Gut dysbiosis in rheumatic diseases: A systematic review and meta-analysis of 92 observational studies

Abstract

Background: Emerging evidence suggests that dysbiosis in gut microbiota may contribute to the occurrence or development of several rheumatic diseases. Since gut microbiota dysbiosis is potentially modifiable, it has been postulated to be a promising preventive or therapeutic target for rheumatic diseases. However, the current understanding on the potential associations between gut microbiota and rheumatic diseases is still inadequate. Therefore, we aimed to synthesise the accumulating evidence for the relation of gut microbiota to rheumatic diseases.

Methods: The PubMed, Embase and Cochrane Library were searched from inception to March 11, 2022 to include observational studies evaluating the associations between gut microbiota and rheumatic diseases. Standardised mean difference (SMD) of α-diversity indices between rheumatic diseases and controls were estimated using random-effects model. β-diversity indices and relative abundance of gut microbes were summarised qualitatively.

Findings: Of the included 92 studies (11,998 participants), 68 provided data for α-diversity. Taken together as a whole, decreases in α-diversity indices were consistently found in rheumatic diseases (observed species: SMD = -0.36, [95%CI = -0.63, -0.09]; Chao1: SMD = -0.57, [95%CI = -0.88, -0.26]; Shannon index: SMD = -0.33, [95%CI = -0.48, -0.17]; Simpson index: SMD = -0.32, [95%CI = -0.49, -0.14]). However, when specific rheumatic diseases were examined, decreases were only observed in rheumatoid arthritis (observed species: SMD = -0.51, [95%CI = -0.78, -0.24]; Shannon index: SMD = -0.31, [95%CI = -0.49, -0.13]; Simpson index: SMD = -0.31, [95%CI = -0.54, -0.08]), systemic lupus erythematosus (Chao1: SMD = -1.60, [95%CI = -2.54, -0.66]; Shannon index: SMD = -0.63, [95%CI = -1.08, -0.18]), gout (Simpson index: SMD = -0.64, [95%CI = -1.07, -0.22]) and fibromyalgia (Simpson index: SMD = -0.28, [95%CI = -0.44, -0.11]), whereas an increase was observed in systemic sclerosis (Shannon index: SMD = 1.25, [95%CI = 0.09, 2.41]). Differences with statistical significance in β-diversity were consistently reported in ankylosing spondylitis and IgG4-related diseases. Although little evidence of disease specificity of gut microbes was found, shared alterations of the depletion of anti-inflammatory butyrate-producing microbe (i.e., Faecalibacterium) and the enrichment of pro-inflammatory microbe (i.e., Streptococcus) were observed in rheumatoid arthritis, Sjögren's syndrome and systemic lupus erythematosus.

Interpretation: Gut microbiota dysbiosis was associated with rheumatic diseases, principally with potentially non-specific, shared alterations of microbes.

Funding: National Natural Science Foundation of China (81930071, 81902265, 82072502 and U21A20352).

Keywords: Gut dysbiosis; Gut microbiota; Meta-analysis; Rheumatic diseases.

Figure 1

Forest plots of α-diversity richness estimators in the gut microbiota of patients with rheumatic diseases compared with healthy controls. Panel a. Observed species in patients with rheumatic diseases versus controls (n = 1,311 versus n = 994, P=0.01; inverse-variance, random-effects). Panel b. Chao 1 in patients with rheumatic diseases versus controls (n = 1,495 versus n = 3,244, P < 0.001; inverse-variance, random-effects). SD, standard deviation; CI, confidence interval.

Figure 2

Forest plots of α-diversity richness/evenness in the gut microbiota of patients with rheumatic diseases compared with healthy controls. Panel a. Shannon index in patients with rheumatic diseases versus controls (n = 2,893 versus n = 7,444, P < 0.001; inverse-variance, random-effects). Panel b. Simpson index in patients with rheumatic diseases versus controls (n = 1,460 versus n = 2,903, P < 0.001; inverse-variance, random-effects). SD, standard deviation; CI, confidence interval.

Figure 3

β-diversity comparison between patients with rheumatic diseases and healthy controls. RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; AS, ankylosing spondylitis; SS, systemic sclerosis; JIA, juvenile idiopathic arthritis; OA, osteoarthritis; FM, fibromyalgia; KD, Kawasaki disease; MPA, microscopic polyangiitis; PsA, psoriatic arthritis; IgG4-D, IgG4-related diseases; BD, Behcet's disease; SjS, Sjögren's syndrome.

Figure 4

Changes in relative abundance of microbes reported by at least two studies from a diagnostic category. AS, ankylosing spondylitis; BD, Behcet's disease; JIA, juvenile idiopathic arthritis; OA, osteoarthritis; RA, rheumatoid arthritis; SjS, Sjögren's syndrome; SLE, systemic lupus erythematosus; SS, systemic sclerosis.