Rheumatoid arthritis (REA) is a chronic autoimmune disease that primarily affects the joints, causing inflammation, pain, and progressive damage to joint structures. Although the exact cause of REA remains unclear, it is believed that there is a combination of genetic, environmental, and immunological factors that contribute to the development and progression of the disease. In recent years, numerous studies have highlighted a possible correlation between intestinal and urinary infections – caused by bacteria or fungi – and the onset or progression of REA. The role of infections in the context of autoimmune diseases is complex and often mediated by mechanisms such as molecular mimicry, aberrant activation of the immune system, and changes in the host microbial ecosystem. Below, the relationship between intestinal or urinary infections (bacterial and fungal) and REA is explored.
Intestinal infections and rheumatoid arthritis
Alterations of the intestinal microbiome (dysbiosis)
The intestinal microbiome plays a crucial role in maintaining immune homeostasis. An imbalance of the gut microbiota, known as dysmicrobism or dysbiosis, has been associated with the onset of several autoimmune diseases, including REA. Intestinal infections, which can alter the composition of the microbiome, have the potential to contribute to the pathogenesis of REA. Some pathogenic intestinal bacteria, such as Escherichia coli, Salmonella or Clostridium difficile, can trigger an aberrant immune response.
Intestinal infections can induce an abnormal production of pro-inflammatory cytokines (such as IL-6, IL-1β and TNF-α), stimulating the activation of autoreactive T cells and macrophages, which attack the joints in the context of ARE. Bacterial or fungal infections can alter the intestinal barrier, allowing the passage of bacterial antigens and toxins into the bloodstream, which could trigger a systemic autoimmune response. Research has shown that some intestinal infections can induce the production of autoantibodies, such as rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibodies, both of which are associated with disease progression.
Fusobacterium nucleatum and Prevotella copri infections
Two intestinal bacteria have been extensively studied in relation to REA:
- Prevotella copri: Numerous studies have shown a higher abundance of this bacterium in patients with rheumatoid arthritis compared to healthy controls. P. copri is thought to stimulate an excessive inflammatory response, contributing to the onset of the disease.
- Fusobacterium nucleatum: This bacterium, associated with inflammatory bowel disease, can promote the production of pro-inflammatory cytokines, influencing the autoimmune response that characterizes REA.
Intestinal fungal infections
Fungal infections, such as those by Candida albicans, can alter the intestinal microbiome and increase intestinal permeability. This allows the passage of fungal and bacterial antigens into the bloodstream, with potential effects of immune activation. The presence of C. albicans has been associated with the production of autoantibodies and immune dysfunction that may contribute to the pathogenesis of REA.
Urinary Tract Infections and rheumatoid arthritis
Recurrent urinary tract infections (UTIs) have also been associated with RAE, although the exact mechanism of this association is not fully understood. It is hypothesized that chronic urinary tract infections may act as a trigger for autoimmune activation through various mechanisms.
Systemic inflammation and autoimmune response
Bacterial urinary tract infections can induce systemic inflammation through the production of inflammatory cytokines that can amplify existing autoimmune responses. This persistent inflammatory state can trigger or exacerbate the progression of REA. Additionally, the release of bacterial products into the bloodstream can stimulate the immune system to react against its own cells and tissues.
Molecular mimicry
Molecular mimicry is an immunological mechanism in which pathogens share similar antigenic epitopes with those of the host, resulting in an immune response that not only attacks the pathogen, but also the host tissues. In particular, some bacteria involved in urinary tract infections may contain proteins similar to those found in joints, leading to an autoimmune response directed against joint tissues. Escherichia coli, a major bacterium that causes urinary tract infections, has been suggested as a potential trigger for ARE. Some of its antigens can mimic molecules found in joints, leading to an autoimmune response involving synovial tissues. Studies have shown that the immune system of patients with REA can produce antibodies against E. coli bacterial proteins that share similar sequences with joint matrix proteins. Several studies have also suggested a role for Proteus mirabilis in the pathogenesis of REA. This bacterium can cause urinary tract infections and, through molecular mimicry, stimulate the production of autoantibodies against collagen found in joints. Proteus mirabilis has been particularly studied, as some peptides derived from it are similar to those present in human tissue, contributing to a possible autoimmune trigger.
Common pathogenetic mechanisms
Several pathogenetic mechanisms could explain the correlation between bacterial or fungal infections and the development or progression of REA. Both intestinal and urinary infections can trigger chronic inflammation (phlogosis), which is a key feature of REA. Sustained inflammation can exacerbate joint destruction and worsen disease symptoms. The intestinal and urinary microbiota play critical roles in regulating the immune system. Infections that modify the composition of the microbiome can disturb the immune balance, leading to aberrant autoimmune responses. These, in turn, can stimulate the production of autoantibodies, such as rheumatoid factor and anti-CCP antibodies, which are key markers in REA.
Epidemiological and clinical evidence
Numerous studies have highlighted a possible correlation between intestinal and urinary tract infections and rheumatoid arthritis. A study published in Cell Host & Microbe demonstrated that the intestinal microbiota of patients with REA differs significantly from that of healthy people, with an increased prevalence of Prevotella copri in patients with early REA. Several epidemiological studies have suggested that recurrent urinary tract infections, particularly those caused by Escherichia coli, may be associated with an increased risk of developing REA. Other studies have indicated that chronic fungal infections, particularly those caused by Candida albicans, may increase the risk of developing REA, mainly through influencing the intestinal microbiome and intestinal permeability.
Summary
Intestinal and urinary tract infections, caused by bacteria or fungi, may contribute to the onset and progression of rheumatoid arthritis through complex mechanisms, including intestinal mucosal permeabilization, induction of chronic inflammation, alteration of the microbiome, and stimulation of the autoimmune response. The interaction between infections, microbiota, and the immune system is one of the emerging areas of research in rheumatoid arthritis, and understanding these mechanisms could open new avenues for the prevention and treatment of this disease.
- edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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