The Gut Microbiota in Osteoarthritis

Where Do We Stand and What Can We Do?

Xiaoxia Hao; Xingru Shang; Jiawei Liu; Ruimin Chi; Jiaming Zhang; Tao Xu

Disclosures

Arthritis Res Ther. 2021;23(42) 

In This Article

Gut Microbiota Modulation as Treatment of OA

Considering the growing global prevalence of OA, effective disease-modifying therapeutic strategy for relieving symptoms and slowing down OA progress are greatly needed. In this context, it is feasible to hypothesize that the modulation of gut microbiota by external approaches may influence the progression OA. To date, some lines of evidence indicate that gut microbiota interventions may be realized through probiotics, prebiotics, nutraceuticals, exercise, and fecal microbiota transplantation (FMT).

Probiotics and prebiotics

Probiotics are composed of live microorganisms, generally lactic acid bacteria, which play a crucial part in the maintenance of healthy gut microbiota homeostasis by promoting the production of antimicrobial substances and immunoglobulins and inhibiting the production of bacterial toxins.[70] Recent observations gave rise to hopes that probiotics would provide beneficial treatment strategy in OA. To date, the most convincing evidence is a randomized double-blind placebo-controlled trial performed by Lei et al., in which a total of 537 patients with knee OA were enrolled and randomized to receive skimmed milk containing either Lactobacillus casei Shirota (LcS) or placebo daily for 6 months.[14] After 6 months of treatment, clinical outcomes assessed by WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) and VAS (visual analog scale) scores were significantly reduced in the LcS group compared to the placebo group. Moreover, systematic inflammation assessed by the serum high-sensitivity C-reactive protein (hs-CRP) was also significantly lower in patients receiving LcS than placebo. This study indicates that LcS consumption could serve as a novel therapeutic option in OA management, improving clinical outcomes probably through reducing serum hs-CRP levels. Another study in experimental rodent model of OA found that oral administration of LcS (2 × 1010 cfu/kg, 500 mg/kg) together with glucosamine (Gln; 250 mg/kg) and type II collagen (CII; 250 mg/kg) is effective to reduce pain compared to the control group, while LcS or Gln or CII/Gln alone failed to improve clinical outcome. This study indicated the synergistic effects of LcS/Gln/CII, while the exact weight of each individual treatment is hard to assess and the sample number is insufficient (n = 8~9 in each group).[15] Sim et al. found that oral administration of tyndallized Clostridium butyricum effectively preserved articular cartilage and synovial membrane and significantly reduced the amount of fibrous tissue, serum concentration of various inflammatory mediators, and bone metabolism markers in a monosodium iodoacetate-induced (MIA) OA rat model.[16] In the same OA model, Kwon et al. claimed that dietary supplements of probiotic complex (12.5 mg/rat) combined with rosavin (100 mg/rat) and zinc (20 mg/rat) to MIA rats (weighted from 140 to 230 g) slowed down OA development through the inhibition of proinflammatory cytokines and cartilage destruction.[17] However, this evidence is far from convincing due to the limited sample number (n = 3) and observation period (13 days). Also, the results were over-interpreted because only pain assessment reached statistical significance while morphology assessments were not significant and the evidence supporting that the combination treatment inhibited inflammation was based on in vitro chondrocyte experiments.

Prebiotics also is selectively utilized by host microorganisms and is able to stimulate the growth of different beneficial bacteria in the gastrointestinal tract.[71,72] Schott et al. provided evidence that supplementation with oligofructose (OFS) prebiotic fiber, a non-digestible plant-derived carbohydrate, fermented by gut microbiota in the colon, could reverse the adverse effects of high-fat diets on gut microbial composition by increasing the abundance of Bifidobacterium, a species with anti-inflammatory properties, resulting in the reduction of systemic and knee joint inflammation, the preservation of articular cartilage, and the suppression of obesity-induced joint structural changes in the context of injury.[18] These findings indicated that prebiotic manipulation of the gut microbiota is a potentially novel candidate therapeutic strategy to treat OA.

Nutraceuticals

The clinical effects of glucosamine sulfate (GS) and chondroitin sulfate (CS) on OA management is still controversial, even some systematic reviews show their symptomatic and structure-modifying effects contributed by the anti-inflammatory effects on cartilage.[73] In the 2019 guidelines, low-dose, short-term pharmaceutical-grade glucosamine and chondroitin sulfate are recommended by the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) whereas Osteoarthritis Research Society International (OARSI) strongly recommends against their use (including all glucosamine and chondroitin formulations).[74]

Oral supplements of GS and CS have limited intestinal absorption and hence the effects of these supplements on the gut microbiome are of great interest. The systematic review performed by Shmagel et al. summarized the evidence supporting the effects of GS or CS on gut microbial composition that CS increased abundance of genus Bacteroides, while the evidence of GC on gut microbiome is limited.[75] Liu et al. found that CS supplementation was associated with increased Bacteroides acidifaciens, reduced inflammatory Proteobacteria, lower serum LPS levels, and increased level of fecal total SCFA and butyrate in the stressed mice, illustrating that the anti-inflammatory and gut-protective effects of CS supplementation may depend on the specific bacterial species.[76] In particular, Bacteroides species account for more than 10% of all human gut microbiota and are primarily responsible for degrading CS, which could help to explain the efficacy of CS as a potential therapeutic drug in OA treatment.[77] Similarly, Coulson et al. demonstrated that oral supplementation with green-lipped mussel extract or glucosamine sulfate have symptom-modulating effects on OA patients by regulating the composition, metabolic, and immunological activities of gut microbiota.[19] Furthermore, GS and CS are also significant components of intestinal mucin, acting as a defense barrier between gut flora and the intestinal wall and potentially affecting gut permeability and intestinal immune responses.[78,79] Advanced understanding of the biological action of GS and CS on shaping gut microbiome provides a novel insight into their potential mechanisms in OA management, while the convincing evidence to link GS/CS, gut microbiota, and OA is still needed.

Exercise

The evidence of exercise therapy has indicated the therapeutic benefits by reducing pain and improving functioning for individuals with OA.[80] Beyond the changes of mechanical loading on cartilage and subchondral bone, exercise may modulate the composition, functions, and metabolites of gut microbiota to exert possible benefits for the host.[81] Several mechanisms are involved in the health-promoting effects of exercise, including the improvement of the Bacteroidetes/Firmicutes ratio, the alteration of bile acid profile, the increased production of SCFAs, the suppression of TLR signaling pathway, the mediation of mucosal immunity via production of immunoglobulin A (IgA), reduced intestinal transit time, and the activation of the HPA axis.[82]

Exercise independently alters the composition and functional capacity of the gut microbiota or together with dietary supplements. Munukka et al. showed that taxonomic shifts included an enriched abundance of Akkermansia and a decrease in Proteobacteria after 6-week exercise among previously sedentary overweight women.[83] In addition, Jacob et al. performed a study to explore the effects of exercise on gut microbiota in lean and obese participants with multiple-day dietary controls, revealing that exercise increased the abundance of Faecalibacterium species and the concentrations of acetate, butyrate, and SCFAs only in lean subjects.[84] These findings suggest that exercise-induced changes in the human gut microbiota are largely dependent on obesity status. Furthermore, in response to exercise, the gut microbiota of lean individuals may be more responsive than that of obese or overweight individuals. Several studies also indicated that exercise might also be associated with diet determining the microbial biodiversity of the gut. Clarke et al. was the first to find that exercise increases gut microbial diversity that was positively correlated with dietary protein consumption in the athlete group.[85]

In spite of the evidence supporting that exercise benefits host by the underlying involvement of gut microbiota, the finding regarding this effects upon the mechanism of exercise in OA patients, so far, is scarce. Rios et al. showed that prebiotic fiber supplementation, aerobic exercise, and the combination of these two interventions completely prevented the development of OA-like knee joint damage in a high-fat/high-sucrose diet-induced rat model of obesity.[20] In particular, the combination of the two interventions resulted in an increased relative abundance of Bifidobacterium and Roseburia negatively associated with knee joint damage induced by diet-induced obesity while a decrease in Clostridium leptum (cluster IV) and Akkemansia muciniphila which exhibited a positive association with joint damage. Future studies should be specifically designed to clarify whether exercise may positively influence this putative gut-joint axis and to investigate the degree to which exercise rebalance gut dysbiosis to influence OA development.

Fecal Microbiota Transplantation (FMT)

FMT is a manipulation aimed to treat diseases associated with gut microbiota by transferring of feces from a healthy donor into the distal gastrointestinal tract of a recipient patient.[86] Promising findings suggest that this method has already emerged as a successful treatment against Clostridium difficile infection[87] and is currently being demonstrated as a potential therapeutic option of inflammatory bowel disease (IBD).[88] Also, emerging evidence demonstrates the promising application of FMT in the management of OA. Huang et al. designed a study to collect fecal samples from human healthy controls, knee OA without metabolic syndrome, and knee OA with metabolic syndrome groups, then transplant pooled samples into germ-free OA mice induced by meniscal/ligamentous injury (MLI). Interestingly, only the microbiota transplantation from the knee OA with metabolic syndrome and MLI resulted in an increase in the severity of OA, which was also consistently associated with elevated inflammatory biomarkers and gut permeability.[21] These findings support that an adverse microbiome would exacerbate the histopathological severity of OA induced by joint injury in a murine model. The study is a paradigm for the application of FMT in the investigation of OA pathogenesis and also give promise to the manipulation of gut microbiota in OA management, while more convincing studies are needed due to the limited sample number (n = 9).

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