Beneficial Effects of Long-Lasting Bicarbonate–Sulfate–Calcium–Magnesium Water Intake on Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)-Related Outcomes via Impacting Intestinal Permeability (IP), IP-Related Systemic Inflammation, a

<b>Background/Objectives</b>: Fonte Essenziale^®, a mineral water rich in bicarbonate, sulfate, calcium, and magnesium, has shown potential in modulating the gut-liver axis and microbiota in hepatic steatosis. However, its long-term effects on intestinal permeability (IP), systemic inflammation (SI), and oxidative stress-key factors in Metabolic dysfunction-associated steatotic liver disease (MASLD)-remain unexplored. <b>Methods</b>: Eighty-seven MASLD patients were randomized into two groups: group A received Fonte Essenziale^® (400 mL/day, fasting) plus a controlled nutritional regimen for 12 months, followed by a 6-month water washout; group B followed only the controlled nutritional regimen. IP markers, SI (IL-1β, IL-6, TNF-α), oxidative stress (dROMs/BAP), and clinical data (including Controlled Attenuation Parameter-CAP) were assessed at baseline (T0), 12 months (T12), and post-washout (T18). Baseline increased IP (in-IP) was defined by fecal zonulin > 110 ng/mL and serum LBPp > 10 µg/mL; improvement (im-IP) required normalization of both. A ≥30% CAP reduction indicated steatosis improvement. <b>Results</b>: Thirty-eight patients in group A and thirty-nine in group B completed the study. At T12, group A showed significant reductions in fecal zonulin (<i>p</i>: 0.0163) and serum LBPp (<i>p</i> < 0.0001), with increased occludin and claudin 1 (all <i>p</i> < 0.0001). Im-IP prevalence was higher in group A (<i>p</i>: 0.0037). Group A also showed significant reductions in IL-1β, TNF-α, IL-6, LPS, and dROM/BAP (all <i>p</i> < 0.05), especially among those with im-IP. CAP, insulin, and HDL levels improved significantly (all <i>p</i> < 0.0001). Multivariate analysis confirmed water intake (aOR: 2.185, <i>p</i>: 0.001) and im-IP achievement (aHR: 1.267, <i>p</i>: 0.021) as predictors of steatosis improvement. Benefits persisted at T18. <b>Conclusions</b>: Prolonged Fonte Essenziale^® intake improved hepatic steatosis and MASLD outcomes by modulating IP, SI, and oxidative stress. This trial has been registered on clinicaltrials.gov (NCT07211113).