Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou, China & Guangdong Provincial Key Laboratory of Bone and Cartilage Regenerative Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Department of Gastroenterology, Huizhou Municipal Central Hospital, Huizhou, China.
Front Endocrinol (Lausanne). 2021 Dec 9;12:774257. doi: 10.3389/fendo.2021.774257. eCollection 2021.
Treatment of osteomyelitis requires prolonged antibiotic therapy which significantly alters the gut microbiota. While the influences on bone mass and microstructure have been extensively studied, it is poorly understood what impact the changes in gut microbiota may have on the host response to osseointegration around an intramedullary nail implanted. Here, we explored the influence of gut microbiota on the bone osseointegration process around an implant under two conditions: implantation of an intramedullary nail in the bone marrow cavity and chronic osteomyelitis (CO) induced by infection. Body weight, hepatorenal functions, serum levels of proinflammatory cytokines were monitored. The composition of gut microbiota was assessed 16S rRNA sequencing, and the bone condition was analyzed micro-computed tomography, hematoxylin and eosin staining, Safranin O-fast green and Goldner's trichrome staining. Osteoblastogenesis and osteoclastogenesis were assessed by detecting tartrate-resistant acid phosphatase and osterix expression. We found that perturbation of gut microbiota (increase in and decrease in ) associated with delayed osseointegration and increased levels of proinflammatory cytokines in the serum (<0.05), lower bone mass (<0.05), deficient endochondral ossification and bone formation, reduced osteoblastogenesis (<0.05) and enhanced osteoclastogenesis (<0.001). Survival rates (=0.002) and bacterial loads (=0.0363) in bone differed significantly between the CO and antibiotic-treated CO mice, but cytokines levels, bone mineral density, and bone formation did not differ, likely because of the severely damaged bone structure. In summary, antibiotic treatment perturbed the gut microbiota and significantly interfered with the bone osseointegration around the nail by increasing proinflammatory cytokine levels in circulation, inhibiting osteoblastogenesis, enhancing osteoclastogenesis, and thus leading to higher pathogen colonization as well as higher mortality postinfection. This report of ours is the first to demonstrate antibiotic-induced alterations in the gut microbiota affect bone osseointegration, helping us understand the role of gut microbiota disorders in osteoblastogenesis and osteoclastogenesis following implant insertion with or without infection.
骨髓炎的治疗需要长期的抗生素治疗，这会显著改变肠道微生物群。虽然已经广泛研究了其对骨量和微结构的影响，但对于肠道微生物群的变化可能对宿主对植入髓内钉周围骨整合的反应有什么影响知之甚少。在这里，我们在两种情况下研究了肠道微生物群对植入物周围骨整合过程的影响：骨髓腔内植入髓内钉和感染引起的慢性骨髓炎（CO）。监测体重、肝肾功能、促炎细胞因子的血清水平。通过 16S rRNA 测序评估肠道微生物群的组成，并通过微计算机断层扫描、苏木精和伊红染色、番红 O-快绿和 Goldner 三色染色分析骨况。通过检测抗酒石酸酸性磷酸酶和osterix 表达来评估成骨细胞生成和破骨细胞生成。我们发现，与骨整合延迟和血清中促炎细胞因子水平升高（<0.05）、骨量减少（<0.05）、软骨内骨化和骨形成不足、成骨细胞生成减少（<0.05）和破骨细胞生成增强（<0.001）相关的肠道微生物群失调（增加和减少）。CO 和抗生素治疗 CO 小鼠的骨内存活率（=0.002）和细菌负荷（=0.0363）有显著差异，但细胞因子水平、骨密度和骨形成没有差异，可能是因为骨结构严重受损。总之，抗生素治疗扰乱了肠道微生物群，并通过增加循环中促炎细胞因子水平、抑制成骨细胞生成、增强破骨细胞生成，从而导致更高的病原体定植和感染后更高的死亡率，显著干扰了钉周围的骨整合。我们的报告首次表明，抗生素诱导的肠道微生物群改变会影响骨整合，有助于我们理解肠道微生物群紊乱在植入物插入后有无感染情况下对成骨细胞生成和破骨细胞生成的作用。
