Contribution of intestinal mucosa to the disease mechanisms of Spondyloarthritis: Unlocking new insights through bioengineered tissue models

Spondyloarthritis (SpA) represents a spectrum of chronic inflammatory rheumatic disorders with similar articular and extra-articular features and a complex pathogenesis stemming from the interplay between genetics, environmental triggers, and immune system dysregulation. The significant prevalence of SpA and its onset in the working age population place a considerable burden on healthcare systems. Furthermore, many patients fail to achieve optimal treatment outcomes and present physical and psychological distress, underscoring the need for improved therapeutic approaches. The emerging concept of the gut-joint axis suggests that disturbances at the intestinal mucosal interface and microbiota level may initiate or amplify inflammatory responses, contributing to the clinical expression of SpA. Unfortunately, traditional pre-clinical in vitro and animal models have intrinsic limitations in replicating the intricate human intestinal mucosa anatomo-functional network, thus constraining translational research. Bioengineered tissue models (BTMs), including organoids, organs-on-a-chip (OoCs), and co-culture systems integrating human-derived cells, offer novel platforms that better mimic human tissue architecture and physiological responses. These advanced models hold promise in elucidating multifactorial disease mechanisms and expediting drug development, potentially facilitating personalized and more effective therapies. This article presents a narrative review of current knowledge about perturbations at the level of human intestinal mucosa during SpA and aims to critically synthesize the conceptual and experimental advances in the emerging field of BTMs to support future translational research in this field. • Gut mucosal and microbiota alterations in spondyloarthritis (SpA) may drive immune dysfunction along the gut-joint axis. • Patient-derived organoids and organs-on-a-chip recapitulate mucosal architecture and microbe–epithelium–immune crosstalk. • Bioengineered tissue models may enable SpA biobanking, flow-integrated modeling, target validation, and drug screening. • Ultimately, an integrated SpA-on-a-chip could stratify patients, predict ex vivo response, and match mechanisms to therapy.