Development of the gastrointestinal tract in young mammals Effects of enteral provocation with protease or phytohaemagglutinin in neonatal rats

The rat, as an altritial species, is born with an immature gastrointestinal tract and intestinal barrier function, which is highly absorptive to milk-borne bioactive molecules that can pass undigested and reach the general circulation of the suckling newborn. This passage occurs by the neonatal-Fc-receptor (FcRn) binding and trancytosis of immunoglobulin G in the proximal small intestine (SI) and by the highly endocytic vacuolated enterocytes non-selectively in the distal SI. Postnatal gut maturation accelerates at weaning, around postnatal day 21, coincident with the dietary transition from milk to solid food. Maturation of the gut can also be precociously induced by provocation with a lectin, phytohaemagglutinin (PHA), mimicking the naturally occurring changes in gut structure and function. The changes occurring during natural or induced gut maturation include stimulation of pancreatic function and cessation of the SI absorptive capacity to macromolecules (gut closure). Intestinal epithelial maturation has been related to the gut immune system and is suggested to depend on T-lymphocytes activation. Recently, the transcription factor B-lymphocyte-induced maturation-protein-1 (Blimp-1) has been proposed to be a key regulator of intestinal maturation in mice. Hence, the present study investigated the events occurring during gut development and the cues initiating the process. The study especially focused on changes in the barrier function and macromolecular permeability, pancreatic function, and the relation to gut immune factors. A novel animal model of pancreatic and pancreatic-like protease-induced precocious gut maturation was established in neonatal rats, and was used in comparison to the existing PHA-induced model, as well as natural gut development. The gut maturational changes observed during natural or induced maturation, by both protease or PHA, included the transition of foetalto adulttype SI epithelium, with reduced FcRn expression in the proximal part and disappearance of vacuolated enterocytes in the distal part, associated with a similar change in intestinal epithelial Blimp1 expression. The early effects after exposure to the provocative agents, PHA and protease, revealed that both agents hampered macromolecular permeability and only protease also caused an increase in epithelial leakiness of the distal SI. These results indicated that protease and PHA affected the intestinal barrier function differently. Furthermore, the provocative agents were also tested in neonatal athymic nude rats, T-cell immunodeficient, and they appeared to be susceptible to induced precocious gut maturation. These results suggested that gut maturation is independent of thymus-derived T-celsl, but the involvement of other immune cells types, possibly innate immune cells, should be further investigated. Thus, the findings of the present thesis will contribute to an increased understanding of initiating cues and the mechanisms of maturation of the intestinal barrier in young mammals. The knowledge obtained could be applied to improve strategies for the treatment of gut-related complications, often affecting premature infants.