Promoting intestinal healing by exclusive enteral nutrition with TGF-β in a mouse model of colitis

ABSTRACT Background and aims Exclusive Enteral Nutrition (EEN) is the first line of treatment for pediatric Crohn’s disease (CD), but its mechanisms of action remain poorly understood. We studied EEN nutritional composition and TGF-β effect in a mouse model of colitis, as well as the role of intestinal microbiota. Methods Mice were treated with Dextran Sulfate Sodium (DSS) during 5 days to induce colitis, until the inflammatory peak (day 7) or gut restitution (day 14). After DSS treatment, some of them received EEN formula such as Modulen IBD® (DM mice) or Infatrini Peptisorb® (DINF mice), with TGF-β supplementation or neutralization, and clinical inflammation was evaluated. After sacrifice, macroscopic and microscopic inflammation were analyzed, as well as intestinal permeability (IP). The composition of mucosal colonic microbiota was analyzed and fecal microbiota transplantation was performed to evaluate its capacity to mediate anti-inflammatory and pro-regenerative effect. Colonic crypts from DSS and EEN mice were cultured as 3D organoids and cellular properties were analyzed. Results DSS mice developed colitis, as evidenced by the weight loss and clinical inflammation. It was accompanied by macroscopic inflammation such as colon thickness and edemas, and an elevated IP. In contrast, EEN mice with TGF-β formula present faster weight recovery and decreased inflammatory parameters, with a normalized IP, suggesting gut restitution and functionality. These functional improvements were not obtained for EEN mice without TGF-β formula. Moreover, EEN with Modulen IBD® (DM mice) modified the microbiota in comparison to DSS condition and attenuated inflammation. In addition, the organoids from DM mice colonic crypts treated had an enhanced survival, and re-epithelialization capacity. Conclusions Both EEN formula have anti-inflammatory properties, certainly by the nutritional composition. However, TGF-β plays a significant role in intestinal restitution and restoring barrier function. These beneficial effects are partly mediated by the microbiota to maintain gut homeostasis.