Update in small bowel physiology : Part 2

ABSTP ACT: The recent advances in clinically important diseases of the small intestine have heen reviewedi 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 1nrestinal func Lion in models of human disease. In this review a summary of Lhe past year's literature is presented which wi ll draw attention to the considerable rrogress in small bowel physiology which will soon be translated into an impwvcd understanding of the pathophysiology of a variety of intestinal disorders. CanJ Gastroenterol 1990;4(8):503-516

T l IE RECENT Al)VANCES IN CL!Nl- cally important diseases o( the small mcesti ne have been reviewed ( I ); however, the ha~b for many of these clinical advances rcMs wi1h important observ.iuonson ;ilcerations in the physiology nf the small imestine, as we ll as mcchanbtic ohscrvations of a lterations in small intcstimil function in models of human di~easc.In this review a ~ummary of the ra:,t year\ li terature i~ presented which will draw mtenrion to the cons 1derahlc rrngres~ in s mall hmvcl physiology which will sllon he trnn~lated into an imrrovcd undersrn ndmg of the pachophysiology of a variety of imest inal disorders.
Villus-crypt axis: Indi rec t evidence suggests that villus cclb arc the si tes pf absorption of nutrients and electrolyte, while crypt cells arc the sites o( secret ion .Th e sodium/hyJr\lgcn and ch loridc/bicarbonate exchanges ()CCur on the il ca l brush hordcr rnernhranc (BBM) a nd probably account for the coupling of sodium and chloride ,1h sorp tion.In v ii !u s ce ll s, sod iu m /hydroge n exchange ac ti vity has htcn d esc ribed on hoth the BRM and hasola tcrnl membrane (BLM), whereas in the crypt cells, sodium/hydrogen excha nge activity is fo unJ only on the BLM.ln contrast, c hloride/bicarbonate exchange activity is founJ only on the BBM in both villus and crypt ccl b (4).BBM vesicle scuJies dcmonstrnte th,11 sodium-stimulated alanine anJ glucose uptake is higher in upper villus versus c rypt ce lls (Figure I) .In cnntrast, chloride/bicarbon ate exch ange b relatively consrn nt, suggesting chat chis exc hanger is on the BBM of both villU1 and crypt ce lls.BBM sodium/ hyJrogen exchange, like glucose a nd alanine uptake, i~ lcs1 in cells harvested from the crypt an<l lo wer vi ll us; sodiurn/ hydr\lgen excha nge activity is onl y present in I3BM from villus cells.These results arc sum-marizeJ sche matically in Figu re 2.
Oral reh ydra ti on solution: Pat tenr, w11h sec rct11ry diarrhea retain the ahdny w ahsorh water a nd ,odium 111 the presence of gl ucose.This oberva.tion has pm\'1Jed a scientifi c rationale for rch yJ rnri ng ~uch patients wii h oral rehydration (glucose-elect rolyte) Sl)l uuon.The impo n an ce of inc ludi ng bicarbonate, citrarc :111d acetate moral rehydration sol ution is 1mcem1in (35).While these t hree anio n~ st imulate 1 1ater and sodium ah~nrpti on from the normal human jej unum , their specific effects in c1c utc diarrheal states c1 re unknown.fi1ca rhon a tc-and chloridecontai n ing g lu cose o r g lyc in e electrolyte solutions induce ,1 sign ificantly great er ahwrpt ion l)f ~odium , potassium and water in rat intestine cu mpareJ with t hose conta ini n g chloride only (36).In cho lera toxintreated small in testine, none of these aniom t1 ffectcd wmer and sodium secre-1100 in the ileum; m fac t, int he jej unum acetate and cit ra te actuall y cnhancc:d the secretory state fo r hoth w,itcr a nd sodium (37 ).Bica rhonatc-frce and h1carbomtc-contain in g o ral rchyJra-11onsolution may be equall y effecti ve in correcting deh ydratio n.A further sr11dy has even suggested that stnol output may be greate r in patients t rented with a bicarhonate-containing oral rehyd ration solut ion (38).This raises the pos-,ihil ity t hat inc lud ing hicc1rhnnate, acetate or citra te 111 oral rehydration ;olution ma y not promote wa ter anJ 1<xltum absorption in the secreting in-tCltine during acute diarrheal disease,.

INTESTINAL ADAPTATION
Small in tcstin c1 l pacing e nhances absorption from the canine small howel JnJ may be of henefit fo r mot ii ity disor-Jer., associa ted with d..:crea~ed transll rime (39) .After Jejuna I and ikal re~ecrnm in rats, postprandial mo tor activity m the small bowel is enhanced ( 40 ).This emrhasizes the role of intesti nal m otility in the process of c1daptat1nn .Glutamine: The inrestine prefers th e amino ac id glu tamine as its major fuel 10urcc.Glutaminase is th e entry e n-:ymc for oxidation of glutaminc.The activity of glutaminase is grea ter in cells 11()lated from the vill us-crypt junction than in cells 1solared from eithe r villus or crypt compartments ( 4 1 ).A lt hough 1ubstantial amo unts of glu tamine ;ire rnken up by mucosa I cell~.most appears mbe mecabolize<l to pyruvate.Up to 20 w30% of plasma glutamine is extracted with eac h ci rc ul ation t h ro ugh the me~e nt e ri c syste m for use by t he enterocytes and colonocytes.C urre nt parentern l nutrition solutions do not contain glutamine or glutamate.When glutamine-containing rornl parenteral nu trit ion (TPN) solution 1s given to n1ts, the intestinal ni trogen conte nt of the stomac h and cnlon is preserved as opposed t n wh e n standa rd TPN is given, ,111d the ni troge n content of small bowe l is greate r than t ha t of c h o w-fed a n im a ls (42).A ddin g glu rnminc inc reases mal rnse activity in th e small bowel and protects the li ver from fa tty infiltrat ion .Short chain fatty acids: S hon chain fat ty ac ids (aceta te, prop ionate a nd huryra te) nre normall y p roduced hy bac terial fcrme m ntion of diernry carbohydrates a nd film: polysaccharides in t h e colon and ahsorhed by colnn ic mucosa.lntraluminal as well as intrape ritonea l injections of sho rt c hain fo tty Hcids stimulate mucosa!proliferation in the Jejunum and ile um of normal ra ts.The addition of short c hain fatt y acids to T PN fo llowin g sm:111 hnwcl resccuon in adult rnts prevents t he resec tion-and TPN-as~oc iated loss of jejuna!mucosa!weigh t, DNA, RNA, p ro tein , ileal mucosa!we igh t and sodi um content (4 3).The time 1s ripe to explore the possible hcncfi ts of glutmnine and shore ch a m fou y ,1Cids m TPN so luuons (or huma ns. Focal epi thelial d bcontinuities of the small intest ine may he raridl y rescaled.S uc h rep,in1ti ve prncc:.sesmay suhstan t ial ly limit the d ele te rious ph ysiologica l impact of superfi cial intestinal injury ( 44 Likewise, phy~1nlog1cal concent rations of rolyamines may he involved 111 the regulatinn nf prmem synthei,is.Putrescine 1s a st imulant to ep1thd 1a l, DNA, RNA and protein syntheses in cultured fetal rat small intestine (55).
Putrcscmc b ,l h1ogen1c am ine which is a favoured subMrnte of the enzyme 508 diamine oxidase.The histaminediamine nxidase system 1s mvolved in muwsal prolifermion.Diamine oxidasc activity increased following 70% 1Tsection of the small intestine in the rm.l lowever, administration of a specific inhibitor nt' diamine oxida~c was without influence on mucosa!proliferation (57).Thi~ rai~es the question or the relevance of d1amine tlxidasc in mucosa!proliferation.
Polyammc levels, especially putrescine, fall after a single whole body dose on Gy irradiation.Therefore, measurement ti polynmine c1.mtent may be useful in monitoring the damage and recovery phases of rad iation injury in the sm::ill intestine (58).Inhibition of mnithine d1.•carboxylase activity by di fluoromethylorn i th inc attenuates prostaglandin-mediated trophic effects on the rat duodenum (59), suggesting that polyamines are required for the prostaglandin-stimularcd growth of rat duoden::il mucosa.
The di cal bowel of the neonatal rigiet has a low capaciry for generating oxidants via xanthine oxidase.A~ well, the neonarnl piglet ileum has higher superoxide dismutase activity and lower glurathione reroxidase acttvicy than is found in older animals (60).Neonatal piglet intestine may therefore have a lower capacity to detoxify hydrogen peroxide than the intestine of older animals.The importance of these obscrvat ions to the development of necrotizmg enterocolitis is unclear.
While the: BBM activity of sucrnsL' 1s cnrreh1ted \\'1th t hl' carhohydrate con tent ofi he diet, 11 is not affru cd hy .1gcrhroughout the adult lifcspan of the rat (77).The acutl' mcrca,e in ,ucr.isespecific activity followmg refccdmg h sim ilar in ,1dult and aged r.it,, suggesting that thl' carh(lhydratc:-d1gc:,ting capacity (1( the small intcsltnl' em eroc yte b not impaired during rhe age ing p rocess .Ind eed, the jejuna!BBM ac tiviti es of sucrase and isnmaltase inc rease with ageing in the nu (78 ).The inc re ased leve l o f intes tinal hydro xylase acriviry may be the consequence of prolonged cellular maturntion along the villi in the proximal intes tine, and of ,1daptatio n to increased con centrations of intrnluminal substrates in the distal intestine .Crypt cell production rate: U nde r steady-state conditions the intestinal crypt cell produc tion rate pa rall els the rate of v illus e pithelial cell loss.S tarvation reduces and refee<ling increases th e crypt cell production rate.C ompared with young a nimals, senescent rats sh ow increased basal DNA synthetic activ ity.S tarvatio n results in sma lle r decreases in DNA labelling nf crypt cells in sen escent rats and a brupt broadening of the prolife rative zone, witho ut con comitant inc reases 111 the numher of villus cells during refeeding.These findings suggest that the tight modulati on o f cell produc tion is disturbed during starvation and rcfceding in the se» esccnt rat.Ageing does no t impair the ahilities of rats 10 ma inta in norm::il v illus cell numbers.It may, h oweve r, be assoc i;itcd with al tered control l)f cell replicatio n and pro life ration (79) .Mechanisms: The mpic nf "neuromuscular func tion and dysfunctio n o f th e gastrointestinal tract in aging" has been rev ie wed (80).Wha t might he the mcchanism(s ) for age-assoc iated alterations in intestirn1l function ?The jejuna!BBM is a relati vely fluid structure at birth whi c h becom es prog ressivel y more rigid with age.Lipid permeability is greatest during the suckling period of rat s but d ec reases the reafter wh e n anima ls are placed o n cho w (8 1).Alterations in lipid permeability are correlated with maturation of the BBM.both in terms o f its lipid fluidity and chemical composition : the sta tic comronent of BBM fluidit y docs n ot cha nge fr o m the su c kling to th e weaning period, but decreased membrane lipid p e rme::ibilit y d ocs c Mre late with decreasing lirid fluidit y, as assessed by pr~lbes sensitive ro the d ynamic compon ent ofBBM lipid fluidity within rhe 510 supe rficial regic)nS o f the bilayer (Figure >) .Small imcstina l BLM lipid compos iti o n and fluidit y also umkrgnes o n-1ogen y during rh c weaning period (82 ).Absorption: Docs age affec t intestinal ahsorptio n !Ye~; for example, age-relnted c h an ges in smlium-d epcnde nr glucose trans po rt h a vc been J csc ri hed in rat small intestine (83 ).S ta lnikowicz and S tess man (84) h nve c unduc ted cl inical studies in 4 , pat1e n ts rangi ng in age from 65 to 96 years.Judged hy the no rmal D-xy lo~e rests in the absence o f stearnrrh ea, they suggested that impairm e nt of intest inal a bsorpti o n in a ge riatric centre was uncommo n. l ll1\V• eve r, g lu cose absorptio n in to BBM vesicles clhta ined fro m human small intestine demonstrated tha t the expected sodium-depe ndent 'oversh oot' phenome no n disappeared in the n ldest subjec ts (8 5) .Age-re l,1ted d eclines in intestin a l c,1lcium a bso rpti o n have been suggested in humans.In age ing rats, in v itro calcium uanspmt actuall y increases in senescence compared to adult animal:, (86) , with mainten an ce o f th e 1,25-(0 H) zD,-stimulated calc ium flu x being similar in six-and 26mo nth -old animals.The issue remains controversial since other workers (87 ) ha ve demon strated a d ecline in the max imum uptake capac ity of calcium in 24 -versus six-mo n t h-old rnts (con current wnh the decline in serum 1,25dih ydroxy D le ve ls) .Ho we ve r, th e calcium upta ke respom e in cells isolated fr o m se n esce nt rats was o nly s lightly less than that in cells from adult animals.Adaptation: The ca pac ity fo r howel mucosa!growth and adaptatio n after enterecromy is preserved into old age, but o ld and nm young anima ls completed their bowel ad aptive hyperplas ia m o re rapidl y and continued co lose weight (88) .Colonization: The ability LO colonize the sm a ll intestine is an impo rta nt virulence attribute of ente rotoxigenic E cnli.Pili arc prmc inaceo us, filamen tous appe ndages of the bacterial surface th at promo te the adhe ren ce lif cnteroroxigenic E coli to th e e pithelium o f the small intestine, the reby fa cilitating intestinal c,)lo niz,irion and causing diarrhea.Pilus-specific receptor~ must be availnhlc o n intestina l epi thelium f1,r pil us-med imcd adherence.In rnntrait to younge r anima ls, o lder pigs arc l\llt coloni zed hy e nt erntox ige n1 L E coli (89).poss ibly d ue to re leascnlrcccptors into the in testi n al lumen where thc1 fac ilitate bac ter ia l clcar,m ce raiher than adhe rence.

MOTILITY
T h e e n teric ne rvous system has been rev iewed ( 16,17).Theoretical m0Jd1 of inrestinal motili ty, inc luding relaxatio n osc illa tor equation~.have been considered (90).lleal brake: Infus ion o f li p id emulstlll\l into the human ileum de lays trnmll nl hot h a solid meal fro m mouth tncc:'um an d a liqu id m eal fro m mo ut h to ileum.T h b h as been te rm ed th e 'ilen l brc1kt'' Delay in smr1l l bowel tra nsit du ring 1le.il infusion of li p id ca n be explained h1 reductio n s in rhc rate nnd degrc( of propaga ti,rn of jej una !cnn tractiom.T he mechanism vari es accord mg to the type of m eal (91 ).W h ile long anJ medium ch ai n fo n y ac ids infu~ed mh, th e ileum exe n an m hi hi rory effect on jejuna [ mmili ty, whe n in.fused d imily in to t h e je junum , t h ese partiall1 d igested triglyceride~ ,iccelenne tran,11, increa~e jejuna I flow and alter the pat, tern nf jej una !con trac u om (92).The in fusion of t he hi le ac ids glycochenodeoxych o lic ac id and glycocholic ac1J in to th e intestine of healthy ~ubJ~Cll may in flu e nce smal l gu t motility (93) For examp le , short ch ai n fauy ac1J, stimu late human ilcal mou lity.Th1 1 respo n se is nor affected hy na lox one or indomc thac in (94 ), a nd may be ,11, snciated with a motor rcspo m c to coloileal reflux.Migrating myoelectric complexes: The mi gra t ing m yoe lcc tric complex i-a cycl ically occu rri ng phen o menon that hegim in th e stomach and duodenum and propaga tes w the ileum.Morphine ini tiates these C{1mplcxcs in the ,mall intestine of fasted humans, and n ha, hce n suggest ed th at an e ndngenou, op ioid may be involved in in itiating endogen o usly occ urring cnmplcxe,.In dogs, endogenous op ioids and npimJ receptors may ph1y a role in conrrnl of initiat ion of migra ting rn yoelectrtc co m p lexes.P r et reat m e nt with naloxorn: ht.'fort.' tht.' a<lm 1111stratton ,11 mnnlin dot.'s not hlock rhc 111111at1on of ,lKh complexes hy motilin, suggt•sung that moul111 .mdexogenous op101ds ,Kt \'la d,ffort.'ntmechanisms 10 1111tiatt.'migrating my1lclt.'cmccomplexes (95 ).Clonidine and cholecystokinin: The .,lpha-2 adrenergic:.agon1~t clon 1d111e afhr, inte~tinal motor function hy interamons w11h111 the brain and direct mtl'ractiom :11 the level of the inteMmt• (96).0rocccaltransit ume,dctermined ~I the lactulose brt.',Hh 112 method, was 111crea~ed an average of 70 1 \1 111 six normal healthy volunteers.Th,s marked t'lfrc:.tot clonidine on small bowel m,llil1ry may exrlam, at least 111 ran, chrnidine\ ant1diarrhcal prnpenu .. •s
The primary cause nf ethanol-induced epithcli,d d:11m1ge m,1y be n:hnd to contraction of the villus core and comp1-css1on of lymphattes ( l 16).In hu1rnrns, inhibiucm offorward prngrcssing and prnpulsinn waves has heen descrihed 111 response tn acute ethanol mgestinn.T his may be due tu decreased synthesis nf the cytoplasmic protein fraction, including the smonth muscle contnKtilc appa ratus ( 11 7).Thus, it is possihlc that functional disturbances 111 ethanol-exposed gut may nrise in part from change;, in smnoth muscle prntein turnover wi th decreased amounts nf contrac tile apparatu~.