DOI: https://doi.org/10.21203/rs.3.rs-2019685/v1
The regulation and maintenance of bone metabolic homeostasis plays a pivotal role in animal skeletal health. Several skeletal diseases have been confirmed to be closely related to ecological dysbiosis and structural changes in the gut microbiota. Gut microbiota and its metabolites, mainly short-chain fatty acids (SCFAs), affect almost all organs, including the skeleton. SCFAs positively affect bone healing by acting directly on cells involved in fracture healing or by shaping appropriate anti-inflammatory and immunomodulatory responses. Moreover, recent studies have shown that SCFAs play a biological role in regulating bone metabolism in four areas: immune function, calcium absorption, osteogenesis and osteolysis, thus havingpotential benefits in maintaining bone health in livestock and poultry. This review focuses on the role of SCFAs in the regulation of bone metabolism by gut microbiota and provides a theoretical basis for studies related to bone health in livestock and poultry.
The bones form the skeleton, which serves multiple purposes, including support to the body’s weight, storing minerals like calcium and phosphorus, and producing blood cells in the bone marrow. Therefore, the regulation and maintenance of bone metabolic homeostasis plays a pivotal role in animal skeletal health. Bone metabolism is characterized by the close cooperation of bone cells (including osteoblasts, osteoclasts and osteoclasts) to maintain the number and integrity of bone microarchitecture, and once the homeostasis of bone metabolism is disrupted may lead to bone loss, consequently greatly increase the risk of skeletal diseases[1]. The normal processes of bone development and homeostasis are disrupted, leading to the development of bone disease, a phenomenon that is widespread throughout the modern poultry industry. Back in the early 1990s, leg disease caused an estimated $80–120 million per year in economic losses to the U.S. broiler industry. This issue still poses a greater threat to the broiler industry with the increased intensive management of poultry today[2], which not only leads to motor dysfunction accompanied by symptoms such as claudication, slow movement, and difficulty in standing[3], but also decreases animal performance and muscle quality[4–5], thereby resulting in huge economic losses. In addition, bone diseases are also common in animals such as pigs, cattle, and sheep. For example, long-term vitamin D deficiency predisposes to osteochondrosis, which leads to difficulty standing, lameness, and fractures[6–8].
Recent studies have found that gut microbiota is one of the important regulatory targets of bone homeostasis and bone health. Intestinal microbes can mediate bone homeostasis by participating in metabolic, immune and endocrine processes[2]. In the gastrointestinal tract (GIT), gut microbiota and host cells interact in ways that are normally beneficial to the host, including promoting the maturation of the intestinal immune system through interaction with immune cells (e.g., macrophages and dendritic cells); and maintaining the integrity of the intestinal barrier by inducing mucus production and providing nutrition to the intestinal epithelial cells[8]. However, alterations in the gut microbiota can disrupt the beneficial microbe-host relationship, which can lead to the development or progression of diseases, including inflammatory bowel disease, cardiovascular disease, asthma, and rheumatoid arthritis[9–11]. Several studies have confirmed that gut microbiota can affect bone metabolic homeostasis through different pathways and that short chain fatty acids (SCFAs), a metabolite of gut microbiota, play a key role in bone metabolism, including immunity, calcium absorption as well as deposition, osteogenesis and osteolysis[12–14]. This paper reviews the current reports on the regulation of bone metabolic homeostasis by SCFAs, aiming to explore and introduce the regulatory role of SCFAs in bone metabolism and provide a theoretical basis for the prevention and treatment of skeletal diseases of livestock and poultry.
Bone metabolism occurs in a dynamic equilibrium between bone resorption and bone formation, and this process requires the synergistic action of both osteoclasts and osteoblasts[3]. Osteoblasts and osteoclasts play different roles in maintaining normal bone mass levels in animals. Osteoblasts are responsible for the synthesis, secretion and mineralization of bone matrix, whereas osteoclasts are mainly responsible for the resorption of the bone matrix[15–16]. In addition, the synergistic effect of osteoblasts and osteoclasts is influenced by several factors, such as stem cell antigens, hormones and growth factors[17].
Animal tissues and organs are inextricably linked to each other. The intestine, as the largest immune organ in the animal body, plays an important role in the immune system and regulates the balance of bone metabolism[18]. Peek et al. confirmed that intestinal inflammation enhances the differentiation function of osteoclasts, significantly increasing bone loss and causing harm to bone health[19]. Moreover, the microorganism in the gut also has a key role in the regulation of bone mass. A study by Xi et al. demonstrated that favorable alterations in gut microecology under the influence of probiotics could alleviate bone loss caused by rheumatoid joints[20]. The above shows a strong correlation between gut and bone health.
In the GIT, microbes and its host have a complex mutually beneficial symbiotic relationship, resulting from their long-term co-evolution and mutual influence. These large and richly diverse microbial communities play an important role in the maintenance of bone health by regulating bone metabolism through their metabolites or gut microbiota-mediated regulators of bone metabolism. It has been shown that gut microbiota can regulate the ratio and relative activity of osteoclasts and osteoblasts through multiple pathways, thereby affecting bone metabolism and its normal growth and development[21]. SCFAs, metabolites of gut microbes, can regulate the differentiation, proliferation and apoptosis of osteoblasts through regulatory T cells (Tregs), thus affecting bone metabolic processes. In addition, Yan et al. reported that SCFAs could regulate serum insulin-like growth factor 1 levels and improve bone growth and health[22]. Therefore, SCFAs may be a key substance in regulating bone metabolism and preventing bone loss by the gut microbiota.
SCFAs, including a class of acid metabolites (C2-C5) such as acetic acid, propionic acid, butyric acid, valeric acid, isobutyl and isovaleric acid, are produced by bacteria in the gut of humans and animals by the fermentation of indigestible carbohydrates and proteins in food [23]. SCFAs are derived from the soluble dietary fiber found in foods such as oligosaccharides (bananas, Onions and asparagus), pectin (apples, apricots, carrots, oranges), kidney beans, oat bran, corn starch, milk, yogurt, and sprouted barley. Resistant starches such as barley, rice, beans, green bananas and potatoes are also important sources of SCFAs[24–27]. These indigestible fibers are not digested and absorbed in the small intestine and are subsequently fermented by microbiota in the cecum and large intestine; SCFAs are mostly produced in the cecum aswell asproximal colon and less in the distal colon[28]. Among them, acetic acid, propionic acid and butyric acid account for 90%−95% of the total amount of SCFAs produced by gut microbiota and are the main components of intestinal SCFAs[29]. Therefore, the above-mentioned three kinds of SCFAs have been studied extensively, especially butyric acid.
SCFAs are closely related to intestinal microecology and are involved in a wide-range of biological processes, including signal transduction, regulation of cytokines, immune cells and intestinal mucosal barrier function[30–31]. Furthermore, SCFAs increase bone formation and improve bone quality through regulating immunity, intestinal barrier function and immune cell activity.
SCFAs can be directly transported throughout the body by the host cells at the intestinal endothelial barrier, thus affecting distant tissues. G protein-coupled receptors (GPRs) are capable of binding to SCFAs, including GPR43, GPR41 and GPR109a[32]. These membrane-bound receptors are expressed on various immune cell types, including monocyte macrophages, and on other non-immune cells such as intestinal epithelial cells, adipocytes and enteroendocrine cells[33]. When these receptors bind to SCFA, it leads to intracellular Ca2+ release and activation of different downstream signaling pathways, such as ERK/MAPK, p38 or Akt/PI3K signaling cascades, thus regulating cellular activity and function[34]. In addition, some SCFAs, such as butyrate, serve as the main source of energy for the vital activities of intestinal epithelial cells, which directly affect the growth and development of these cells. Nonetheless, a certain number of SCFAs reach the bloodstream through transport systems (SMCT1/Slc5a8 pathway, MCT1/Slc16a1 pathway or passive diffusion) and are transported to the whole body through the transport system. Once SCFAs enter the circulatory system, they will affect the metabolism and function of peripheral tissues (adipose tissue, skeletal muscle, bone, etc.) by activating GPRs[35–36].
However, butyric acid exhibits the most extensive biological activity among SCFAs, including regulating inflammation, maintaining immune homeostasis, and reducing bone loss from inflammation. Butyric acid can downregulate the pro-inflammatory mediators NO, IL-6 and IL-12 produced by lipopolysaccharide (LPS)-induced macrophages and can also promote the production of IL-22 through GPR41 and HDAC inhibition[37]. Butyric acid inhibits LPS-induced maturation and biological activity of monocyte-derived dendritic cells and promotes the polarization of early CD4 + T cells into IL-10-producing Tregs[38]. While, butyric acid regulates the inflammatory state of the body by activating GPRs in the intestinal mucosal epithelium, reducing the synthesis and secretion of pro-inflammatory factors such as Tumor necrosis factor-α(TNF-α) and Cyclooxygenase-2, thereby reducing the bone loss brought about by inflammation[10, 39].
Furthermore, butyric acid alleviates intestinal inflammation and reduces osteoclast differentiation by attenuating TNF-α-mediated immune responses and reducing inflammatory vesicles such as NLRP3[40]. Butyrate has also been reported to regulate Claudin-2 expression, reduce intestinal permeability through an IL-10 receptor-dependent mechanism, and strengthen intestinal barrier function by increasing colonic mucin and tight junction protein production[1, 41], enhancing immune response system function thus reducing bone loss[42]. Kaisar et al. found that butyrate inhibited the expression of the pro-inflammatory factor IFN-γ caused by the overactivation of the IFN-γ/ STAT1 signaling pathway[43]. Moreover, butyrate can also modulate the immune effect and relieve osteoarthritis by inhibiting the activity of inflammation-related pathways NF-κB and JAK/ STAT and IL-12p70, IL-23, and preventing the polarization of early CD4+ T lymphocytes into Th1(T helper cells 1) and Th17[44]. In short, Butyric acid has a positive effect on the maintenance of bone health by regulating the immune function of the animal body and alleviating bone destruction and loss.
Acetic acid is one of the most abundant SCFAs produced by the gut microbiota[45]. It positively impacts bone health by maintaining the integrity of the intestinal mucosal barrier, preventing the invasion of pathogenic bacteria and enhancing the host's immune function. In animals, acetic acid is mainly present as free acid in tissues, excreta and blood[46]. It was found that acetic acid increases the production of IgA in the colon, alters the ability of IgA to bind to specific intestinal bacteria, and alters the colonization of these bacteria, enhancing the immune barrier function of the intestinal mucosa, thereby indirectly reducing the release of pro-inflammatory factors (TNF-α, IL-1β, etc.), inhibiting osteoclast activity and reducing bone loss[47, 48]. In addition, acetic acid can activate the GPR41 receptor on the surface of immune cells, enhancing the immune effect and facilitating the maintenance of bone health[49–50]. Maslowski et al. displayed that acetic acid significantly improved intestinal function, reduced DNA-dependent activator of IFN-regulatory factors and inflammatory mediator myeloperoxidase levels and TNF-α, thus facilitating the remission of the inflammatory response and reducing osteoclast production and differentiation[51]. The above facts indicated that acetic acid enhances immune function and reduces the release of pro-inflammatory factors, thereby inhibiting the activation of osteolytic effects.
Propionic acid is an organic acid that occurs naturally as a result of the kind of bacterial action found on the skin or in the GIT. Propionic acid in the gut plays a variety of roles after passing through the bloodstream, including affecting hepatic cholesterol metabolism, promoting calcium absorption, increasing calcium deposition, and facilitating bone production[52–53]. In addition, it was found that propionic acid not only activates NLRP3 inflammatory vesicles in intestinal epithelial cells, induces IL-18 secretion, and improves the integrity of the intestinal mucosal epithelial barrier, but also inhibits histone deacetylase and decreases NF-κB activity, thereby reducing the release of inflammatory factors TNF-α, IL-6, and IL-8 and affecting the structure and function of the intestinal mucosal barrier[54]. Osteoporosis is closely associated with the cellular imbalance of the immune system and immune-mediated effects on bone structure through the intestine have been demonstrated[55]. Interestingly, SCFAs intake resulted in increased bone mass in mice accompanied by a decrease in inflammation-induced bone loss. In a study of the effects of propionic acid supplementation on human bone metabolism, Duscha et al. found that propionic acid intake induced a significant increase in serum osteocalcin (a marker of bone formation) levels and a significant decrease in β-CrossLaps (a marker of bone resorption) levels; suggesting that propionic acid induces increased bone formation and decreased bone resorption[56].
The GIT displayed high propionate and butyrate levels and low valeric acid levels[57]. However, Yuille's study confirmed that total specific inhibition of HDAC and promotion of differentiation of Tregs into T cells by increasing the ability of intestinal flora to produce butyric and valeric acid could enhance bone immunity indirectly[58]. Studies have shown that although valeric acid levels are low in animals, dietary fiber intake helps to increase valeric acid levels and that higher valeric acid levels reduce the release of pro-inflammatory factors and mitigate bone destruction[58, 59]; suggesting that the immunomodulatory ability of valeric acid and its potential therapeutic value for inflammation-induced bone diseases.
There are similarities in the functions of the different SCFAs. For example, they can regulate the structure of the gut microbiota (regulating pH in the gut and reducing the colonization of pathogenic bacteria), which facilitates the establishment of the intestinal immune barrier, and inhibit the release of inflammation-related signaling molecules (IL-6, IL-7, Receptor activator for nuclear factor-κB ligand, (RANKL)), which reduces osteoclast differentiation and thus facilitates bone health. The above facts show that intestinal health is closely related to bone health.
There are differences in the type of SCFAs produced by fermentation of different kinds of gut microbiota (As shown in Table 1). According to Wolin et al., the fermentation products of Lactobacillus spp. are mainly lactic acids. The fermentation products of Synechococcus spp. are mainly acetic acid and butyric acid, whereas the fermentation products of Bifidobacterium spp. are mostly acetic acid, lactic acid, and formic acid[60]. It can be seen that different gut microbiota produce different SCFAs. In addition, dietary fiber is essential in terms of the composition and metabolic activity of the gut microbiota and can influence the level of SCFAs. Diet has a decisive role in the structure of the gut microbiota and the level of SCFAs. Therefore, it is possible to modify the structure of gut microbiota through diet to regulate SCFAs. Even short-term dietary interventions can have a significant impact on gut microbiota structure. In particular, those diets based exclusively on animal products, consuming reduced-fat foods high in protein and low in carbohydrates or fiber, can increase the relative abundance of the Bacteroidetes and decrease the relative quantity of the Firmicutes, leading to an imbalance in the structure of the microorganism, while affecting SCFAs concentrations in the intestine[61]. In conclusion, long-term poor dietary habits may increase the risk of intestinal diseases, and the intake of more fermentable dietary fiber can regulate the structure of the microorganism and thus positively affect the prevention of diseases.
When studying the concentration of SCFAs under different gut microbiota structures, it was found that the ability of the gut microbiota to produce SCFAs was enhanced by adding certain probiotics[62]. For example, in a broiler cecum model, supplementation with L. salivarius ssp. increased the concentration of propionate and butyrate in the cecum[63]. Furthermore, in previous studies by Guss, it was found that changing the composition of gut microbiota by taking antibiotics, dietary changes and adding probiotics can affect bone health[64]. These studies indicate that the structure of gut microbiota can be altered by diet, which further leads to changes in SCFA concentration, and that different species of gut microbiota produce different types and amounts of SCFAs. In addition, it also suggests that the gut microbiota may have a regulatory effect on bone metabolism through SCFAs.
As bioinformatics and molecular biotechnology have developed, increasing studies have demonstrated gut microbiota metabolites regulate bone metabolism[65–66]. Among its metabolites, SCFAs have been shown to affect almost all body organs, including the bone[67]. SCFAs can participate in bone metabolism by directly acting on osteoblasts, osteoclasts, chondrocytes, and fibroblasts, or indirectly by regulating the absorption of mineral elements, and can also affect bone metabolism by modulating the immune system[68–69]. SCFAs exhibit a wide range of bone metabolism activities and positively affect bone quality improvement.
SCFAs promote the maturation of the host immune system and regulate bone metabolism through the immune system[70]. Studies have shown that gut microbiota can interact with immune cells and dendritic cells to promote the production of molecules such as SCFAs, indole derivatives, polyamines and secondary bile acids[71]. Among them, the receptors of SCFAs are expressed on immune cells, and the binding of SCFA to the corresponding receptors has a regulatory effect on T-cell function and immune cell differentiation, thereby enhancing immune function and reducing bone loss caused by inflammation. In addition, there is evidence that in osteoporosis caused by estrogen deficiency, T cells can increase the production of pro-inflammatory and pro-osteoclastic cytokines in bone tissue, such as TNF-α and RANKL, and that the upregulation of the expression of these factors in osteoblasts enhances the osteoclastogenesis induced by Th17 to stimulate the regulation of bone resorption[72]. SCFAs play an important role in bone metabolism and bone mineral density due to their close relationship with immune cells and bone cells.
In addition, it has been reported that butyrate and propionate can regulate intestinal immune function by inhibiting histone deacetylase (HDAC)[73]. Chang et al. demonstrated that butyrate produced by gut microbiota acts as an inhibitor of HDAC and modulates the function of macrophages in the lamina propria of the mouse gut[74]. Related studies have shown that the inhibition of HDAC increases the development and function of Tregs. Therefore, it may be one of the mechanisms by which SCFAs enhance the production of Tregs in the GIT[75]. The interaction of SCFAs with GPRs not only drives the differentiation of T cells into Tregs, but also promotes differentiation into effector T cells[76]. Park and colleagues suggested that SCFAs may induce helper T cells to differentiate into Th1 and Th17, thereby increasing host resistance to pathogen attack[77–78]. SCFAs such as butyrate and propionate also regulate antigen presentation through HDAC inhibition by interacting with GPRs and have an inhibitory effect on dendritic cell development. Together, it can be seen that gut microbiota can affect the overall immune function of the host through SCFAs, immune cells and immune factors act on bone tissue, to affect the biochemical activity of osteoblasts in this process, and exert a regulatory effect on bone homeostasis and bone mass.
SCFAs can increase calcium element deposition and bone mineral density (BMD) and mechanical strength. Calcium is an essential element for bone formation and sufficient calcium is necessary to improve bone quality and increase bone mechanical strength[79–80]. Maintaining calcium balance plays a crucial role in achieving good peak bone mass and inhibiting the development of bone loss. Prebiotics are food components that selectively stimulate the growth or activity of one or several bacteria in the colon, thus exerting a beneficial effect on the host and having a role in regulating the gut microbiota structure [81]. It has been reported that SCFAs produced by the fermentation of prebiotics by gut microbiota can promote calcium absorption and significantly improve bone strength and bone mineral density in mice[82]. A study found that daily prebiotic fiber intake can enhance calcium absorption in adolescent children, which is beneficial to the bone development of adolescent-aged children[83]. Dietary fiber intake affects calcium absorption: increased levels of intestinal SCFAs after fermentation by gut microbiota can reduce the pH of the intestinal microecology, thus reducing the formation of calcium phosphate and increasing calcium production and absorption[84]. A study by Wallimann et al. confirmed that butyric acid significantly increases calcium deposition at the site of bone injury and promotes bone healing[85].
Furthermore, the effect of SCFAs on calcium deposition may not only be reflected in changes in intestinal pH. Indeed, SCFAs have been shown to increase calcium transport by regulation of signaling pathways[86, 87]. Furthermore, the SCFAs can indirectly improve calcium absorption by modulating the production of intestinal serotonin, namely 5-hydroxytryptamine (5-HT)[88]. Serotonin, a molecule that interacts with osteoblasts, has been used as a potential regulator of bone mass to prevent osteoporosis by increasing bone formation[89]. Duodenal enterochromaffin cells have the biological function of synthesizing 5-HT, and can promote the synthesis of 5-HT under the action of SCFAs[90]. It has been reported that 5-HT can interact with osteoblasts, especially by activating the 5-HT1B receptor on preosteoblasts to reduce osteoblast proliferation and thus improve the bone loss caused by osteoporosis[91]. In conclusion, SCFAs can directly or indirectly regulate bone formation, thereby increasing bone mineral density and bone strength and reducing fracture risk.
SCFAs can promote bone formation by regulating osteoblast activity. Osteoblasts have a pivotal role in bone formation and activation of Wnt signaling in osteoblasts is critical for osteoblast proliferation and bone homeostasis[87]. Studies have demonstrated that the Wnt signaling pathway has a crucial role in bone development and endostasis; moreover, SCFAs can activate the wnt pathway and induce the expression of the transcription factor osterix, thereby promoting osteoblast differentiation[49, 87]. In addition, this signaling pathway induces the expression of osteoprotegerin (OPG), an osteoclast suppressor in osteoblast lineage cells, inhibiting bone resorption[2]. It was found that butyrate can affect normal osteoblasts, increase osteoblast mineralization to promote bone formation and inhibit osteoclast differentiation by promoting OPG production in a human study[92].
SCFAs can indirectly regulate bone metabolism through Tregs. Tregs are cells that regulate the body’s immune function by actively regulating the activation and proliferation of potentially self-reactive T cells present in the normal organism. In addition to their immunomodulatory functions, Tregs can also exert some regulatory effects on bone homeostasis. They inhibit osteoclastogenesis, promote osteoblast differentiation, and are required for parathyroid hormone-stimulated bone formation[93]. Tregs were isolated from SPF mice and cultured in vitro with SCFAs. It was found that in the presence of propionate, the proliferation of Tregs can be promoted, thereby enhancing the regulation of bone homeostasis by Tregs[94]. Supplementation with probiotics can alleviate pathological bone loss to some extent. Our study has demonstrated that L. rhamnosus JYLR-005 prevented thiram-induced Tibial Dyschondroplasia by improving bone-related growth performance in broilers, including tibia weight, length, and mean diameter[95]. Tyagi et al. found that supplementation of L. rhamnosus in mouse diets can affect bone homeostasis, and the results presented that L. rhamnosus increased the volume of bone trabeculae and promoted increased bone formation[96]. It was attributed to the production of butyrate in the gut after L. rhamnosus ingestion, which induced the proliferation of Tregs in the intestine and bone tissue. The same results were obtained in an experiment where butyrate was fed directly to germ-free mice[97]. These studies suggested that SCFAs may indirectly regulate bone homeostasis through the biological function of Tregs.
SCFAs can modulate the activity of osteoclasts, which in turn regulates bone resorption. Osteoclasts are key cells involved in the regulation of bone resorption and are essential for maintaining the homeostasis of bone metabolism. Montalvany-Antonucci studied the effect of SCFA on alveolar bone and found that SCFA acts as a regulator of bone resorption and reduces osteoclast differentiation dependent on the activation of free fatty acid receptor 2[98].
Osteoclast generation and bone resorption are energy-consuming processes closely related to energy metabolism. Lemma demonstrated that the energy required for osteoclast differentiation mainly from oxidative phosphorylation, while peripheral cellular activities associated with bone matrix degradation are powered by glycolysis[99]. In the study of Lucas et al., the protective effect of SCFAs on bone mass was associated with inhibition of osteoclast differentiation and bone resorption. It is because propionate and butyrate induce a shift in the metabolic direction of osteoclasts, leading to enhanced glycolysis without significant changes in oxidative phosphorylation levels, resulting in downregulation of essential osteoclast genes, such as TRAF6 and NFATc1, affecting RANKL-induced osteoclast differentiation, thereby reducing the number of osteoclasts and regulating bone homeostasis[100]. Wauquier et al. found that GPR40 receptor-deficient mice exhibited features of osteoporosis, suggesting that GPR40 receptors positively affect bone density and demonstrating a mediating role for GPR40 receptors in fatty acid-induced bone remodeling[101]. An in vitro experimental study by Wallimann et al. revealed that many genes related to osteoclast differentiation after butyric acid treatment were differentially present in osteoclast precursor cells. Moreover, differentially expressed genes on osteoblast precursor cells can markedly reduce osteoclast formation and bone resorption activity[85]. Based on the above findings, SCFAs are shown to be an effective regulator of osteoclast metabolism and bone homeostasis.
In recent years, the problem of bone diseases has become more prevalent as livestock and poultry industries have become increasingly intensive. Effective control and treatment of skeletal diseases is an urgent need of era, and it is especially important to find reasonable methods and approaches for prevention and treatment. There has been continuous evidence that SCFAs that act indirectly on gut microbiota regulation can modulate bone metabolism and reduce bone loss directly, thereby positively contributing to bone health. SCFAs modulate the immune system, calcium absorption, and bone cell regulation, thereby contributing to bone health (Table 2). Therefore, providing animals with appropriate SCFAs can improve bone health and their growth performance. The complex effects of SCFAs on skeletal development offer the possibility of more efficient treatment of bone diseases. However, More studies are required to determine the optimal ratios and doses for clinical application, and the effects of SCFAs on skeletal development. In the future, with the development of biomedical technology, we anticipate that the potential role of SCFAs in skeletal development will be further explored; SCFAs are crucial for the regulation of bone metabolism and maintenance of bone health, and these new findings will make clinical treatment of bone diseases even more effective, better serve livestock and poultry producers.
BMD, Bone mineral density; GIT, Gastrointestinal tract; GPRs, G protein-coupled receptor; HDAC, Histone deacetylase; 5-HT, 5-hydroxytryptamine; LPS, Lipopolysaccharide; OPG, Osteoprotegerin; RANKL, Receptor activator for nuclear factor-κB ligand; SCFAs, Short chain fatty acids; Th, T helper cells; TNF-α, Tumor necrosis factor-α; Tregs, regulatory T cells.
Author contributions
C.H contributed to the conceptualization, resources, funding acquisition, and revision and editing of the manuscript. Y.F.H. performed the literature review and drafted the manuscript. A.S. contributed to the revision and editing of the manuscript. L.X.L. and T.T.X. collected the literature and reviewed the text. All authors contributed to the article and approved the submitted version.
Funding
This study was supported by the China Postdoctoral Science Foundation (No. 2020M672234), the Outstanding Talents of Henan Agricultural University (No.30500421), and the Key Scientific Research Project of Henan Higher Education Institutions of China (No. 21A230013).
Conflict of Interest:
The authors declare no competing or financial interests.
Table 1. Gut microbiota for the synthesis of short-chain fatty acids.
|
Phylum |
Class |
Order |
Family |
Genus/Species |
SCFAs |
Reference |
|
Actinobacteria |
Actinobacteria |
Bifidobacteriales |
Bifidobacteriaceae |
Bifidobacterium adolescentis |
Propionic acid |
[106] |
|
|
|
|
|
Bifidobacterium sp. |
Acetic acid |
|
|
Bacteroidetes |
Bacteroidetes |
Bacteroidetes |
Bacteroidaceae |
Bacteroides fragilis |
Propionic acid Butyric acid |
[102, 106, 107] |
|
|
|
|
|
Bacteroides sp. |
Acetic acid Propionic acid |
|
|
|
|
|
|
Bacteroides thetaiotaomicron |
Propionic acid Butyric acid |
|
|
|
Bacteroidetes |
Bacteroidetes |
Prevotellaceae |
Prevotella stercorea |
Acetic acid Valeric acid |
[108] |
|
Firmicutes |
Bacilli |
Lactobacillales |
Streptococcaceae |
Streptococcus sp. |
Acetic acid |
[102, 109] |
|
|
Clostridia |
Clostridiales |
Clostridiaceae |
Clostridium beijerickii |
Propionic acid Butyric acid |
[102, 103, 104, 106, 107, 109] |
|
|
|
|
|
Clostridium botulinum |
Propionic acid Butyric acid |
|
|
|
|
|
|
Clostridium butyricum |
Butyric acid |
|
|
|
|
|
Lachnospiraceae |
Coprococcus comes |
Propionic acid Butyric acid |
|
|
|
|
|
|
Coprococcus eutactus |
Propionic acid Butyric acid |
|
|
|
|
Vellionellales |
Veillonellaceae |
Megasphaera elsdenii |
Acetic acid Propionic acid Butyric acid Valeric acid |
[105, 109] |
|
|
|
|
|
Megasphaera sp. |
Acetic acid Propionic acid Butyric acid Valeric acid |
|
|
Proteobacteria |
Gammaproteo bacteria |
Enterobacteriales |
Enterobacteriaceae |
Salmonella sp. |
Propionic acid |
[109] |
|
Verrucomicrobia |
Verrucomicrobia |
Verrucomicrobiales |
Verrucomicrobiaceae |
Akkermansia muciniphila |
Acetic acid Propionic acid |
[106] |
Note: Only part of the gut microbiota that can produce SCFA is listed in the table
Table 2. The function and role of SCFA.
|
Function |
Types of SCFA |
Object of study |
Effect |
Reference |
|
Immunity |
Butyric acid |
Broilers |
The addition of sodium butyrate to broiler diets can improve the growth performance of broilers and can be used to regulate the body's immune response and help to reduce the production of bone inflammation. |
[110] |
|
Butyric acid |
Broilers |
Butyric acid as a feed additive can significantly reduce the level of IL-6 and IL-1β, relieve the development and spread of inflammation, and facilitate the growth and development of broilers. |
[111] |
|
|
Acetic acid Butyric acid Isobutyric acid |
Mice |
The production of SCFAs has a mitigating effect on OP development. |
[112] |
|
|
The regulation of calcium |
Acetic acid Propionic acid Butyric acid |
Laying hens |
Promote intestinal absorption of calcium. |
[86] |
|
Acetic acid Propionic acid Butyric acid Valeric acid |
Mice |
Increases calcium deposition at the site of bone injury and accelerates bone formation |
[113] |
|
|
Acetic acid Propionic acid Butyric acid Isobutyric acid Valeric acid Isovaleric acid |
Rats |
Increases mineral availability by increasing calcium dissolution at lower pH, thereby increasing bone mineral content and deposition. |
[114] |
|
|
Osteogenesis |
Butyric acid |
Human beings |
Increased mineralization of osteoblasts promotes bone formation and inhibits osteoclast differentiation by promoting OPG production by human osteoblasts |
[93] |
|
Butyric acid |
Mice |
Butyrates can increase the number of Tregs in the intestine and bone marrow. Tregs can stimulate CD8 + T cells, which can secrete Wnt10b and promote bone formation by activating Wnt signalling in osteoblasts. |
[55,87] |
|
|
Propionic acid |
SPF Mice |
Propionate can promote the proliferation of Tregs, thereby enhancing the regulation of Tregs on bone homeostasis. |
[95] |
|
|
Butyric acid |
Mice |
Induced proliferation of Tregs in the gut and bone tissue and increased trabecular bone volume, and promoted bone formation in mice. |
[96] |
|
|
Osteoclastogenesis |
Butyric acid |
Rats, Mice |
Butyrate can inhibit the production of osteoclast precursor cells by inhibiting the activity of Histone deacetylase (HDAC). Butyric acid inhibits the formation of osteoclasts and the expression of osteoclast-specific mRNA under the stimulation of RANKL. |
[115] |
|
Isovaleric acid |
Mice |
Isovaleric acid suppresses differentiation of bone marrow-derived macrophages into OCs by RANKL. Isovaleric acid inhibited the expression of OC-related genes. |
[116] |
|
|
Acetic acid Propionic acid Butyric acid Valeric acid |
Mice |
Genes related to osteoclast differentiation are differentially expressed in osteoclast precursor cells, which can significantly reduce osteoclast formation and bone resorption activity. |
[85] |
Note: OP, Osteoporosis; HDAC, Histone Deacetylase; RANKL, Receptor Activator of Nuclear Factor-κB Ligand.