Osteoporosis and osteoarthritis are serious diseases that threaten human health and are associated with considerable morbidity. In the past, osteoporosis and osteoarthritis were both considered skeletal diseases and not closely related to other body systems (1). Osteoporosis worldwide causes 8.9 million fractures, which means that every three seconds osteoporosis fracture occurs (2). Osteoporosis are affect 200 million women in worldwide which mean that women aged 60 was approximately one-tenth, women aged 70 was one-fifth, women aged 80 was two-fifths, and women aged 90 was two-thirds (2). A significant economic burden is associated with osteoporosis fractures (3). Osteoarthritis is also a disease that seriously endangers the health of the elderly., Osteoarthritis affect 30.8 million adults in the United States and 300 million individuals in worldwide (4). Osteoarthritis often leads to pain, dysfunction, and a decline in quality of life, which brings a serious financial burden to society. Osteoarthritis is estimated to cost $303 billion dollars annually in medical costs and lost earnings (5). Therefore, it is very important to pay attention to the prevention and treatment of osteoporosis and osteoarthritis.

Currently, there are many studies on the relationship between intestinal flora and bone metabolism (6). The interactions of the host microbiota are key factors for health and can ultimately be used to develop a stable microbial community (7). The gut microbiota can serve to provide essential vitamins; regulate the host’s intestinal epithelium, immune system, maintain the nutritional metabolism, exogenous and drug metabolism of the host, as well as the structural integrity of the intestinal mucosal barrier; pathogen resistance (8, 9). The gut microbiota has been associated with several chronic conditions, such as inflammation (10), obesity (11), and metabolic disease (12). In addition, depletion of the gut microbiota can affect both the intestines and central nervous system, indicating the existence of a microbiota-gut-brain axis (13). Obesity-associated circulating metabolites are also linked to gut microbes (14). Microbiota interacts with physiological aging processes, which can be used to develop microbiota-based health surveillance systems for older adults (15).

The gut microbiota is affected by different environments. Initially, the gut microbiota obtains radon from the mother through the birth canal (16). The gut microbiota gradually stabilizes after the age of three years old. The composition of the intestinal flora is a dynamic balance that can be affected by diet. However, the gut microbiota is subsequently shaped by medical practices and lifestyle changes (17). Many factors, such as antibiotics, C-section, washing of the skin, and oral ingestion of antibacterial agents, can change this dynamic balance (18–20). The interaction between intestinal microbes and commonly used non-antibiotic drugs is complex and mutual: the composition of the intestinal flora will be affected by the drug, and the intestinal flora will also change the structure and properties of the drug (21).

Gut microbiota can be depleted by antibiotics or can be studied in germ-free mice. Antibiotic-induced depletion of the gut microbiota also has an impact on bone metabolism (22), such as impacting bone growth and preserving the progression of osteoarthritis (23–25). Germ-free mice can also experience bone loss but reduced development of osteoarthritis (26, 27). In this essay, we review recent studies addressing the role of depletion of gut microbiota in osteoporosis and osteoarthritis and discuss the proposed mechanisms.

There are many common mechanisms for the effects of gut microbiota on osteoporosis and osteoarthritis, and in the first part of this study, we systematically summarize the factors affecting osteoporosis and osteoarthritis, including factors that affect nutrient absorption, change hormone levels, and mediate the immune response.

There are many potential mechanisms of gut microbiota depletion in osteoporosis, such as impaired intestinal barrier function, endocrine function, immune function and gut microbial excretion byproducts. Changes in bacterial species in the gut microbiota can influence intestinal barrier function, which can affect the processes of nutrient absorption. Intestinal microbiota may affect intestinal pH (55) and affect the synthesis of vitamins B and K (56), which plays an important role in controlling calcium absorption (57). The depletion of gut microbiota in diet-induced obesity mediates changes in the ileum and allows macromolecular substances to pass quickly through the intestinal wall of the intestinal epithelium (58). However, damage to intestinal barrier function can also influence the composition of gut microbiota by increasing lipopolysaccharide (LPS) (38). Gut hormones also have many key roles in bone metabolism, which involves the accumulation of various signaling pathways, including G protein-coupled receptors, nutrient transporters, and ion channels (59). Both antibiotic-induced and germ-free models represent a basic model to understand the relationship between microbiota and the immune system by regulating T helper 17 lymphocytes, TNF, interleukin 17, and the RANK ligand system (46, 60). Intestinal microbial consumption affects host endocrine function through several bacteria-derived metabolites, including glucagon-like peptide 1 and peptide YY (61). Gut microbial excretion byproducts, for example, Glucagon-like peptide 1 is an amino acid hormone and is also secreted by endocrine L cells. It plays a regulating role in the process of osteoporosis by changing the balance between the differentiation of mesenchymal stem cells of the bone into osteocytes and adipocytes (62). Peptide YY is also a negative regulator of osteoblast bone formation (63) ( Table 1 and Figure 1 ).

Several studies have found that depletion of gut microbiota by antibiotic treatment affects growth in early life in mice. Antibiotics induced depletion of gut microbiota in postpubertal skeletal development by an osteoimmune response, which alters the gut bacterial composition and skeletal morphology. In addition, depletion of gut microbiota can contribute to a state of dysbiosis-mediated hyper immunity caused by inhibited the presentation of class II antigens of the major histocompatibility complex (64). Tavakoli et al. examined whether the gut microbiome contributes to bone loss in stearoyl-coenzyme desaturase mice and found that depletion of the gut microbiota significantly improved decreased bone mass. This occurred by increasing osteoblasts and osteoblast-related gene expression and impairing the intestinal barrier due to inflammation (65). Low-dose penicillin-induced depletion of gut microbiota in preadolescent mice, leading to alterations of metabolites and abnormal intestinal immunity (66). Therapeutic-dose pulsed antibiotic treatment-induced depletion of gut microbiota can accelerate body mass and bone growth (67). Cho et al. create a model of obesity in dogs by injecting subtherapeutic antibiotics and found that depletion of gut microbiota can change carbohydrate metabolism into short-chain fatty acid metabolism, providing evidence of metabolic homeostasis (68). Female bending strength was less induced by depletion of gut microbiota, and B and T cell populations were also depleted, suggesting an association between alterations in the immune cell population and bone tissue material properties (69). The effect of microbiota perturbation with antibiotics is often affected by sex, age, and the dose of antibiotic drugs (70–73).

Germ-free (GF)animals are another way to study depletion of the gut microbiota, and they can also be used to examine the effect of specific microbes on osteoporosis and osteoarthritis (74, 75). Irie et al. investigated germ-free mice to evaluate age-related immune and inflammatory systems and found that depletion of gut microbiota led to alveolar bone loss in GF mice (76). Colonization of GF mice with SPF increases bone formation, which provides IGF-1 to simulate the development of skeletal bone (41). Li et al. found that the inflammatory response is caused by a lack of steroids that regulate the intestinal microbiota, leading to loss of trabecular bone. The results show that the gut luminal microbiota increases gut permeability and triggers inflammatory pathways (77). Schwarzer et al. used Nod1−/− or Nod2−/− mice with germ-free mice to reduce bone mass (78). Quach et al. investigated the influence of different microbial communities on different mice and the success rate of fecal transplantation in sterile mice. This result shows that bone mass, bone parameters, osteoclast precursors, and T cell populations did not change significantly (79). Compared with conventional rats, GF mice increased bone mass and decreased the number of osteoclasts on the surface of each bone. This indicates that the bone immune status and the bone resorption mechanism mediated by osteoclasts have changed (27). In addition, the gut microbiota prevents excessive mineralization by enhancing osteoblast and osteoclast activity through transcription factors, such as Gata-binding protein 3 (80) ( Table 1 ).

More and more evidence shows that some factors related to OA, such as aging, gender, diet, and obesity, can re-adjust the gut microbiota while promoting systemic inflammation. This suggests that microorganisms may participate in OA, although limited and disturbing. Convincing research confirms that this hypothesis will interfere with intestinal flora.

The possible mechanisms of depletion of gut microbiota in osteoarthritis include chronic inflammatory factors, lipid metabolites, and innate immunity. Since elevated LPS levels are associated with obesity and metabolic syndrome, and obesity and metabolic syndrome are closely related to the risk of osteoarthritis, it is easy to assume that at least one microbial community is associated with osteoarthritis, inflammation, low levels, and metabolic endotoxicity Related. Macrophage activation and joint damage (81). The increase in lipopolysaccharide (LPS) and LPS binding protein (LBP) is related to the severity of knee osteophytes and the frequency of macrophage activation in the synovium (82). In addition, an interesting study by Christopher et al. found that the characteristics of microbial DNA in human and mouse cartilage and its changes are related to the occurrence and development of human osteoarthritis (82). Because of this factor between the intestinal flora and osteoarthritis, there is an urgent need to develop effective disease-modifying therapies to relieve symptoms and slow the progression of osteoarthritis. In this case, it can be assumed that the regulation of intestinal flora by external means may affect the progression of osteoarthritis.

Fecal microbiota transplantation (FMT) is a surgical procedure used to treat diseases related to the gut microbiota, including the delivery of stool from a healthy donor to the recipient’s distal gastrointestinal tract (83). The new results show that FMT has broad application prospects in OA management. Huang et al. investigate a study to collect stool samples from healthy individuals in the OA group without metabolic syndrome and from healthy individuals in the OA group with metabolic syndrome and then transplant the collected samples to meniscus/ligament rupture osteoarthritis (MLI) Of sterile mice. Interestingly, transplantation of OA in knee joints with metabolic syndrome and MLI may lead to worsening of osteoarthritis. These results indicate that the weak microbiome in the mouse model may exacerbate the histopathological severity of osteoarthritis due to joint damage. This study illustrates the application of FMT in the study of the pathogenesis of osteoarthritis, and also provides hope for manipulating the intestinal flora to treat osteoarthritis. However, due to the limited sample size, more convincing research is needed (84).

Depletion of gut microbiota OA caused by antibiotics has also been investigated, and this depletion can alleviate the progression of osteoarthritis (25). Depletion of the gut microbiota can also slow osteoarthritis outcomes by reducing the state of inflammation and lowering the expression of Wnt signaling modulatory proteins (85). In addition, due to the instability of the medial meniscus, depletion of the intestinal microflora in GF mice may reduce the incidence of osteoarthritis (26), which can regulate inflammation associated with the innate immune system (86).

A previous study found that obesity-associated OA can also be affected by the depletion of gut microbiota (87). In addition, lipopolysaccharide also plays an important role in the pro-inflammatory response of the lack of intestinal flora caused by gram-negative bacteria (88). Ulici et al. found that depletion of gut microbiota induced by germ-free mice could also reduce the development of osteoarthritis, which may have been caused by the lower level of lipopolysaccharide (26). Lipid metabolites also play an important role in destroying intestinal flora (44). Serum and synovial fluid lipodystrophy are also important predictors in the development of osteoarthritis (89) ( Table 2 ).

Although depletion of gut microbiota is increasingly valued in the study of osteoarthritis and osteoporosis, it is not yet available as a means of treatment. many studies found that potential benefits of probiotic supplementation such as L. paracasei, L. casei 393-fermented milk, L. helveticus-fermented milk, L. casei and L. acidophilus and Enterococcus faecium on bone health in both healthy and pathological states which regulate of luminal pH; secretion of antimicrobial peptides; enhancement of barrier function by increasing mucus production and modulation of the host immune system (90).

Osteoporosis and osteoarthritis are major public health problems and the main cause of global pain, disability, fracture risk, and socio-economic costs. Therefore, determining the pathogenesis of osteoporosis and osteoarthritis is essential for the development of new therapeutic interventions to prevent and alleviate the disease.

As an important way to regulate bone metabolism, the gut microbiota has attracted increasing attention. Depletion of the gut microbiota as a method to study its function still lacks in-depth research. In this review, we summarized the evidence supporting the gut-joint axis hypothesis and the interaction of gut microbiota with osteoarthritis or surgical factors and suggested the prospects for use of gut microbiota in the treatment of osteoarthritis and surgery Therefore, it is important to further analyze the role of gut microbiota depletion in osteoporosis and osteoporosis.

The detailed mechanism of the gut-joint axis is unclear. Intestinal flora can affect joints by regulating inflammation and metabolism, but cartilage metabolism is still different from the intestinal flora. In this case, a variety of recombinant sciences, such as metabolomics and transcriptomics, help to decipher this complex problem through molecular resolution by combining specific metabolites, genes, or signaling pathways. In addition, single-cell technology should reveal the correlation between different cell subpopulations and the gut microbiota. In addition to mechanism studies, there is evidence that inflammation and intestinal diseases may be related to new biomarkers that can predict the progression of OA and OP and monitor the effectiveness of therapeutic interventions.

Conception and design: ZYG and KT. Acquisition, analysis, and interpretation of the data: ZYG, SFL, XL, LYL, QGZ and ZQG. Drafting and writing: KT. All authors contributed to the article and approved the submitted version.

This work was partly supported by the Clinical research project of Shanghai Tenth People’s Hospital (Grants no. YNCR2C027).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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