Benefits of Probiotics in Rheumatic Diseases

Rheumatic diseases are chronic conditions which affect a large proportion of the population worldwide. Among them, inflammatory chronic diseases including rheumatoid arthritis (RA), spondyloarthritis (SpA), crystal-induced arthritis (CIA) and connective tissue autoimmune diseases, such as systemic lupus erythematosus (SLE) and systemic sclerosis (SSc), are the most common. Osteoarthritis (OA), by contrast, is classified as non-inflammatory arthritis. Although different risk factors are supposed to intervene in their development, these heterogeneous conditions share common clinical outcome including joint pain, disability and comorbidities.Over the last years increasing attention have been paid to the role of diet in the pathogenesis and progression of rheumatic diseases. It has been observed that healthy dietary habits and the consumption of foods rich in bioactive compounds, omega-3 fatty acids and antioxidants are associated with a lower risk to develop these diseases and a less severe clinical outcome (1). In particular, an important link between gut microbiota and rheumatic disease clinical features raised the possibility to modulate disease progression and presentation through microbiome manipulation. In this setting, a crucial emerging role seems to be played by probiotics, live microorganisms that, when administered in adequate amounts, confer a health benefit on the host (2).The most commonly used are Lactobacilli, Bifidobacteria and Streptococci, either as single species or in mixed culture. Their health effects are supported by randomized controlled clinical trials (RCTs), systematic reviews and meta-analyses conducted on infectious and antibiotic-associated diarrhoea, gut transit, irritable bowel syndrome, abdominal pain and bloating, ulcerative colitis and necrotizing enterocolitis (3,4).Although still limited, a growing interest is addressed to the effect of probiotics in rheumatic diseases. Evidence derives from randomized clinical trials conducted in chronic conditions including RA, OA, gout and SpA (Table 1). These studies suggest that probiotic supplementation might have beneficial effects both in systemic inflammatory markers and disease activity indices.Many experimental preclinical studies on RA pointed out the immunomodulatory and antiinflammatory effects of different strains of probiotics. They showed to prevent arthritis, to downregulate T helper 1 effector functions, to reduced T cell proliferation, to decrease proinflammatory and increase anti-inflammatory cytokines production in mice (5,6).A few studies have, instead, evaluated their role in patients affected with RA through RCT trials. Notwithstanding, the results are promising and support probiotics supplementation in RA. Three of those studies have been conducted over a period of 8 weeks. The first study showed the effectiveness of adjunctive treatment with Bacillus coagulans 6086 lactic acid-producing bacteria in patients suffering from RA (7). Although the low population size, the treatment resulted in greater improvement in pain scale, patient global assessment, self-assessed disability and serum CRP biomarker compared with subjects randomized to placebo. The second study included 22 RA patients and 24 controls assuming placebo and demonstrated a significant decrease in DAS-28 (a composite disease activity measure in RA), serum hs-CRP, tender and swollen joint count (8). Using the same cohort these authors observed a significant decrease in serum proinflammatory cytokines (9)Osteoarthritis represents the most frequent joint disease (arthropathy) among the global population and a leading cause of pain and disability. Although the processes which lead to cartilage degeneration have been largely investigated and the role of subclinical inflammation in OA pathogenesis is well established, at present no pharmacological treatment are available to cure or to slow down the progression of the disease. This is the main reason why patients with OA often search for alternative medications or supplement their diet with antioxidant and bioactive natural substances (13). Evidence from animal studies indicate a relationship between gut microbiota and OA development (14). In particular, dysbiosis has been postulated as a causal factor in the initiation and propagation of obesity-associated OA (15). Clinical studies are still limited. A large RCT considered the effect of Lactobacilli Shirota (LcS) in 461 patients with knee OA who were asked to ingest skimmed milk containing LcS (cases) or placebo (controls) daily for 6 months (16). The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), a composite score including pain and motion in OA, significantly improved in the group of patients receiving LcS.Gout is caused by the precipitation of pro-inflammatory monosodium urate crystals in the joint. It's a frequent rheumatic disease whose prevalence is rising worldwide mainly due to the general increase of hyperuricemia in the population. Hyperuricemia has been shown to be associated with metabolic syndrome and to play important roles in cardiovascular and kidney diseases. Although many factors are involved in the disease, diet plays an important role in gout as it can influence circulating levels of uric acid (17) and specific inflammatory pathways (18). At current, only a small RCT has been carried out on the effect of probiotics in patients affected with gout (table 1). This study showed a decrease in Spondyloarthritis encompass different clinical phenotypes including psoriatic arthritis and ankylosing spondylitis. These patients often present symptomatic or asymptomatic signs of bowel disease and increased intestinal permeability which allows luminal antigens or bacteria to interact with the host immune system more readily. Probiotics could therefore find a rationale in these subjects for their capacity to strengthen the epithelial barrier and to modulate intestinal microbiota. Only an RCT study has been carried out in SpA patients so far. A probiotic combination has been orally administered in patients with active ankylosing spondylitis and the effect on clinical indexes has been investigated over a period of 12 weeks (table 1). The group of patients taking probiotics did not demonstrate significant benefit over the placebo group (22).A pilot non-controlled study carried out on 18 patients with SpA associated with ulcerative colitis showed that a combination of Lactobacillus Acidophilus and Lactobacillus Salivarius ameliorate SpA through a reduction in disease activity and patients' perception of pain (23). Data on other SpA such as psoriatic arthritis are still lacking.Thanks to their effect on the innate immune system, probiotics supplementation might exert some benefit on autoimmune diseases including SLE and SSc. For the moment evidences are scarce, but some experimental studies are encouraging. Using mouse model of SLE some authors have demonstrated that probiotic supplementation ameliorates disease activity, Treg regulation, and typical comorbidities occurring in SLE including cardiovascular complications (24,25).As far as SSc is concerned, some RCTs have been carried out only in patients with gastrointestinal involvement. One of these has shown that an 8-week probiotics supplementation did not have any effect in reducing gastrointestinal symptoms but lead to a decrease in Th17 cell levels indicating an immunomodulatory capacity of the probiotic strains used (Table 1)(26). Another trial confirmed the inefficacy of probiotics in systemic sclerosis associated gastrointestinal disease but SSc clinical outcomes were not addressed in that study (27).While the local effect of probiotics on gut health have been well documented, their systemic anti-inflammatory and immunomodulating potential is still largely unclear.Probiotics exert a protective role against diarrhea and enterocolitis by maintaining intestinal barrier function and integrity and competing with other bacteria for mucosal adhesion sites. Their healthy effect on the intestinal mucosa has been recently associated with polyamine production (28). Probiotics also protect from intestinal inflammation through the increased production of short chain fatty acids (SCFA), microbiota metabolites including butyrate, acetate and propionate, which derive from intestinal bacteria fermentation of dietary fibers.Besides their local effect on gut health, SCFA have shown to significantly impact on peripheral immune response and systemic inflammation through the regulation of different immune cell functions (29).SCFA have demonstrated to promote the resolution of the inflammatory process decreasing NK-kB activity and enhancing the production of anti-inflammatory mediators including TGFß and IL-10 (30). Through their interaction with G protein-coupled and free fatty acid receptor signaling SCFA have shown to decrease pro-inflammatory cytokines and adhesion molecules in cell cultures (31). Further experimental studies showed that these fatty molecules can affect cell function at intracellular levels influencing acetylation and deacetylation of histones and, consequently, gene transcription (32).Some studies carried out in animal models of arthritis provides evidence that SCFA might exert beneficial functions in RA. One of these showed that SCFA butyrate suppresses antigen-induced arthritis by inhibiting germinal center B cell and plasmablast differentiation in mice (33). Using the same model other authors demonstrated that butyrate inhibits cytokine production by invariant NKT cell, a cell subset implicated in synovial inflammation and joint destruction (34). An increase polarization towards a Treg phenotype with a decrease in Th17 cell has been observed in a different animal model of RA along with the inhibition of pro-inflammatory cytokines (35).Rheumatic diseases are frequent chronic inflammatory conditions often involving autoimmune processes. Most of these diseases are currently well cured especially after the development of different biological drugs which target specific proteins and receptors.Others, like OA and certain severe forms of SSc, have still no cure and represent a burden in terms of patients' quality of life.It is well known that the pharmacological therapy plays a fundamental role in the management of rheumatic patients and it is usually a treatment for life. Besides standard therapies, dietary supplementation with probiotics is worth to be investigated in deep by larger population studies, in order to identify their precise effect on disease activity and clinical improvement.Both authors have made a substantial, direct and intellectual contribution to the work, and approved it for publication.This work was supported by Institutional funds from the University of Padova (grant n. DOR1921798/19 to PS).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.This article in the form of "opinion" wants to contribute to the knowledge of the influence of probiotics in rheumatic diseases. There is, in fact, a range of beneficial effects exerted by these healthy microorganisms with regard to inflammation and immunity which provides a rationale for probiotic supplementation in these conditions. We outline the evidences from randomized controlled trials carried out in rheumatoid arthritis, osteoarthritis, gout and spondyloarthritis and provide a possible explanation about their mechanism of action.

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