WO2001069238A2 - Absorption intestinale de macromolecules - Google Patents

Absorption intestinale de macromolecules Download PDF

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Publication number
WO2001069238A2
WO2001069238A2 PCT/NL2001/000203 NL0100203W WO0169238A2 WO 2001069238 A2 WO2001069238 A2 WO 2001069238A2 NL 0100203 W NL0100203 W NL 0100203W WO 0169238 A2 WO0169238 A2 WO 0169238A2
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Prior art keywords
intestinal
food
speciahty
wau
segment
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PCT/NL2001/000203
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WO2001069238A3 (fr
Inventor
Theodoor Abram Niewold
Jan Van Der Meulen
Marius Joseph Antonius Nabuurs
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ID Lelystad Instituut voor Dierhouderij en Diergezondheid BV
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ID Lelystad Instituut voor Dierhouderij en Diergezondheid BV
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Priority to AU42864/01A priority Critical patent/AU4286401A/en
Publication of WO2001069238A2 publication Critical patent/WO2001069238A2/fr
Publication of WO2001069238A3 publication Critical patent/WO2001069238A3/fr
Anticipated expiration legal-status Critical
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5082—Supracellular entities, e.g. tissue, organisms
    • G01N33/5088—Supracellular entities, e.g. tissue, organisms of vertebrates

Definitions

  • the invention relates to the field of gut-(patho)physiology and is in particular related to the intestinal uptake of fluids, electrolytes and (macro)molecules .
  • the mucous surface and epithelial and subsequent layers of the intestines fulfil by default an important function in uptake and molecular transport of substances in food and drink and at the same time serve to protect the body against possible invading undesired substances.
  • fluid, electrolytes or distinct macromolecules are, selectively or by simple diffusion, transported through the mucous layer, taken up by the epithelium and transported through the intestinal wall to the lymph- and blood-vessels that transport the desired molecules further, whereas at the same time the mucous surface and epithelial layer provide solid protection against harmful and unwanted or toxic substances or molecules that are for example formed during microbial fermentation in the gut and thus protect the body against invading enteric pathogens, such as viruses or bacteria.
  • the tissue of the intestinal wall thus needs to actively maintain a complex functional integrity that is often under siege by external or internal influences.
  • said integrity is challenged.
  • a major cause of death of intensive care patients in hospitals is related to an increase of intestinal permeability for macromolecules.
  • the intestines in general function less than desirable in maintaining said integrity; oral food intake than often results in the intestinal uptake of large measures of (not yet digested) macromolecules and/or relative little uptake or even loss of water and salts resulting in a decreased or even negative net-absorption of essential fluid and electrolytes.
  • Oral feeding protocols bear thus the risk of disturbing the crucial fluid balance of the patient which may result in additional shock or disease, sometimes leading to death. Therefore, to avoid for example the risks of oral food intake in post-operative care, intensive care patients often remain longer on parenteral feeding than strictly deemed desirable from the viewpoint of restoring intestinal function.
  • Another example where the functional integrity of the intestinal surfaces is under siege is seen in the field of athletics, especially with those sports, such as long-distance running or cycling, where endurance is tested.
  • intestinal disturbances are seen during or after exercise that are related to the phenomenon that during mid- or long-term exercise most part of the blood supply is directed to the muscles, thereby leaving the intestines at least partly ischaemic.
  • the ischaemic state of the intestine may lead to acidosis, which can cause damage to the intestinal epithelial cells and loss of epithelial integrity, again resulting in decreased or even negative net-absorption.
  • the loss of epithelial integrity increases permeability leading to increased macromolecular transport over the epithelial barrier which means that unwanted compounds wind up the tissue of the intestinal wall or even in the bloodstream. It can also influence water or electrolyte transport over the intestinal wall, leading to intestinal fluid loss generating diarrhoea, in the worse cases macro-molecules can leak back into the intestine, whereby intestinal protein or even intestinal blood loss is seen causing proteinaceous or even bloody diarrhoea. Food digestion under these circumstances is sub-optimal which prevents replenishment of energy supply during exercise and increases the time necessary for recuperation after exercise.
  • stomach ache is related to a discrepancy between the increased need for oxygen in the intestinal tissues after eating, and the (due to age decreased) ability of the blood supply to the intestines to fulfil that need.
  • a relative intestinal ischaemia is thought to be related to intestinal malfunction.
  • test results often vary greatly, which can only be countered by using large, financially often prohibitive numbers.
  • Analysis of the intestinal effect of food is further complicated by the varying response dependent on each individual haemodynamic state related to age, health status, fitness, physical activity (e.g., exercise and sports) and genetic background.
  • no one in his right mind contemplates using intensive care patients for such experiments, thus, where insight in the preferred composition of oral food for intensive care patients is needed, little or no possibilities exist to test experimental food compositions or compounds therefor.
  • to select and obtain better speciality foods tailored for various needs experimental models are needed.
  • the invention provides a method for determining molecular transport through an intestinal wall or segment thereof comprising up- or down-regulating oxygen supply to said wall or segment.
  • the invention provides a methodology for evaluation of the effects of (components of) foods, drinks and speciality foods or drinks related to various different hemodynamic states of a person who consumes the food or drink.
  • the present invention provides an in vivo environment and thus allows for testing of compounds on intestinal function in an intact physiological environment (e.g. intact intestinal circulation, enervation), measuring intestinal permeability separately.
  • the invention provides a test method for determining molecular transport through an intestinal wall or segment thereof comprising regulating perfusion of blood vessels in said wall or segment. Perfusion can be regulated by several methods. It is for example provided to test an experimental animal or a volunteer before, during or after resting or exercise. During exercise, the blood distribution of the body is in general lead away from the intestines, for example in favour of supply to the muscles, thereby creating a phase of relative ischaemia in at least parts of the intestines.
  • the invention furthermore provides testing experimental subjects in artificially compromised haemodynamic states, for example after having been provided with above normal haematocrite values, as for example can be observed in athletes having trained at high altitude or having been provided with erythropoetin or with intensive care patients having for example suffered extensive blood plasma loss, or having been provided with below normal haematocrite values, as for example can be observed during anaemia, during kidney malfunction or after excessive fluid loss therapy.
  • the invention also provides testing experimental subjects having been provided with erythrocytes having above or below normal capacity for uptake, transport or delivery of oxygen.
  • the invention provides a method according to the invention further comprising rendering at least part of said intestinal wall or segment at least partly ischaemic, that is deplete of normal oxygen levels.
  • Ischaemia herein refers to local tissue anaemia for example caused by reducing arterial influx or venous efflux of blood to or from said tissue or by other causes of reduced oxygen supply.
  • the invention provides a method according to the invention wherein a blood vessel leading to (such as one of the branches of the arteria mesenterialis or arteria renalis) or from (such as one of the branches of the venae portae) said part is at least partly clamped.
  • the invention provides use of one or more of the following test methods: the testing by small intestinal segment perfusion (SISP) for evaluation of food uptake, evaluation of food uptake in different haemodynamic states; ischaemic reperfusion (IR)-SISP, or evaluation of intestinal epithelial integrity and permeability in a diffusion chamber (DC) alone or after (IR)-SISP.
  • SISP small intestinal segment perfusion
  • IR ischaemic reperfusion
  • DC diffusion chamber
  • IR intestinal epithelial integrity and permeability in a diffusion chamber
  • a method as provided by the invention allows rational design of food formulas tailored to different metabolic states. Said use finds its application in the formulation of speciality foods or drinks such as probiotics, sport foods, or medical (par)enteral food. Furthermore, the invention provides said use for evaluation of compounds or components modifying the permeability of the epithelial barrier for oral vaccination, and for the induction of oral tolerance for prevention and cure of (food) allergy. In addition, a method as provided by the invention allows evaluation of compounds for non-pharmaceutical prevention of infectious enteral disease.
  • the invention provides a method wherein said transport is macromolecular transport.
  • said transport is macromolecular transport.
  • the blood circulation of the intestine of an experimental subject such as a pig is manipulated as to mimic different physiological states i.e., resting, moderate or strenuous exercise. This enables evaluation of food uptake under different haemodynamic conditions, and measurement of the influence of food on the occurrence of intestinal acidosis.
  • a marker such as a specific electrolyte, a (an)organic salt, oxygen, hydronium ions, etc., optionally labeled or identifiable by nuclear emission signals or radio-activity, horse-radish-peroxidase, fluoresceinated compounds of varying molecular mass, labeled antigens or toxins
  • a marker such as a specific electrolyte, a (an)organic salt, oxygen, hydronium ions, etc., optionally labeled or identifiable by nuclear emission signals or radio-activity, horse-radish-peroxidase, fluoresceinated compounds of varying molecular mass, labeled antigens or toxins
  • the effect of food on enteral disease can for example be tested by bringing the relevant pathogen in the intestinal segment.
  • a sample of the intestinal epithelial layer is put in a diffusion chamber (DC), and measurements on integrity and permeability are performed by electrophysiology or by using a marker for trans-epithelial transport of macromolecule s .
  • the invention provides a method wherein said transport comprises fluid and/or electrolytes.
  • SISP small intestinal segment perfusion
  • the difference between the input and outflow of fluid and/or electrolytes from the intestinal segment is measured and for example expressed as net absorption, or as differences between the sodium/potassium ratios in the intestinal lumen or the blood, in time.
  • the effect of food composition on net absorption can be measured. Segments can for example be infected with viral and bacterial intestinal pathogens, and the effect of the pathogens on net absorption can be studied in detail. Furthermore, the effect of food components on enteral infection can be evaluated. This enables a rational approach for food design, especially for enteral disease patients and individuals at risk.
  • the invention also provides use of a method according to the invention in selecting or obtaining at least one component for a speciality food.
  • Use of a method provided by the invention provides information about the uptake of food and quantifies the physiological consequences of food, for example taking the physiological (haemodynamic) status of the individual into account.
  • a striking example in this respect is the consequence of the presence of glutamine in food.
  • Glutamine is the preferred fuel for intestinal cells. Under normal circumstances, resting or moderate exercise, glutamine is beneficial. However, more strenuous exercise, or blood loss leads to redistribution of blood away from the intestine, leading to relative ischaemia, especially prominent with athletes during recovery from exercise. A similar relative ischaemia is often seen with intensive care patients, and among many elderly.
  • Use of a method provided by the invention allows rational design of speciality foods or drinks particularly suited for an intensive care patient, an athlete, a very young person, a diseased person or an elderly person, whose intestinal integrity may from time to time be under siege due to for example relative intestinal ischaemia.
  • the invention thus provides a method for selecting or obtaining a speciality food or drink tailored for the needs or desires of an individual who's functional integrity of the intestinal wall is at least at times under siege comprising testing at least one candidate component for said speciality food for its effect on molecular transport through an intestinal wall or segment thereof and selecting a component for inclusion in said speciality food that has a desired effect on said molecular transport.
  • testing of an already composed or existing food or drink for its effect on said molecular transport is provided as well.
  • the invention also provides a speciality food or drink selectable or obtainable by a method according to the invention.
  • a speciality food or drink according to the invention comprising hydrolysed polysaccharides or functional equivalent thereof.
  • hydrolysed polysaccharides protects against increased intestinal permeability during intestinal ischaemia.
  • the invention for example provides a speciality food or drink tailored for an intensive care patient or tailored for the needs or desires of an athlete who's functional integrity of the intestinal wall is at times under siege, especially wherein said food or drink is intended for use during a phase of relative intestinal ischaemia to prevent damage to the functional integrity of an intestinal wall, thereby preventing any of a wide variety of intestinal failure, such as stomach ache, fluid or electrolyte loss, or diarrhoea.
  • a drink is a sport drink containing optimized amounts of glutamine, glutamine in certain concentrations, as shown herein, surprisingly being found to be detrimental to an intestinal wall during a phase of relative intestinal ischaemia.
  • the invention provides use of a speciality food or drink as provided by the invention, especially wherein said food or drink is intended for use during a phase of relative or absolute intestinal ischaemia to prevent damage to the functional integrity of an intestinal wall, thereby preventing any of a wide variety of intestinal failure or loss of functional integrity of an intestinal wall, such as seen with stomach ache, fluid or electrolyte loss, or diarrhoea.
  • a speciality food or drink as provided by the invention, especially wherein said food or drink is intended for use during a phase of relative or absolute intestinal ischaemia to prevent damage to the functional integrity of an intestinal wall, thereby preventing any of a wide variety of intestinal failure or loss of functional integrity of an intestinal wall, such as seen with stomach ache, fluid or electrolyte loss, or diarrhoea.
  • Pigs were chosen herein as experimental subject and are the preferred species as model for the human, however, other animals, or ex vivo maintained intestines or parts thereof, can be selected as well.
  • pigs were sedated with 0.1 ml azaperone (Stressnil), per kg bodyweight, after 15 minutes, inhalation anesthesia was performed with a gas-mixture of 39% oxygen, 58% nitrous oxide and an initial 3% halothane; after 10 minutes 2% halothane.
  • Stressnil 0.1 ml azaperone
  • the abdominal cavity was opened and about 40 cm caudal from the ligament of Treitz, the first segment of 20 cm length was prepared by inserting a small inlet tube in the cranial site of a segment and by inserting a wide outlet tube into the caudal site of a segment.
  • Four other pairs of segments were similarly prepared at 25%, 50%, 75%, and 95% of the total length of the small intestine.
  • Segments were then perfused with 80 ml of fluid containing 9 g NaCl, 1 g Bacto casaminoacids (Difco), and 1 g glucose per liter distilled water for 10 hours (ml/h). After perfusion was ended, fluid remaining in a segment was blown out into the collecting bottle; then pigs were euthanised by barbiturate overdose. The surface area of each segment was measured. Net absorption was defined as the difference between inflow and outflow in ml/cm 2 . Intestinal pH was measured in the effluent.
  • IR-SISP Manipulation of the blood circulation of the intestine of the pig to mimic different physiological states i.e., resting, moderate or strenuous exercise was performed as follows.
  • Pigs were premedicated with pentobarbital 20 mg/kg body weight intravenously. Then, they were orally intitbated and ventilated (12 breath per minute) with a blender (SLO1; Ohio medical products, Minneapolis, MN) and a volume controlled ventilator (900 A; Siemens, Elema, Sweden). Ventilation was kept unchanged for the duration of the experiment. Body temperature was stabilized by a heating blanket. Anaesthesia was maintained by continuous intravenous infusion of pentobarbital 6 mg/kg/h in the right vena jugularis externa and pancurium bromide 2 mg/kg h by a catheter placed in the left vena jugularis externa.
  • the pig was placed in the lateral position and an incision was made at 2 cm parallel to the rib cage.
  • the superior mesenteric artery (SMA) was prepared free and an ultrasonic flow sensor was placed around the vessel.
  • a flow probe (Transonic) was placed around the SMA. After a period of equilibration the normal flow rate was estabhshed.
  • SISP segments were placed as described above, for the determination of the luminal pH, segments could be fitted with intestinal tonometer (Tonometrics, Worcester, MA). The tonometer was filled with 2.5 ml physiological saline.
  • a clamp was placed around the SMA, and the blood flow was reduced to a level of 75% for a period of 60 min. After this period of relative ischaemia, the clamp was removed to allow reperfusion for 2h. This mimics an ischaemic phase follows by reperfusion such as seen during and after transient exercise. Clamping could also be continued to mimic continuous relative ischaemia.
  • the Diffusion Chamber is a double-cell acrylic chamber (WPI, Sarasota, FL, USA) in which a living membrane is interposed separating the two cells.
  • An oxygenated buffer solution is circulated through each cell by independent reservoirs.
  • the pH of the solutions was maintained between 7.35 and 7.45 by manipulation of the percentage of CO2.
  • the reservoirs are jacked with a recirculating water bath to maintain reservoir temperature at 37°C.
  • Two calomel and two Ag-AgCl electrodes are connected to the cells via agar bridges. This allows measurement of transmembrane potential difference (DV) and appUcation of a fixed current.
  • DN is proportional to total ionic flux, which is an indicator of tissue viability, and indirect measurement of cell metabolism.
  • Pigs were anesthetized with halothane or if samples are used from IR-SISP see there. Under sterile conditions, the ileum was exposed. The mesenteric vasculature was clamped, and 4- to 6-cm ileal segments without visible Peyer's patches were quickly excised. The seromuscular layer was stripped from the submucosa and mucosa. The mucosal preparations were immediately mounted in the diffusion chamber separating the mucosal from the serosal reservoir. After mounting, membranes required 15 minutes to stabilize prior to measurement.
  • DN and R were measured repeatedly at 15 minute intervals for 2 hours.
  • Macromolecular permeability was measured using horse-radish peroxidase (HRP) as a model macromolecule. Briefly, 10-5 M (0.4 mg/ml) HRP was added to the chamber at the mucosal side. Samples ( 0.25 ml) were taken at the serosal side at regular intervals (30 min). HRP concentrations were determined enzymatically. Macromolecular permeability was expressed as pmol HRP/cm 2 /h).
  • MSG Monosodium glutamate
  • CRS Chinese restaurant syndrome
  • SISP segments were filled with respectively saline, 1, 2 or 3 % MSG in saline (each in duplo).
  • Pre-I R permeability was lower than 1 pmol HRP/cm 2 /3h. I/R in the presence of saline only, and with different concentrations of MSG showed a significantly higher permeability. The addition of different concentrations of
  • MSG increased the significance of the difference when compared to the pre-I/R sample.
  • IR-SISP was performed with 1 h of ischaemia (I-phase), and 2 h of reperfusion (R-phase). Samples of tissue from each phase were tested in the diffusion chamber. The effect of hPS (2.10-5M) was measured by adding it to perfusate during the I-phase, or the R-phase, or at the mucosal side in the diffusion chamber. Permeability was measured by the HRP method.
  • hPS protects against increased permeability when added in vivo during the I-phase. No effect was seen when hPS was added in vivo during the R-phase. When hPS was added in the diffusion chamber, it had no effect on the permeability of I-phase or R-phase derived intestinal epithelium. Conclusions: hPS protects against increased permeability if present during the ischemic phase in the in vivo IR-SISP as estabhshed in the diffusion chamber (DC). When virgin isolated epithelial layers from both the I and R phase were exposed to hPS in the diffusion chamber this effect was not seen.
  • SISP was performed with enterotoxic E. coli F4 in the perfusion buffer.
  • Segment were placed as triplets, one containing only buffer and E. coli, a second one containing an additional 10% of normal plasma powder, the third contained
  • E. coli F4 reduced the net absorption as expected, anti-E. coli F4 hyper immune plasma powder abolished this effect.
  • E. coli F4 and rotavirus are pathogens under certain conditions. In those situations both cause increased permeability. Juveniles have naturally a higher permeability than adults. Adults have a higher permeability post-injury (post- infection etc.), in the regeneration phase. It appeared that both E. coli F4 and rotavirus attenuate the juvenile and adult regeneration permeability as demonstrated by DC. The activity is currently being identified to specific compounds (proteins and others) and fragments thereof responsible for this effect .
  • permeabiHty For several purposes, modulation of permeabiHty rather than blocking or total and/or permanent permeabiHty is desired.
  • permeabiHty in the case of oral vaccination one wants the permeabiHty to have either a selective character, i.e. only for the vaccin, or be transient, i.e. permeability only as long as it takes to enable the vaccin to pass the intestinal barrier.
  • DMSO permeabiHty in the diffusion chamber (DC), and is a very promising agent for achieving transient intestinal permeabiHty for its very short physiological half-life. Furthermore, DMSO is an approved pharmaceutical additive (for other purposes), without any known side effects or contra-incHcations.

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Abstract

L'invention concerne le domaine de la( patho)physiologie intestinale, et notamment l'absorption intestinale de fluides, d'électrolytes et de (macro)molécules. L'invention concerne également un procédé permettant de déterminer un transport moléculaire à travers la paroi intestinale ou un segment de celle-ci, qui consiste à réguler négativement ou positivement la fourniture d'oxygène à ladite paroi ou audit segment de celle-ci. L'invention concerne enfin une méthodologie permettant d'évaluer les effets des aliments et des boissons (ou de leurs composants), et en particulier des aliments et des boissons associés à différents états hémodynamiques d'une personne qui consomme un aliment ou une boisson.
PCT/NL2001/000203 2000-03-13 2001-03-12 Absorption intestinale de macromolecules Ceased WO2001069238A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU42864/01A AU4286401A (en) 2000-03-13 2001-03-12 Intestinal uptake of macromolecules

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP00200895.1 2000-03-13
EP00200895 2000-03-13

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WO2001069238A2 true WO2001069238A2 (fr) 2001-09-20
WO2001069238A3 WO2001069238A3 (fr) 2002-02-07

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Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5116819A (en) * 1989-05-05 1992-05-26 Clintec Nutrition Co. Enteral diet for patients with pulmonary disease
NL1011680C2 (nl) * 1999-03-26 2000-09-27 Nutricia Nv Voedingssamenstellen die licht negatief geladen, niet-verteerbare polysacchariden bevatten en gebruik ervan voor het verminderen van transport door tight junctions.
NL1013175C2 (nl) * 1999-09-29 2001-03-30 Nutricia Nv Voedingssamenstellingen die niet-verteerbare polysacchariden bevatten en gebruik ervan voor het verminderen van transport door tight junctions.

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AU4286401A (en) 2001-09-24

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