Divergent intestinal barrier and neuroimmune responses to supervised exercise across fibromyalgia, irritable bowel syndrome, and their comorbidity phenotypes: a prospective interventional study.

BACKGROUND: Fibromyalgia (FM) and irritable bowel syndrome (IBS) are overlapping functional somatic syndromes characterized by gut-brain axis dysregulation and low-grade systemic inflammation. We investigated whether a 16-week supervised combined exercise program is associated with phenotype-specific biomarker changes in patients with FM, IBS, or their comorbidity (FM+IBS). METHODS: In this prospective, single-center, pre-post interventional study, 55 patients (FM, n=15; FM+IBS, n=21; IBS, n=19) completed a 16-week supervised program of aerobic, resistance, and flexibility training three times weekly. Pre- and post-intervention assessments included a panel of intestinal barrier, neuroimmune, and inflammatory biomarkers, together with the Global Physical Capacity Score (GPCS). RESULTS: In the FM+IBS group, exercise was associated with significant reductions in urinary lactulose excretion (mean delta: -0.160%, p=0.001), L/M ratio (mean delta: -0.011, p=0.026), serum zonulin (mean delta: -6.2 ng/mL, p=0.016), fecal zonulin (mean delta: -65.9 ng/mL, p=0.007), and urinary indoxyl sulfate (mean delta: -23.6 mg/L, p=0.046), with post-intervention L/M values falling below the 0.030 pathological threshold. In the IBS group, serum 5-HT increased (mean delta: +30.0 ng/mL, p=0.028) and IBS-SSS decreased by 85.8 points (p<0.001), exceeding the minimally important difference; both findings were confirmed in a sensitivity analysis restricted to 14 female patients (5-HT: p=0.033; IBS-SSS: p=0.004). In the FM group, IL-6 increased (mean delta: +0.37 pg/mL, p=0.013) and GPCS improved (p=0.047). BDNF, I-FABP, DAO, and LPS remained unchanged across all groups. CONCLUSIONS: Sixteen weeks of combined exercise were associated with phenotype-specific biological patterns. FM+IBS patients showed reductions in barrier-related markers, supported by two independent assays (L/M ratio and indoxyl sulfate), while IBS patients exhibited enhanced serotonergic signaling and symptom relief, both robust to sex-stratified sensitivity analysis. The isolated IL-6 increase in FM patients requires caution, since an acute myokine effect and a chronic inflammatory drift are both compatible with a single measurement taken 16 weeks apart. These exploratory findings, constrained by this proof-of-concept design, support phenotype-stratified randomized controlled trials with active comparators to validate and characterize these differential responses.