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

The Interactions Between Gut Microbiota and OA-relevant Factors

Accumulating evidence reveals that gut microbiota could be re-sharped by some OA-relevant factors, such as aging, gender, diet, and obesity, parallelly boosting the systematic inflammation, suggesting the possibility of the microbe involvement in OA, while limited convincing studies have validated this speculation by the interventions on gut microbiota. Still, the knowledge of the interactions between the OA-relevant factors and gut microbiota adds a novel layer of our understanding of the complexity of OA pathogenesis and also provides a new perspective on OA investigation.

Age

Aging has been shown to be associated with an increased incidence of osteoarthritis.[25] Previous studies have illuminated several potential mechanisms by which the aging-associated changes in articular tissues promote the progression of OA, such as pervasive aging-relevant chronic low-grade inflammation (also known as "inflammaging"), cellular senescence, mitochondrial dysfunction and oxidative stress, dysfunctional energy metabolism, and alternated mechanical properties extracellular matrix attributed to the accumulation of advanced glycation end products (AGEs).[26,27]

In recent years, researchers are becoming increasingly interested in elucidating aging-related differences in the gut microbiota among elderly adults and young individuals to improve the understanding of aging-related mechanisms and discover novel therapies. Aging-related alterations in gut physiology, such as degenerative changes in enteric nervous system, gastric hypochlorhydria, drug perturbation, and motility disorders, have significant impacts on the diversity, composition, and functional features of gut microbiota.[28] The aging-related changes of gut microbiota were characterized by reduced diversity, decreased abundance of dominant species, increased abundance of subdominant species, and a swift of increased proteolytic and decreased saccharolytic bacteria.[29–31] For instance, Biagi et al. observed that the structure of the gut microbiota of centenarians differs significantly from that of non-centenarian adults, characterized by an enrichment in Proteobacteria, a phylum including many potentially pathogenic bacteria. Furthermore, these alterations in centenarians are associated with increased levels of proinflammatory markers, suggesting the potential role of gut microbiota in this pervasive systematic inflammation.[32] Given that aging is a persistent factor, the aging-associated differences in gut microbiota and relevant inflammatory status may be an important determinant of onset and progression of OA, while the intervention of aging-relevant microbiota is still needed to validate the involvement of gut microbiota in aging-relevant OA phenotypes.

Gender

It is a striking observation that females are at greater risk for developing knee, hip, and hand OA compared to males and tend to be more severe.[33] The underlying mechanisms behind the increased incidence of OA with sex difference remains to be unclear, while this higher prevalence of OA observed in women at the time of menopause has been attributed to the hypothesis that hormonal factors, such as estrogens, play a role in the development of OA, for instance, estrogens increase the sensitivity to inflammatory stimuli and responses in female.[34] Moreover, some possible conjectures also have been proposed for explaining the discrepancy of gender-dependent influence in OA, such as sex differences in gut microbiota composition.[35]

Comparing the gut microbiota composition of 341 female with 348 male mice, Elin et al. showed a decreased relative abundance of Porphyromonaceae and Rikenella and a higher abundance of Ruminococcus, Coprococcus, and Dorea in male mice, while a higher presence of Allobaculum, Anaeroplasma, and Lactobacillaceae and Veilonellaceae in female mice, demonstrating that sex differences exist in microbiota composition.[36] A recent clinical study was conducted in a subgroup of 75 patients (39 men and 36 women), who had similar dietary background and matched by age, to analyze differences in fecal samples intestinal microbiota composition by 16S DNA sequencing, observing that women had a higher abundance of Bacteroides and Bilophila compared to men while men present higher abundance of Veillonella and Methanobrevibacter.[37]

The different composition of gut microbiota between males and females may be mediated by sex hormones. Although no study has validated that these gender-relevant difference of gut microbiota contributes to the higher OA prevalence of female individuals, Li et al. built the link between sex steroid, bone loss, and gut microbiota. Their study showed that sex steroid deficiency led to the increase of gut permeability and sex steroid deficiency-induced bone loss is gut microbiota-dependent.[38] Given that subchondral bone loss is a phenotype of OA, this evidence gives a clue that gut microbiota might be involved in OA subchondral bone loss and the gender divergence in gut microbiota might have an indispensable role in the definition of gender differences in the prevalence of OA.

Genetics

Genetic factor is responsible for 60% of hand and hip OA and 40% of knee OA.[39] An increasing number of susceptibility loci, such as insulin-like growth factor 1 gene (IGF1), growth differentiation factor 5 gene (GDF5), and vitamin D receptor gene (VDR), are proven to contribute to genetic predisposition of OA onset.[40,41]

Solovieva et al. found that VDR gene polymorphisms play a role in the etiology of symmetrical hand OA in Finnish population.[42] Moreover, the effect of VDR polymorphisms on the risk of OA may be modified by daily calcium intake. Interestingly, the influence of VDR gene variation on gut microbiota was also demonstrated in a genome-wide association analysis (GWAS) study performed by Wang et al..[43] Still, no evidence supports the role of genetic susceptibility of VDR gene in the interaction between host and gut microbiota on OA onset and progression while we believe that this critical gene in bone and joint health may contribute to the individual difference of OA patients by the involvement in host-gut interaction. In the context, elucidating the association between gut microbiota and genetic factors is an important contribution to our comprehension of how these manipulations of the bacteria or its metabolites affect bone and cartilage growth in individual levels.

Diet

Several dietary factors have been reported to be involved in the pathophysiology of OA, such as polyunsaturated fatty acids, antioxidants, and amino acids.[44,45] Baker et al. found a positive connection between the n-6 polyunsaturated fatty acid (PUFA), arachidonic acid (AA), and synovitis but an inverse relation between total plasma n-3 PUFA, docosahexaenoic acid (DHA), and patellofemoral cartilage loss, suggesting that systemic levels of n-3 and n-6 PUFAs which are manipulated by diet may be associated with articular-cartilage composition and structural damage.[46] Previous studies have showed that the intake of dietary antioxidants such as vitamin C, D, and K, involved in regulating collagen formation, bone metabolism, and cartilage mineralization, may prevent the progression of OA.[44] Although the effects of dietary supplements on OA prevention are controversial, it is no doubt that these nutrients are indispensable and at least benefit metabolic health. In this context, the improved understanding of how these dietary factors contribute to the maintenance of joint fitness is helpful to interpret the association between OA and unfavorable diet and give promise to diet-based supplemental strategies.

Gut microbiota is highly shaped and modulated by the host's dietary components.[47] Kaliannan et al. found that mice fed a diet high in n-6 PUFAs can increase the proportions of LPS-producing and/or proinflammatory bacteria including Proteobacteria and its members, and decrease levels of LPS-suppressing and/or anti-inflammatory bacterial groups, such as Bifidobacterium, Lactobacillus, Clostridium, and Enterococcus faecium, while transgenic conversion of tissue n-6 to n-3 fatty acids dramatically exhibited opposite effect, suggesting that the tissue n-6/n-3 PUFA ratio modifies gut microbiota profile composition and gut permeability, leading to differential inflammatory status and metabolic syndrome.[48] Moreover, recent evidence showed that vitamin D may influence disease risk by modifying the diversity of gut microbiota. The effects of vitamin D on Bacteroides phylum are not conclusive while some studies have reported that a low vitamin D diet or vitamin D receptor (VDR) knock-out results in a more inflammatory fecal microbiome characterized by an increased Bacteroidetes.[49,50] Interestingly, very high-dose vitamin D diet is unexpectedly associated with an increase in Bacteroidetes, particularly of the orders Bacteroidales and Flavobacteriale, with a decrease in circulating vitamin D,[51] suggesting that vitamin D may influence host systematic immunology by modifying the diversity of gut microbiota in a complex feedback loop. Vitamin D may play a role in maintaining the mucosal barrier integrity by upregulating the expression of tight junction and adherent junction proteins and suppressing epithelial cell apoptosis.[52] Also, dietary glutamine supplementation alters composition and metabolism of intestinal microbiota, inducing a shift in the Firmicutes/Bacteroidetes ratio and enhanced intestinal secretory IgA (SIgA) secretion.[53] Although these interesting findings indicate that dietary nutrients influence host physiological functions dependent on intestinal microbiota, limited evidence supports that dietary nutrients can modify the OA-relevant microbiota, as a result of which the link between diet, gut microbiota, and OA is still not convincing and needs more experimental validations.

Obesity and Metabolic Syndrome

Obesity is an established risk factor for osteoarthritis not only in weight-bearing joints, such as knee and hip, but also in non-weight-bearing joints, such as hand and temporomandibular joints, indicating that obesity contribute to the systemic factors relevant to OA.[54,55] Metabolic syndrome-associated osteoarthritis (Met-OA) is the phenotype of OA characterized by obesity, diabetes, dyslipidemia, and hypertension.[56] Present studies have demonstrated several mechanisms linking osteoarthritis to obesity and metabolic syndrome partially, such as insulin resistance, the potential implication of oxidized low-density lipoprotein (ox-LDL) on ectopic bone formation and synovium inflammation, and the potential involvement of gut microbiota.[57]

The most accepted connection between OA and obesity and metabolic syndrome is the low-grade chronic inflammation partially induced by the elevated microbiota-derived proinflammatory metabolites and relevant gut microbiota components, such as LPS. Collins et al. found that systematic LPS concentration was associated Lactobacillus species abundance and increased joint damage was associated with the abundance of Lactobacillus and Methanobrevibacter species and body fat, but not body mass, in a high-fat/high-sucrose diet-induced obese rat model.[11] Another observation performed by Guss et al. in a load-induced model of OA with/without a high-fat diet in Toll-like receptor-5 deficient (TLR5KO) mice that spontaneously develop metabolic syndrome due to gut microbiota alterations, suggests that severe obesity and inflammation increased load-induced cartilage damage and the modification of metabolic syndrome-associated phylotypes of gut microbiota may contribute to development of cartilage pathology and subchondral bone morphology.[12] More importantly, the finding of Schott et al. suggests that oligofructose supplementation restored the lean gut microbiome in obese mice by supporting favorable Bifidobacterium pseudolongum and reduced OA progression, which sheds light to potential novel OA therapeutics involving strategic manipulation of specific microbial species inhabiting the intestinal space.[18]

Central Nervous System (CNS)

It has been known for some time that the role of the central nervous system (CNS) is related to chronic pain in OA patients.[58] Progress of CNS theory in OA was accelerated in the early 1950s when neurophysiology was advancing.[59] So far, the new components of the CNS theory in OA pathophysiology include hypothalamic-pituitary (HPA) axis, nucleus tractus solitarus (NTS), hypothalamic suprachiasmatic nuclei (SCN), and other associated higher centers, and each with their own feedback circuits from the gut microbiota, OA joints, and cellular metabolism. Progression of OA is increasingly linked to dysregulation of central feedback circuits (e.g., HPA axis and NTS), which control circadian rhythm, gut microbiome, metabolism, and redox regulation.[60]

Gut microbiota is regarded as one key element of the gut-brain axis in the CNS theory. Briefly, CNS modulates the gastrointestinal tract and enteric nervous system through sympathetic and parasympathetic axis while intestinal microbiota influence CNS function through vagal afferent nerves, immune system, HPA axis, and bacterially derived neurotransmitters.[61,62] Additionally, due to the findings of Liang et al. that the absolute amount of fecal bacteria and the abundance of Bacteroidetes exhibited circadian rhythmicity, gut microbiota may communicate with host's circadian clock to regulate cartilage homoeostasis.[63,64] The interaction between CNS, gastrointestinal tract, and joint is an active area that remains to be investigated. Targeting gut microbiota to restore the balance of gut-brain axis might offer novel disease-modifying therapies for OA patients.

Joint Injury

Joint injury is a well-established risk factor for development of OA, including anterior cruciate ligament (ACL) rupture, meniscal tear, and intra-articular fracture. Nearly 12% of all OA cases may be due to initial trauma.[65] Therefore, a better understanding of mechanisms triggered by joint injury is beneficial to develop more targeted strategies for prevention and treatment of post-traumatic OA (PTOA). Accumulating evidence demonstrates that perpetuating inflammation response to joint injury plays a critical role in the progression of PTOA, including the production of inflammatory mediators, such as cytokines/chemokines and damage-associated molecular patterns (DAMPs), low-grade synovial immune infiltration, and innate inflammatory pathway activation involving multiple tissues.[66]

Toll-like receptors (TLRs), most studied in PTOA among several receptors, are associated with proinflammatory innate immune response to injury through recognizing fragments of the cartilage extracellular matrix, microbiome-derived metabolites. Additionally, the combination of LPS and DAMPs resulting from joint damage, synergistically activates macrophages to express elevated levels of OA-related cytokines.[23,67] Beyond the impact of post-injury inflammation responses on cartilage and subchondral bone, a direct correlation between gut microbiota and development of injury-induced OA has been previously demonstrated. Significantly, in animal models induced by destabilized medial meniscus (DMM) surgery, the severity of PTOA was reduced in the germ-free situation compared to specific pathogen-free (SPF) mice, providing evidence for a role of the gut microbiota in PTOA pathogenesis.[13] These findings have illustrated the complexity of the inflammatory response to joint injury and gut microbiota is thought to be involved in PTOA progression.

Other OA Risk Factors

Other OA-relevant risk factors, such as smoking and alcohol consumption, are also identified as a perturbation on gut microbiota. It is wildly accepted that smoking and alcohol contribute to the unfavorable changes of the integrity of gastrointestinal barrier. Also, alcohol causes the depletion of anti-inflammatory bacteria, eventually resulting in intestinal damages.[68] Besides, in a population-based cross-sectional study, Lee et al. built the link between gut microbiota composition and current smokers.[69] Still, the connection between these OA-relevant risk factors, OA, and gut microbiota has not been demonstrated yet.

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