Update in small bowel physiology : Part 1

The recent advances in clinically important diseases of the small 
intestine have been reviewed; however, the basis for many of these clinical 
advances rests with important observations on alterations in the physiology of 
the small intestine, as well as mechanistic observations of alterations in small 
intestinal function in models of human disease. In this review a summary of the 
past year's literature is presented which will draw attention to the considerable 
areas of progress in small bowel physiology which will soon be translated into an 
improved understanding of the pathophysiology of a variety of intestinal disorders.

Human intestinal vesicles: n-glucose and L-leuc1ne Lransport have been c haracter izeJ 1n human tntest inal BBM ve 1cles nbtameJ from organ donor intestine.The magnitude of their transport under sodium gradient conJ1tio ns 1s higher for prox11nal than J1srnl mtestinc ( 11 ).EaJ1c-Hofstce plm ana lysis suggests that there 1s a high-affinit) transport system a long the length of the human sma ll mtesrinc.A second lowaffinity high-flux transport system is lim1teJ to the JeJunum.It has hecn sugge:;reJ chat two glucose trnnsporters coexist 111 animnl intesunc ( 12 ).n-glucose transport 111to rat JCJunal BBM \'Csicles 1s un affec ted hy the va nauon in morphology nrising from the tec hnique used to punfy the membranes.Membrane preparauons yielded s imilar 1-lofstee transformations, Jisplaymg the curvi linear relationship thought to be consistent with the cxbtencc of multi -244 pie BBM t ranspnrters for D-glucose ( 13).Both high -and low-affinity transporter, for P-glucose arc fully expressed 111 the small 111tc,r111e when glucose uptake is measured 111 BBM vesicles of newhnrn pig lets ( 14).It must be stressed, hnwevcr, th,ll two glucose transporters in the BBM have nm been iJcnrif1cJ by methoJ~ of molecular hiolog).Adaptive regulation: The BBM gl ucose Lranspmtcr is suhicct to aJaptive rcgulal ll)n.It 1s poss1hlc hut a, yet unproven, that l here is ,1 smglc RBM sodium/ glucose cncrnnsporrer which has different kmettc pn1pemes dependent, for example, on the dietary content of lipids.Brasuus anJ co-workers ( 15) h,1, e deml,mtr.nedthat RBM w,1c.lest,ht,11m•d from JeJun,11 cntcroc y1cs of rats fed fob titl (an omcga-3 polyunsaturated fatty ac1d-contaming lipiJ) have a higher maximal transport race than ves icles obrn ineJ from animab fed hurter fat (saturated fatty ,1Ci<ls).Races of sn<lium-depenJent glucose transport are high in the villus tip hut lower in enterocyte from the crypts ( 16).These kmettc differences may be due to variations in the fluiJicy of the BBM ( 17).
Thus, the n -xylosc tolerance tcst I ikely reflects the stare of the jqunal mucosa I BBM surface area and priss1vc intestinal permeahility ra th c 1 than active nutrient ahsorption Lapacity.

AMINO ACIDS, PROTEINS AND PEPTIDES
Proteins wh 1ch contain large amounts o f prnl 111e arc not readily hydrolyzed hy most digest ivc proteases.Yet proteins such as collagen, gl ,adtn and casein arc 11nportant dietary constituents.BBM carboxypepu dase may play an important role in the digestion of proline -con ta in111g pe ptide~ and proteins ( 31 ).The rnrhoxypepuJase in BBM of rat enterocyie, ,, d ist met from pancre,itic proreases, h a, maxunal acnvity in the 111id-region of the small intestine, and is twice as acrive in villus as in crypt cells.
Glutamine, a neutral nonessential amino ac id, acts as a precursor for other am ino acids and for vario us nucleoude,.The small mtcstine is a major si re of glurnmine metabolism.Gl uramme 1s delivered to th e small intestine from the lumen as well a, from the arterial blood supply, a nd b rapidly h ydrolyzed under the action of RBM transpeptidases and intracellular glutammases.(,l urnm tne uptake into dog RRM \'esicles occ ur~ v ia two tran~port processes: a sndium -depcndent high-affini1 y sy,tem si milar to the nelllral BBM sy,tcm a nd a ,od1umind cpcndent lower-affin it y pathway (32).
Taurme is a hera-c11ninn acid that represents lll1c d the most ,thundant free a111inn acid, tn 1hc hndy.It c.an he ~ynt lws1:ed in adult humans, hut h10synthet ic cnp,ictty 1s almo.st negl1g1hlc in rhc human fetus and tnfant.Thus, m resunal ahsorptton of dietary rnunne pmhably reprt'sents the only source of this essential nutrient during ea rl y postnatal develnpment.Intestinal absorp-r1on may abo he important in meeting taurine requirements in adu lts.Uptake 1s s11dium-dependent, with one chloride and rh ree sodium ions involved for the transport of each rnurine molec ule ( 1, ).
Regu lation llf int estinal ahsl1rpuon 1:-,y dietary substrate lc\'els has reLeiveJ much attention in rhe case o f sugar and amino aLids.The naturally 11ccurring d ipeptide carnosme ts absorhed mtact from the gllt lumen and ts not hydrolyzed until it reaches the liver and kidneys.A high protein diet stimulatl's carnmtne uptake into evened intestinal sleeves llf mice, even in the presence nf peptidase 111hihirnrs that hlock cell .,urface hydrolysis of d ipeptidcs.Thus, carnnsine uptake is reguhited hy dietary le,•cls of am mo acids, pl'ptides and proteins, a ll of which see m e4uall y effecm•e in the 1nd11ctinn of cam 11stne rrnnsporter., ( 38).Howevl'r, tlw regulatlirs of ead1 pn,cess m vol\'ed CAN J GASTR\1f:NTl::Rtll Vrn 4 Nl) 6 Sl• l'Tl:MBER/lx ,URLR 1990 Small bowel physiology I in protetn Jigest1un a re not nece,,nrily that proce~s's .,uhstrate ( 39).Food hypersensitivity: T h e top ic of disea~es of fi1od hypcrscm1t1\'ity has hcen reviewed (40).Food mcolerance ts a common hut controversial cl mical problem.The 1m1Jortry nf a ll erg iL re,,cn ons appear to be due to a type I 1m-munogll1bu I in E (IgE)-dependenc h ypersensitiv ity.In an animal ml1del of a naph ylaxis, munune-mediated rea ction lll (ood protein wall associa ted with diarrhea as well as altered intestinal myoclcctri c a nd motor activity (41).The mucosa may appea r struc turall y normal hy light microscopy.In 10 intanr.sand children \\•tth c h mnic d iarrhea .1,suLiatedwith dietary protein int11lernnce, the most striking and con-,is tent f1nd111g on scanning and electron microscopy llf en tcrocyccs was the widespread lo~s nf surface glycocalyx lrom the surfacc nf entcrncyics (42).
Immediate (type I) hypersensitivity reacuon~ m the gut are frequently accompanied by disturbed intestina l func -1 ion including vomittng, abdominal cra mps and diarrhea.When rats a rc infect cd with Tnchinella s/>iralis, there is mast cell prol ,fcrntion tn the muscle layers of the small bowel.Re-exposure to antigen resu lts in nrnsc cell degm nu I ,ll inn, 5-h ydroxyt ryp ra mi ne release and cnntrnc t ion of smooch muscle ( 4, ).The extent and seventy of mucosa I damage ,n t h e prox ,m a !duodenum and jejunum h as a c ritical heari ng on the development of clinical symptoms m chi ldren with cow's milk protein-sensiti ve enteropa thy ( 44 ).An assncrnt1on between n on-lgE milk enteropathy and previous m tav irus infernon has been demonstrated (45).It h as been postulated th a t viral infections induce dcregulat ion ofT suppressor cell funct ton leading to increased lgE synthesis.D ie tary prote in h ypersensi tivi ty is probably not the cause of colic m most healthy ynung mfants (46).Cow's milk allergy occurs with gastro-intestim1l manifestation:, during ea rly infancy and c;in be e lic ited by the ingesti on nf s ing le cnw's milk proteins.Developmental changes a lte ring the in-ternct1on between these proteins and c lements of the sma ll intestmal mucosa!FIN( ,l:R( )T!" cc a/ harrier an.• \lf mtcrl'M w thl' pcd 1a-tric1,tn.Nl'whmn BRM binds morl' cow\ mi lk protcm, than adult com rob with incre.1scdhindmgnf lmvcr rcl;111vt• to higher molecular wc1ghr protl'111s.
Maximal transport rntc (Vm,,x) anJ M1chael1s consta nt (Km) were tdentified.Pretreatment of the cells with a monospecific an11h0Jy to MrARP in-hihtteJ influx of o lcate, ,ls well as long c hain fatty aetds and n-monopa lmni n but not I -alan111c.In the presem.l' of ann -MrARP 111 vivo, oleate ahsorpuon was reduceJ (Figure 2).T his transpmt syMem has a high affinity for frmy acid with a Km of 93 nM.The preJomtnantly noncompern1vl' 111h1h1tton of o leate uptake suggested that this monospccific polyclnnal rahhtt anubody m,1y internet wnh va rious domains of the Ml ARI', leadtng to conformattonR I c hanges 111 t he protein, which a re accompa111cd hy 11npairmcnt of Its carrier funcuon.
ThL• small 111tcst111e contributes up LO I 0% of total cholesterol synthesis in pauents wnh normocholesterolcmia and up to 50% in those with hypcr-tholcstcwlem1a. Jn the 111tesune, htlc ac ids appear to he strong regulators of cholesterogenes1s.There is ;i lesser degree of feed hack regulauon of intestinal L holes1erngcnes1s by exogenous cholesterol.Cholesterol synthesis has been studied 111 organ culture of smnll howel h1opsie~ from children wll h different forms of malabsorption; for example, mtesr111al chole:,rernl synthesis is increased 111 pnt icnts with ccliac d isease (75).The mcrea:,ed intestinal cholesterol symhes1s and e~terification which uccur, in d1nbetes mell1tus 1~ rever~eJ by 111sul111 therapy, due to a direct effcLt of insul111 on the cncerocytcs (76).Thus, the regulntory system fiir choleMernl 111 entemcytes differ:, from that 111 mo t organs.

VITAMI NS
With ageing, there is a shift from porrnl w lymphatic transport of vitamin E, with an overall agc-a,sociated increase 111 the total vitamin E ahsorbed (86.87).
Thiamine ab orption occurs hy active transport at low conccntrat1om and by passive diffusion ,lt high concentrations.Severe fnlate deficiency has no cffeu on th1am me absorption (88).
The co ingestion of a I ight meal u( varied composition and calc ium enhances the effi c ien cy of calcium absorption (98).Lactose enhances calc ium ahsurption i• subj ects wtth normal lactase activity but decrease~ it in lactase-dcfi cient patients (99).Cilucose and galacwse inc rease calcium absorpuon, whereas laccitol decreases calcium absorption ( 100 ).Thus, dieta ry factors influence calcium absorptio n.Vitamin D, is absorbed in the in te~tine by a nonsaturahle passive transepithelial process.After penetrating rhe BBM, vitamin [)3 is transferred hy a carrier protein through the cycosnl to the intracellular organelles (J OJ).
Phospha te: In BBM vesicles isolated from human jejunum, both sod iumgradient-Jepende nt ca rrier-mediated transport anJ pass ive d iffus ion of phrn,phace have been identified (1 02 ).Uptake is primarily by passi ve diffusion, with most transep1thclial uptake occurring in che proximal small intestine.A 130 kDA polypeptide ha~ been tenrativcl y ide ntified as the intest in a l sodiu m-phosph ate cmramporce r.This polypept ide ba nd conrairn; both sodi um and phosphate suhstrate sites ( 103).
Zinc: Zinc is esse nti a l for human health; many meta lloenzymes involved in the me t,1bo l ism of carbohydrates.lipids, prote in and nucleic acids require : inc for their functions.Poor inrnke of : inc and ribsnrption defects have been prop osed as m ajo r ca uses of zinc deficiency.Acroderma t itis entertl• pathica is a zinc ma labsorption syndrom e which is transmitted v ia an autosoma l r ecess ive m ode of inh eritance, rind which, if untreated with zinc, is farn l in ea rl y childhood.Zinc absorpt ion involves both carrier-and nonmediaced components.ln 1mm the jejunum has the highest rate of absorption of : inc which is stimu lated by the presence of glucose in the intestinal lumen (104) .Zinc transport may invo lve chc action of a low mo lecular we1ghr zinc-binding liga nd wh ic h 1s present in huma n milk Hnd c hel<1 tes : inc ,111d carries it across the BRM.This I igand has nnt been identified 111 ww 's milk.In the rat small intestine it appears m he an arnchidonic ac id-like substance ( 105).7inc uptak e across the RBM hut not across rhe RLM is mc reased fo ll owing a shorr period of dietary zinc restriction ( 106).Zinc malahsorpt io n appears tll contribute to :111c deficiency in nonalcoholic c 1r-rhnt1cs a nd seems to result , in part, from pathologica l c ha nge~ in the mucosa ( 107).Iron: Em emcytes appear to be responsible for the regulation nf iron ahsorption.T here b enhanced uptake and transfer of iron tn the body when the dietary cnntent of mm 1s reduced or when bod y iron scores arc depleted.Ahsmbed iron stimulates ferritin synthesis in iron -defi c ient and iron -repleted anima ls.Iron defic ie ncy is associated with decreased mucosa!fe rri tin levels and increased mucosa!rransfcrrin content.The iron content nf the duodena l mucnsa of iron-defic ient animals is les~ than th at of control animab.As iron ab~orption and retention b greater in iron-deficient an imals, chis suggests H mucosa !m ec hanism which transfe rs mm to the blood side of mucosa more efficiently than in cont rol animals.This mechanbm might be at the basolateral side tif the absorb ing entemcytes ( I 08).
Desferrioxaminc is an irnn-chclac -CAN J GASTROENTFRt1L V()I 4 No 6 SEPTEMRER/0CTORER 1990 Small bowel physiology I ing agent tha t, admmistered o rall y, interferes with gut ahsorption nf inorgani c iro n .Administered pare ntera ll y, it himb iron and is excreted ,ls fcrrioxamine in bile and urine.Parenrerall y administered dcsfcrrioxrim i n e can enter the sma ll intesti na l mucosn, hind intrace ll ular imn a nd hlock the ahsorption of in o rgan ic iron, transferrin iron and hemoglobin mm ( 109).This suggests ch at all three iron spec ies enrer a common c hclarnble pool within the small intestinal mucosa, and may share a common pathway of ahsorpuon.
Bran inhibits the ahsorptilln l,f no nheme iron in man, due to its phytate content.S hore term stud ies suggesr tha1 hi gh bran and phytate in rake over prolo nged periods might induce chan -ge~ in the intestinal absorption of mm.From a long term perspective, iron absorptitin is fo rtunately similar in vege-1 ;1r1.in., with a regular high phyrnte intake a~ in a contro l group ( J JO). Egg white and soy bea n protein inhibit iron absorptio n in humans, whereas substitutin n of heef, lamb, pork, li ver, fish llr c hicken for egg white resu lts in enhanced iron absorption .Casein and whey protem 111 hovme mi lk appear to be responsible, at least in pare, for the poor bimw.1 ilahiliry of iron in some infont formu las ( 111 ).Thus, the intest ma! absorption nf iron is influenced by bndy stores of iron but also by the contem of ocher nutrients in the inte~tinal m ucnsa.