Through the interaction of several cell types throughout the mucosa, including B cells, T cells, monocytes, macrophages, NK cells, and dendritic cells (DCs), GM may have an impact on the innate and adaptive immune system, resulting in a putative immunomodulator [
25,
26]. It has been demonstrated that cell wall elements, such as peptidoglycan [
27], can bind to receptors on the surface of monocytes and macrophages, thereby indirectly inducing the production of cytokines by immune cells [
28]. The disruption of a harmonic balance of the cross-talk gut–immune system can lead to increased LPS, cytokine release, and systemic inflammation, ultimately contributing to the pathogenesis of OA (Fig. 1) [
29]. In the next paragraphs, an overview of the interaction between the GM and the immune system will be given mainly in the light of OA pathogenesis (Fig. 1).
Microbial Symphony: the gut microbiota (GM) is a meticulous orchestra director through his intricate interactions with the immune System. When impaired, i.e., dysbiosis, an outburst of cytokine release with increased LPS translocation in the bloodstream and, therefore, a systemic inflammation, which starts as a low-grade inflammation, contributes to the pathogenesis of osteoarthritisFig. 1
Microbial Symphony: the gut microbiota (GM) is a meticulous orchestra director through his intricate interactions with the immune System. When impaired, i.e., dysbiosis, an outburst of cytokine release with increased LPS translocation in the bloodstream and, therefore, a systemic inflammation, which starts as a low-grade inflammation, contributes to the pathogenesis of osteoarthritisFig. 1
Microbial Symphony: the gut microbiota (GM) is a meticulous orchestra director through his intricate interactions with the immune System. When impaired, i.e., dysbiosis, an outburst of cytokine release with increased LPS translocation in the bloodstream and, therefore, a systemic inflammation, which starts as a low-grade inflammation, contributes to the pathogenesis of osteoarthritis
Gut Microbiota and Innate Immunity
The first line of defense, innate immunity, employs proteins encoded in the germline to identify pathogens and stimulate immune responses. Upon encountering a pathogen, the innate immune cell either eliminates it or activates the adaptive immune response to combat it. OA pathogenesis and progression are significantly influenced by the activation of the innate immune system, which identifies damage-associated molecular patterns (DAMPs) via interactions with pattern-recognition receptors (PRRs) [
30]. DAMPs are molecules released from injured or dying cells as a part of the innate immune response due to trauma or a pathogen infection [
31]. DAMPs resemble microbe- or pathogen-associated molecular patterns (MAMPs or PAMPs), the main source of which is the GM [
32]. PRRs are cytosolic and endosomal receptors found on the cell surface. They include Toll-like receptors (TLRs), NOD-like receptors, and others [
33]. PRRs, which are abundantly present on the outer membrane of macrophages and other immune cells, can discern a vast array of danger signals; this is comparable to how GM metabolites influence the innate immune system. When PRRs detect danger signals, the inflammatory signaling pathway is subsequently activated [
34].
Concurrently identifying microbial DNA and the intestinal microbiome in the knees of patients with OA, it was hypothesized that enteric dysbacteriosis could accelerate the progression of OA by stimulating the innate immune system [
35]. Furthermore, Liu et al. [
23] demonstrated that the GM, components associated with GM, and their corresponding metabolites affected OA by stimulating innate immune responses at both the local and systemic levels. The following events in sequence represent the mechanism by which the innate immune system influences OA:
(1)
Synovial joint immune cells are stimulated and produce DAMPs through interactions with constant PRRs [
36].
(2)
The innate immune response is triggered by host reactions to DAMPs [
36].
(3)
Prompt-onset inflammatory responses are initiated [
36].
In addition to macrophages, neutrophils, dendritic cells (DCs), natural killer (NK) cells, and mast cells comprise the innate immune cells.
Macrophages play a key role in breaking down each component of innate immunity, mediating the immune response between OA and GM. It has been shown that in the OA synovial membrane and cartilage, macrophages and their mediators were highly connected to inflammatory alterations and devasting reactions [
37].
The so-called “two-hit theory” has described the involvement of LPS in knee OA patients’ joint space size, pain intensity, and pathogenesis and severity of osteophytes [
38]. This theory additionally provides potential mechanisms by which LPS contributes to the progression of OA. The first hit takes place when lipopolysaccharide (LPS) stimulates joint macrophages via CD14–TLR4–MD-2 complexes. Subsequently, LPS triggers a comprehensive inflammatory response and joint structure degradation via coexistence and complementarity mechanisms, including the inflammasome pathway or DAMPs [
39]. Furthermore, fibroblast-like synoviocyte pyroptosis can be induced by LPS through the action of either nod-like receptor protein (NLRP) 1 or NLRP3 inflammasomes. This process is known to contribute to the advancement of OA [
40]. LPS is essential for the pathogenesis of osteoarthritis and macrophage-associated inflammatory responses, both of which are critical components of innate immunity.
Furthermore, fecal microbiota transplantation (FMT) from subjects with OA and metabolic syndrome accelerates OA in mice, which activates TGF-b signaling pathways to regulate multiple immune cells, such as macrophages, NK cells, DCs, T cells, and B cells [
41].
Neutrophils are among the most abundant cells of innate immunity. It has been demonstrated that the number of neutrophils was greatest in knee synovial fluid with increased levels of TGF-b and elastase, which are strongly linked to the severity of radiographic knee OA. Moreover, neutrophils and macrophages in knee OA joints have a mutually beneficial interaction in both the progression and worsening of OA [
42].
DCs are antigen-presenting cells that come from monocytes. They link the innate and adaptive immune systems by recognizing and responding to PAMP and DAMP [
43]. In normal conditions, certain subsets of DCs reside in the intestinal mucosa. Upon encountering microorganisms, they undergo a transformation into an inflammatory state through the suppression of disabled homolog 2 (DAB2) gene expression. This process is hindered by the interactions between TLR ligands TRIF and MyD88 [
44]. Butyrate and propionate, which are short-chain fatty acids (SCFA) GM metabolites, may inhibit the growth of DCs by blocking the Na(+)-coupled monocarboxylate transporter (Slc5a8) through the inhibition of HDACs [
45]. Moreover, propionate can safeguard against allergic inflammation by regulating DCs. Another study demonstrated that the surface components and metabolites of
Lactobacillus reuteri can stimulate the maturation of immature DCs and increase the production of the anti-inflammatory cytokine IL-10 by DCs [
46]. If we shift to the joints where OA develops, DCs may initiate and accelerate the advancement of OA through the TLR family, particularly TLR4, as it has been proven in mice with OA where Nie et al. demonstrated a notable increase in the expression of TLR 1–8 in DCs [
44,
47].
NK cells are a subset of lymphocytes that comprise around 15% of all lymphocytes in the bloodstream. They are characterized by the presence of CD56 and the absence of CD3. NK cells play a crucial role in the innate immune system by eliminating pathogens using death-inducing receptors or by releasing soluble chemicals such as perforin and granulysin [
48].
It has been found that NK cells constituted over 30% of the CD45 + lymphocytes in the synovium of individuals with OA with the presence of the chemoattractant receptors CCR5 and CXCR3 [
49]. Compared to NK cells found in the blood, NK cells in the synovium of patients with OA have a silent phenotype indicative of post-activated exhaustion [
50]. However, the production of IFN-g by these NK cells can stimulate neutrophils, macrophages, and DCs. Furthermore, the expression of NKG2D by NK cells can stimulate the activation of T lymphocytes [
51].
Mast cells are watchful agents of the innate immune system and promptly react to both internal danger signals and external infections. Mast cell degranulation, which involves the release of preformed mediators such as pro-inflammatory lipids, tryptases, histamine, chemokines, and cytokines, can be induced by several factors, including the IgE receptor FcεRI, IL-33, and complement receptor C5aR [
52]. When we focus on GM, butyrate inhibits the production of cytokines, specifically IL-6 and TNF-α, in mast cells generated from murine bone marrow. This suppression is achieved by suppressing HDAC activity in the cells [
53]. Moreover, propionate and butyrate can prevent the release of granules from human or mouse mast cells, whether or not IgE is involved. This suppression is linked to the inhibition of HDAC [
54].
LPS can stimulate fully developed mast cells to generate tryptase, chymase, and carboxypeptidase [
55]. If we look at the joint side, it has been observed that mast cells are dispersed in varying patterns inside osteophytes and knee synovial fluid, potentially exacerbating the inflammatory pathophysiology of osteoarthritis [
56]. This led researchers to introduce a novel classification system for the synovial tissue in patients with OA based on the levels of mast cells (low, medium, and high). They identified specific markers for mast cells in a mouse model and found that blocking histamine activity can decrease the severity of OA symptoms and the release of substances associated with OA [
57].
Gut Microbiota and Adaptive Immunity
Recent studies have specifically focused on the impact of adaptive immunity on the GM and osteoarthritis OA. An investigation of immune cells, their cytokines, and synovial inflammation in OA found that the predominant immune cells present in OA synovial tissues were mast cells, macrophages, and T cells. B, NK, and plasma cells were also detected in smaller quantities. Furthermore, they observed a high abundance of cytokines associated with T cells or macrophages in OA synovial tissues, suggesting that T cells and macrophages were activated in these tissues [
58]. Another study discovered that T cells and macrophages were responsible for producing most pro-inflammatory cytokines, even without additional stimulation. Notably, CD4 + and CD69 + T cells were highly abundant [
59]. Furthermore, there was a significant correlation between the quantity of CD4 + T cells in synovial tissues and the severity of pain, as measured by the visual analog scale (VAS) [
59].
Currently, there is a consensus that there are notable changes in Th17 cells, Th9 cells, T memory cells, cytotoxic T cells, regulatory T (Treg) cells, and Th1 cells in the synovial fluid, synovial tissues, and peripheral blood of individuals with OA [
60].
The GM has been suggested as a potential risk factor for OA and may regulate the T-cell response, particularly for Th17 cells [
24]. Th17 cells, the first form of CD4 + T cells, are distinguished by their ability to produce pro-inflammatory cytokines, including IL-22, IL-21, and IL-17. The induction of Th17 cells can be triggered by pro-inflammatory cytokines such as IL-21, IL-6, and TGF-b [
61]. TGF-b plays a two-fold role in immune regulation. Small quantities of TGF-b promote the development of Th17 cells, whereas large quantities of TGF-b stimulate the formation of Treg cells, which suppress inflammation [
61]. Disruptions in the composition of microorganisms in the intestines can influence the transformation of CD4 + T cells into either regulatory T cells or effector T cells. This process is essential for maintaining a balanced immune system and preventing joint inflammation [
24]. How do perturbations in GM lead to activation of Th17 cells? On the one hand, segmented filamentous bacteria can cause the buildup of Th17 cells in the synovial fluids and synovium of individuals with OA. This is achieved by increasing the synthesis of local serum amyloid A, which in turn stimulates DCs in the lamina propria to induce the formation of Th17 cells [
24].
On the other hand, the concurrent administration of
L. acidophilus, vitamin B, and curcumin in a rat model of OA resulted in pain relief, preservation of cartilage, modulation of the anabolic/catabolic equilibrium, and reduction of pro-inflammatory cytokines, such as MCP-1, TNF-α, IL17, and IL-1b. Moreover, T follicular helper (TFH) cells can control the activation of B cells to produce immunoglobulins by releasing IL-21. Butyrate is essential for maintaining the balance of the GM as It can stimulate the production of inducible Treg (iTreg) cells by increasing histone acetylation, which promotes gene expression by blocking HDAC activity [
62].
Regarding B cells, they are responsible for producing immunoglobulins and modulating immune responses. Regulatory B cells (Bregs) function as immunosuppressive cells by upholding immunological tolerance through the secretion of IL-10, IL-35, and TGFb1, which in turn suppress the activation of Th1 cells, Th17 cells, and CD8 + T cells. They also play a role in controlling the differentiation of macrophages and DCs. Additionally, Bregs promote the development of regulatory T cells (Tregs) [
63,
64]. An example of the link between GM and B cells is that the administration of butyrate as a supplement enhanced the activation of AhR in Bregs, leading to the alleviation of arthritis [
65]. A study reported that individuals with RA had lower levels of SCFAs, such as valerate, butyrate, propionate, and acetate, and it was also observed that the amounts of these SCFAs were positively associated with the frequency of Bregs in the peripheral blood, rather than Tregs [
66]. Administration of SCFAs alleviated arthritic symptoms, enhanced the occurrence of Bregs, and decreased the occurrence of transitional B and follicular B cells in collagen-induced mice arthritis by activating the FFA2 receptor [
66]. In another study, SCFAs administration led to an increase in the expression of Bregs and an improvement in the clinical scores of arthritis in mice with collagen-induced arthritis. This effect was observed to rely on the inhibitory activity of HDAC [
67]. These data suggest that the GM may have a similar regulatory influence on Bregs in OA.