With progress in research on the microbiome and the gradual elucidation of the relations between the gut microbiota and various diseases, there has been increasing interest in both basic and clinical research regarding the treatment of various diseases using probiotics. Several of these studies have demonstrated the effectiveness of probiotics in the treatment of various diseases. Treatment with probiotics has been shown to have therapeutic effects in infectious diseases, autoimmune conditions, allergies, and behavior disorders, including Alzheimer’s disease, through changes in the intestinal environment evoked by the gut microbiota, and it is being discussed as to whether probiotics can be applied as an adjuvant therapy in the treatment of COVID-19 [16]. There have been several studies on therapeutic effects of probiotics in RA, an inflammatory and autoimmune disease, and investigations are still ongoing. In contrast, there have been insufficient studies on the therapeutic effects of probiotics in OA. OA can be seen as a form of chronic low-grade inflammation, and the therapeutic effect of probiotics can be expected through the gut–joint axis concept; therefore, further research regarding this issue is needed.
Several strains of probiotics have been studied to date. Studies of L. casei strain Shirota revealed its effects and mechanism of action in experimental OA. The clinical efficacy of this organism in actual patients, as compared to a placebo control group, was also investigated [9]. Another study demonstrated the efficacy of applying L. acidophilus in MIA-induced OA [10]. The effects of S. thermophilus have been studied in experimental OA, and in actual patients [11].
Several recent reports have described the therapeutic effects of the administration of probiotics and prebiotics. Although the detailed mechanisms of action have not been identified, these studies showed that alteration of the gut microbiota affects the production of short chain fatty acids (SCFAs) and other metabolites, mediating anti-inflammatory effects and changes in gut permeability, resulting in therapeutic effects [17–19]. It has been reported that SCFAs, acetate, butyrate, and propionate have anti-inflammatory effects mediated through G protein-coupled receptors (GPCRs) or through reduction of histone deacetylases (HDACs) [20]. In addition, it is well known that SCFAs are involved in the activity of several types of immune cells, and it has been reported that SCFAs play important roles in the differentiation of Treg cells. Butyrate is known to determine the number and function of Treg cells in the intestine [13], and to prevent cartilage degradation by reducing type II collagen degradation [21]. L. rhamnosus is known to have an immunomodulatory effect through changes in the intestinal environment and various effectors, and to affect bone formation and chondrocyte differentiation. L. rhamnosus is known to produce metabolites, such as lactate and acetate, in the intestine, and acetate is converted to acetyl-CoA through butyrate-producing bacteria resulting in the production of butyrate [12, 22, 23]. When the degree of inflammation is severe in OA patients, the composition of Streptococcus spp. increases and the composition of Lactobacillus spp. decreases [24, 25]. L. rhamnosus is a strain that is widely used and has already been applied in various inflammatory diseases, including RA, to confirm its therapeutic effect [26, 27].
Therefore, we performed animal experiments to examine whether L. rhamnosus (LR-2) has a therapeutic effect against OA through an anti-inflammatory action mediated via butyrate production. Administration of L. rhamnosus (LR-2) increased the PWT, PWL, and weight bearing of MIA-induced OA rats, and the levels of PPAR-γ and GABA expression in the dorsal root ganglion (DRG) were elevated. On the other hand, the expression levels of MCP-1 and CCR2 were reduced, suggesting that pain severity was reduced through the nociceptive pathway [28].
The evaluation of cartilage destruction is an important index for the progression of OA. In this study, both the OARSI score and total Mankin score on H&E staining of the knee joint were lower after L. rhamnosus (LR-2) administration than in the vehicle controls, indicating the suppression of OA progression. In IHC analysis of the joint synovium, the group administered L. rhamnosus (LR-2) showed decreased levels of the inflammatory cytokine, IL-1β, and the catabolic factor, MMP3, and increased levels of the anti-inflammatory cytokine, IL-10, and the anabolic factor, TIMP3. These observations suggested that when L. rhamnosus (LR-2) was administered, cartilage destruction was inhibited through the regulation of inflammatory/anti-inflammatory effects and catabolic/anabolic responses [29, 30]. In addition, after administration of L. rhamnosus (LR-2) to IL-1β-stimulated human chondrocytes, the expression levels of the anabolic factors, TIMP1, 3, and IL-10, were confirmed to increase, indicating that cartilage destruction was inhibited through the regulation of catabolic/anabolic responses. Furthermore, structural changes in the small intestine after administration of L. rhamnosus (LR-2) were confirmed by H&E staining, and the expression levels of MCP-1 and CCR2, chemokines that induce inflammation and tissue injury, were shown to be decreased by IHC staining in the L. rhamnosus (LR-2) group. Also, IL-6 was decrease but IL-10 was significantly increase than vehicle treated group. These results support the cartilage protective effect of L. rhamnosus (LR-2) mediated through changes in the intestinal immune system and environment.
The results of this study showed that L. rhamnosus (LR-2) protects cartilage through regulation of inflammatory/anti-inflammatory effects and catabolic/anabolic responses in MIA-induced OA. This suggests the possibility of using L. rhamnosus (LR-2) as a therapeutic agent in OA patients. Further detailed investigations of the mechanism of action are still required, along with clinical studies.
Furthermore, it is necessary to discover additional probiotic strains with therapeutic effects and to clarify the mechanism of action of each strain. Therefore, it will be necessary to examine whether different strains act via the same therapeutic mechanism, whether a greater therapeutic effect can be achieved due to synergistic effects when two or more strains are administered in combination, or whether there are no differences from the administration of a single strain. Although further studies are required, based on the results presented here, it is expected that probiotics will be useful as pharmabiotics soon.