Background Ghrelin levels and obestatin/ghrelin ratio have been proposed as activity markers in ulcerative colitis, but no data are available in celiac disease (CD) and irritable bowel syndrome (IBS). Our aims were as follows: (a) to assess obestatin and ghrelin concentrations in adult active CD patients, diarrhea-predominant IBS (IBS-d), and healthy controls (HC) in relation to intestinal permeability; (b) to evaluate the ghrelin-obestatin profile in CD patients after a 1-year gluten-free diet (GFD); and (c) to establish the impact of ghrelin genetics. Methods The study included 31 CD patients, 28 IBS-d patients, and 19 HC. Intestinal permeability, assayed by high-performance liquid chromatography determination of urinary lactulose (La)/mannitol (Ma), and circulating concentrations of obestatin, ghrelin, and their ratio were evaluated at enrollment and after GFD. The ghrelin single nucleotide polymorphisms Arg51Gln (rs34911341), Leu72Met (rs696217), and Gln90Leu (rs4684677) were analyzed. Results Intestinal permeability was impaired in CD patients and ameliorated after GFD. Ghrelin was significantly (P = 0.048) higher and the obestatin/ghrelin ratio was significantly (P = 0.034) lower in CD patients compared with both IBS-d and HC, and GFD reduced the peptide levels, but without reaching the concentrations in HC. Significant differences (P < 0.05) were found in the Leu72Met polymorphism among groups, with the reduction of the GT genotype and the T allele in both CD and IBS-d patients compared with HC. Conclusion Intestinal permeability is altered in CD, but not in IBS-d patients, and ghrelin levels increase in CD patients as observed in other inflammatory conditions. Moreover, a role for ghrelin genetics is hypothesized in sustaining the many pathogenetic components of these different pathologies, but with a similar symptom profile. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.