Gut microbiota tryptophan metabolite indole-3-propionic acid alleviates inflammatory bowel disease-related osteoporosis in a mouse model

Qiu Xueli; Cui Hao; Wu Chenyang; Tao Lide; Yao Yuqian; Tian Bo; Bai Jinyu; Zhang Yingzi

doi:10.12307/2026.615

Abstract：BACKGROUND:The gut-bone axis refers to the interaction network through which gut microbiota and its metabolites influence bone development,metabolism,and health by regulating host immune,endocrine,and metabolic pathways.Previous studies have demonstrated that disturbances in gut microbiota have been shown to interact with inflammatory bowel disease-associated osteoporosis. OBJECTIVE:To investigate the protective effects and potential mechanisms of the gut microbiota tryptophan metabolite,indole-3-propionic acid,in inflammatory bowel disease combined with osteoporosis. METHODS:Male Balb/c mice,aged 6-8 weeks,were randomly divided into three groups:control,model,and indole-3-propionic acid groups.In the latter two groups,1.5%sodium dextran sulfate was added to the drinking water for 12 weeks to induce chronic enteritis,and then in the indole-3-propionic acid group,intraperitoneal injections of indole-3-propionic acid at a dose of 20 mg/kg were administered three times per week,for 4 weeks.Severity of colon inflammation was assessed by hematoxylin-eosin staining,colon length measurement,and ELISA detection of intestinal inflammatory cytokine levels.Bone mass and structure of the femur were analyzed by Micro-CT scanning.Viability of osteoblasts and osteoclasts and bone metabolism were assessed using tartrate-resistant acid phosphatase staining,hematoxylin-eosin staining,calcein double labeling and immunofluorescence staining. RESULTS AND CONCLUSION:(1)The colon length in the model group was shorter than that in the control group,while indole-3-propionic acid treatment improved the colon length.Hematoxylin-eosin staining of the colon showed that the model group exhibited disrupted colon structure,disordered crypt arrangement,and extensive infiltration of inflammatory cells.After the administration of indole-3-propionic acid,the infiltration of inflammatory cells was significantly reduced,and the colon structure was restored.(2)ELISA results indicated that the levels of intestinal inflammatory cytokines were significantly elevated in the model group compared with the control group(P<0.000 1).After treatment with indole-3-propionic acid,the levels of intestinal inflammatory cytokines were significantly reduced(P<0.001).(3)Micro-CT scanning and three-dimensional reconstruction showed that indole-3-propionic acid significantly alleviated bone loss in the mouse model of chronic enteritis.(4)Tartrate-resistant acid phosphatase staining and hematoxylin-eosin staining revealed that indole-3-propionic acid reduced the number of osteoclasts and increased the number of trabeculae.Calcein double labeling experiments showed that indole-3-propionic acid treatment improved bone formation capacity.Immunofluorescence analysis indicated that indole-3-propionic acid promoted the expression of SP7.These findings suggest that indole-3-propionic acid improves bone metabolism by reducing intestinal inflammation,inhibiting osteoclast activity,and upregulating osteoblast function,highlighting its potential application in the treatment of osteoporosis associated with inflammatory bowel disease.