Age-Dependent Intestinal Repair: Implications for Foals with Severe Colic

Colic is a leading cause of death in horses, with the most fatal form being strangulating obstruction which directly damages the intestinal barrier. Following surgical intervention, it is imperative that the intestinal barrier rapidly repairs to prevent translocation of gut bacteria and their products and ensure survival of the patient. Age-related disparities in survival have been noted in many species, including horses, humans, and pigs, with younger patients suffering poorer clinical outcomes. Maintenance and repair of the intestinal barrier is regulated by a complex mucosal microenvironment, of which the ENS, and particularly a developing network of subepithelial enteric glial cells, may be of particular importance in neonates with colic. Postnatal development of an immature enteric glial cell network is thought to be driven by the microbial colonization of the gut and therefore modulated by diet-influenced changes in bacterial populations early in life. Here, we review the current understanding of the roles of the gut microbiome, nutrition, stress, and the ENS in maturation of intestinal repair mechanisms after foaling and how this may influence age-dependent outcomes in equine colic cases.

Bacillus Subtilis Expressing Epidermal Growth Factors Induces Intestinal Repair and Growth-Promoting in Mice

Background: Probiotics are widely acknowledged for their pro-health attributes, but the efficacy of traditional probiotics is quite limited. This limitation can be overcome using a gene engineered to enhance the efficacy of existing probiotics. In this study, a strain of Bacillus subtilis (WB800) expressing the eukaryotic protein porcine epidermal growth factor (pEGF) was generated via genetic modification, and mice with intestinal injury were used as a model to evaluate the potential of this bioengineered probiotic in preventing or treating intestinal damage. Integration of the pEGF gene into the B. subtilis WB800 genome using an integrated expression vector pDG1730 resulted in stable expression of pEGF in B. subtilis (dubbed WB-EGF). Results: Female the Institute for Cancer Research (ICR) mice with intestinal damage received recombinant WB-EGF (1×108 –8×108 CFU/mL) for 10 d before collection of blood and intestinal tissues. Mice receiving WB-EGF had significantly higher body weight and longer intestinal villi than those of mice treated with Luria-Bertani (LB) broth or B. subtilis transformed with an empty vector. Cell proliferation assays confirmed enhanced intestinal cell proliferation in mice receiving WB-EGF. Conclusions: This study provides evidence that WB-EGF may have use as a novel therapy for early prevention or treatment of intestinal damage and for promoting intestinal development. The recombinant B. subtilis strain developed here can expected to provide protection when used as a feed additive in animals with gastrointestinal infections.

Organoid-based modeling of intestinal development, regeneration, and repair

The intestinal epithelium harbors a remarkable adaptability to undergo injury-induced repair. A key part of the regenerative response is the transient reprogramming of epithelial cells into a fetal-like state, which drives uniform proliferation, tissue remodeling, and subsequent restoration of the homeostatic state. In this review, we discuss how Wnt and YAP signaling pathways control the intestinal repair response and the transitioning of cell states, in comparison with the process of intestinal development. Furthermore, we highlight how organoid-based applications have contributed to the characterization of the mechanistic principles and key players that guide these developmental and regenerative events.

Activation of mTORC1 by LSECtin in macrophages directs intestinal repair in inflammatory bowel disease

Damage to intestinal epithelial cells and the induction of cellular apoptosis are characteristics of inflammatory bowel disease. The C-type lectin receptor family member LSECtin promotes apoptotic cell clearance by macrophages and induces the production of anti-inflammatory/tissue growth factors, which direct intestinal repair in experimental colitis. However, the mechanisms by which the phagocytosis of apoptotic cells triggers the pro-repair function of macrophages remain largely undefined. Here, using immunoprecipitation in combination with mass spectrometry to identify LSECtin-interacting proteins, we found that LSECtin interacted with mTOR, exhibiting a role in activating mTORC1. Mechanistically, apoptotic cells enhance the interaction between LSECtin and mTOR, and increase the activation of mTORC1 induced by LSECtin in macrophages. Elevated mTORC1 signaling triggers macrophages to produce anti-inflammatory/tissue growth factors that contribute to the proliferation of epithelial cells and promote the reestablishment of tissue homeostasis. Collectively, our findings suggest that LSECtin-dependent apoptotic cell clearance by macrophages activates mTORC1, and thus contributes to intestinal regeneration and the remission of colitis.