Over the past twenty years, the link between gut microbes and human autoimmune diseases has attracted extensive attention. Available studies have shown that alterations in gut microbiota are closely related to the development of autoimmune diseases. A variety of factors may influence gut microecology and lead to gut dysbiosis, which may influence systemic inflammatory or autoimmune responses through mechanisms such as aberrant microbial translocation, molecular mimicry, and regulatory T cells/ T helper 17 cells imbalance, then lead to autoimmune diseases. Rheumatic diseases are a group of chronic diseases involving bones and joints, their surrounding soft tissues, and other related tissues and organs. The etiology is varied and the pathogenesis is unclear, but most of them are closely related to autoimmune reactions. This review introduces the alterations of gut microbiota in several common rheumatic diseases and focuses on the promise of antibiotics, probiotics, and fecal microbiota transplantation in rheumatic diseases.
RA: Rheumatoid Arthritis; HCs: Healthy Controls; PAD: Peptidyl Arginine Deiminase; Acpas: Anti-Citrullinated Protein Antibodies; SLE: Systemic Lupus Erythematosus; F/B: Firmicutes/Bacteroidetes; RG: Ruminococcus gnavus; LN: Lupus Nephritis; SLEDAI: SLE Disease Activity Index; ANA: Anti-Nuclear Antibody; GF: Germ-Free; SFB: Segmented Filamentous Bacteria; AS: Ankylosing Spondylitis; IBD: Inflammatory Bowel Disease; Treg: Regulatory T Cells; Th17: T Helper 17 Cells; E. gallinarum: Enterococcus gallinarum; IFN: Interferon; MLN: Mesenteric Lymph Nodes; GI: Gastrointestinal; IL: Interleukin; CIA: Collagen-Induced Arthritis; Tcrs: T-Cell Receptors; Scfas: Short-Chain Fatty Acids; L. reuteri: Lactobacillus reuteri; pdc: Plasmacytoid Dendritic Cell; APC: Antigen-Presenting Cell; Th1: T Helper 1 Cell; L. animalis: Lactobacillus animalis; TGF-b: Transforming Growth Factor b; FMT: Fecal Microbiota Transplantation; AIA: Adjuvant-Induced Arthritis; ESR: Erythrocyte Sedimentation Rate; CRP: C-Reactive Protein; T1D: Type 1 Diabetes; DAS-28: Disease Activity Score-28; RF: Rheumatoid Factor; HAQ-DI: Health Assessment Questionnaire Disability Index; SRI-4: SLE Responder Index-4
Microbiota is defined as the ecological communities of commensal, symbiotic, and pathogenic microorganisms living in and on the human body [1]. Abundant and genetically diverse microorganisms are colonized in our body, whose total number is about 100 trillion, outnumbering human cells tenfold [2]. The human gut is the richest in microorganisms, whose number of genes is ~150 times larger than those of humans [3].
The relationship between microorganisms and human hosts is mutually beneficial, the gut microbiota provides us with fundamental protective, metabolic and immune capacities, such as food processing, vitamin synthesis, maintenance of host nutrition and energy balance, and regulation of immunity. In turn, the human body provides a suitable environment and essential nutrients for them [4,5]. Many investigations have demonstrated that gut microbiota is crucial in the normal development and maturation of the immune system [6-12], and gut microbiota dysbiosis can lead to immune dysregulation and various autoimmune diseases [13-19].
Rheumatic diseases are a group of autoimmune disorders of unknown pathogenesis, and genetic and environmental factors (including microbes) are possible reasons. Currently, numerous studies have explored the role of microbiota in autoimmune diseases and demonstrated an evident correlation between them. The review aims to explore gut microbiota alterations in several common rheumatic diseases and the prospects for microbiologically relevant therapeutic strategies.
RA is a chronic, systemic autoimmune disorder with erosive, symmetrical polyarthritis as the main clinical manifestation, which can eventually lead to joint deformity and loss of function. The etiology of RA is not fully understood, and it is currently thought to be related to genetic and environmental factors.
Many studies have demonstrated a correlation between periodontal disease and RA. Periodontal disease is more prevalent and more symptomatic in RA patients compared with Healthy Controls (HCs) [20]. Symptoms of RA also decrease after treatment for periodontal disease [21]. Porphyromonas gingivalis, a periodontopathic bacterium, can produce Peptidyl Arginine Deiminase (PAD), an enzyme that can convert arginine to citrulline [22,23]. Interestingly, under certain conditions, the citrullination of proteins is associated with the production of Anti-Citrullinated Protein Antibodies (ACPAs) [24,25]. Therefore, P. gingivalis may induce the production of ACPAs, which are highly specific for RA.
Currently, numerous research has confirmed the existence of gut dysbiosis in RA patients. Research shows that RA patients have a reduced microbial diversity than HCs, which is linked to autoantibody levels and disease duration. And the microbial profile of RA is characterized by the reduction of abundant taxa and expansion of rare taxa and Actinobacteria [26]. In new-onset untreated RA patients, the abundance of Prevotella was increased and the number of Bacteroides was decreased, and Prevotella (Prevotella copri) was closely related to the disease [17]. In addition, a metagenomic analysis demonstrated that Lactobacillus csalivarius was overabundant, while Haemophilus spp. were depleted in RA fecal samples [27]. Furthermore, it was found that both Prevotella copri and Collinsella, which were enriched in RA patients, exacerbated disease severity in mouse model of arthritis, indicating that these two bacteria may be involved in the development of RA [26,28].
SLE is a systemic autoimmune disease that mainly affects women of childbearing age, characterized by the formation of immune complexes and pathogenic autoantibodies. The pathogenesis of SLE remains elusive, however, increasing evidence suggests that gut dysbiosis is involved in SLE development.
Hevia, et al. [29] conducted the first human study, analyzing stool samples from 20 SLE patients and 20 HCs, and found that SLE patients had a lower Firmicutes/Bacteroidetes (F/B) ratio. Later, a larger human study including 45 SLE patients and 48 HCs also observed a decreased F/B ratio in SLE patients. At the genus level, a prevalence of Rhodococcus, Prevotella, Eggerthella, Flavonifractor, Eubacterium, and Klebsiella and a decline of Dialister and Pseudobutyrivibrio were observed and suggested a gut microbiota profile for SLE patients [30]. Recently, a study demonstrated that SLE patients had a fivefold increase of Ruminococcus gnavus (RG) in the gut compared with controls, and expansion of RG was positively correlated with overall disease activity and was most prominent in those with Lupus Nephritis (LN) [31]. In addition, it was found that in patients with SLE, the abundance of Clostridium species ATCC BAA-442 was positively correlated with the SLE Disease Activity Index (SLEDAI) score [32].
A previous study in lupus-prone mice observed an enrichment of Lachnospiraceae and a higher abundance of Lachnospiraceae was linked to the earlier onset of lupus and more severe symptoms [33]. Furthermore, an unexpected connection was found between gut microbiota and Anti-Nuclear Antibody (ANA). Germ-free (GF) lymphotoxin-deficient mice mono-colonized with Segmented Filamentous Bacteria (SFB) were found to produce more ANAs than lymphotoxin-deficient controls mono-colonized with Escherichia coli, which demonstrated that ANA production is influenced by gut commensals, particularly increased colonization of SFB. This study indicates that neonatal colonization of the gut can influence systemic autoimmunity in adult life [34].
AS is a spondyloarthropathy that mainly affects the axial skeleton and is characterized by inflammatory low back pain. In severe cases, spinal stiffness and deformity may occur. In China, AS has a prevalence of about 0.20-0.40%, with almost 80% of patients being young adults [35,36]. Regarding pathogenesis, it is currently believed that it is mainly due to the combined effect of genetic and environmental factors.
HLA-B27 is a major genetic risk factor for AS [37]. About 90% of AS patients are HLA-B27 positive, however, in all HLA-B27 positive individuals, less than 5% are affected [38]. Studies suggest that HLA-B27 may induce the development of AS by affecting the gut microbiota. A study conducted in transgenic rats found that HLA-B27 was correlated with alterations in the cecal microbiota [39]. A subsequent study observed significantly different microbiota composition between HLA-B27-positive and HLA-B27-negative healthy individuals, indicating that genetic background may affect gut microbial composition [40].
Research has demonstrated that gut microbiota is involved in the pathogenesis of AS. For example, HLA-B27 transgenic rats did not develop inflammation of the gut and joints in a GF environment, however, when they were exposed to normal gut bacteria, colitis and arthritis would appear [41]. In addition, in AS patients, the distinctive fecal microbiota feature is associated with levels of fecal calprotectin, a marker of gut inflammation [42].
Currently, increasing studies have shown the presence of gut dysbiosis in AS patients. An earlier study found a significant increase in the proportion of sulfate-reducing bacteria and a decrease in the abundance of Clostridium leptum in the stools of patients with AS compared with HCs [43]. Recently, A study identified terminal ileum dysbiosis in AS patients. Specifically, compared with HCs, Lachnospiraceae, Bacteroidaceae, Porphyromonadaceae, Rikenellaceae, and Ruminococcaceae increased in abundance, while Veillonellaceae and Prevotellaceae decreased in abundance [44]. Similar to alterations observed in SLE [31], Breban, et al. [40] found that AS patients have a 2-fold to 3-fold increase in RG abundance compared with HCs, which was significant and paralleled with disease activity in patients having an Inflammatory Bowel Disease (IBD) history. In addition, Chen, et al. [45] revealed that AS patients with different phenotypes have specific gut microbiota alterations separately. They found that Prevotella_2 was more abundant in axial AS patients, while Collinsella, Streptococcus, and Comamonas were more enriched in peripheral AS patients. In this study, an 8 genera-based model (a classification model based on gut microbial characteristics) could accurately distinguish AS patients from HCs, which might be instructive in future clinical diagnosis.
Recently, increasing studies have demonstrated that gut microbiota dysbiosis may induce autoimmune disease via certain mechanisms, which mainly include aberrant microbial translocation, molecular mimicry, and regulatory T cells/ T helper 17 cells (Treg/Th17) imbalance (Figure 1).
An intact gut barrier helps prevent the over-activation of the immune system, maintaining the balance between gut microbes and host immunity. Gut commensals and their components translocate to other tissues or organs outside the gut when the gut barrier is compromised, triggering autoimmunity by interacting with the immune system abnormally [46] (Figure 1A).
Recently, Enterococcus gallinarum (E. gallinarum), a gut pathobiont, was detected in liver biopsies of patients with SLE or autoimmune hepatitis, but not in healthy individuals [47]. The study demonstrated that E. gallinarum translocated from the gut into the liver and other systemic tissues, then interacted with the host immune system, activating the type I Interferon (IFN) pathway and inducing the production of autoantibodies [47]. Moreover, in mono-colonized and autoimmune-prone mice, pathobiont translocation could induce autoantibodies and cause mortality. However, using a vaccine against E. gallinarum could prevent translocation, reduce autoantibodies and increase survival in mice [47]. Additionally, Lactobacillus reuteri, which is enriched in the gut of lupus-prone mice, can also translocate to the liver, spleen, and Mesenteric Lymph Nodes (MLN), then engage type I IFN pathways and aggravate lupus-like symptoms [48]. The above findings suggest that enteric pathogens can translocate to organs outside the gut and trigger or promote autoimmunity.
In the development of autoimmunity, molecular mimicry is considered an important mechanism due to the sequence similarity between certain microbial peptides and autoantigens [46] (Figure 1B).
Many commensals present in the skin, oral cavity, and Gastrointestinal (GI) tract were found to express orthologs of the human Ro60 autoantigen, an RNA-binding autoantigen targeted in SLE [49,50]. In SLE patients, commensals could trigger autoimmune responses through cross-reactivity of T cells (which were commensal-reactive) with Ro60 autoantigen. For example, Bacteroides thetaiotaomicron can induce lupus-like symptoms via molecular mimicry, because it is the ortholog of human autoantigen Ro60 [49]. In addition, Roseburia intestinalis can induce autoimmunity via molecular mimicry as well, due to the homology of its peptide with β2-glycoprotein I [51].
A recent study revealed that in SLE patients, the expansion of RG was positively correlated with increased disease activity and LN [31]. In eight strains of RG, RG2 cell wall lipoglycans have antigenic properties, which could react with native DNA, and trigger an anti-ds DNA antibody response [31]. The findings above indicate that SLE and LN may be triggered or aggravated by molecular mimicry between RG strain and native DNA molecules [52]. Recently, a stool analysis using metagenomic shotgun sequencing found that in untreated AS patients, gut microbiota was disturbed, and some enriched species may trigger autoimmunity through molecular mimicry. Specifically, AS-enriched species include Acidaminococcus fermentans, Parabacteroides distasonis, Prevotella copri, Eubacterium siraeum, and Bacteroides coprophilus. Bacterial peptides of these species could induce the increase of IFN-γ producing cells via mimicking type II collagen [53].
The imbalance between pro-inflammatory Th17 cells and anti-inflammatory Treg cells is also one of the important mechanisms involved in autoimmunity development, with a reduced Treg/Th17 cell ratio leading to an exacerbation of autoimmunity [46] (Figure 1C).
Recently, increasing investigations have shown that rheumatic diseases are related to Treg/Th17 imbalance. For example, selective depletion of Treg cells leads to the worsening of delayed-type hypersensitivity arthritis in C57BL/6 mice, which could be counteracted by an anti-interleukin-17 (IL-17) monoclonal antibody, which was used for IL-17 blockade [54]. IL-17 is a major pro-inflammatory cytokine, produced mainly by Th17 cells [55]. Furthermore, multiple investigations have shown that gut microbiota is linked to Treg/Th17 imbalance. Maeda, et al. [28] transferred feces from RA patients (with altered gut microbiota) to GF arthritis-prone SKG mice and found that gut dysbiosis activated autoreactive T cells in mice, increased intestinal Th17 cells, and caused joint inflammation. Under GF conditions, both Th17 cells in the gut and the severity of arthritis were reduced in the K/BxN arthritis mouse model, but these could be restored after ingestion of SFB [16]. Additionally, in Collagen-Induced Arthritis (CIA) models, SFB could trigger lung autoimmunity by inducing Gut-Lung Axis Th17 cells expressing dual T-cell Receptors (TCRs) [56].
Among the gut microbial metabolites, Short-Chain Fatty Acids (SCFAs) derived from the breakdown of dietary fiber by bacteria, are the most studied and considered important in Treg/Th17 balance. SCFAs can enhance intestinal integrity and inhibit intestinal inflammation through mechanisms such as Treg cell induction [57]. A recent study showed that administration of butyrate (one of the SCFAs) in the CIA mouse model suppressed arthritis by increasing systematic Treg cells, decreasing Th17 cells, and inhibiting inflammatory cytokine expression [58].
In recent years, probiotics, antibiotics, as well as Fecal Microbiota Transplantation (FMT) have shown good prospects in the treatment of rheumatic diseases by regulating gut microbiota and promoting the balance of gut microecology.
Probiotics are living microorganisms that can bring health benefits to the host when administered in sufficient quantities [59. Studies have revealed that in RA patients, Lactobacillus casei 01 and Lactobacillus acidophilus supplementation have improved disease activity and inflammatory status [60,61]. Faecalibacterium, a butyrate-producing bacteria, can reduce the occurrence of RA by maintaining the integrity of gut epithelium and anti-inflammatory properties [62-64]. In Adjuvant-Induced Arthritis (AIA) rat model, Lactobacillus casei (ATCC334) ameliorated gut dysbiosis, markedly inhibited the induction of arthritis, and protected bones from damage [65]. In addition, Prevotella histicola, a unique commensal bacterium, administered enterally could suppress HLA-DQ8 mice arthritis via mucosal regulation [66]. In SLE patients, it was found that Lactobacillus spp. depletion was greatest before disease onset, suggesting that Lactobacillus may be involved in preventing SLE [67]. A previous study in young, female lupus-prone mice also observed a significant decrease in lactobacilli. The study also showed that retinoic acid could restore lactobacilli in lupus-prone mice and improve symptoms, which suggests that intaking of dietary supplement retinoic acid and probiotic lactobacilli may be promising in relieving inflammatory flares in SLE patients [33]. In the early days, Jenks and colleagues [68] examined the influence of orally administered probiotics on patients with active spondyloarthritis. However, in this study, probiotics did not demonstrate a noticeable benefit over placebo. At present, the research on probiotics in AS is not mature enough, and further research is needed to explore the impact of probiotics on AS.
In the early stage, the Netherlands and the United States conducted three large, double-blind, placebo-controlled studies to realize the impact of minocycline on RA patients [69-71]. Two of the studies targeted RA patients with a long history [69,70], and the third study targeted early RA patients [71]. All three studies showed that minocycline was superior to placebo in several laboratory and clinical parameters, including hemoglobin level, Erythrocyte Sedimentation Rate (ESR), and joint swelling and tenderness. There is no study on the treatment of SLE patients with antibiotics at present, but there are relevant animal experiments. Studies conducted in MRL/LPR mice and NZB/WF1 lupus mice found that treatment with broad-spectrum antibiotics or vancomycin could clear harmful bacteria in the gut, improve the gut barrier function, and thus improve lupus-like symptoms [47,72]. In addition, antibiotic treatment can enrich probiotics and alleviate Treg/Th17 imbalance in lupus mice [72]. However, two other studies showed that antibiotic treatment had no significant effect on gut microbiota and lupus progression in lupus mice [73], and even aggravated lupus-like disease in mice [74] A previous study has shown that after 12 weeks of treatment with moxifloxacin, AS patients had a significant attenuation in inflammatory symptoms and a marked reduction in the mean of ESR and C-Reactive Protein (CRP) [75]. Recently, a study demonstrated that rifaximin significantly attenuated symptoms of AS mice and down-regulated inflammatory factors. Rifaximin also changed the gut microbiota composition, increasing the ratio of Bacteroidetes/Firmicutes, and selectively enhancing some probiotic populations, including Lactobacillus [76].
In summary, antibiotics may be a novel treatment strategy for patients with rheumatic diseases, but a large number of clinical studies are still needed for further discussion.
Nowadays, the therapeutic potential of FMT in autoimmune diseases is constantly being investigated, since gut dysbiosis is a key characteristic of most autoimmune diseases.
FMT is the transfer of fecal bacteria from a healthy donor into the recipient's GI tract to alter the recipient's microbial composition and provide health benefits [77]. Earlier studies demonstrated that recurrent Clostridium difficile infections can be effectively treated with FMT. Recently, a randomized controlled trial demonstrated that in patients with new-onset Type 1 Diabetes (T1D), FMT could halt the decrease of endogenous insulin production and stabilize residual beta cell function [78]. Recently, A case report [79] has shown that a young patient with a 5-year history of RA was admitted to the hospital for active RA flare and was successfully cured with FMT, which manifested as a decrease in Disease Activity Score-28 (DAS-28) and Rheumatoid Factor (RF) and improvement of the health assessment questionnaire Disability Index (HAQ-DI). For now, no more data is available regarding the effect of FMT on RA patients, however, relevant clinical trials are in progress. Recently, an explorer clinical trial evaluated the safety and efficacy of FMT in SLE patients [80]. The results demonstrated that FMT recipients had no serious adverse effects and 42.12% of patients reached the SLE Responder Index-4 (SRI-4) primary outcome. Moreover, SCFAs-producing bacteria were significantly increased in FMT recipients, while inflammation-related bacteria decreased. For now, no data is available regarding the effect of FMT on AS patients.
The results above indicate that FMT may be a safe and feasible treatment option for patients with rheumatic diseases. However, to fully evaluate FMT's safety and efficacy, larger randomized trials are needed.
At present, microbiology-related research is very popular in medical disciplines. Although there have been many studies in this area, the real causal relationship between microorganisms and the occurrence and development of disease is still unclear. The pathogenesis of rheumatic diseases is considered to be associated with genetic and environmental factors. Studies have shown that there is a close relationship between gut microbiota and rheumatic diseases. Several mechanisms have been proposed to explain the role of gut microbiota in rheumatic diseases, such as aberrant microbial translocation, molecular mimicry, and Treg/Th17 imbalance. However, these cannot fully explain the pathogenesis of rheumatic diseases, and related researches are still in progress.
Antibiotics, probiotics, FMT, and other therapeutic strategies through the manipulation of gut microbiota have great therapeutic potential in rheumatic diseases. These treatments may help improve the symptoms of patients, reduce the occurrence of serious complications, and even prevent the occurrence of diseases. However, these are still in the primary stage and need further exploration.
Figures were created by Figdraw.
The authors declare that they have no conflicts of interest.
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