Mas, E. | Search bioRxiv

bioRxiv2023

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

Background and aimsExclusive Enteral Nutrition (EEN) is the first line of treatment for pediatric Crohns disease (CD), but its mechanisms of action remain poorly understood. We studied EEN nutritional composition and TGF-{beta} effect in a mouse model of colitis, as well as the role of intestinal microbiota. MethodsMice 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(R) (DM mice) or Infatrini Peptisorb(R) (DINF mice), with TGF-{beta} 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. ResultsDSS 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-{beta} 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-{beta} formula. Moreover, EEN with Modulen IBD(R) (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. ConclusionsBoth EEN formula have anti-inflammatory properties, certainly by the nutritional composition. However, TGF-{beta} plays a significant role in intestinal restitution and restoring barrier function. These beneficial effects are partly mediated by the microbiota to maintain gut homeostasis.

physiology↗

bioRxiv2023

Deciphering the interplay between biology and physics: finite element method-implemented vertex organoid model raises the challenge

Understanding the intertwining of biology and mechanics in tissue architecture is a challenging issue, especially when it comes to the 3D tissue organization. Addressing this challenge requires both a biological model allowing multiscale observations from the cell to the tissue, and theoretical and computational approaches allowing the generation of a synthetic model, relevant to the biological model, and allowing access to the mechanical constraints experienced by the tissue. Here, using human colon epithelium monolayer organoid as biological model, and combining vertex and FEM approaches, we generated a comprehensive elastic finite element model of the human colon organoid and demonstrated its flexibility. This FEM model provides a basis for relating cell shape, tissue deformation, and strain at the cellular level due to imposed stresses. In conclusion, we demonstrated that the combination of vertex and FEM approaches allows for better modeling of the alteration of organoid morphology over time and better assessment of the mechanical cues involved in establishing the architecture of the human colon epithelium.

biophysics↗