A healthy intestinal permeability facilitates the selective transport of nutrients, metabolites, water, and bacterial products, involving cellular, neural, hormonal, and immune factors. An altered intestinal permeability indicates pathologic phenotypes and is associated with the exacerbation of obesity and related comorbidities. To investigate the impact of altered permeability in obese patients undergoing a calorie-restrictive dietary regimen (VLCKD), we collected urinary and fecal samples from obese patients with both normal and altered permeability (determined based on the lactulose/mannitol ratio) before and after treatment. The analysis of volatile organic compounds (VOCs) aids in understanding the metabolites produced by the intestinal microbiota in this unique ecological niche. Furthermore, we examined clinical and anthropometric variables from the cohort and compared them to significant VOC panels. Consequently, we identified specific markers in the metabolomics data that differentiated between normal and altered profiles before and after the diet. These markers indicated how the variable contribution specifically accounted for interleukins and lipopolysaccharides (LPS). The targeted metabolomics experiment detected no differences in measured short-chain fatty acids (SCFA). In summary, our study evaluated metabolomic markers capable of distinguishing low-grade inflammation conditions, exacerbated in more advanced stages of obesity with altered intestinal permeability.