Hip Fracture Management, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, P.R. China
- School of Medicine, Southeast University, Nanjing, Jiangsu, P.R. China
- Orthopaedic Trauma Institute (OTI), Southeast University, Nanjing, Jiangsu, P.R. China
- Trauma Center, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, P.R. China
| | - Cheng Zhang
- Department of Orthopaedics, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, P.R. China
- Multidisciplinary Team (MDT) for Geriatric Hip Fracture Management, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, P.R. China
- School of Medicine, Southeast University, Nanjing, Jiangsu, P.R. China
- Orthopaedic Trauma Institute (OTI), Southeast University, Nanjing, Jiangsu, P.R. China
- Trauma Center, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, P.R. China
| | - Liu Shi
- Department of Orthopaedics, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, P.R. China
- Multidisciplinary Team (MDT) for Geriatric Hip Fracture Management, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, P.R. China
- School of Medicine, Southeast University, Nanjing, Jiangsu, P.R. China
- Orthopaedic Trauma Institute (OTI), Southeast University, Nanjing, Jiangsu, P.R. China
- Trauma Center, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, P.R. China
| | - Yun-Feng Rui
- Department of Orthopaedics, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, P.R. China
- Multidisciplinary Team (MDT) for Geriatric Hip Fracture Management, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, P.R. China
- School of Medicine, Southeast University, Nanjing, Jiangsu, P.R. China
- Orthopaedic Trauma Institute (OTI), Southeast University, Nanjing, Jiangsu, P.R. China
- Trauma Center, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, P.R. China
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Abuqwider J, Altamimi M, Mauriello G. Limosilactobacillus reuteri in Health and Disease. Microorganisms 2022; 10:microorganisms10030522. [PMID: 35336098 PMCID: PMC8953724 DOI: 10.3390/microorganisms10030522] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 02/22/2022] [Accepted: 02/24/2022] [Indexed: 02/01/2023] Open
Abstract
Limosilactobacillus reuteri is a microorganism with valuable probiotic qualities that has been widely employed in humans to promote health. It is a well-studied probiotic bacterium that exerts beneficial health effects due to several metabolic mechanisms that enhance the production of anti-inflammatory cytochines and modulate the gut microbiota by the production of antimicrobial molecules, including reuterin. This review provides an overview of the data that support the role of probiotic properties, and the antimicrobial and immunomodulatory effects of some L. reuteri strains in relation to their metabolite production profile on the amelioration of many diseases and disorders. Although the results discussed in this paper are strain dependent, they show that L. reuteri, by different mechanisms and various metabolites, may control body weight and obesity, improve insulin sensitivity and glucose homeostasis, increase gut integrity and immunomodulation, and attenuate hepatic disorders. Gut microbiota modulation by ingesting probiotic L. reuteri strains could be a promising preventative and therapeutic approach against many diseases and disorders.
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Affiliation(s)
- Jumana Abuqwider
- Department of Agricultural Science, University of Naples Federico II, 80049 Naples, Italy;
| | - Mohammad Altamimi
- Department of Nutrition and Food Technology, Faculty of Agriculture and Veterinary Medicine, An-Najah National University, Nablus P.O. Box 7, Palestine;
| | - Gianluigi Mauriello
- Department of Agricultural Science, University of Naples Federico II, 80049 Naples, Italy;
- Correspondence: ; Tel.: +39-081-2539452
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Evidence and possible mechanisms of probiotics in the management of type 1 diabetes mellitus. J Diabetes Metab Disord 2022; 21:1081-1094. [PMID: 35673472 PMCID: PMC9167374 DOI: 10.1007/s40200-022-01006-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Accepted: 02/12/2022] [Indexed: 10/19/2022]
Abstract
Abstract Type 1 diabetes mellitus (T1DM) is one of the most common chronic immune-mediated diseases. The prevalence is worldwide especially among children and young adults. The destruction of the pancreatic β-cells due to some abnormalities in the immune system characterizes T1DM. Considering the high burden of the disease and its impact on human health, researchers have made great efforts during the last decades; investigating the disease pathogenesis and discovering new strategies for its management. Fortunately, probiotics have been found as potential remedies for T1DM. This review aims to explore the potentialities of probiotics in managing T1DM and its complications. Based on the outcomes of human and animal studies carried out from 2016 to 2021, the review hopes to assess the effectiveness of probiotics in the prevention and treatment of T1DM and its complications. We first tried to explain the disease's pathogenesis, and highlighted the possible mechanisms involved in these potentialities of probiotics. We concluded that, probiotics can be used as possible therapeutic tools for the management of T1DM. Possible mechanisms of action of probiotics include; the modulation of the gut microbiota, the regulation of inflammation-related cytokines, the production of short chain fatty acids (SCFAs), and the regulation of GLP-1. However, we recommend further studies especially human trials should be carried out to investigate these potentialities of probiotics. Highlights • T1DM is highly prevalent worldwide, causing high morbidity and mortality especially among children and young adults• Gut microbiota plays a significant role in the pathogenesis of T1DM via an interconnection with the immune system• Probiotics can be used as possible therapeutic tools for the management of T1DM• Possible mechanisms of action of probiotics include the modulation of the gut microbiota, the regulation of inflammation-related cytokines, the production of SCFAs, and the regulation of GLP-1.
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de Sire A, de Sire R, Curci C, Castiglione F, Wahli W. Role of Dietary Supplements and Probiotics in Modulating Microbiota and Bone Health: The Gut-Bone Axis. Cells 2022; 11:cells11040743. [PMID: 35203401 PMCID: PMC8870226 DOI: 10.3390/cells11040743] [Citation(s) in RCA: 58] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2021] [Revised: 02/04/2022] [Accepted: 02/09/2022] [Indexed: 02/04/2023] Open
Abstract
Osteoporosis is characterized by an alteration of bone microstructure with a decreased bone mineral density, leading to the incidence of fragility fractures. Around 200 million people are affected by osteoporosis, representing a major health burden worldwide. Several factors are involved in the pathogenesis of osteoporosis. Today, altered intestinal homeostasis is being investigated as a potential additional risk factor for reduced bone health and, therefore, as a novel potential therapeutic target. The intestinal microflora influences osteoclasts’ activity by regulating the serum levels of IGF-1, while also acting on the intestinal absorption of calcium. It is therefore not surprising that gut dysbiosis impacts bone health. Microbiota alterations affect the OPG/RANKL pathway in osteoclasts, and are correlated with reduced bone strength and quality. In this context, it has been hypothesized that dietary supplements, prebiotics, and probiotics contribute to the intestinal microecological balance that is important for bone health. The aim of the present comprehensive review is to describe the state of the art on the role of dietary supplements and probiotics as therapeutic agents for bone health regulation and osteoporosis, through gut microbiota modulation.
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Affiliation(s)
- Alessandro de Sire
- Physical Medicine and Rehabilitation Unit, Department of Medical and Surgical Sciences, University of Catanzaro “Magna Graecia”, 88100 Catanzaro, Italy
- Correspondence: (A.d.S.); (W.W.)
| | - Roberto de Sire
- Gastroenterology Unit, Department of Clinical Medicine and Surgery, University Federico II of Naples, 80126 Naples, Italy; (R.d.S.); (F.C.)
| | - Claudio Curci
- Physical Medicine and Rehabilitation Unit, Department of Neurosciences, ASST Carlo Poma, 46100 Mantova, Italy;
| | - Fabiana Castiglione
- Gastroenterology Unit, Department of Clinical Medicine and Surgery, University Federico II of Naples, 80126 Naples, Italy; (R.d.S.); (F.C.)
| | - Walter Wahli
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Clinical Sciences Building, Singapore 308232, Singapore
- Toxalim Research Center in Food Toxicology (UMR 1331), French National Research Institute for Agriculture, Food, and the Environment (INRAE), F-31300 Toulouse, France
- Center for Integrative Genomics, University of Lausanne, Le Génopode, CH-1015 Lausanne, Switzerland
- Correspondence: (A.d.S.); (W.W.)
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Guo X, Zhong K, Zou L, Xue H, Zheng S, Guo J, Lv H, Duan K, Huang D, Tan M. Effect of Lactobacillus casei fermented milk on fracture healing in osteoporotic mice. Front Endocrinol (Lausanne) 2022; 13:1041647. [PMID: 36387894 PMCID: PMC9649960 DOI: 10.3389/fendo.2022.1041647] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2022] [Accepted: 10/04/2022] [Indexed: 11/13/2022] Open
Abstract
The interaction between the gut microbiota and the host has been described experimentally by germ-free animals or by antibiotic-disturbed gut microbiota. Studies on germ-free mice have shown that gut microbiota is critical for bone growth and development in mice, emphasizing that microbiota dysbiosis may interfere with normal bone development processes. This study aimed to clarify the effect of antibiotic treatment on disturbed gut microbiota on bone development in mice and to investigate the effect of probiotic treatment on fracture healing in mice with dysbiosis. Our results showed that 4 weeks old female Kunming mice showed significantly lower abundance and diversity of the gut microbiota and significantly lower bone mineral density after 12 weeks of antibiotic treatment and significantly increased levels of RANKL and Ang II in serum (p<0.05). Mice with dysbiosis received 5 mL of Lactobacillus casei fermented milk by daily gavage after internal fixation of femoral fractures, and postoperative fracture healing was evaluated by X-ray, micro-CT scan, and HE staining, which showed faster growth of the broken ends of the femur and the presence of more callus. Serological tests showed decreased levels of RANKL and Ang II (p<0.05). Similarly, immunohistochemical results also showed increased expression of α smooth muscle actin in callus tissue. These results suggest that oral antibiotics can lead to dysbiosis of the gut microbiota in mice, which in turn leads to the development of osteoporosis. In contrast, probiotic treatment promoted fracture healing in osteoporotic mice after dysbiosis, and the probiotic effect on fracture healing may be produced by inhibiting the RAS/RANKL/RANK pathway.
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Affiliation(s)
- Xing Guo
- Department of Burn and Plastic Surgery, Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Kai Zhong
- Department of Orthopaedics, Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - LongFei Zou
- Department of Orthopaedics, Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Hao Xue
- Department of Orthopaedics, Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - ShuLing Zheng
- Department of Orthopaedics, Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Jiang Guo
- Department of Orthopaedics, Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Hui Lv
- Department of Orthopaedics, Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Ke Duan
- Department of Orthopaedics, Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - DengHua Huang
- Department of Orthopaedics, Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - MeiYun Tan
- Department of Orthopaedics, Affiliated Hospital of Southwest Medical University, Luzhou, China
- *Correspondence: MeiYun Tan,
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Sirufo MM, De Pietro F, Catalogna A, Ginaldi L, De Martinis M. The Microbiota-Bone-Allergy Interplay. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 19:ijerph19010282. [PMID: 35010543 PMCID: PMC8750778 DOI: 10.3390/ijerph19010282] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 12/22/2021] [Accepted: 12/24/2021] [Indexed: 12/18/2022]
Abstract
Emerging knowledge suggests an increasing importance of gut microbiota in health and disease. Allergy and bone metabolism are closely interconnected, and the possible negative effects of common therapies are not the only aspects of this relationship. The immune system is influenced by the microbiota-host interactions, and several pieces of evidence suggest the existence of an interplay between microbiota, bone metabolism, and allergies. Understanding these inter-relationships is essential for the development of new potential strategies of treatment and prevention targeting microbiota. A wide range of substances and germs, prebiotics and probiotics, are capable of influencing and modifying the microbiota. Prebiotics and probiotics have been shown in several studies to have different actions based on various factors such as sex, hormonal status, and age. In this review, we summarize the latest knowledge on the topic, and we discuss practical implications and the need for further studies.
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Affiliation(s)
- Maria Maddalena Sirufo
- Department of Life, Health and Environmental Sciences, University of L’Aquila, Piazzale Salvatore Tommasi n. 1, 67100 L’Aquila, Italy; (M.M.S.); (F.D.P.); (A.C.); (L.G.)
- Allergy and Clinical Immunology Unit, Center for the Diagnosis and Treatment of Osteoporosis, AUSL 04, 64100 Teramo, Italy
| | - Francesca De Pietro
- Department of Life, Health and Environmental Sciences, University of L’Aquila, Piazzale Salvatore Tommasi n. 1, 67100 L’Aquila, Italy; (M.M.S.); (F.D.P.); (A.C.); (L.G.)
- Allergy and Clinical Immunology Unit, Center for the Diagnosis and Treatment of Osteoporosis, AUSL 04, 64100 Teramo, Italy
| | - Alessandra Catalogna
- Department of Life, Health and Environmental Sciences, University of L’Aquila, Piazzale Salvatore Tommasi n. 1, 67100 L’Aquila, Italy; (M.M.S.); (F.D.P.); (A.C.); (L.G.)
- Allergy and Clinical Immunology Unit, Center for the Diagnosis and Treatment of Osteoporosis, AUSL 04, 64100 Teramo, Italy
| | - Lia Ginaldi
- Department of Life, Health and Environmental Sciences, University of L’Aquila, Piazzale Salvatore Tommasi n. 1, 67100 L’Aquila, Italy; (M.M.S.); (F.D.P.); (A.C.); (L.G.)
- Allergy and Clinical Immunology Unit, Center for the Diagnosis and Treatment of Osteoporosis, AUSL 04, 64100 Teramo, Italy
| | - Massimo De Martinis
- Department of Life, Health and Environmental Sciences, University of L’Aquila, Piazzale Salvatore Tommasi n. 1, 67100 L’Aquila, Italy; (M.M.S.); (F.D.P.); (A.C.); (L.G.)
- Allergy and Clinical Immunology Unit, Center for the Diagnosis and Treatment of Osteoporosis, AUSL 04, 64100 Teramo, Italy
- Correspondence: ; Tel.: +39-0861-429548
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Billington EO, Mahajan A, Benham JL, Raman M. Effects of probiotics on bone mineral density and bone turnover: A systematic review. Crit Rev Food Sci Nutr 2021:1-12. [PMID: 34748440 DOI: 10.1080/10408398.2021.1998760] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Probiotic supplements have been shown to improve bone health in animal models, although it remains uncertain whether these beneficial effects extend to humans. We undertook a systematic review of the literature to determine the effects of probiotic interventions on skeletal outcomes in postmenopausal women. MEDLINE, EMBASE, CENTRAL, and the Cochrane Database of Systematic Reviews were searched from inception to October 2020 for controlled trials comparing the effects of probiotic-containing supplements with placebo on bone mineral density (BMD) or bone turnover markers. Risk of bias was assessed using the Cochrane Risk of Bias 2 Tool. Of 338 records identified, six randomized, placebo-controlled trials (n = 632) were eligible for inclusion. All studies assessed postmenopausal women for durations of 6-12 months; three were considered to be at high risk of bias. Four studies examined Lactobacillus-containing probiotics, one assessed a proprietary blend of lactic acid bacteria, and one evaluated Bacillus subtilis. Effects of probiotic interventions on BMD were inconsistent, with the majority of studies demonstrating no benefit at the spine or hip. Probiotic effects on bone turnover markers were similarly heterogeneous. High quality studies are needed to determine whether probiotic interventions have a role in maintaining bone health in humans.
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Affiliation(s)
- Emma O Billington
- Division of Endocrinology & Metabolism, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.,McCaig Institute for Bone & Joint Health, University of Calgary, Calgary, Alberta, Canada
| | - Amita Mahajan
- Division of Endocrinology & Metabolism, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Jamie L Benham
- Division of Endocrinology & Metabolism, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.,Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Maitreyi Raman
- Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.,Division of Gastroenterology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
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Probiotics as a New Regulator for Bone Health: A Systematic Review and Meta-Analysis. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:3582989. [PMID: 34394379 PMCID: PMC8355998 DOI: 10.1155/2021/3582989] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Revised: 07/15/2021] [Accepted: 07/21/2021] [Indexed: 01/14/2023]
Abstract
Despite the proposed role of the gut microbiota-bone axis, findings on the association between probiotic consumption and bone health are conflicting. This systematic review aimed to assess the effect of probiotic consumption on bone health parameters. A systematic literature search of relevant reports published in PubMed/Medline, Web of Science, SCOPUS, EMBASE, and Google scholar before December 2020 was conducted. All clinical trials or experimental studies, which examined the relationship between probiotic consumption and bone health parameters, were included. No limitation was applied during the search. After screening articles based on inclusion criteria, 44 studies remained. In clinical trials, probiotic consumption affects bone health parameters such as serum calcium levels (3.82; 95% CI: 1.05, 6.59 mmol/l), urinary calcium levels (4.85; 95% CI: 1.16, 8.53 mmol/l), and parathyroid hormone (PTH) levels (−5.53; 95% CI: −9.83, −0.86 ng/l). In most studies, Lactobacillus species such as L. helveticus, L. reuteri, and L. casei were consumed and women aged 50 years or older were assessed. Spinal and total hip bone mineral density (BMD) was not affected significantly by probiotic consumption. In 37 animal experiments, probiotic or symbiotic feeding mostly had effects on bone health parameters. Some strains of Bifidobacterium and Lactobacillus including L. reuteri, L. casei, L. paracasei, L. bulgaricus, and L. acidophilus have indicated beneficial effects on bone health parameters. In conclusion, this systematic review and meta-analysis indicate that probiotic supplementation might improve bone health. Further studies are needed to decide on the best probiotic species and appropriate dosages.
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49
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Lu L, Chen X, Liu Y, Yu X. Gut microbiota and bone metabolism. FASEB J 2021; 35:e21740. [PMID: 34143911 DOI: 10.1096/fj.202100451r] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 06/03/2021] [Accepted: 06/04/2021] [Indexed: 02/05/2023]
Abstract
Osteoporosis is the most common metabolic skeletal disease. It is characterized by the deterioration of the skeletal microarchitecture and bone loss, leading to ostealgia, and even bone fractures. Accumulating evidence has indicated that there is an inextricable relationship between the gut microbiota (GM) and bone homeostasis involving host-microbiota crosstalk. Any perturbation of the GM can play an initiating and reinforcing role in disrupting the bone remodeling balance during the development of osteoporosis. Although the GM is known to influence bone metabolism, the mechanisms associated with these effects remain unclear. Herein, we review the current knowledge of how the GM affects bone metabolism in health and disease, summarize the correlation between pathogen-associated molecular patterns of GM structural components and bone metabolism, and discuss the potential mechanisms underlying how GM metabolites regulate bone turnover. Deciphering the complicated relationship between the GM and bone health will provide new insights into the prevention and treatment of osteoporosis.
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Affiliation(s)
- Lingyun Lu
- Department of Endocrinology and Metabolism, Laboratory of Endocrinology and Metabolism, Rare Disease Center, West China Hospital, Sichuan University, Chengdu, China.,Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaoxuan Chen
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Yi Liu
- Department of Rheumatology and Immunology, Rare Disease Center, West China Hospital, Sichuan University, Chengdu, China
| | - Xijie Yu
- Department of Endocrinology and Metabolism, Laboratory of Endocrinology and Metabolism, Rare Disease Center, West China Hospital, Sichuan University, Chengdu, China
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50
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Zhong X, Zhang F, Yin X, Cao H, Wang X, Liu D, Chen J, Chen X. Bone Homeostasis and Gut Microbial-Dependent Signaling Pathways. J Microbiol Biotechnol 2021; 31:765-774. [PMID: 34176870 PMCID: PMC9705830 DOI: 10.4014/jmb.2104.04016] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 05/27/2021] [Accepted: 06/13/2021] [Indexed: 12/15/2022]
Abstract
Although research on the osteal signaling pathway has progressed, understanding of gut microbial-dependent signaling pathways for metabolic and immune bone homeostasis remains elusive. In recent years, the study of gut microbiota has shed light on our understanding of bone homeostasis. Here, we review microbiota-mediated gut-bone crosstalk via bone morphogenetic protein/SMADs, Wnt and OPG/receptor activator of nuclear factor-kappa B ligand signaling pathways in direct (translocation) and indirect (metabolite) manners. The mechanisms underlying gut microbiota involvement in these signaling pathways are relevant in immune responses, secretion of hormones, fate of osteoblasts and osteoclasts and absorption of calcium. Collectively, we propose a signaling network for maintaining a dynamic homeostasis between the skeletal system and the gut ecosystem. Additionally, the role of gut microbial improvement by dietary intervention in osteal signaling pathways has also been elucidated. This review provides unique resources from the gut microbial perspective for the discovery of new strategies for further improving treatment of bone diseases by increasing the abundance of targeted gut microbiota.
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Affiliation(s)
- Xiaohui Zhong
- Wuxi School of Medicine, Jiangnan University, Wuxi 214122, P.R. China
| | - Feng Zhang
- Wuxi School of Medicine, Jiangnan University, Wuxi 214122, P.R. China,Clinical Assessment Center of Functional Food, Affiliated Hospital of Jiangnan University, Wuxi 214125, P.R. China,Nutritional Department, Affiliated Hospital of Jiangnan University, Wuxi 214125, P.R. China
| | - Xinyao Yin
- Wuxi School of Medicine, Jiangnan University, Wuxi 214122, P.R. China
| | - Hong Cao
- Clinical Assessment Center of Functional Food, Affiliated Hospital of Jiangnan University, Wuxi 214125, P.R. China,Department of Endocrinology, Affiliated Hospital of Jiangnan University, Wuxi 214125, P.R. China,Nutritional Department, Affiliated Hospital of Jiangnan University, Wuxi 214125, P.R. China
| | - Xuesong Wang
- Wuxi School of Medicine, Jiangnan University, Wuxi 214122, P.R. China,Department of Orthopedics, Affiliated Hospital of Jiangnan University, Wuxi 214125, P.R.China
| | - Dongsong Liu
- Department of Orthopedics, Affiliated Hospital of Jiangnan University, Wuxi 214125, P.R.China
| | - Jing Chen
- Department of Orthopedics, Affiliated Hospital of Jiangnan University, Wuxi 214125, P.R.China
| | - Xue Chen
- Wuxi School of Medicine, Jiangnan University, Wuxi 214122, P.R. China,Corresponding author Phone: +86-15861589177 E-mail:
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