Probiotic-derived extracellular vesicles: the next breakthrough in postbiotics for rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by systemic inflammation and joint damage. Emerging evidence highlights the role of gut and oral microbiota in RA pathogenesis, with microbial dysbiosis potentially exacerbating inflammation and immune dysregulation. Although probiotics have shown potential in modulating the oral and gut microbiota and improving RA symptoms, a promising cell-free substitute is provided by postbiotics, including probiotic-derived extracellular vesicles (EVs). These bioactive nanoparticles transport functional metabolites capable of modulating immune responses, reducing inflammation, and restoring gut barrier integrity. Probiotic-derived EVs are, for instance, able to promote M2 macrophage polarization and suppress pro-inflammatory cytokines, thus highlighting their therapeutic potential. Nonetheless, challenges remain in standardizing EVs production, optimizing administration routes, and ensuring clinical safety. The targeting and effectiveness of probiotic EVs may be improved by developments in omics sciences and biotechnology techniques, making them the next breakthrough in postbiotics for the treatment of RA. This review examines how probiotic-derived EVs interact with the host, focusing on their crosstalk with immune cells and subsequent immune modulation. We highlight their potential for RA treatment, discuss clinical challenges, and explore their use in personalized medicine.

Keywords: arthritis; dysbiosis; extracellular vesicles; immunomodulation; inflammation; oral-gut-joint axis; probiotics; therapeutic strategies.

Figure 1

Schematic representation of the systemic and local effects of bacteria-derived EVs in RA and healthy joints. In RA, dysbiotic oral and gut microbiota release EVs that can induce systemic immune dysregulation and promote local joint inflammation, thereby exacerbating disease severity and progression. Conversely, probiotic-derived EVs exert protective effects by reducing pro-inflammatory cytokine production, inhibiting osteoclast activation, and restoring intestinal barrier integrity.

Figure 2

Overview of the probiotic-derived EVs interactions with the host mucosa, with the immune system and distant organs. Probiotic-derived EVs interact with the intestinal epithelium and Peyer’s patches, modulating the local immune response and the intestinal barrier integrity. Upon entering circulation, these EVs can also reach distant organs such as inflamed RA joints.

Figure 3

Mechanisms of EVs release in Gram+ and Gram- bacteria. Gram+ bacteria mainly release EVs through active budding of the cytoplasmic membrane. On the other hand, Gram- bacteria can produce EVs via membrane blebbing or through explosive cell lysis, which releases vesicles that contain components from the inner and/or outer membrane.

Figure 4

Immunomodulatory effects of probiotic-derived EVs in RA. Probiotic-derived EVs may suppress pro-inflammatory M1 macrophages and osteoclast activity, while promoting a shift toward anti-inflammatory M2 macrophages and enhancing T cell responses. Both M2 macrophages and T cells contribute to increased IL-10 secretion, collectively supporting inflammation resolution and bone protection in RA.

Figure 5

Key factors affecting the clinical translation of probiotic-derived EVs. Standardization, mechanistic insight, and scalability remain major production challenges. Clinical translation is limited by safety concerns, delivery strategies, and lack of studies in RA. Advances in multi-omics, EV engineering, targeted delivery, and organ-on-chip platforms offer promising solutions.

Figure 6

Experimental models to investigate the effects of probiotic-derived EVs in RA. A spectrum of experimental systems is available to model RA pathogenesis, differing in complexity and physiological relevance. These range from 2D and 3D cultures of human synovial fibroblasts to clinical trials involving RA patients, with an incremental increase in physiological fidelity. Animal models provide high biological complexity and disease relevance but are limited by interspecies genetic differences. An advanced joint-on-chip model, incorporating multiple human cell types, including synovial fibroblasts, chondrocytes, and osteoblasts, within a 3D microfluidic platform, would offer a controlled, human-relevant system to evaluate the therapeutic potential of probiotic-derived EVs.