The Immature Gut Barrier and Its Importance in Establishing Immunity in Newborn Mammals

The gut is an efficient barrier which protects against the passage of pathogenic microorganisms and potential harmful macromolecules into the body, in addition to its primary function of nutrient digestion and absorption. Contrary to the restricted macromolecular passage in adulthood, enhanced transfer takes place across the intestines during early life, due to the high endocytic capacity of the immature intestinal epithelial cells during the fetal and/or neonatal periods. The timing and extent of this enhanced endocytic capacity is dependent on animal species, with a prominent non-selective intestinal macromolecular transfer in newborn ungulates, e.g., pigs, during the first few days of life, and a selective transfer of mainly immunoglobulin G (IgG), mediated by the FcRn receptor, in suckling rodents, e.g., rats and mice. In primates, maternal IgG is transferred during fetal life via the placenta, and intestinal macromolecular transfer is largely restricted in human neonates. The period of intestinal macromolecular transmission provides passive immune protection through the transfer of IgG antibodies from an immune competent mother; and may even have extra-immune beneficial effects on organ maturation in the offspring. Moreover, intestinal transfer during the fetal/neonatal periods results in increased exposure to microbial and food antigens which are then presented to the underlying immune system, which is both naïve and immature. This likely stimulates the maturation of the immune system and shifts the response toward tolerance induction instead of activation or inflammation, as usually seen in adulthood. Ingestion of mother's milk and the dietary transition to complex food at weaning, as well as the transient changes in the gut microbiota during the neonatal period, are also involved in the resulting immune response. Any disturbances in timing and/or balance of these parallel processes, i.e., intestinal epithelial maturation, luminal microbial colonization and mucosal immune maturation due to, e.g., preterm birth, infection, antibiotic use or nutrient changes during the neonatal period, might affect the establishment of the immune system in the infant. This review will focus on how differing developmental processes in the intestinal epithelium affect the macromolecular passage in different species and the possible impact of such passage on the establishment of immunity during the critical perinatal period in young mammals

Behavioral and Cognitive Improvement Induced by Novel Imidazoline I2 Receptor Ligands in Female SAMP8 Mice

As populations increase their life expectancy, age-related neurodegenerative disorders such as Alzheimer's disease have become more common. I2-Imidazoline receptors (I2-IR) are widely distributed in the central nervous system, and dysregulation of I2-IR in patients with neurodegenerative diseases has been reported, suggesting their implication in cognitive impairment. This evidence indicates that high-affinity selective I2-IR ligands potentially contribute to the delay of neurodegeneration. In vivo studies in the female senescence accelerated mouse-prone 8 mice have shown that treatment with I2-IR ligands, MCR5 and MCR9, produce beneficial effects in behavior and cognition. Changes in molecular pathways implicated in oxidative stress, inflammation, synaptic plasticity, and apoptotic cell death were also studied. Furthermore, treatments with these I2-IR ligands diminished the amyloid precursor protein processing pathway and increased Aβ degrading enzymes in the hippocampus of SAMP8 mice. These results collectively demonstrate the neuroprotective role of these new I2-IR ligands in a mouse model of brain aging through specific pathways and suggest their potential as therapeutic agents in brain disorders and age-related neurodegenerative diseases. Keywords Imidazoline I2 receptors (2-imidazolin-4-yl)phosphonates Behavior Cognition Neurodegeneration Neuroprotection Agin

PROVIRON PPL20203_07

T1, T3, T5 histology scans jejunum PROVIRON samples 18/04/2023 Metadata file Excel include

Early effects on the intestinal barrier and pancreatic function after enteral stimulation with protease or kidney bean lectin in neonatal rats

Gut maturation naturally accelerates at weaning in altricial mammalian species, such as the rat. Mimicking this, gut development can also be induced precociously, 3–4 d earlier than it would occur naturally, by enteral exposure to phytohaemagglutinin (PHA), or various proteases. We investigated the early effects of gut provocation on intestinal barrier and pancreatic functions, to get a better understanding of the mechanisms that initiate gut maturation. The effects of oral administration of protease (trypsin) or PHA to 14-d-old suckling rats were studied during 24 h in comparison with water-fed controls. Intestinal in vivo permeability was assessed by oral administration of different-sized marker molecules and measuring their passage into the blood or urine 3 h later. A period of 24 h following oral administration, both PHA and protease provocation stimulated small intestinal (SI) growth and pancreatic secretion, as indicated by decreased pancreatic trypsin and increased luminal enzyme content. Within 1 h of oral administration, both treatments prevented the absorption of macromolecules to blood that was observed in controls. PHA treatment hindered the passage of fluorescein isothiocyanate-dextran (FD) 4 to blood, whereas protease treatment temporarily increased plasma levels of FD4, and the urine lactulose:mannitol ratio, indicating increased intestinal leakiness. Following protease treatment, fluorescence microscopy showed decreased vesicular uptake of FD70 in the proximal SI and increased epithelial fluorescence in the distal SI. In conclusion, PHA and protease differed in their early effects on the intestinal barrier; both exerted a blocking effect on epithelial endocytosis, whereas protease treatment alone temporarily increased epithelial leakiness, which seemed to be confined to the distal SI

Induction of precocious intestinal maturation in T-cell deficient athymic neonatal rats

Aim: To investigate whether gut maturation could be induced precociously in an athymic T-cell deficient neonatal rat model. Methods: Fourteen day-old athymic (nude) rats (NIH-Foxn 1rnu) were gavaged with either phytohaemagglutinin - a lectin from red kidney beans (PHA); trypsin - a protease (Prot); or water - vehicle (control) as a single dose on one day or once a day for 3-day. The nude rats were either nurtured by their mothers or cross-fostered by conventional foster dams of the Sprague-Dawley strain from days 3-5 after birth. At 17 d of age, 72 h after administration of the first treatment, intestinal macromolecular permeability was tested in vivo, prior to euthanasia, after which blood and gut organs were sampled. Results: Provocation with both, PHA and protease, resulted in increased gut growth and maturation in nude rat pups independent of nursing. Foetal-type enterocytes were replaced by non-vacuolated adult-type enterocytes in the distal small intestine epithelium. Decreased intestinal macromolecular permeability (gut closure) was observed, with reduced permeability markers (BIgG and BSA, P < 0.001) in circulation. Increased pancreatic function, with an increased trypsin to protein ratio in pancreas homogenates, was observed independent of nursing in the nude pups. Immunostaining showed the presence of a few CD3+-cells in the intestinal mucosa of the nude pups. The number of CD3+-cells remained unaltered by provocation and no differences were observed between the nursing sets. Growth and vitality of the nude pups were dependent on nurturing, since cross-fostering by conventional dams increased their macromolecular absorptive capacity (BSA, P < 0.05), as well as their passive immunity (RIgG, P < 0.05). Conclusion: Precocious gut maturation can be induced by enteral provocation in athymic rat pups, similarly to in euthymic pups, thus showing an independence from thymusderived T-cells

Maturation of the intestinal epithelial barrier in neonatal rats coincides with decreased FcRn expression, replacement of vacuolated enterocytes and changed Blimp-1 expression

Background: The intestinal barrier is immature in newborn mammals allowing for transfer of bioactive macromolecules, e.g. protecting antibodies, from mother's milk to the blood circulation and in neonatal rodents lasts until weaning. This passage involves the neonatal-Fc-receptor (FcRn) binding IgG in the proximal and highly endocytic vacuolated enterocytes in the distal immature small intestine (SI). Recent studies have suggested an involvement of the transcription factor B-lymphocyte-induced maturation-protein-1 (Blimp-1) in the regulation of SI maturation in mice. Hence, the objective of the present study was to monitor the development of the intestinal barrier function, in relation to Blimp-1 expression during both natural and precociously induced intestinal maturation in rats. Results: During the suckling period IgG plasma levels increased, while after gut closure it temporarily decreased. This corresponded to a high expression of FcRn in the proximal SI epithelium and the presence of vacuolated enterocytes in the distal SI. The immature foetal-type epithelium was replaced after weaning or induced precocious maturation, by an adult-type epithelium with FcRnneg cells in the proximal and by non-vacuolated enterocytes in the distal SI. In parallel to this epithelial shift, Blimp-1 expression decreased in the distal SI. Conclusion: The switch from foetal- to adult-type epithelium, with decreased proximal expression of FcRn and distal replacement of vacuolated enterocytes, was concurrent in the two SI regions and could be used for monitoring SI maturation in the rat. The changes in expression of Blimp-1 in the distal SI epithelium followed the maturation pattern

Interaction of CP levels in maternal and nursery diets, and its effect on performance, protein digestibility, and serum urea levels in piglets

Reduced protein levels in nursery diets have been associated with a lower risk of postweaning diarrhea, but the interaction with CP levels in maternal diet on the performance of the offspring remains unclear. The objective of this study was to determine the effect of protein content in sow gestation and piglet nursery diets on the performance of the piglets until slaughter. This was studied in a 2 × 2 factorial trial (35 sows, 209 piglets), with higher or lower (H or L) dietary CP in sow diets (168 vs 122 g CP/kg) during late gestation. A standard lactation feed was provided for all sows (160 g CP/kg). For both sow treatments, half of the litters received a higher or lower CP in the piglet nursery diet (210 vs 166 g CP/kg). This resulted in four possible treatment combinations: HH, HL, LH and LL, with sow treatment as first and piglet treatment as second letter. For each phase, all diets were iso-energetic and had a similar level of essential amino acids. Ps*p is the p-value for the interaction effect between sow and piglet treatment. In the nursery phase (3.5–9 weeks of age), a tendency toward interaction between piglet and sow treatments with feed efficiency (Ps*p = 0.08) was observed with HH having the highest gain:feed ratio (G:F) (0.74 ± 0.01), LH the lowest (0.70 ± 0.01) and the other two groups intermediate. In the growing-finishing phase, an interaction was observed between the piglet and sow diets with decreased G:F for LH (Ps*p = 0.04) and a tendency toward interaction with increased daily feed intake for LH (Ps*p = 0.07). The sow diet showed a tendency toward a long-lasting effect on the dressing percentage and meat thickness of the offspring, which was higher for the progeny of H sows (Ps < 0.01 and Ps = 0.02, respectively). At 23 weeks, serum urea concentrations tended to be lower for the HH and LL groups (Ps*p = 0.07). Fecal consistency scores were higher at day 10–day 14 after weaning for piglets from L sows (Ps = 0.03 and Ps < 0.01, respectively). At day 7 after weaning, fecal consistency score was higher for piglets fed the higher protein diet (Pp < 0.01). At 8 weeks of age, the apparent total tract digestibility of CP (ATTDCP) interacted between piglet and sow diet (Ps*p = 0.02), with HH showing the highest digestibility values. In conclusion, the protein levels in sow late-gestation and piglet nursery diets interacted with feed efficiency, ATTDCP and serum urea concentrations in the nursery phase

Correlation between the maturational appearance of adult-type epithelium in the proximal and the distal SI.

<p>Appearance of FcRn^neg cells in the proximal SI and non-vacuolated cells in the distal SI in 17 days old rats treated with PHA or protease for 3 days, to induce precocious gut maturation, compared to control rats.</p