Inconsistent effects of gluten on obesity: is there a role for the haptoglobin isoforms?

Summary Background and aims There is no clear evidence about the effects of gluten intake on obesity. It is known that gluten's effects on gut permeability are mediated by zonulin, a protein identified as pre-haptoglobin 2, a physiological regulator of the intestinal barrier. We investigated the obesogenic and inflammatory effects of gluten and its association with the haptoglobin genotype. Methods This was a single blinded, crossover study, including 40 overweight or obesity women free of celiac disease. Participants adopted a gluten-free diet (GFD) for 8 weeks and consumed a gluten-free muffin (GF-M) or a gluten-containing muffin (GLU-M, 24 g gluten) for 4 weeks, switching muffin type during the subsequent 4 weeks. During a follow-up period of 4 weeks we evaluated the usual diet (UD). Food diaries were collected to estimate the macronutrient intake and dietary inflammatory index (DII®). Bodyweight and composition, resting energy expenditure (REE), and cytokines were assessed. Haptoglobin alleles (Hp1 and Hp2) were genotyped to characterize zonulin expression. Results Energy and macronutrient intakes were similar during both periods, except for protein intake, which was higher during GLU-M. DII scores indicated a more inflammatory profile during the GF-M and GLU-M periods compared to UD. No differences were observed in body composition or REE between interventions when the Hp genotype was not considered. Nonetheless, those carrying the Hp2-2 genotype (overexpressing zonulin) presented lower REE and higher levels of IL6 and IL1beta only during gluten intake (GLU-M and UD) compared to age- and body mass index-matched Hp1-1 carrier. These results suggest an obesogenic and inflammatory action of gluten only in those overexpressing zonulin (Hp2-2). Conclusion These results highlight the importance of zonulin as the mediator of gluten obesogenic and inflammatory effects. Our data suggest that in the presence of gluten, zonulin release is associated with a reduction of REE and an increase of inflammatory markers that are not seen in zonulin low producers.