Table 1.

Characteristics of included studies.

Author, Year	Aim of the Study	Study Design	ParticiPants	Treatment	Outcome Measures	Reported Results
Coulson et al. (2013) [24]	Evaluate how the efficacy of nutraceuticals in treating OA may be altered according to the different microbiota profiles of the gastrointestinal tract and allow the formulation of a hypothesis that partly explains the inconsistent and controversial results of osteoarthritis (OA) clinical studies with green-lipped mussel (GLM) and glucosamine.	Clinical trial	40 patients (29 women) Mean age: 58.6 ± 8.9 years Inclusion criteria: Patients with knee OA eligible for ACR.	3000 mg/day green-lipped mussel extract (GLM) or 3000 mg/day glucosamine sulphate for 12 weeks.	- Microbiota analysis in feces (T0 and T12) through viable plate counting and MALDI-TOF mass spectrometry-based colony identification. - WOMAC, Lequesne algofunctional index, SF12 score (quality of life) measure and GSRS (T0, T6 and T12) - Other: BP, height, BMI, WHI and CRP.	Results Significant improvement (p < 0.05) in all WOMAC [pain, stiffness, flexibility and function] and GSRS measures. Although without significant changes in the microbiota, in both groups ↓ Clostridium and Staphylococcus and ↑ Lactobacillus, Streptococcus and Eubacterium. In the GLM group ↑ Bifidobacterium and ↓ Enterococcus and yeasts. In the GS group ↓ Bacteroides and ↑ yeasts and coliforms, most notably Escherichia coli.
Boer et al. (2019) [25]	Verify the relationship between joint pain and the composition of the gastrointestinal microbiome, and knee pain related to osteoarthritis in the Rotterdam Study.	Case-Control	1427 patients (821 women) Mean age: 56.8 ± 5.9 years Inclusion criteria: Patients with knee OA (cases) and without knee OA (controls) from Rotterdam Study.	-	-- 16S rRNA gene-based Illumina sequencing for microbiome profiling. - WOMAC Index.	Results - Microbiome ß-diversity was significantly associated with knee WOMAC scores. - A greater relative abundance of Streptococcus was found in individuals with higher pain values on the WOMAC scale, regardless of tobacco, alcohol consumption and BMI. - There was a significant association between the relative abundance of Streptococcus spp. and knee WOMAC-pain scores (p = 1.4 × 10−4). This association was robust and driven by local inflammation in the knee joint.
Huang et al. (2016) [26]	To analyze the relationship of lipopolysaccharide (LPS), a decisive proinflammatory product of the microbiome, with the level of inflammation, symptoms and radiographic alterations in osteoarthritis of the knee.	Cohort study	25 patients from the Etarfolatide cohort (18 women) Mean age: 62.4.1 ± 15.8 years Inclusion criteria: radiographic knee OA (unilateral or bilateral [K/L] grade 1–4).	-	- LPS was measured using the EndoZyme Assay (recombinant factor C based), carefully optimized for systemic and synovial fluid analyses. - LBP was tested in both serum and synovial fluid for association with OA phenotypic outcomes (commercial sandwich ELISA kit). - Models were adjusted for age, gender and BMI. - WOMAC Index.	Results - Serum LPS and LBP were associated with the abundance of activated macrophages in the knee joint capsule (p = 0.01) and synovium (p = 0.036). - SF LPS and LBP were associated with the abundance of activated macrophages in the synovium (p = 0.001 and p = 0.021, respectively). - Serum LPS, LBP and SF LPS were associated with knee osteophyte severity (p = 0.030, p = 0.017 and p = 0.001, respectively). - SF LPS was positively associated with knee joint space narrowing severity (p < 0.001) and total WOMAC score (p = 0.008). - Serum LBP tended to show a positive association with knee pain score (p = 0.076). - SF LBP was significantly associated with self-reported knee pain score (p = 0.039). - Both LPS and LBP concentrations were significantly lower in SF than in paired serum (p < 0.0001). - Serum LPS and LBP concentrations were highly correlated (p < 0.001) and individually correlated with BMI (p < 0.017) and plasma sCD14 (p < 0.001).

ACR: American College of Rheumatology; BMI: body mass index; BP: blood pressure; GLM: Green-lipped mussel extract; GS: glucosamine sulphate; GSRS: Gastrointestinal Symptom Rating Scale; K/L: Kellgreen/Lawrence grading system; LBP: LPS binding protein; LPS: lipopolysaccharide; OA: Osteoarthritis; SF: Synovial fluid; SF-12: 12-Item Short Form Survey; T₀: At the beginning; T₆: At 6 weeks; T₁₂: At 12 weeks; WHI: Waist hip index; WOMAC: Western Ontario and McMaster Universities Osteoarthritis Index; ↓ Decrease; ↑ Increase.