© Borgis - Postępy Nauk Medycznych 5/2015, s. 347-350
Kateryna Goncharova1, 2, Marek Pieszka3, Rafal Filip4, *Stefan G. Pierzynowski1, 4
Oś zewnątrzwydzielnicza trzustka-mózg – badania na modelu świni domowej
Exocrine pancreas-brain axis – studies on pig models
1Department of Biology, Lund University, Sweden
Head of Department: prof. Christer Löfstedt, PhD
2Department of Cytology, Bogomoletz Institute of Physiology, Kiev, Ukraine
Head of Department: prof. Galyna Skibo, MD, PhD
3Department of Animal Nutrition and Feed Science, National Research Institute of Animal Production, Balice, Poland
Head of Department: prof. Franciszek Brzóska, PhD
4Institute of Rural Medicine, Lublin, Poland
Head of Department: prof. Iwona Bojar, MD, PhD
Badania biomedyczne dowiodły, że zarówno przyzwyczajenia dietetyczne, styl życia (włączając w to skład i jakość diety), jak i aktywność fizyczna mają ogromny wpływ na ogólny stan zdrowia ludności na świecie. Nowe zalecenia dietetyczne, w tym wykorzystanie żywności funkcjonalnej, mogą zmniejszyć skutki niedożywienia, powstałego zazwyczaj w wyniku złych nawyków jedzeniowych i złej jakości żywności. Jednakże czynnik wewnętrzny – niestrawność – jest główną przyczyną niedożywienia obserwowanego we współczesnym starzejącym sie społeczeństwie. Jest on przede wszystkim wynikiem zaniechania produkcji enzymów trzustkowych w wieku starszym. Brak lub niski poziom enzymów trzustkowych jest powszechnie określony jako niewydolność zewnątrzwydzielnicza trzustki (NZT). NZT dzielimy na fizjologiczną – występującą u noworodków, oraz spontaniczną – pojawiającą się w podeszłym wieku. W obu przypadkach pozytywne efekty przynosi enzymatyczna terapia zastępcza preperatami trzustkowymi, np. Creon 10 000, lub enzymami trzustko-podobnymi pochodzenia mikrobiologicznego. Ostra niewydolność trzustki jest często związana ze zmianami neurologicznych, takimi jak obniżenie funkcji poznawczych i świadomości. Jednakże brakuje badań poświęconych funkcji mózgu i jego morfologii w warunkach NZT oraz skutków suplementacji diety enzymami trzustkowymi – zarówno w modelach ludzkich, jak i zwierzęcych.
Celem niniejszego przeglądu badań własnych jest pokazanie wpływu obecności aktywnych enzymów trzustkowych lub trzustko-podobnych w jelicie na morfologię i funkcje mózgu w modelu świńskim.
Biomedical research has proven that both diet and life style practices, including food compositiion, food quality, eating behavior, and physical activity profoundly affect the overall health status of the world’s population. New treatment approaches, including the use of functional food compounds can ameliorate the effects of the malnutrition which usually arises as a result of poor eating behaviours and poor food quality. Maldigestion, which is the main component of the malnutrition observed in modern society, is mainly a consequence of the lack of pancreatic enzymes. The absence or low level of pancreatic enzymes is commonly described as exocrine pancreas insufficiency (EPI). The EPI which occurs in newborns is an accepted physiologiocal state, while in the elderly it occurs as a result of age-related impairment of the exocrine pancreas. In both cases however, enzyme replacement therapy with pancreatic or pancreatic-like enzymes of microbial origin is applied to the patients. Pancreatic insufficiency (lack of active pancreatic enzymes in the gut) is often associated with marked neurological alterations related to cognitive function. However, studies dedicated to the investigation of brain function and morphology under conditions of malnutrition caused by EPI and the subsequent effects of dietary supplementation with pancreatic enzymes , are lacking – both in human and animal models.
The main aim of the present review was to describe the effects of the presence of active pancreatic or pancreatic-like enzymes within the gut, on brain morphology and function in a pig model.
Abbreviations: CCK – cholecystokinin; CFA – coefficient of fat absorption; EPI – exocrine pancreatic insufficiency; IgG – immunoglobulin G; LCPUFA – long chain polyunsaturated fatty acids; NCAM – neural cellular adhesion molecule; NEFA – non-esterified fatty acids; PLEM – pancreatic-like enzymes of microbial origin; TG – triacylglycerides
Exocrine pancreatic insufficiency (EPI) is a major consequence of diseases that lead to the loss of pancreatic parenchyma (pancreatitis, cystic fibrosis or obstruction of the main pancreatic duct; decreased pancreatic stimulation, celiac disease) and/or the acid-mediated inactivation of pancreatic enzymes (Zollinger-Ellison syndrome). In addition, gastrointestinal and pancreatic surgical resections (e.g. gastrectomy, duodenopancreatectomy, gastric by-pass surgery) are frequent causes of EPI (1). Low levels of pancreatic enzyme secretion are also observed in piglets as well as in both pre-term and full term human babies (2-4) and elderly people (5, 6). A deficiency in pancreatic digestive enzymes may result in the maldigestion and malabsorption of essential nutrients, which can in turn lead to malnutrition and weight loss in adults and to impaired growth and development in young individuals, if left untreated (7). Conventional treatment of EPI involves replacement of pancreatic enzymes with a pancreatic enzyme preparation from pigs. But despite high doses of pancreatic enzymes used during therapy, normalisation of digestion does not often occur and only partial corrections of the malnutrition have been reported (8-10).
Acute and chronic pancreatic insufficiency is often associated with marked neurological alterations related to cognitive function (11). Many patients with chronic pancreatitis report symptoms that are associated with a decrease in cognitive function, such as depressive symptoms (12-14), sleep disturbances (15) and the use of opioid medication (16).
The potential application of pig models, which mimick EPI conditions, in the exploration of brain development and function in infants and individuals with chronic malfunction of the exocrine pancreas, such as patients with cystic fibrosis, patients following oncology surgery and the elderly (6, 17, 18) was investigated. We have proved that the EPI pig model is a sensitive tool which allows us to test the effects of the presence of active enzymes within the gut on the neurological status of the animal. Thus, the EPI pig model could serve as a promising, sensitive tool for the investigation of the mechanisms responsible for pancreatitis-related neurological alterations and their correction.
In elderly humans pancreatic function is reduced. Previous studies (5) have confirmed that the function of the pancreas in the elderly is impaired. Thus, one can postulate that low levels of pancreatic enzyme secretion are characteristic of both neonates and the aged. In both cases, the pancreas responds poorly to exogenous stimuli, such as the gut hormones of the cholecystokinin (CCK) family and secretin, which play an important role in the regulation of exocrine pancreas secretion.
A number of different animal models which mimick the lack of active pancreatic enzymes within the gut have been developed. The most common models used for this purpose are rodents (rats, mice) and pigs (both minipigs and regular pigs) (19). The porcine models are of importance for applied physiology and medicine, since at the functional and developmental level, humans and pigs share many similarities with regards to the gastrointestinal tract, genitourinary structures and the development of the brain and pancreas (20-22).
In the studies reviewed, it was of high priority to reveal the coherent possibilities of pig EPI models to serve as experimental tools mimicking conditions in human individuals with chronic malfunction of the exocrine pancreas/lack of active pancreatic enzymes in th gut. A coherent animal model which would allow us to investigate the neurological status of such patients, as decribed above, could serve as a powerful tool in understanding the mechanisms responsible for pancreatitis-related neurological alterations and the correction of such alterations.
Physiological EPI in newborn ungulates ensures proper brain development
Immature gut function is comparable in all newborn mammals, including humans, and coincides with very low levels of exocrine pancreatic enzyme secretion (3, 23). Moreover, even existing enzymes activity in newborn pigs (ungulates) is blocked during first hours of life by specific pancreatic and colostrum trypsin inhibitors. The activation of trypsinogen to trypsin (international classification number – 188.8.131.52) initiates the activation of other pancreatic enzymes by trypsin, as well as the autocatalytic activation of trypsinogen to trypsin. Trypsin inhibitors, from the pancreas itself or from the colostrum fed to the piglets, during the first few hours of life block the function of other active pancreatic enzymes. These circumstances allow for the absorption of IgG from the gut into the bloodstream, before gut closure takes place, usually between 24-36 hours after birth. Following the first 24 hours after birth, colostrum production is converted to milk production. Thus, the concentrations of Casal – a colostrum trypsin inhibitor, and that of Bowman – a pancreatic trypsin inhibitor, are reduced. The pancreatic enzymes – even though they are secreted in very small amounts at this stage, can begin to function resulting in digestion of the milk ingested by the newborn. One should keep in mind that milk of an ideal composition requires very low amounts of pancreatic enzymes to be digested into the simple components required for appropriate absorption from the gut (4). Pancreatic function begins to improve after weaning, when the pigs start to consume dry food (24). Pancreatic enzyme activity reaches optimal levels approximately 2-3 weeks after weaning.
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