Intestinal absorptive function

Transcription

1 Gut 1994; supplement 1: S5-S9 Intestinal absorptive funtion S5 Queen's Medial Centre, niversity Hospital, Nottingham R C Spiller Correspondene to: Dr R C Spiller, Queen's Medial Centre, niversity Hospital, Nottingham NG7 2H. R C Spiller Abstrat The normal gut is adapted to intermittent feeding with omplex maromoleular substrates of low sodium ontent. The high permeability of the upper small intestine to sodium, together with sodium rih saliva and panreatiobiliary seretions results in large sodium fluxes into the lumen. These substantial sodium influxes are mathed by equally large effluxes from the ileum and proximal olon, whih are omparatively impermeable to sodium and apable of ative sodium absorption. Resetion of these distal, sodium absorbing regions of the intestine, lead to problems with sodium depletion. Controliled transit of hyme is essential to permit time for optimium digestion and absorption and a range of feedbak ontrol mehanisms exist. Partially digested nutrients, both in the duodenum and ileum, exert inhibitory feedbak to delay delivery of further nutrients and here again surgery may ompromise these reflexes. Brush border hydrolase values are strongly influened by luminal nutrient onentrations, being impaired by malnutrition and total parenteral nutrition, but restored by enteral feeding. Visous fibre slows absorption and may delay transit through mehanisms that are as yet unertain. Whether and how novel substrates ativate normal ontrol mehanisms will be important fators determining their effetiveness and patient aeptability. (Gut 1994; supplement 1: S5-S9) Absorption in its most restrited sense onsists of the proess whereby nutrients pass from the gut lumen either aross the brush border ell membrane after binding to a speifi transport protein, or through the interellular tight juntion, in effet rossing the barrier between the external melieu and the organism. This proess requires a very extensive 'preproessing' of food to permit the intimate ontat between substrate and enteroyte needed to permit the binding of nutrient to the various transport proteins. Preproessing of food before absorption Food is usiwlly omposed of maromoleules, often part of other organisms and hene has omplex strutures suh as ell walls that require breaking down before the nutrients an be aessed. This is best illustrated by onsidering the digestion of starh. Mehanial and hemial degradation begins with ooking, whih hydrates the long starh polymers ausing them to lose some of their ordered array permitting better aess of salivary amylase.1 Grinding by the teeth and later by the ation of the 'antral pump', ombined with the ation of salivary amylase, redues the food to an homogenous hyme, whih is pumped into the duodenum at a rate of about 1-2 kallmin. One within the duodenum, starh is hydrolysed extremely rapidly beause of a superabundane of panreati amylase, whih leaves the ot 1-4 gluoidi bonds in starh, reduing the polymer to maltose, maltotriose, and ao limit dextrins. Attahed to the brush border, faing into the gut lumen are the brush border hydrolases, large glyoproteins now sequened, whih inlude maltase, isomaltasesurase, and gluosidases apable of reduing ot limit dextrins and other polymers ontaining less than six gluose monomers, to gluose monomer. This then binds to the gluose/ sodium otransporter, a 72 kilo dalton protein, whose affinity for gluose is appreiably inreased when it ombines with sodium. Depending upon exatly where in the body the ell membrane is derived, either one or two sodium moleules bind to the transport protein. This then undergoes onformational hange, whih transports the gluose and sodium aross the ell membrane to be released into the ytoplasm.2 In effet this system uses the hemial gradient of sodium aross the enteroyte brush border membrane, generated by the 'pumping' ation of the basolateral Na+/K+ ATPase, to energise ative gluose transport. Delivery of nutrients to the small intestine mptying of gastri hyme is to a onsiderable extent ontrolled by feedbak inhibition, whereby nutrients and hyperosmolar solutions within the duodenum inhibit antral peristalsis and redue fundal tone, ausing food to be redistributed more proximally within the stomah. This 'duodenal brake' is the first of many suh ontrol loops whereby the arrival of exess nutrients distally delays further delivery, hene permitting more time for digestion and absorption. Suh feedbak loops are vital beause of the very variable nutrient ontent and digestibility of food. Detetors positioned distally an assess how suessful digestion has been and moderate the flow of hyme to minimise malabsorption. The best example of what happens if these feedbak loops are lost is the malabsorption that ommonly aompanies the preiptious and unontrolled gastri emptying seen in patients with the 'dumping syndrome' after vagotomy and pyloroplasty, or to a lesser degree in most patients with a gastroenterostomy. Gut: first published as /gut.35.1_Suppl.S5 on 1 January Downloaded from on 16 August 218 by guest. Proteted by opyright.

2 S6 Spiller Input Jejunal Hours Figure 1: Flow through the upper gastrointestinal trat studied over 2 hours by means of a slow marker infusion tehnique ombined with aspiration from the upperjejunum and distal ileum.4.a Ileal nteral nutrition to a large extent avoids suh problems by in effet doing most of the mehanial and hemial preproessing for the patient. Thus ommerial enteral diets are homogenised, isotoni, and often partially digested. Furthermore by using a pump to deliver nutrients at 1 al/min problems with abnormal gastri emptying an be avoided exept in exeptional ases suh as severe head injury, when gastri stasis an be profound.3 Intestinal absorption Before onsidering absorption from enteral diets it is worth onsidering the normal response to feeding as these are the onditions that the gut has evolved to ope with. Figure 1 shows that although input into the organism is pulsatile, the stomah redues this very onsiderably so that the flutuation in flow is less in the jejunum, and the ileum is exposed to still smaller variations.4 In general there are important differenes between the jejunum, whih is exposed to high flow and high onentrations of nutrients ompared with the ileum, whih reeives a smaller load and must absorb from lower onentrations. These differenes in load result in quite onsiderable regional differenes in absorptive harateristis as is learly seen with sodium absorption. SODIM ABSORPTION Most of our food has a low sodium onentration omparative with blood. A normal beefburger meal, if homogenised, has a sodium onentration of only 35 mmol. Sodium rih saliva raises this somewhat but in the stomah aid seretion lowers the sodium ontent still further. The duodenum is therefore exposed to a sodium onentration of 2-3 mmol. The jejunum annot, however, maintain suh a gradient being highly permeable to sodium, whih is rapidly sereted into the gut lumen.5 This seretion, ombined with the very rapid simultaneous absorption of water, means that, by the time the hyme reahes the ileum, the sodium onentration has reahed 12 mmol. The ileum reeives approximately 4 mmol of sodium per 24 hours, whih it redues to about 2,4 6 the olon absorbing 95/o of this to result in stool output of 1-2 mmol/24 h. The ileum is adapted to absorbing sodium against its eletrohemial gradient and this requires that the ileum be impermeable to sodium. It is, however, more permeable to hloride ions and so does not generate muh of a lumen-serosa potential differene when exposed to an isotoni salt solution. By ontrast the olon is highly impermeable to both sodium and hloride and generates a high eletrohemial gradient by ative eletrogeni sodium transport, lowering the luminal sodium onentration to 2-3 mmol and the luminal-serosa potential differene to -35 mv.7 SIGNIFICANC OF RGIONAL DIFFRNCS IN ABSORPTION These differenes beome of great importane when the funtions of various regions of the.gut are lost by disease or surgial resetion. Ileal resetion results in a doubling of the sodium load to the olon, although this an usually be ompensated for by inreased oloni absorption,8 stool output does inrease in most ases.9 The major problem is when the olon is also reseted when the vast sodium flow from the jejunum beomes stoma effluent. This point is well made by the studies on the short bowel patients (Fig 2). Patients with less than 1 m of jejunum remaining ould not absorb suffiient salt to avoid desalination and were dependent on daily intravenous saline.1 In these patients salt balane is highly prearious but vital to ontrol. The situation an be muh improved by areful hoie of fluids._ o ). (I). o. ocu n1 CLQ Ji 6r 4 H 2 H -2 CllnI{ 1 = = 8r 6 H- 4 F- 2 H -zul o o 1 o Jejunal length (m) Figure 2: Influene ofjejunal length on salt and energy balane in patients with jejunostomy. Fourteen patients with extensive small bowel resetion and a high jejunostomy and one patient with ajejunoretal anastomosis had balane studies. No patient with less than 1 m of jejunum ould maintain a positive sodium balane by the enteral route alone. 1 I. a - - a Gut: first published as /gut.35.1_Suppl.S5 on 1 January Downloaded from on 16 August 218 by guest. Proteted by opyright.

3 Intestinal absorptive funtion S7 one the impliations of the higih jejunal per- Drinking nutrition. Six subjets were intubated and terminal ileal TABL II Flow and motility during ontinuous enteral meability to sodium are appreiated. flow assessed using a slow marker infusion tehnique for low sodium fluids suh as water auses massive five hours fasting and duringfive hours of ontinuous sodium seretion and hene negrative balane enteralfeeding with 1 kal/min of a mixed nutrient whereas the use of high sotdium drinks polymeri diet. While intraduodenalfeeding abolished fasting ativity intragastni feeding did not. (Data from minimises the negative balane. There is a referene 18) linear relation between sodium ( onentration and sodium absorption from nutr*ient solutions Intragastri Intraduodenal (Fig 3). Net absorption only ours from Terminal ileal Fasting 3 ( 1) -6 ( 3) saline, non-nutrient solutions per-fused into the flow (ml/min) Fed -4 (1) 2- ( 7)* Motility MMC/5 h Fasting 7-2 (1-8) 7-8 (2-8) jejunum if the sodium onentration exeeds Fed 11 1 (2 4) Absent 127 mmol,5 whereas net absorrption ours from nutrient solutions with sodium on- this Data expressed as mean (SM); *p< 5. entrations greater than 9 immol,"i enhanement is a result of the otransport of operating onditions are refleted in differ- sodium enes in transport proesses. Thus in the rat sodium and gluose. Thus optiimum balane an be ahieved by the use of fluids two distint transport proesses for gluose ontaining 9 mmol sodium ttogether with have been shown. One, whih predominates nutrients suh as starh or amino aids, similar proximally, is haraterised by a high Vmax and to the solutions used so suessfully in the Km, ideal for transporting large amounts of treatment of holera. gluose from solutions of high onentration, while the other, whih predominates in the ileum'6 has a low Vmax and Ki, well suited for NTRINT ABSORPTION transport of smaller loads from solutions of a There are important differenes for nutrients muh lower onentration. The renal (as for sodium) between the jejunum, whih gluose/sodium transporter likewise has two is exposed to high loads of nutirients at high forms, one in the proximal onvoluted tubule onentrations (Table I),12 an( d the ileum, with a high Vmax and Km, and another in the whih must absorb small amountts of nutrients distal tubule, whih is exposed to muh lower from a low onentration,13-15 generating high gluose onentrations with a low Vmax and onentration gradients. These ( differenes in low Km. This more distal transporter generates a muh bigger onentration gradient and requires the otransport of two sodium TABL I Postprandial nutrient luminal onentrations of arbohydrate, protein, andfat moleules/gluose moleule (ombined data from referenes1 2-1 instead of the one 5) that suffies in the proximal tubule. Thus the Carbohydrate Protein Fat energy for transport ultimately derives from Free gluose Oligopeptide FFA the Na+/K+ ATPase pump, whih generates g/l (mm) g/l (mm) g/l (mm) the lumen-ytoplasmi sodium gradient. Jejunum Ileum FFA=f z-._, o. Cu + z Importane of motility for absorption free fatty aid. ffiient absorption is dependent on adequate mixing both to permit breakdown of food to a homogenous hyme and also to permit lose ontat between nutrients and their transport 3 proteins lying in the brush border membrane. The entry of nutrients into the duodenum after 2 a normal meal auses a radial hange in 2r Nutrients motility patterns, the normal ylial fasting Nutrients ativity, the 'migrating motor omplex', being 1 - Saline replaed by irregular fed ativity designed to o/,r'a mix the hyme and, by onstantly 'kneading' o it, pushing the absorptive surfae into the /o hyme and so speeding up absorption. The -1 _ preise pattern of the mixing ativity is /O influened by the nature of the nutrient, -2 gluose produing the least ativity while fat indues the most ontrations, all of whih are non-propulsive. 17 The swith from fasting to fed ativity requires a minimum amount of alories, -4' probably about 1-2 kal/min. This is the value Na+ onentration (mmol/1) of alorie load that enteral diets provide and a reent study'8 from Central Middlesex Figure 3: Correlation between Na + onentration and nutrient absorption. Sodium absorp,tion from a 25 m jejunal segment was assessed using a jejunal perfusion tehnique. Hospital (Table II) has shown that while Isotonii nutrient solutions made up ofpartially hydrolysed starh andfree amino aids with intraduodenal infusion at 1 kal/min does varyinig sodium onentrations were studied eah in seven subjets. Sodium absorption was abolish fasting ativity, intragastri infusion at stronglty orrelated (r= 95, p<o1) with initial sodium onentration."1 The dotted line the same rate does not. This shows that it is the shows the relation between sodium absorption and infused onentration for a non-nutrient, salinel/ 'mannitol solution5 illustrating the enhanement of sodium absorption in the presene intraduodenal onentration that is ritial, of nutrients. rather than the preise load. Delivery into the Gut: first published as /gut.35.1_Suppl.S5 on 1 January Downloaded from on 16 August 218 by guest. Proteted by opyright.

4 S8 Spiller stomah presumably auses suffiient dilution of feed by gastri juie so that the intraduodenal onentrations fail to reah the level for swithing off fasting ativity. This does not, however, seem to impair absorption, beause in the same study oloni inflow did not rise above fasting onentrations. This probably reflets the fat that in humans migrating motor omplexes rarely pass the whole way down the small intestine, most fading out in the distal ileum. Indeed slow ontinuous feeding by the nasogastri route probably improves absorption by avoiding the surges in flow harateristi of normal episodi feeding. Thus when normal diets have been ompared with similar amounts of alories fed nasogastrially by ontinuous infusion the faeal or stomal losses have been shown to be signifiantly less.19 This is of great signifiane in the early nutritional rehabilitation phase after bowel resetion. In addition to the feedbak inhibition from nutrients in the duodenum on gastri emptying there are more distal sensors espeially in the ileum of both humans2 21 and laboratory animals,22 23 whih detet malabsorbed nutrients, espeially fat, and exert an inhibitory effet not only on gastri emptying24 but also on duodenal and jejunal motility, delaying transit.2 25 This results in inreasing the time available for absorption. This has been shown to inrease the ompleteness of absorption, at least for arbohydrate in normal subjets.26 These early studies on this phenomenon, 'the ileal brake' were performed by infusing nutrients diretly into the ileum. There are of ourse other ways in whih malabsorption an be mimiked. Amylase inhibitors delay starh digestion and were used by Layer et a127 to inrease the amount of gluose in the distal ileum. Their study showed that impairing starh digestion aused an early inflow of starh into the ileum, ileal flow then levelled off as a onsiderable inhibition of gastri emptying then ensued. This shows how the ileal brake an at to ompensate for defets in the absorptive apparatus. Similar reflexes are probably ativated when various visous fibres are added to enteral diets. Thus it is known that guar delays absorption of gluose by a ombination of delaying gastri emptying and more importantly delaying the absorption from the lumen of the small intestine.28 Similar studies by Jenkins et a129 showed that the delay in gluose absorption did not interfere with overall absorption so that although absorption of xylose was redued at two hours, by eight hours total absorption was unhanged. Although the fibre added to enteral feeds annot be very visous without bloking the feeding tube, the fibre that has been used an be shown to redue the area under the onentration time urve for both foli aid and zin during the first few hours, as well as delaying mouth to aeum transit.3 Thus nutrients are probably retained from longer in the gut lumen and pass further down the gut, ativating ompensatory reflexes, whih delay transit and permit more time for absorption. FFCT OF MALNTRITION AND STARVATION ON FFICINCY OF ABSORPTION Patients fed by enteral nutrition have often had a previous period of starvation or total parenteral nutrition during whih luminal nutrient onentrations will have been very muh redued. This has been learly shown to redue brush border hydrolase onentrations without hanging the jejunal morphology in humans,31 and in smaller laboratory animals to redue muosal mass. In vitro studies32 have furthermore shown that the number of gluose otransporters ould be inreased in this situation by infusing nutrients into the jejunum. Fortunately the impairment of absorption aused by luminal deprivation of nutrients is rapidly (15-24 hours) orreted by refeeding enterally. Absorption is normally highly effiient, both for water and eletrolytes as well as for nutrients. This effiieny depends on many adaptive responses, whih our within very different time sales. Control of the transit of hyme down the gut depends on negative feedbak inhibition of transit by malabsorbed nutrients reahing more distal parts hanges that our within a few minutes. Over several hours or days hanges in luminal nutrient onentration also lead to adaptive hanges in brush border hydrolases and transport proteins,3' 32 while longer periods are assoiated with morphologial hanges. Luminal nutrients are vital to maintain effiient absorption, a fat that should enourage the use of the enteral nutrition as soon as is possible. Novel substrates will need to be assessed arefully to ensure that they stimulate the appropriate gut reeptors and eliit responses that permit ontrolled transit down the gut. Surose polyester, a syntheti fat substitute, was an interesting example of a novel, nonnutritive substane whih, although it tasted like fat, did not ativate the 'duodenal brake' and atually emptied from the stomah like water.33 Care will be needed to ensure that the ontrols on motility operate normally in the presene of novel nutrients if their use is not to be marred by preipitous transit through the gut. 1 Fleming S, Vose JR. Digestibility of raw and ooked starhes from legume seeds using the laboratory rat. JNutr 1979; 19: Baly DL, Horuk R. The biology and biohemistry of the gluose transporter. Biohim Biophys Ata 1988; 947: Ott L, Young B, Phillips R, MClain C, Adams L, Dempsey R, et al. Altered gastri emptying in the head-injured patient: relationship to feeding intolerane. J Nuerosurg 1991; 74: monts P, Vidon N, Bernier JJ, Rambaud JC. tude sur 24 heures des flux liquidiens intestinaux hez l'homme normal par la tehnique de la perfusion lente d'un marqueur non absorbable. Gastroenterol Clin Biol 1979; 3: Fordtran JS, Retor FC, Carter NW. The mehanisms of sodium absorption in the human small intestine. Jf Clin Invest 1968; 47: Phillips SF, Giller J. The ontribution of the olon to eletrolyte and water onservation in man. Jf Lab Glin Med 1973; 81: Davis GR, Santa Ana CA, Morawski SG, Fordtran JS. Permeability harateristis of human jejunum, ileum, proximal olon and distal olon: results of potential differene measurements and unidiretional fluxes. Gastroenterology 1982; 83: Debongnie JC, Phillips SF. Capaity of the human olon to absorb fluid. Gastroenterology 1978; 74: Gut: first published as /gut.35.1_Suppl.S5 on 1 January Downloaded from on 16 August 218 by guest. Proteted by opyright.

5 Intestinal absorptive funtion S9 9 Arrambide KA, Santa Ana CA, Shiller LR, Little KH, Santangelo WC, Fordtran JS. Loss of absorptive apaity for sodium hloride as a ause ofdiarrhea following partial ileal and right olon resetion. Dig Dis Si 1989; 34: Nightingale JMD, Lennard-Jones J, Walker R, Farthing MJG. Jejunal efflux in short bowel syndrome. Lanet 199; 336: Spiller RC, Jones BJM, Silk DBA. Jejunal water and eletrolyte absorption from proprietary enteral feeds in man: importane of sodium ontent. Gut 1987; 28: Miller, Malagelada JR, Go VLW. Postprandial duodenal funtion in man. Gut 1978; 19: Adibi SA, Merer DW. Protein digestion in human intestine as refleted in luminal muosal and plasma amino aid onentrations after meals. J Clin Invest 1973; 52: Borgstrom B, Dahlqvist A, Lundh, Sjovall. Studies of intestinal digestion and absorption in the human. J Clin Invest 1957; 36: Mansbah CM, Cohen RS, Leff PB. Isolation and properties of the mixed lipid mielles present in intestinal ontent during fat digestion in man. J Clin Invest 1975; 56: Freeman HJ, Quamme GA. Age-related hanges in sodiumdependent gluose transport in rat small intestine. Am Jf Physiol 1986; 251: G Shemann M, hrlein H-J. Postprandial patterns of anine jejunal motility and transit of luminal ontent. Gastroenterology 1986; 9: Raimundo AH, Rogers J, Spiller RC, Grimble GK, Silk DBA. ffet of ontinuous intraduodenal enteral feeding on human oloni inflow volumes and small bowel motility. Gastroenterology 1989; 96: A Cosnes J, Parquet M, Gendre JP, Le Quintre Y, Levy, Raizman A, et al. L'alimentation enterale ontinue reduit la diarrhee et la steatorrhee des resetions ileales. Gastroenterol Clin Biol 198; 4: Spiller RC, Trotman IF, Higgins B, Ghatei MA, Grimble GK, Lee YC, et al. The ileal brake-inhibition of jejunal motility after fat perfusion in man. Gut 1984; 25: Spiller RC, Trotman IF, Adrian T, Bloom SR, Misiewiz JJ, Silk DBA. Further haraterisation of the ileal brake reflex in man - effet of ileal infusion of partial digests of fat, protein and starh on jejunal motility and release of neurotensin enterogluagon and peptide YY. Gut 1988; 29: Brown NJ, Read NW, Rihardson A, Rumsey RD, Bogentoft C. Charateristis of lipid substanes ativating the ileal brake in the rat. Gut 199; 31: Dreznik Z, Broksmith D, Meininger TA, Soper NJ. Inhibitory effet of ileal oleate on post prandial motility of the upper gut. AmJPhysiol 1991; 261: G Fone DR, Horowitz M, Read NW, Dent J, Maddox A. The effet of terminal ileal triglyeride infusion on gastroduodenal motility and the intragastri distribution of a solid meal. Gastroenterology 199; 98: Welh IML, Davison PA, Worlding J, Read NW. ffet of ileal infusion of lipid on jejunal motor patterns after a nutrient and nonnutrient meal. Am J Physiol 1988; 255: G Holgate AM, Read NW. ffet of ileal infusion of intralipid on gastrointestinal transit, ileal flow rate, and arbohydrate absorption in humans after ingestion of a liquid meal. Gastroenterology 1985; 88: Layer P, Zinsmeister AR, DiMagno P. ffets of dereasing intraluminal amylase ativity on starh digestion and postprandial gastrointestinal funtion in humans. Gastroenterology 1986; 91: Blakburn NA, Redfern JS, Jarjis H, Holgate AM, Hanning I, Sarpello JHB, et al. The mehanism of ation of guar gum in improving gluose tolerane in man. Clin Si 1984; 66: Jenkins DJA, Wolever TMS, Leeds AR, Gassull MA, Haisman P, Dilawari J, et al. Dietary fibre, fibre analogues, and gluose tolerane: importane of visosity. BMJ 1978; 1: Shinnik FL, Hess RL, Fisher MH, Marlett J. Apparent nutrient absorption and upper gastrointestinal transit with fibre-ontaining enteral feedingsl13 Am Jf Clin Nutr 1989; 49: Guedon C, Shmitz J, Lerebours, Metayer J, Audran, Hemet J, et al. Dereased brush border hydrolase ativities without gross morphologial hanges after prolonged total parenteral nutrition of adults. Gastroenterology 1986; 9: Kotler DP, Levine GM, Shiau Y-F. ffets of nutrients, endogenous seretions, and fasting on in vitro gluose uptake. Am J Physiol 198; 238: G Cortot A, Phillips SF, Malagelada J-R. Parallel gastri emptying of nonhydrolysable fat and water after a solidliquid meal in humans. Gastroenterology 1982; 82: Gut: first published as /gut.35.1_Suppl.S5 on 1 January Downloaded from on 16 August 218 by guest. Proteted by opyright.