Table 3.
Microbiota-related animal experiments and clinical trials in the management of EIMs.
| Disease | Subject | Intervention | Findings | Reference |
|---|---|---|---|---|
| (A) Probiotics | ||||
| Reactive arthritis | Salmonella Enteritidis-infected BALB/c mice | Lactobacillus casei (oral) | Consumption of L. casei reduced the bacterium invasiveness, degree of intestinal inflammation and synovitis, levels of TNF-α in knees and gut, levels of IL-17 in popliteal and mesenteric lymph nodes. | 148 |
| Rheumatoid arthritis | IFA and CII-immunized Wistar rats | Lactobacillus casei CCFM1074 (oral) | L. casei CCFM1074 regulated gut microbiota and unsaturated fatty acid metabolism, reducing arthritic symptoms, Th17 cells, plasma IL-6 and increasing Tregs in MLNs. | 149 |
| CII-immunized HLA-DQ8 mice | Prevotella histicola (oral) |
P. histicola produced AMPs and TJPs, significantly reduced intestinal permeability. P. histicola reduced Th17 responses, promoted production of Tregs and IL-10, significantly reducing incidence and severity of arthritis. |
150 | |
| AS with quiescent UC | Patient (a pilot study, 18 patients) | Lactobacillus acidophilus and lactobacillus salivarius (oral, 4 weeks) | The probiotics reduced scores of Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and visual analogue scale (VAS). | 151 |
| Psoriasis | Imiquimod-induced BALB/c mice | Lactobacillus pentosus GMNL-77 (oral) | GMNL-77 significantly reduced pro-inflammatory cytokines in the skin, T cells for IL-17 and IL-22 production in the spleen, and areas of erythematous scaling lesions. | 152 |
| Patient (a randomized, double-blind study, patients [26 psoriasis, 22 UC, 22 health]) | Bifidobacterium infantis 35624 (oral, 6 weeks for UC and 8 weeks for others) | B. infantis 35624 significantly reduced TNF-α in psoriasis patients, IL-6 in UC patients and CRP in both. | 153 | |
| Patient (a randomized, double-blind study, 90 patients [45 probiotics + betamethasone +calcipotriol, 45 placebo + betamethasone + calcipotriol]) | 1:1:1 mixture of Bifidobacterium longum CECT 7347, B. lactis CECT 8145, and Lactobacillus rhamnosus CECT 8361 (oral, 12 weeks) | Probiotics significantly reduced Psoriasis Area and Severity Index at 6 weeks and the risk of relapse at 6 months. | 154 | |
| Experimental autoimmune uveitis | IRBP, heat-inactivated MTB antigen and Pertussis toxin-immunized C57BL/6J mice | Escherichia coli Nissle 1917 (oral) | Probiotics promoted intestinal AMP production, prevented macrophage-induced inflammation and reduced T cell-mediated pro-inflammatory responses in extra-intestinal lymph nodes, eventually alleviating EAU. | 155 |
| IRBP and Pertussis toxin-immunized C57BL/6 mice | IRT-5: Lactobacillus casei, L. acidophilus, L. reuteri, Bifidobacterium bifidum, and Streptococcus thermophilus (oral) |
IRT-5 significantly reduced retinal histology score, percentage of CD8+ IL-17hi and CD8+ IFNγhi cells. | 156 | |
| Periodontitis | Patients (a randomized, double-blind study, 41 patients [20 SRP + probiotics, 21 SRP + placebo]) | Bifidobacterium lactis HN019 (oral, 30 days) | B. lactis HN019 promoted clinical, microbiological, and immunological benefits to the management of periodontitis. | 157 |
| Patient (a randomized, double-blind study, 40 patients [20 SRP + probiotics, 20 SRP + placebo]) | Lactobacilli reuteri (oral, 3 weeks) | L. reuteri significantly improved the plaque index, gingival index, bleeding on probing, and probing depth, and reduced the surgery risk. | 158 | |
| (B) Prebiotics | ||||
| Arthritis | HLA-B27 transgenic rats | 1:1 mixture of long-chain inulin-type fructans and short-chain inulin fraction oligofructose (oral) | Prebiotics significantly reduced the incidence rate of arthritis and colitis. | 159 |
| Periodontitis | Cotton ligature-treated Wistar rats | Mannan oligosaccharide (oral) | Prebiotics significantly protected against alveolar bone loss, reduced IL-10, IFN-γ, TNF-α and IL-1β, and further restored villous height and crypt depth. | 160 |
| (C) Postbiotics | ||||
| Arthritis | CFA and CII-immunized DAB/1J mice | Lithocholic acid (oral) | LCA significantly reduced arthritis score and pro-inflammatory cytokines. | 161 |
| CFA-immunized Sprague Dawley rats | Indole-3-Carbinol (oral) | I3C significantly reduced clinical symptoms, ESR, TNF-α, IL-6 and histopathological changes. I3C protected the liver as well. |
162 | |
| AS | Patients (36 patients) | Low starch diet (oral, 9 months) | A low starch diet reduced clinical symptoms, requirement of NSAIDs, seral levels of ESR and IgA. | 163 |
| Experimental autoimmune uveitis | IRBP, heat-inactivated MTB antigen and Pertussis toxin-immunized C57Bl/6J and Kaede transgenic mice IRBP and heat-inactivated MTB antigen-immunized B10.RIII mice |
SCFAs (oral) | SCFAs significantly reduced uveitis severity in C57BL/6 mice. SCFAs increased Tregs in cervical lymph nodes, reduced Th1 and Th17 in mesenteric and cervical lymph nodes at 4 weeks. Propionate significantly reduced Th1 trafficking from gut to the spleen, and migration toward eyes tended to be reduced. |
120 |
| PSC | Patient (a randomized, double-blind phase II clinical trial, 161 patients, 102 with IBD) | NorUDCA (oral, 12 weeks) | NorUDCA significantly reduced ALP in a dose-dependent manner. Well tolerated. |
164 |
| Patient (a randomized, double-blind phase II clinical trial, 76 patients, 43 with IBD) | Obeticholic acid (oral, 24 weeks) | OCA (5–10 mg) significantly reduced ALP in patients. The most common adverse event was pruritus. |
165 | |
| Patient (a randomized, double-blind phase II clinical trial, 52 patients, 31 with IBD) | cilofexor (oral, 12 weeks) | Cilofexor 100 mg significantly reduced ALP, GGT, ALT, AST, C4 and BAs. Well tolerated. |
166 | |
| IBD-induced secondary liver injury | DSS-administered C57BL/6J mice | Milk fat globule membrane (oral) | MFGM reduced DSS-induced hepatic injury. MFGM improved gut barrier, and increased GST activity in the liver. |
167 |
| Periodontitis | Patient (a randomized, double-blind study, 36 patients [19 SPT + postbiotics, 16 SPT + placebo]) | Heat-killed Lactobacillus plantarum L-137 (oral, 12 weeks) | The postbiotics decreased the depth of periodontal pockets more effectively. | 168 |
| Ovariectomized Sprague-Dawley female rats | Berberine (oral) | Berberine significantly reduced alveolar bone loss. | 85 | |
| (D) Antibiotics | ||||
| Ankle enthesitis (peripheral SpA) | DSS-administered SKG mice | Meropenem and vancomycin (oral) | Meropenem and vancomycin attenuated ankle enthesitis, decreased Th1 and Th17 cell levels in the spleen. | 169 |
| Experimental autoimmune uveitis | IRBP-induced B10.RIII mice | Metronidazole, vancomycin, neomycin, ampicillin (oral) | Both oral metronidazole and vancomycin alone reduced ocular inflammation significantly by increasing Tregs and decreasing Teffs. Gut microbial diversity clustering was associated with uveitis clinical scores. |
170 |
| PSC | Patient (a randomized, double-blind pilot study, 35 patients, 29 with IBD) | Vancomycin, metronidazole (oral, 12 weeks) | Both vancomycin and metronidazole decreased bilirubin, Mayo PSC risk score, etc. Only patients treated with vancomycin reached the primary endpoint [decrease in alkaline phosphatase (ALK) at 12 weeks], and with less adverse effects. |
171 |
| Patient (a randomized, triple-blind clinical trial, 29 patients [18 vancomycin + UDCA, 11 placebo + UDCA], 21 with IBD) | Vancomycin (oral, 125 mg q6h, 12 weeks) | Vancomycin reduced clinical symptoms, ALP, GGT, ESR and Mayo PSC risk score significantly. | 172 | |
| Patient (a randomized, double-blind study, 80 patients [39 metronidazole + UDCA, 41 placebo + UDCA], 65 with IBD) | Metronidazole, UDCA (oral, 36 months) | Combination of MTZ and UDCA significantly reduced ALP and New Mayo Risk Score. | 173 | |
| Patient (a pilot study, 16 patients, 14 with IBD) | Minocycline (oral, 100 mg bid, 1 year) | Minocycline significantly reduced ALP and Mayo risk score, but not serum bilirubin or albumin. Well tolerated. |
174 | |
| Meta-analysis for patients with PSC | Vancomycin seemed as the most effective antibiotic with regard to clinical improvement and adverse effects. | 175 | ||
| C57BL/6 mice, treated with fecal samples from a patient with PSC | Metronidazole, vancomycin (oral) | Vancomycin or metronidazole reduced the Th17 immune response. | 67 | |
| Periodontitis | Meta-analysis for patients with periodontitis | Amoxicillin plus metronidazole were associated with the best clinical outcomes (including probing pocket depth, bleeding on probing, and clinical attachment level). | 176 | |
| (E) FMT | ||||
| PSC | Patient (a pilot study, 10 patients, 10 with IBD) | A single FMT | FMT significantly reduced ALP (＜50%) in 3/10 patients at 24 weeks. | 177 |
Abbreviations: UC, ulcerative colitis; EIMs, extra-intestinal manifestations; SpA, spondyloarthropathy; AS, ankylosing spondylitis; EAU, experimental autoimmune uveitis; PSC, primary sclerosing cholangitis; IgA, immunoglobulin A; ESR, erythrocyte sedimentation rate; CRP, C-reactive proteins; TNF-α, tumor necrosis factor-α; IFN, interferon; IL-6, interleukin 6; IL-10, interleukin 10; IL-17, interleukin 17; IL-22, interleukin 22; Tregs, regulatory T cells; Th1 cells, T helper type 1 cells; Th17 cells, T helper type 17 cells; Teffs, effector T cells; IFA, incomplete Freund’s adjuvant; CII, type II collagen; LCA, lithocholic acid; I3C, indole-3-carbinol; IRBP, interphotoreceptor retinoid-binding protein; MTB, Mycobacterium tuberculosis; UDCA, ursodeoxycholic acid; NorUDCA, norursodeoxycholic acid; OCA, obeticholic acid; DSS, dextran sodium sulfate; MFGM, milk fat globule membrane; MTZ, metronidazole; BAs, bile acids; AMPs, anti-microbial peptides; TJPs, tight junction proteins; ALP, alkaline phosphatase; GGT, gamma-glutamyltransferase; ALT, alanine transaminase; AST, aspartate transaminase; GST, glutathione-S-transferase; MLNs, mesenteric lymph nodes; NSAIDs, non-steroidal anti-inflammatory drugs; SRP, scaling and root planning; SPT, supportive periodontal therapy.