Host-Microbiome Synergistic Control on Sphingolipid Metabolism by Mechanotransduction in Model Arthritis

Chronic inflammatory autoimmune disorders are systemic diseases with increasing incidence and still lack a cure. More recently, attention has been placed in understanding gastrointestinal (GI) dysbiosis and, although important progress has been made in this area, it is currently unclear to what extent microbiome manipulation can be used in the treatment of autoimmune disorders. Via the use of appropriate models, rheumatoid arthritis (RA), a well-known exemplar of such pathologies, can be exploited to shed light on the currently overlooked effects of existing therapies on the GI microbiome. In this direction, we here explore the crosstalk between the GI microbiome and the host immunity in model arthritis (collagen induced arthritis, CIA). By exploiting from samples of limited invasiveness (blood and stools), we assess the host-microbiome responses to standard therapy (methotrexate, MTX) combined with mechanical subcutaneous stimulation (MS) and to mechanical stimulation alone. When MS is involved, results reveal the sphingolipid metabolism as the trait d'union among known hallmarks of (model) RA, namely: Imbalance in the S1P-S1PR1 axis, expansion of , and invariant Natural Killer T (iNKT)-penia, thus offering the base of a rationale to mechanically modulate this pathway as a therapeutic target in RA.