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Evidence links osteoporosis development to gut microbiota composition and microbial metabolite profiles. This work analyzes an OVX estrogen-deficiency osteoporosis mouse model, identifying gut microbiota alterations and reduced tryptophan metabolite levels, particularly indoleacrylic acid (IA). IA limits RANKL-driven osteoclast activity by inhibiting AhR and c-Fos expression, reducing p-p65 nuclear translocation, and thereby suppressing resorption; IA also shows therapeutic protection in vivo.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/gut-metabolite-indoleacrylic-acid-suppresses-osteoclast-formation-by-ahr-mediated-nf-b-signaling-pathway/458509/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/gut-metabolite-indoleacrylic-acid-suppresses-osteoclast-formation-by-ahr-mediated-nf-b-signaling-pathway/458509.png","ImageObject",300,407,{"name":92,"@type":93},"Terk","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-03","2026-09-30",true,{"@type":102,"interactionType":103,"userInteractionCount":52},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What is the study aiming to clarify about gut microbiota metabolites and bone health?","Question",{"text":112,"@type":113},"The study investigates whether gut tryptophan metabolites influence bone homeostasis, specifically whether indoleacrylic acid affects osteoclast formation and osteoclast resorption activity.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"What changes occur in the OVX osteoporosis mouse model in this research?",{"text":117,"@type":113},"The model shows altered gut microbiota and decreased tryptophan metabolite levels, including reduced serum IA, indoleacetic acid (IAA), and indolepropionic acid (IPA), alongside reduced Lactobacillus and Clostridium abundance.",{"name":119,"@type":110,"acceptedAnswer":120},"How does indoleacrylic acid (IA) suppress osteoclast formation mechanistically?",{"text":121,"@type":113},"IA inhibits RANKL-induced AhR and c-Fos expression, reduces nuclear translocation of p-p65 in bone marrow macrophages, and can be reversed by AhR overexpression, supporting an AhR-dependent mechanism.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},458509,1790977239,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":52,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":56,"language":139,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":140,"faqs":141,"seo_title":142,"seo_description":67,"update_tm":143,"read_time":144,"preview_page_count":4},1099525198933,"https://ap-avatar.wpscdn.com/davatar_155a257f0dc6eb9ab79c44ca47cae57d","Ivyspring  \nInternational Publisher  \nInternationalJournal of Biological Sciences  \n2026; 22(2): 951-969. doi: 10.7150/ijbs.124766  \nResearch Paper  \nGut Metabolite Indoleacrylic Acid Suppresses Osteoclast Formation by AHR mediated NF-κB Signaling Pathway  \nJinwu Bai1,2\\#, Gao Si1,2\\#, Ruideng Wang3\\#, Shilong Su1,2, Jixing Fan1,2, Xi He4, Yang Lv1,2􀀍, Shan Gao1,2􀀍, Fang Zhou1,2􀀍  \n1. Department of Orthopedics, Peking University Third Hospital, Beijing 100191, China.  \n2. Engineering Research Center of Bone and Joint Precision Medicine, Peking University Third Hospital, Beijing 100191, China.  \n3. Department of Trauma Orthopedics, Shenzhen Second People's Hospital (The First Affiliated Hospital of Shenzhen University), Shenzhen, 518000, China.  \n4. School of Biological Sciences and Medical Engineering, Beihang University, Beijing 100191, China.  \n\\# Contributed equally to this research.  \n􀀍 Corresponding authors: Fang Zhou ([zhouf@bjmu.edu.cn](zhouf@bjmu.edu.cn)); Shan Gao ([gaoshan@bjmu.edu.cn](gaoshan@bjmu.edu.cn)); Yang Lv (lvyang[42@126.com](42@126.com)) .  \n© The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License ([https://creativecommons.org/licenses/by/4.0/](https://creativecommons.org/licenses/by/4.0/)). See [https://ivyspring.com/terms](https://ivyspring.com/terms) for full terms and conditions.  \nReceived: 2025.09.05; Accepted: 2025.11.25; Published: 2026.01.01  \nAbstract  \nBone homeostasis relies on the coordinated activities of bone-forming osteoblasts and bone-resorbingosteoclasts. Disruption of this balance leads to osteoporosis, a highly prevalent bone disease with substantial health impacts in middle-aged and older adults. There is accumulating evidence linking the development of osteoporosis to alterations in the gut microbiota and its metabolite profile. The gut metabolite indole and its derivatives were shown to have beneficial effects in multiple metabolic diseases. However, their effects on bone homeostasis remain unclear. This study identified alterations in the gut microbiota and decreases in levels of tryptophan metabolites in an ovariectomized (OVX) estrogen deficiency-induced osteoporosis mouse model, characterized by decreased abundance of Lactobacillus and Clostridium species in the gut and reduced serum levels of indoleacrylic acid (IA), indoleacetic acid (IAA), and indolepropionic acid (IPA). IA showed a significant positive correlation with bone mass. Specifically, IA inhibited RANKL-induced aryl hydrocarbon receptor (AhR) and c-Fos expression, reducing nuclear translocation of p-p65 in bone marrow macrophages (BMMs), ultimately resulting in suppression of osteoclast resorption activity. AhR acts as a key positive regulator in the process of osteoclastogenesis, and its overexpression restored IA-mediated inhibition of osteoclast formation. In vivo, daily IA supplementation protected mice against OVX-induced bone loss, with higher PINP and lower CTX-1 levels. Taken together, these findings identified IA as a promising therapeutic candidate capable of suppressing osteoclastogenesis through an AhR-dependent mechanism, providing mechanistic insight and a potential strategy for the treatment of postmenopausal osteoporosis.  \nKeywords: indoleacrylic acid, osteoclast formation, gut microbiota, aryl hydrocarbon receptor, NF-κB signaling pathway  \nIntroduction  \nBone remodeling sustains skeletal integrity through a continuous process in which osteoclasts resorb old bone and osteoblasts deposit new bone [1] . However, pathological conditions such as aging and metabolic diseases can disrupt this equilibrium and lead to osteoporosis, a disease characterized by deterioration of the bone microarchitecture, increased fragility, and elevated fracture risk [2] . Current  \npharmacotherapies, including bisphosphonates and selective estrogen receptor modulators, remain the cornerstone of osteoporosis management but are associated with risks of serious ad","cbCairCovla8q6uC","https://ap.wps.com/l/cbCairCovla8q6uC","pdf",12600989,"English","# Abstract\n# Keywords\n# Introduction","[{\"question\":\"What is the study aiming to clarify about gut microbiota metabolites and bone health?\",\"answer\":\"The study investigates whether gut tryptophan metabolites influence bone homeostasis, specifically whether indoleacrylic acid affects osteoclast formation and osteoclast resorption activity.\"},{\"question\":\"What changes occur in the OVX osteoporosis mouse model in this research?\",\"answer\":\"The model shows altered gut microbiota and decreased tryptophan metabolite levels, including reduced serum IA, indoleacetic acid (IAA), and indolepropionic acid (IPA), alongside reduced Lactobacillus and Clostridium abundance.\"},{\"question\":\"How does indoleacrylic acid (IA) suppress osteoclast formation mechanistically?\",\"answer\":\"IA inhibits RANKL-induced AhR and c-Fos expression, reduces nuclear translocation of p-p65 in bone marrow macrophages, and can be reversed by AhR overexpression, supporting an AhR-dependent mechanism.\"}]","Gut Metabolite Indoleacrylic Acid Suppresses Osteoclast Formation by AHR mediated NF-κB Signaling Pathway | PDF",1790753527,48]