Neuroimmunomodulation induced by mud-bath therapy: clinical benefits and bioregulation of the innate/inflammatory responses induced by a peloid enriched with rosmarinic acid in elderly patients with osteoarthritis.

Balneotherapy using peloids (mud-bath therapy) is one of the most effective non-pharmacological approaches for managing osteoarticular and musculoskeletal disorders, such as osteoarthritis (OA). Recent studies have shown that peloids enriched with rosmarinic acid (RosA) enhance the therapeutic effects of mud therapy in elderly OA patients. The objective of this study was to evaluate whether the normalization of the interaction between the hormetic stress response, mediated by cortisol, and the inflammatory response, mediated by IL-8 (measured in blood by ELISA), underlies the clinical benefits of a hyperthermic mud-bath intervention using a RosA-enriched peloid, a polyphenolic acid with anti-inflammatory and immunomodulatory properties. Additionally, we aimed to investigate whether this neuroimmune regulation contributes to enhancing the innate immune response, specifically the phagocytic and microbicidal activity of neutrophils (assessed by flow cytometry). Twenty-three elderly OA patients participated in the mud-bath intervention, a 10-day cycle of hyperthermic balneotherapy using a RosA-fortified peloid and mineral medicinal water at 40 °C. Significant increases in systemic cortisol levels, along with a notable decrease in IL-8 and enhanced phagocytic and microbicidal activity of neutrophils, were observed following the intervention. These effects were accompanied by improved knee mobility and reduced pain. In conclusion, hyperthermic mud-bath therapy with a RosA-enriched peloid induces immunoneuroendocrine stabilization, which underlies the clinical benefits of the balneological intervention. Finally, concepts such as neuroimmunomodulation, hormesis, and the bioregulation of the innate and inflammatory immune responses in the context of balneotherapy are also discussed.