Key points

Introduction

Osteoarthritis (OA) is a destructive joint disease that afflicts 655 million people globally. Despite being the most prevalent form of arthritis and the leading cause of disability in the Unites States, there is no clinically accepted disease-modifying drug available for OA patients. OA has multifactorial etiologies including genetic predisposition, aging, obesity, and joint injury. It induces pathologic changes in the cartilage, subchondral bone, ligaments, synovial membrane, and in the knee joint menisci. Mounting evidence indicates that both systemic and localized joint inflammation play a role in the onset and progression of OA, and as reviewed by Sun and colleagues , increasing attention has been directed toward the gut microbiome as a potential contributor to an OA disease-causing proinflammatory state.

Microbiome is defined as the characteristic microbial community occupying a reasonably well-defined habitat that has distinct physio-chemical properties. This language not only refers to the microorganisms involved but also encompasses their structural elements, metabolites, mobile and relic genetic elements, and molecules that contribute to establishing the surrounding environmental conditions. The gut microbiome is referred specifically to the ecosystem within the gastrointestinal tract composed of bacteria, archaea, bacteriophages, and fungi. Having more than 10 times the gene diversity of the human genome, the microbiome’s composition is shaped by diet, genetics, environmental factors, disease, and early childhood experiences.

Imbalance within the microbial community and the loss of diversity can result in a so-called “dysbiosis” which leads to an increased abundance of microbes that promote inflammatory responses and activate the immune system. Dysbiosis has been previously identified in a range of diseases, including amyotrophic lateral sclerosis, Parkinson’s disease, Alzheimer’s disease, rheumatoid arthritis (RA), Crohn’s disease, type 2 diabetes, metabolic syndrome, and osteoporosis. Animal studies have also established a link between gut microbiota dysbiosis and OA progression, suggesting that rectifying the dysbiosis could protect against OA. This connection is particularly compelling in case of OA of obesity-associated and post-traumatic OA. Although some evidence suggests that an overabundance of a particular microbial strain can trigger OA disease or predict an increased risk for OA development, the gut-joint connection involves molecular and immune system interactions that only recently have been hypothesized. In dysbiosis, an increased abundance of proinflammatory bacteria leads to the production of microbial metabolites and molecules, such as lipopolysaccharides (LPS), which compromise the integrity of the gut barrier and increase gut permeability. Consequently, microbially derived molecules can enter the bloodstream, travel to distant organs—including joints—and activate innate and adaptive immune responses, resulting in inflammation, pain, and joint damage. Additionally, immune activation within the colon wall triggers the recruitment of innate and adaptive immune cells, which not only drive localized inflammation but can also migrate to distant tissues via blood and lymphatic vessels, further contributing to inflammatory responses. ^, In summary, despite this growing body of data supporting a connection between the gut microbiome and OA, a comprehensive understanding of the underlying mechanism(s) of the gut-joint connection is still to be fully elucidated.

In recent years, a growing body of evidence suggests that microbiomes beyond the gut niche may have a role in OA. Most prominent is the concept that the historically considered sterile joint cavity may have its own microbiome. Presence of a joint microbiome adds to the complexity of the role of microbiome in OA and opens new opportunities for development of innovative OA management strategies.

In this narrative review, we overview clinical and preclinical studies published, in the past 48 and 36 months, respectively, that have enhanced our understanding of the gut microbiome’s influence on OA progression. Additionally, we will shed the light on emerging evidence supporting existence of a joint-specific microbiome, and we will discuss the limitations of those studies and provide recommendations for future study of the joint niche as a mechanism of pathogenesis in OA.

Clinical studies on the gut microbiome-osteoarthritis connection

Work to study if OA is associated with the gut microbiome has been prompted by the first deep analysis of microbial community structure in human knee OA patients recruited into the Rotterdam cohort (N = 1427) and the LifeLines DEEP cohort (N = 867) by Boer and colleagues . Correlations between MRI and a defined signature of dysbiosis in the gut community was not uncovered in these large cohorts, but Streptococcus species were associated with pain in OA patients, prompting others to pursue study of the interplay between gut dysbiosis and OA disease. While preclinical-translational research has begun to elucidate underlying mechanisms of gut-joint communication, clinical investigations have largely remained exploratory and hypothesis-generating. Highlight of the clinical studies published in the past 48 months is presented in Table 1 .

A study by Liu and colleagues , using 16S ribosomal RNA (rRNA) sequencing to evaluate the gut microbiota of 40 men and women with knee OA and 40 healthy controls, revealed no significant difference in alpha diversity (within-sample diversity). However, they observed significant alterations in beta diversity (community composition), with OA patients showing increased abundances of aerobic and gram-negative bacteria. Gram-negative bacteria are known contributors to systemic and joint inflammation through LPS production, which increases gut permeability and triggers innate immune responses. Additionally, the phylum Bacteroidota , class Bacteroidia , order Bacteroidales had higher relative abundances in OA patients , whereas Prevotella copri species was more abundant in healthy individuals. Predictive functional profiling revealed a decrease in pathways related to DNA transcription, amino acid metabolism, adenosine triphosphate metabolism, and phospholipid metabolism in the gut microbiome of OA patients, while pathways associated with glucose metabolism, protein acetylation, and aspartate kinase were all increased. Similarly, Ning and colleagues also reported a lower relative abundance of provotella copri in OA patients when compared to the gut microbiome of Kashin-Beck disease patients, although their study lacked a healthy control group.

Wang and colleagues explored shifts in the gut microbiome in normal body mass index (BMI) patients with knee OA using both 16S rRNA and shotgun metagenomic sequncing. While 16S analysis showed no changes in alpha diversity, beta diversity analysis showed significant dissimilarity between OA patients and controls. Consistent with findings of previous investigations, Proteobacteria was identified as dominant phylum in OA patients. Increased abundance of Prevotella_7 , Clostridium, Flavonifractor, and Klebsiella were observed in OA patients compared to the healthy individuals, while Agathobacter, Ruminococcus , Roseburia , Subdoligranulum , and Lactobacillus were decreased. Shotgun sequencing provided additional resolution, revealing reduced alpha diversity based on Simpson indices in OA patients, along with lower abundances of Bacteroides vulgatus , Bacteroides stercoris , and Bacteroides uniformis , and higher abundances of Escherichia coli , Klebsiella pneumoniae , Shigella flexneri , and Streptococcus salivarius .

Chen and colleagues adopted a multikingdom approach to characterize the gut bacteriome, mycobiome, and virome in normal BMI OA patients and healthy volunteers using whole-genome shotgun sequencing. They identified differences in the abundances of 279 bacterial species, 10 fungal species, and 627 viral operational taxonomic units. Although there was no difference in alpha diversity indexes, bacteriome analysis revealed the abundance of Anaerostipes hadrus , Prevotella sp900313215 , Eubacterium hallii , and Blautia A were higher in OA patients, while Bacteroides plebeius , Roseburia inulinivorans , Dialister sp900343095 , Phascolarctobacterium faecium , and several members of Faecalibacterium and Prevotella copri were depleted.

When Loeser and colleagues conducted a study on obese hand and knee OA patients, they detected increased levels of LPS in the serum of OA patients, but minimal changes in the composition of the gut microbiome compared to healthy individuals. Rushing and colleagues expanded on this by performing untargeted metabolomics on fecal samples from OA patients to assess shifts in functional microbial metabolites. They observed significant differences in microbial metabolites including increased dipeptides and tripeptides in OA cases, with perturbations seen in propionic acid, indoles, and tryptophan metabolites. The 2 most perturbed pathways map to leukotriene metabolism and tryptophan metabolism. Tryptophan, a key precursor for microbial biosynthesis, plays a critical role in balancing gut microbiota and intestinal immune tolerance. This study highlights the importance of exploring the functional shifts in the commensal community and not solely focusing on compositional changes as a measure of disease-related microbial alterations.

Wei and colleagues explored gut microbiome changes in symptomatic hand OA patients using 16S rRNA sequencing. While alpha diversity was unaffected, compositional changes revealed higher abundances of Bilophila and Desulfovibrio and lower abundances of Roseburia . Predicted pathway analyses indicated increased amino acid metabolism and reduced carbohydrate, starch, and lipid metabolism in the gut microbiome of hand OA patients. Plasma metabolite analysis revealed lower levels of indole-3-lactic acid, a tryptophan-derived metabolite associated with immune modulation. Another study investigated the association between gut microbiome and osteophyte formation in knee OA patients. They revealed 16 bacterial genera that were significantly different between control and OA microbiota and identified Blautia as positively correlated with osteophyte formation.

In a pilot study, Ramasamy and colleagues examined the gut microbiome differences in knee OA patients and normal individuals with or without vitamin D deficiency, finding distinct microbial signatures characterized by increased abundances of Peptococcus , Shimwellia , and Propionibacterium . Combined OA and vitamin D deficiency caused a distinct microbiome composition characterized by enriched Bacteroides and Parabacteroides Pseudobutyrivibrio , Odoribacter, and Butyricimonas .

Wang and colleagues investigated the impact of electroacupuncture on knee OA, focusing on its effects on gut microbiome composition. They reported that electroacupuncture improved clinical outcome measures, including reductions in numerical rating scale scores and Western Ontario and McMaster Universities Osteoarthritis Index total, pain, and stiffness scores. Gut microbiota analysis revealed that Bacteroides and Agathobacter were negatively correlated with these outcome measures, whereas Streptococcus abundance was positively correlated. As mentioned earlier, the association between gut Streptococcus species and OA pain had been previously reported in the Rotterdam cohort and LifeLines DEEP cohort. Streptococcus metabolites and membrane vesicles have been shown to cross the gut barrier, activate macrophages in the synovium, and contribute to joint inflammation and damage.

In the only clinical study applying an intervention to modify the gut microbiome in OA, Fortuna and colleagues evaluated the effects of 6 months of prebiotic oligofructose supplementation in obese knee OA patients. They observed improvement in pain outcomes and functional measures that approached significance, with a P value = .059. Oligofructose supplementation increased the relative abundance of Bifidobacterium , which was positively correlated with improvements in the 6-minute walk test distance. These findings are consistent with preclinical evidence from Schott and colleagues , demonstrated in an obese mouse model of post-traumatic OA (PTOA) that oligofructose mitigated gut dysbiosis, increased the abundance of Bifidobacterium pseudolongum , and reduced systemic inflammation by downregulating tumor necrosis factor (TNF) and monocyte chemotactic protein-1 expression. This study highlights the potential of safe, microbiome-targeted interventions, such as prebiotics, to confer joint health benefits. Future clinical studies should prioritize investigating microbiome-modulating strategies to better understand their therapeutic potential in providing disease modification in OA.

Limitations and future directions

Despite notable advancements, clinical study of the gut microbiome-OA connection has some limitations. Studies recruit patients with diverse OA etiologies, leading to variability in microbiome findings. Lack of longitudinal tracking of microbiome changes over time in relation to OA progression hinders the ability of discovering key microbial players. Sequencing data analyses measure relative rather than absolute abundances. Absence of healthy control samples in some studies limits the ability to draw definitive conclusions about OA-related microbiome shifts. Moreover, lack of standardized methodology for fecal sample collection, preparation, sequencing, or data analysis across studies, and inconsistencies in the taxonomic levels at which results are reported, further hinder comparisons between studies and the ability to draw generalizable conclusions.

Despite these challenges, several studies have reported consistent findings. For instance, increased beta diversity and unchanged alpha diversity in the gut microbiomes of OA patients suggest that OA-associated dysbiosis stems from compositional changes rather than alterations in microbial richness. A decrease in the relative abundance of species Provotella copri , and genus Roseburia and Agathobcter in OA patients has been reported in multiple studies ( Table 1 ). Whether these taxa could serve as potential diagnostic biomarkers for OA warrants further investigation.

Furthermore, the increased accessibility and widespread adoption of whole-genome shotgun sequencing has significantly enhanced our ability to identify key microbial species and strains and has supported exploration of shifts in major metabolic pathways that may be associated with OA. Additionally, it has facilitated multikingdom investigations, providing a more comprehensive understanding of microbial ecosystems. It is notable that recent studies have shifted focus from purely compositional analyses to exploring microbial metabolites, which play crucial roles in modulating host biology. This growing interest in the study of microbial metabolites in conjunction with shotgun metagenomics has provided a more comprehensive understanding of the compositional and functional implications of the OA-associated microbiome. This integrative approach will provide opportunities to uncover mechanistic insights into the gut-joint axis and identifying novel therapeutic targets.

Preclinical studies on the gut microbiome-osteoartheritis connection

Preclinical studies investigating the gut microbiome and its role in OA have primarily utilized rodent models of post-traumatic OA. Although the rodent microbiome differs from that of humans, it shares key major phyla and 80 genera. This makes them a useful tool for studying gut microbiome changes in human diseases preclinically.

Numerous studies between published between 2010 and 2021 have set the stage for more recent work aiming to establish a gut-joint axis in animal models. Thus, over the past 36 months, evidence supporting a causal role for gut microbiome dysbiosis in OA progression has grown ( Table 2 ). Schlupp and colleagues utilized male and female mice with destabilization of the medial meniscus (DMM)-induced OA and performed reciprocal microbiota transplants between sexes. Their findings, supported by micro-computed tomography (CT) and histology, demonstrated that the previously reported slower OA progression in female mice is rooted in their female-specific microbiota. Furthermore, associations between Osteoarthritis Research Society International (OARSI) scores and the relative abundances of Lactobacillus , Adlercreutzia , rc4-4 , Sutterella , and Clostridiales were identified. Similarly, Prinz and colleagues linked the resistance to OA development in “superhealer” MRL/MpJ mice to their unique microbiota through reciprocal fecal transplants with wild type C57/BL6 mice using micro-CT and histologic analysis of knee joint tissues in a DMM-induced OA model.

Table 2

Recent animal studies investigating the role of the gut microbiome in osteoarthiritis

Authorship	Animal Model	Intervention	Sequencing	Major Findings
Schlupp et al, 2024	Mice, M & F DMM-induced osteoarthiritis	Reciprocal FMT between 2 sexes	16S rRNA	Males have worse OARSI scores, synovitis, and osteophyte formation. Female to male FMT improved osteoarthiritis (OA) outcome and male to female FMT did the opposite. Association between OARSI scores and Lactobacillus , Adlercreutzia rc4-4 , Sutterella , and Clostridiales
Prinz et al, 2024	Mice M & F MRL/MpJ super healer and C57/BL6 DMM-induced OA	Reciprocal FMT between 2 breeds	16S rRNA	MRL to B6 FMT before DMM mitigated OA according to OARSI score, synovitis, and osteophyte formation. Lactobacillus correlated with better and Rikenellaceae correlated with worse OA outcome.
Hao et al, 2022	Rats, M DMM & ACL transection	Treadmill exercise	16S rRNA	Exercise maintained subchondral bone integrity and reduced cartilage degradation OA caused the following Lactobacillus ↑ Turicibacter ↑ Adlercreutzia ↑ Cetobacterium ↑ Exercise in OA model caused the following: Adlercreutzia ↓ Cetobacterium ↓
O-Sullivan et al, 2022	Mice, F PMM-induced OA	Probiotic : Lactobacillus acidophilus gavage	16S rRNA	Supplement reduced joint pain according to von Frey and hot plate tests. Reduced cartilage degradation. Akkermansia muciniphila ↑ Lachnospiraceae (NK4A136) ↑
Cho et al, 2022	Rats, M MIA-induced OA	Probiotic: Lactobacillus Metabolite : butyrate	16S rRNA	Probiotic reduced cartilage damage and pain. Faecalibacterium ↑ Butyrate reduced cartilage damage and pain.
Tang et al, 2022	Rats, M MLI-induced OA	Probiotics mixture: Bacillus subtilis and Enterococcus faecium	16S rRNA	No changes in gut microbiome composition were detected. Improved gut barrier. Reduced lipopolysaccharides. Nontargeted metabolomics of fecal samples. Changes in microbial metabolic pathways. In OA, energy metabolism pathways were enriched in microbiome. Probiotic-enriched linoleic acid metabolism, fatty acid biosynthesis, and bile acid biosynthesis.
Sophocleous et al, 2023	Mice, M DMM-induced OA	Microbiome depletion by antibiotics, then FMT healthy microbiome and Probiotic mixture: Lacticaseibacillus, paracasei 8700:2, Lactiplantibacillus plantarum HEAL9 and L. plantarum HEAL19	NA	FMT + Probiotic protected cartilage according to OARSI score. Subchondral bone trabecular thickness increased; bone volume increased based on micro-CT.
Sane et al, 2023	Rats, M MIA-induced OA	Probiotics: Bifidobacterium longum membrane lipoproteins	NA qPCR	Probiotic reduced cartilage degradation Lactobacilli ↑ Mucispirillum schaedleri ↑ Parabacteroides ↓ Goldsteini ↓ Akkermansia ↓
Xu et al, 2022	Rats, F ACL transection	Probiotic: Miya ( Clostridium butyricum)	16S rRNA	Supplementation was chondroprotective. Induced alterations in glycogen and succinate dehydrogenase within the tibialis muscle. Miya in OA causes the following: Lactobacillus ↑ Oscillospira ↑ Clostridium ↑ Coprococcus ↑
Wu et al, 2024	Rats, M ACL transection	Prebiotic: 20% plant polysaccharides supplementation	16S rRNA	High fiber causes the following: Reduced gut permeability and systemic inflammation Reduced cartilage damage Bacilotta ↑ Monoglobus ↑ Muribaculaceae ↑ Clostridia ↑ SESN2 expression in chondrocytes ↑
Zheng et al, 2024	Rats, M MIA-induced knee OA	Prebiotic: Mulberry derived polysaccharides FMT: from supplemented rats to nonsupplemented rats	16S rRNA	Supplementation reduced cartilage degradation and subchondral bone damage, improved gait, reduced serum inflammatory cytokines. FMT replicated the benefits in nonsupplemented rats. supplement: Christensenellaceae_R-7_group ↑ Ruminococcaceae ↑
Guan et al, 2023	Mice DMM-induced OA and ferroptosis	Metabolite: Capsiate	16S rRNA	Supplementation reduced cartilage degradation, lowered OARSI score, and reduced osteophyte formation. It acts through SLC2A1(GLUT1 transporter gene) OA causes the following: Firmicute ↑ Actinobacteriota ↑ Bacteroidota ↓ Verrucomicrobiota ↓ Desulfobacterota ↓ Proteobacteria ↓ Cyanobacteria ↓
Chang et al, 2024; Chang et al, 2021	Mice, F OA induce by octacalcium phosphate injection into knees	Nutraceutical: chondroitin sulfate oligosaccharides	Shotgun	Supplementation maintains cartilage integrity, reduces MMP13 and ADAMTS. Firmicutes / Bacteroidetes ratio ↓ Akkermansia ↑ Clostridium ↓
Zhang et al, 2022	Rats, M Sodium iodoacetate-induced OA	Nutraceutical: chondroitin sulfate	16S rRNA	Supplement enhanced athletic ability, reduced serum cytokines, reduced cartilage degradation. Rickettsiales, Chloroplast , and Erysipelotrichales had positive correlation with inflammatory cytokines
Liu et al, 2022; Liu et al, 2023; Liu et al, 2022	Mice, M Pathogen free DMM-induced OA	Nutraceutical: Milk-derived extracellular vesicles	16S rRNA	Supplement reduced cartilage degradation, improved OARSI scores Proteobacteria ↓ Firmicutes ↑ Ruminococcaceae ↑ Akkermansiaceae ↑

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