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- Arevalo Sureda, Ester
(författare)
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Development of the gastrointestinal tract in young mammals : Effects of enteral provocation with protease or phytohaemagglutinin in neonatal rats
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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 foetal- to adult- type 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.
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| 2. |
- Arévalo Sureda, Ester, et al.
(författare)
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Early effects on the intestinal barrier and pancreatic function after enteral stimulation with protease or kidney bean lectin in neonatal rats
- 2018
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Ingår i: British Journal of Nutrition. - 1475-2662. ; 119:9, s. 992-1002
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 3. |
- Arévalo Sureda, Ester, et al.
(författare)
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Maturation of the intestinal epithelial barrier in neonatal rats coincides with decreased FcRn expression, replacement of vacuolated enterocytes and changed Blimp-1 expression
- 2016
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:10
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 4. |
- Goncharova, Kateryna, et al.
(författare)
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Importance of neonatal immunoglobulin transfer for hippocampal development and behaviour in the newborn pig
- 2017
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 12:6
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Tidskriftsartikel (refereegranskat)abstract
- Neurological disorders are among the main clinical problems affecting preterm children and often result in the development of communication and learning disabilities later in life. Several factors are of importance for brain development, however the role of immunoglobulins (passive immunity transfer) has not yet been investigated. Piglets are born agammaglobulinemic, as a result of the lack of transfer of maternal immunoglobulins in utero, thus, they serve as an ideal model to mimic the condition of immunoglobulin deficiency in preterm infants. Thirty six, unsuckled newborn piglets were fed an infant formula or colostrum and supplemented orally or intravenously with either species-specific or foreign immunoglobulin and then compared to both newborn and sow-reared piglets. Two days after the piglets were born behavioural tests (novel recognition and olfactory discrimination of conspecifics scent) were performed, after which the piglets were sacrificed and blood, cerebrospinal fluid and hippocampi samples were collected for analyses. Both parameters of neuronal plasticity (neuronal maturation and synapse-associated proteins) and behavioural test parameters appeared to be improved by the appearance of species-specific porcine immunoglulin in the circulation and cerebrospinal fluid of the piglets. In conclusion, we postulate possible positive clinical effects following intravenous infusion of human immunoglobulin in terms of neuronal plasticity and cognitive function in preterm infants born with low blood immunoglobulin levels.
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| 5. |
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| 6. |
- Marungruang, Nittaya, et al.
(författare)
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Impact of dietary induced precocious gut maturation on cecal microbiota and its relation to the blood-brain barrier during the postnatal period in rats
- 2018
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Ingår i: Neurogastroenterology and Motility. - : Wiley. - 1350-1925. ; 30:6
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Tidskriftsartikel (refereegranskat)abstract
- Background Precocious maturation of the gastrointestinal barrier (GIB) in newborn mammals can be induced by dietary provocation, but how this affects the gut microbiota and the gut‐brain axis remains unknown. The objective of this study was to investigate effects of induced GIB maturation on gut microbiota composition and blood‐brain barrier (BBB) permeability. Methods Suckling rats were studied at 72 h after gavage with phytohemagglutinin (PHA) or microbial protease (PT) to induce maturation of GIB. For comparison, untreated suckling and weaned rats were included (n = 10). Human serum albumin (HSA) was administered orally and analyzed in blood to assess permeability of the GIB, while intraperitoneally injected bovine serum albumin (BSA) was measured in the brain tissue for BBB permeability. The cecal microbial composition, plasma lipopolysaccharide‐binding protein (LBP) levels and short‐chain fatty acids in serum and brain were analyzed. Key Results Cessation of HSA passage to blood after PHA or PT treatment was similar to that seen in weaned rats. Interestingly, concomitant increases in cecal Bacteroidetes and plasma LBP levels were observed after both PHA and PT treatments. The BBB passage of BSA was surprisingly elevated after weaning, coinciding with lower plasma LBP levels and specific microbial taxa and increased acetate uptake into the brain. Conclusions & Inferences This study provides evidence that the gut microbiota alteration following induced precocious GIB maturation may induce low‐grade systemic inflammation and alter SCFAs utilization in the brain which may also play a potential role in GIB‐BBB dysfunction disorders in neonates.
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| 7. |
- Prykhodko, Olena, et al.
(författare)
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Pancreatic and pancreatic-like microbial proteases accelerate gut maturation in neonatal rats.
- 2015
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:2
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Tidskriftsartikel (refereegranskat)abstract
- Postnatal gut maturation in neonatal mammals, either at natural weaning or after precocious inducement, is coinciding with enhanced enzymes production by exocrine pancreas. Since the involvement of enzymes in gut functional maturation was overlooked, the present study aimed to investigate the role of enzymes in gut functional maturation using neonatal rats.
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| 8. |
- Sureda, Ester Arévalo, et al.
(författare)
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Induction of precocious intestinal maturation in T-cell deficient athymic neonatal rats
- 2017
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Ingår i: World Journal of Gastroenterology. - : Baishideng Publishing Group Inc.. - 1007-9327. ; 23:42, s. 7531-7540
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 9. |
- Weström, Björn, et al.
(författare)
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The Immature Gut Barrier and Its Importance in Establishing Immunity in Newborn Mammals
- 2020
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 11
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Forskningsöversikt (refereegranskat)abstract
- 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.
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