Introduction: The incidence and mortality of bone diseases are still steadily increasing, creating a significant financial burden for societies across the world. To prevent the occurrence of bone diseases, slow their progression, or reverse the injuries they cause, new alternatives or complementary treatments need to be developed. The gut microbiota plays a role in bone metabolism and the pathogenesis of osteoporosis. Objective: It was to analyze through a systematic review the main considerations and clinical findings of the bone formation process through the modulation of the gut microbiota, as well as the functions of microRNAs and exosomes. Methods: The systematic review rules (PRISMA) were followed. The search was carried out from August to September 2022 in the Scopus, PubMed, Science Direct, Scielo, and Google Scholar databases, using scientific articles from 2001 to 2022. The quality of the studies was based on the GRADE instrument and the risk of bias was analyzed according to the Cochrane instrument. Results and Conclusion: A total of 126 articles were found. A total of 34 articles were fully evaluated and 26 were included in this systematic review. Most studies showed homogeneity in their results, with I2 =98.8%>50%. The symmetrical funnel plot does not suggest a risk of bias between small sample-size studies. The gut microbiota plays an important role in the modulation of bone healing and bone health through the traffic of inflammatory TNF+ T and Th17 cells to the bone marrow, influencing the inflammatory state of the patient, determining the “brain-gut-bone” axis. It has been shown that the diversity of the gut microbiota is decreased in patients with osteoporosis, leading to a state of dysbiosis. There is a relationship between the microbiome, osteoblasts, osteoclasts, and nuclear factor ligand receptor-kappa-B (RANKL) activator. Studies have proposed several mechanisms of gut microbiome interaction with osteoclastogenesis and bone health, including microRNA, insulin-like growth factor 1, and immune system mediation. Therefore, bone regeneration requires that the basic biological principles of osteogenesis, osteoinduction, osteoconduction, and biocompatibility are followed.
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