Association Between Gut Microbiota and Osteoarthritis: A Review of Evidence for Potential Mechanisms and Therapeutics

Abstract

Osteoarthritis (OA) is a multifactorial joint disease characterized by degeneration of articular cartilage, which leads to joints pain, disability and reduced quality of life in patients with OA. Interpreting the potential mechanisms underlying OA pathogenesis is crucial to the development of new disease modifying treatments. Although multiple factors contribute to the initiation and progression of OA, gut microbiota has gradually been regarded as an important pathogenic factor in the development of OA. Gut microbiota can be regarded as a multifunctional "organ", closely related to a series of immune, metabolic and neurological functions. This review summarized research evidences supporting the correlation between gut microbiota and OA, and interpreted the potential mechanisms underlying the correlation from four aspects: immune system, metabolism, gut-brain axis and gut microbiota modulation. Future research should focus on whether there are specific gut microbiota composition or even specific pathogens and the corresponding signaling pathways that contribute to the initiation and progression of OA, and validate the potential of targeting gut microbiota for the treatment of patients with OA.

Keywords: gut microbiota; gut-brain axis; immune system; metabolism; osteoarthritis.

Figure 1

Mechanisms underlying that gut microbiota can affect the structure and function of intestinal barrier. I Probiotics Lactobacillus rhamnosus GG (LGG) or commercially available probiotic supplement VSL#3 enhanced the integrity of intestinal barrier through inhibiting the decreased expression of tight junction protein in intestinal epithelium, caused by sex steroid deficiency (Li et al., 2016a). II Prebiotics-induced gut microbiota improved intestinal barrier function, depending on glucagon-like peptide-2 (GLP-2) (Cani et al., 2009). III Microbial metabolites such as taurine, histamine and spermine, protected the intestinal barrier by shaping the host-microbiome interface through co-regulating NLRP6 inflammasome signaling, epithelial interleukin-18 (IL-18) secretion, and downstream antimicrobial peptide profiles (Levy et al., 2015). IVCommensal lactobacilli’s metabolites of tryptophan contributed to immune barrier by binding to aryl hydrocarbon receptor (AhR) (Zelante et al., 2013). V Short chain fatty acids (SCFAs), originating from fermentation of dietary fiber by gut microbiota (Ulici et al., 2018), promoted intestinal homeostasis through several hematopoietic cell types (Levy et al., 2017), such as neutrophil (Vinolo et al., 2011). VI SCFAs contributed to maintaining mucosal immunity by up regulating mucin (MUC) gene expression in intestinal epithelial goblet cells (Gaudier et al., 2004). VII SCFAs promoted tight junction assembly by activating adenosine monophosphate-activated protein kinase (AMPK) (Peng et al., 2009). VIII Outer membrane vesicles (OMVs), produced by pathogenic and commensal Gram-negative bacteria, disrupted the integrity of the mucosal epithelium (Kaparakis-Liaskos and Ferrero, 2015). IX The regulated cross talk between gut microbiota and gut-associated lymphoid tissue (GALT) contributed to the intestinal barrier (Kalinkovich and Livshits, 2019). X Lipopolysaccharide (LPS) regulated the intestinal barrier by activating intestinal cannabinoid type 1 receptor (CB1R) (Zoppi et al., 2012). XI Bile acids, an intestinal metabolite, protected the intestinal barrier, controlled by the gut microbiota through the farnesoid X receptor (FXR) and the G protein-coupled bile acid receptor 1 (GPBAR1) or (TGR5) (Levy et al., 2017).

Figure 2

Pathways of the effect of gut microbiota on OA via macrophages. I Metabolites and membrane vesicles produced by Streptococcus spp. caused joint inflammation and injury by passing through the intestine-blood barrier to activate macrophages in the synovial lining (Boer et al., 2019). II Metabolites and membrane vesicles in the circulation, produced by Streptococcus spp., activated macrophages to pro-inflammatory macrophages and triggered a low-level systemic inflammatory state that aroused or aggravated joint inflammation and injury (Boer et al., 2019). III Obesity-induced gut microbiota accelerated knee OA by contributed to the systemic inflammation and the migration of macrophages to the synovium (Schott et al., 2018). IV Oligofructose, an indigestible prebiotic fiber, can reversed the pathway in III through inhibiting the up-regulation of monocyte chemotactic protein 1 (MCP-1) and tumor necrosis factor (TNF) (Schott et al., 2018). V Obesity-induced gut microbiota activated inflammation (John and Mullin, 2016; Portune et al., 2017), causing activated macrophages to migrate to adipose tissue that released pro-inflammatory cytokines into the circulation (Weisberg et al., 2003; Xu et al., 2003; Lumeng et al., 2007), aggravating systemic inflammation, and promoting the development of OA.

Figure 3

Pathways of peptidoglycan (PGN) involved in OA. I PGN affects the development of OA by inducing the expression of matrix metalloproteinases (MMPs) and pro-inflammatory cytokines through activating Toll-like receptor 2 (TLR2) on synovial fibroblasts (Kyburz et al., 2003). II PGN affects the development of OA by recognizing NOD-like receptor 1 (NOD1) and promoting systemic innate immunity (Clarke et al., 2010). III PGN affects the development of OA by recognizing NOD-like receptors (NLRs), activating NLRP1 and NLRP3 inflammasome, and promoting the increase of pro-inflammatory cytokines.

Figure 4

Mechanisms by which lipopolysaccharide (LPS) affects the development of OA. I LPS is involved in OA by activating innate immune response via the formation of the LPS–LBP–CD14–TLR4–MD-2 complex, increasing NF-κB levels, up regulating TNF, IL-1β, IL-6, IL-8 and RANKL levels, raising the production of MMPs and further reinforcing NF-κB activation. II LPS is involved in OA by activating complement pathway in chondrocytes (Haglund et al., 2008). III LPS is involved in OA by inducing inflammation in adipose tissue, precipitated systemic changes in cytokines, adipokines and growth factors, and finally affecting the local inflammatory environment inside the knee joint (Bleau et al., 2015). LPS, lipopolysaccharide; LBP, LPS binding protein; MD-2, myeloid differentiation protein-2; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; TNF, tumor necrosis factor; IL-1β, interleukin-1-beta; RANKL, receptor activator of NF-κB ligand; PTX3, long pentraxin 3; MMPs, matrix metalloproteinases.

Figure 5

Effect of gut microbiota on the adaptive immunity. I Gut microbiota determined the direction of differentiation of primitive CD4+ T cells into effector T cells or Treg cells (Honda and Littman, 2012). II Lipopolysaccharide (LPS) helped to induce naive immune cells to mature immune cells by activating Toll-like receptor 4 (TLR4) to cause an inflammatory cascade (Chen et al., 2011; Chu and Mazmanian, 2013; Kim, 2013). III Vitamin B9 contributed to the survival of Treg cells (Kunisawa et al., 2012). IV Butyrate modulated the generation and differentiation of Treg cells by up regulating histone acetylation (Arpaia et al., 2015) and enhancing fatty acid oxidation dependent on carnitine palmitoyl transferase 1A (CPT1A) (Hao et al., 2021). IFN, interferon.

Figure 6

Mechanisms of gut microbiota’s contributing to OA through affecting energy metabolism. I Gut microbiota contributed to obesity and metabolic diseases by helping to obtain energy and increase host fat storage via pathways involved in the physiology and motility of the digestive tract, the digestion of polysaccharides, the metabolism and transformation of choline, the interaction between SCFAs and GPCRs, FIAF, FXR, and AMPK. II LPS-mediated inflammatory pathway or metabolic endotoxemia contributed to obesity and insulin resistance by affecting the regulation of insulin secretion that can protect articular cartilage through inhibiting MMPs expression dependent on pro-inflammatory cytokines. SCFAs, short chain fatty acids; GPCRs, G protein-coupled receptors; FIAF, fasting-induced adipose factor; FXR, farnesoid X receptor; AMPK, adenosine monophosphate-activated protein kinase; LPS, lipopolysaccharide; TNF, tumor necrosis factor; MMPs, matrix metalloproteinases.

Figure 7

Pathways of the effect of gut microbiota on OA though affecting bone metabolism. SCFAs mixture, a short chain fatty acids mixture, containing acetate, butyrate and propionate; IGF-1, insulin growth factor-1; TGF-β-BMP pathway, the transforming growth factor β–bone morphogenetic protein signaling pathways.

Figure 8

The potential role of microbiome-gut-brain axis in OA. ENS, enteric nervous system; HPA axis, hypothalamic-pituitary axis; NTS, nucleus tractus solitaries; SCN, hypothalamic suprachiasmatic nucleus.

Figure 9

The role of the gut microbiota in the initiation and progression of OA.