Exploration of the relationship between diet and inflammatory mediators in chronic pain syndroms

Introduction: Chronic pain represents a significant clinical challenge, impacting daily functioning and overall quality of life. Several studies have demonstrated the relationship between diet and chronic pain disorders, but it is still unclear how nutrition influences chronic pain. The body recognizes foods through immunoglobulin G (IgG) mapping which contributes to the creation of a personal food profile. High levels of IgG4 activate inflammatory processes. Moreover, gut inflammation amplifies the transcription of proinflammatory factors, increases intestinal permeability and influences various metabolic pathways, such as tryptophan metabolism (in particular the serotonin and kynurenine pathways). Exosomes, biological microvesicles, are produced by the gut and they carry signaling molecules, contributing to regulatory processes. Methods: In the human part, in two different steps, two groups of subjects suffering nononcological chronic pain were recruited and several questionnaires about their health, especially concerning pain, gastrointestinal conditions and psychological state, were administered. IgG4 were determined in the first step. The Dietary Inflammatory Index (DII) and tryptophan metabolites were analyzed in the second step. All subjects were asked to follow a diet for 4 weeks (IgG4 antibody-guided exclusion diet, first step, or antiinflammatory diet, second step). In the in vitro part, a gut barrier inflammation model was set up utilizing Caco-2 cells with lipopolysaccharides (LPS) and/or serotonin. Proinflammatory cytokines (IL-1³ and IL-6) were measured in cell supernatants. Exosomes were isolated from Caco-2 cell supernatants; they were characterized and their incorporation into nervous system cells was evaluated. Results: 54 subjects (43 women and 11 men) were included in the first step of the study and 38 women were included the second step. In the first step, at visit 1, most subjects showed medium/high levels of IgG4 to at least one food. In the second step, all subjects had inflammatory DII values. Pain conditions and quality of life parameters were improved in the chronic pain sufferers with both nutritional approaches. In the second step, the chronic pain intensity was correlated with the subjects9 gastrointestinal functions and there was a significant correlation between VAS intensity and some urinary tryptophan metabolites (quinolinic acid, QA, and 5-hydroxyindole acetic acid, 5-HIAA). 6 Caco-2 cells treated with LPS for 24 hours released pro-inflammatory cytokines (IL-1³ and IL-6). Exosomes released by Caco-2 cells were on the order of 1010 particles/mL, with a size of approximately 100 nm or slightly larger, and they were positive for the markers CD-9, CD-81, and TSG-101. Exosomes released by Caco-2 cells were incorporated into central nervous system cells (neurons and astrocytes) at 6 hours. Conclusions: Pain conditions and other quality of life parameters were improved in the chronic pain sufferers merely from a change in food consumption. Moreover, the communication between nutrition/gut and brain seems to be supported by microvesicles called exosomes.