Medscape.com
Mohamed K. Bedaiwi, Robert D. Inman
Curr Opin Rheumatol. 2014;26(4):410-415.
Abstract
Purpose of review
The gut microbiome plays an integral role in the development and maintenance of the host immune system. Expanding knowledge about this microbial microenvironment has raised the possibility of new treatments based on this knowledge. In this review, we describe the recent evidence of the impact of the gut microbiome on arthritis and possible novel therapeutic approaches to alter the gut flora.
Recent findings
Recent studies support the growing evidence of microbiome as a causative agent underlying certain rheumatic diseases like ankylosing spondylitis and rheumatoid arthritis. There is intriguing yet still inconclusive evidence to support the use of probiotics as a treatment for these diseases.
Summary
There is recently a new level of understanding how the microbiome interacts with the immune system. Gene–environment interaction is another important element that sets the stage for initiation of autoimmune disease, which calls for further investigation. Probiotics could be an appealing therapeutic strategy, but further interventional studies exploring the dynamic interaction of microbiome and probiotics are still needed.
Introduction
Although most rheumatic diseases have a significant heritable component, predisposing genetic factors may require some environmental trigger to initiate the immunopathological events responsible for disease manifestation. A variety of investigations implicate a relationship between the gut microbiome and the development of certain rheumatic diseases. It is known that the microorganisms which populate the gastrointestinal tract profoundly influence the host immune system. However, despite intensive study of these organisms, there is as yet no definitive proof that bacteria play a causal role in rheumatoid arthritis (RA) or ankylosing spondylitis (AS). Yet, many studies of the microbiome have provided new understanding of the complexities of the host commensal microbiota.[1]
This article reviews the recent evidence for the potential role of microbiota in the pathogenesis of RA and AS, and addresses the possibility of therapeutic modulation of the gut microbiome.
Biology of Human Microbiota
Although many organs have their distinctive local microbial flora, the gastrointestinal tract has the largest proportion.[2] In 1676, Van Leeuwenhoek reported his discovery of microorganisms when he described ‘animalcules’ recovered from his mouth. It is now recognized that gut microorganisms may constitute up to 3 lbs of body weight. Microbial colonization has an important impact on the immune system development earlier in infant life. Organisms may play a protective role against certain autoimmune diseases, as exemplified by nondiabetic mice with an overrepresentation of Bacteroidetes in the microbiota.[3] In contrast, evidence has provided some links between the gut microbiome and the development of some rheumatic diseases. In addition to impacting the immune system, endogenous gut microbes may regulate the body weight by influencing the host’s metabolic and neuroendocrine homeostasis.[4]
Microbiome in Rheumatoid Arthritis
RA is a chronic systemic autoimmune inflammatory disease, with complex genetic and autoimmune factors contributing to it.[5] In the late 1970s, the importance of the histocompatability complex (HLA) region to the pathogenesis of RA was recognized, with HLA-Dw4 being more common among RA patients compared with healthy individuals.[6,7] This suggested the possibility of arthritogenic peptides being presented by proteins encoded by HLA-DRB1 genes. Subsequently, a large number of studies have examined and expanded the genetic basis of RA.
Yet, the genetic predisposition to RA does not predict disease development accurately. Twin and sibling studies have shed light on the genetic factors in RA. Monozygotic twins have a higher concordance than dizygotic twins for the development of RA. In two studies[8,9] of twins, the concordance for monozygotic twins was 13 versus 3.5% for dizygotic twins. This low percentage of concordance has suggested possible interaction between gene and environmental triggering factors.
Periodontal disease has been strongly linked to RA, with patients demonstrating a higher prevalence and severity of periodontal disease. Periodontal disease further shows correlation with disease activity, as patients with periodontitis have higher disease activity scores.[10] Furthermore, treatment of periodontitis has been shown in some studies to reduce disease activity as measured by Disease activity score28, Erythrocyte sedimentation rate, and serum TNF-α.[11] In a cross-sectional study of RA patients, recovery of Prevotella intermedia and Porphyromonas gingivalis in subgingival dental plaque as well as in synovial fluid supports a microbiome role in initiating or maintaining the chronic inflammation of RA.[12–14]
Studies of synovial fluid with PCR probes specific for the 16S rRNA demonstrated the presence of P. gingivalis DNA with greater frequency in RA patients than controls (15.7 versus 3.5%, P = 0.045), and RA patients in this study[15] demonstrated a correlation between dental health and burden of disease imposed by RA.
These recent findings have supported the recommendations by rheumatologist to encourage RA patients to obtain early, intensive dental care. In one study,[16] more advanced forms of periodontitis were found in early RA patients compared with controls, and RA patients had more missing teeth and greater periodontal friability on probing despite comparable oral hygiene. The characteristic oral organisms in this study were Tannerella forsythia subgingivally and Streptococcus anginosus supragingivally. The investigators concluded that in early RA, there is a greater risk of periodontal and alveolar bone disease.[16]
Breaking tolerance RA could occur in reaction to periodontal pathogens. Antibody reactivity to peptidylarginine deiminase (PADI) was higher in RA patients compared with individuals with periodontitis and controls.[17] Other than a potent citrullinating enzyme which might contribute to anti-CCP antibodies in RA, this report presents PADI as a possible therapeutic target as well.
Other than gut microbiota, lung organisms may have their own unique contribution to the host immune system. Earlier reports using spirometry and high-resolution computed tomography lung imaging found lung inflammation in autoantibody-positive individuals without inflammatory arthritis, and findings were similar to airway abnormalities seen in patients with early RA.[18]
That report has been followed with a recently published data to support the concept of a pathogenic role for lung microbes. Preclinical RA (i.e. anti-CCP-positive but with no clinical arthritis) is characterized by differences in lung microbiota in comparison to healthy control individuals.[19]
Further studies to define a potential role for Prevotella copri in the pathogenesis of RA utilized stool samples from RA patients and controls, and found that the presence of P. copri was strongly correlated with disease in recent-onset, untreated RA patients. Increases in Prevotella load correlated with a reduction in Bacteroides and a loss of reportedly beneficial microbes in these RA patients. In addition, unique Prevotella genes were found to be correlated with the activity of disease.[20]
Microbiome in Spondyloarthritis
The term ‘spondyloarthritis’ (SpA) refers to a group of disorders that includes AS, undifferentiated SpA, reactive arthritis, and the arthritis accompanying psoriasis and inflammatory bowel diseases. For the SpA group as a whole, there is a strong genetic relation with HLA-B27, especially for AS. However, the strongest genetic association (HLA-B27) accounts for only 30% of the heritability, thus a large part of the genetic susceptibility remains unknown and this has led to an intense effort to identify additional predisposing factors.[21]
In studying a possible role for microbiota in the pathogenesis of AS, it has been observed that active AS patients have a higher serum IgA Klebsiella pneumoniae in comparison with RA and healthy controls, whereas inactive AS patients had no such antibody elevation,[22] with possible flare of anterior uveitis in relation to Klebsiella colonization in bowel flora.[23] In these studies, it was noted that serum antibodies could be detected against pullulanase-D peptide, which contains a sequence having homology with HLA-B27.[22] However, subsequent studies did not provide confirmation of the specificity of anti-Klebsiella antibodies in AS.[24]
HLA-B27 may indirectly alter the bacterial flora. It has been demonstrated that transfected monocytes with HLAB-27 showed reduced proliferative response to endotoxin.[25,26]
Initial studies[27,28] of animal models which might link the genetic component of SpA to environmental factors found no spontaneous development of inflammatory process in HLA-B27 transgenic mice. On the other hand, rats transgenic for human HLA-B27 and β2-microglobulin spontaneously develop an inflammatory response in the form of nail changes, hair loss, and arthritis, thus mimicking the spectrum of clinical manifestations seen in SpA. These studies indicated the need for gut colonization with conventional bacterial flora in concert with genetic predisposition to initiate the inflammatory response.[29] Recently, an RA-like arthritis accompanied by a positive autoantibody profile has been developed in SKG mice.[30] SKG mice raised in a specific pathogen-free environment stayed healthy until exposed to curdlan (a β-1,3-glucan derived from the cell wall of yeast, fungi, and bacteria). Thereafter, the mice developed peripheral and axial arthritis associated with extra-articular manifestations similar to SpA.[1]
Inflammatory bowel disease (IBD) shares a wide spectrum of manifestations with HLA-B27-related SpA. There is now mounting evidence that certain bowel flora play a causative agent in IBD,[31,32] in concert with numerous genetic factors like NOD2 and CARD9 to initiate the immune response.[33,34] Many observational studies have supported the notion of subclinical gut inflammation commonly occurring in SpA, with as many as two-thirds of SpA patients demonstrating this phenomenon. In a recent study,[35] the absence of CD14+ macrophages and a large increase in CD163+ (M2) macrophages were observed in AS, supporting the concept of subclinical ileal inflammation in the AS patient. It has been observed that the eventual development of symptomatic IBD occurs in approximately 6.5% of SpA patients presenting without symptoms of IBD.[36]
The prevalence of gut inflammation in nonradiographic axial SpA and AS was comparable in one study[37] which addressed this question, although other parameters including male sex, high disease activity, restricted spinal mobility, and younger age were independently associated with gut involvement.
In a recently published observational study,[38] the results showed higher antiflagellin antibody-positivity rates and acute-phase reactants in AS patients compared with mechanical back pain patients.
In one recent report, a cohort of 68 patients with AS had an ileocolonoscopy and MRI of the sacroiliac joints, and the result showed higher radiological inflammatory MRI scores in axial SpA patients with chronic gut inflammation compared with axial SpA patients showing normal gut histology. These findings indicated that greater Sacroiliac joint bone marrow edema was correlated with chronic gut inflammation.[39]
Although there have been numerous studies suggesting a link between microbiome and SpA, the precise mechanism by which those environmental factors initiate the immune response still needs further investigation.
Probiotics as a Therapeutic Modulation of the Microbiota
Probiotics are defined as ‘live microorganisms which when administered in adequate amounts confer a health benefit on the host’.[40] Evidence suggests that probiotic bacteria modulate both innate and adaptive immunity in the host and may have therapeutic applications of chronic inflammatory diseases. Lactic acid bacteria (LAB) and bifidobacteria are the most known types of bacteria used as probiotics, but certain yeasts and bacilli have also been used.
Probiotics as a modality of treatment will require extensive study to understand their anti-inflammatory effect, long-term efficacy, and the mechanism of action by which they exert their therapeutic role.
Bifidobacterium animalis subspecies lactis IPLA R1 and Bifidobacterium longum IPLA E44 strains have been tested for their safety and their ability to modulate the intestinal microbiota in vivo. The oral administration of B. animalis IPLA R1 and B. longum E44 is considered nontoxic, and has the capacity to modulate the intestinal microbiota of rats by influencing short-chain fatty acids and the bifidobacterial population levels.[41] Oral administration of Lactobacillus casei suppresses the type II collagen-reactive effector function of Th1-type cellular and humoral immune responses.[42] When L. casei was tested in rat collagen-induced arthritis (CIA), arthritis scores and proinflammatory cytokine levels were observed to be lower compared with control rats and with CIA treated with indomethacin.[43] Previous evidence had showed the ability of L. casei to suppress the type II collagen-reactive effector function of Th1-type cellular and humoral immune responses in rat arthritis.[42] HLA-B27 transgenic rats with Bacteroides vulgatus-induced colitis have been treated with antibiotics to prevent and treat colitis, Lactobacillus rhamnosus GG prevented the relapse of colitis with significantly reduced histologic scores.[44]
But there are few studies on the efficacy of probiotics in human arthritis. The effect of L. casei was recently tested in RA patients and showed significantly lower serum proinflammatory cytokines (TNF-α, IL-6, and IL-12) in the probiotic-treated group, with higher level regulatory cytokine (IL-10) as well; clinically, the disease activity score was significantly decreased with L. casei 01 supplementation.[45] Studying the possible mechanisms by which L. casei protects against RA progression showed the effect of oral administration of L. casei to suppress the type II collagen-reactive effector function of Th1-type cellular and humoral immune responses in arthritic inflammation.[42]
One pilot study[46] assessed the effect of probiotics (Lactobacillus acidophilus and Lactobacillus salivarius) in patients with quiescent ulcerative colitis and active SpA, and there was a significant reduction of Bath AS Disease Activity Index and Visual analogue scale score. Despite a theoretical rationale for this therapy in AS patients, another randomized controlled trial of a 12-week course of an oral probiotic in active AS showed no significant benefit over placebo in any of the core outcome domains.[47]
As there are increasingly sophisticated tools for characterizing the gut microbiome, the complex interrelationships between gut flora, immune response, and arthritis will gradually be resolved.
Conclusion
Microbiota have a substantive impact on the immune system development and it remains an attractive, but unproven, theory that predisposing genetic factors may interact with microbiota to trigger peripheral or axial arthritis. Table 1 presents a list of pathogens that have been linked to arthritis.
Our review summarizes the recent evidence of oral and lung organisms in relation to RA. Regarding SpA, the recent finding of a correlation of axial inflammation, as detected by MRI, with subclinical gut inflammation may support the previous finding of gut–joint interactions in HLA-B27 transgenic rats. More evidence is needed to confirm the impact of the role of microbiota in arthritis, and further studies are needed to evaluate the role of probiotics as a novel therapeutic modality for arthritis.
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