Given the immeasurable human distress and health care burden associated with intestinal

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1 SPECIAL ARTICLE Emerging Therpies for Intestinl Filure Kelly A. Tppenden, PhD, RD Given the immesurble humn distress nd helth cre burden ssocited with intestinl filure, medicl therpies imed t intestinl rehbilittion re needed. Following mssive smll-bowel resection, the residul intestine is known to dpt structurlly nd functionlly in n ttempt to compenste for the resected portion. However, prenterl nutrition my be ssocited with mny short- nd long-term complictions, including prevention of intestinl dpttion nd promotion of mucosl trophy due to lck of stimulus provided by orl or enterl nutrition. However, dt herein demonstrte tht the ddition of butyrte, short-chin ftty cid produced in the colon by dietry fiber fermenttion, stimultes intestinl dpttion when dded to prenterl nutrition, indicting tht current solutions could be formulted to optimize intestinl dpttion nd to reduce dependence of individuls with intestinl filure receiving long-term prenterl nutrition regimens. Arch Surg. 21;1(6):2-32 It is truly plesure for me to prticipte in this symposium honoring Stnley J. Dudrick, MD, nd his pivotl contributions to our prctice of clinicl nutrition. Like those who spoke before me, I m grteful for the strong influence tht he hs used to positively mentor me; however, I differ from those sme individuls becuse I did not inherit his influence s birthright ssocited with my cdemic pedigree. In fct, I first met Dr Dudrick s young grdute student from Cnd, who ws t my first US meeting. I did not know soul! On his own initition, Dr Dudrick kindly styed fter my minisymposium presenttion nd discussed my reserch with me. He told me how importnt this work ws nd encourged me to keep it up becuse the future of our field depended on young scientists such s myself. I hve herd these words from him mny times since then, nd over time I begn to believe in myself s tht scientist tht he sw. I tell this story to demonstrte how grcious Dr Dudrick is with his mentoring influence. One does not need to hve gone to certin school or trined with prticulr individul. Dr Dudrick evlutes ech individul for where they Author Affilition: Deprtment of Food Science nd Humn Nutrition, University of Illinois t Urbn Chmpign. re t nd gives them encourgement nd his very best dvice. As he sid, we re responsible for the future of our discipline; however, rmed with the confidence nd wisdom tht he hs shred with us, I m confident tht we will strive to honor his legcy with our strongest commitment. With this commitment in mind, I would like to discuss the work of my reserch group tht focuses on intestinl filure. The hllmrks of intestinl filure re dirrhe, dehydrtion, electrolyte disturbnces, mlbsorption, nd progressive mlnutrition. The development of prenterl nutrition (PN) by Dr Dudrick is considered the most importnt fctor responsible for sving the lives of individuls with severe intestinl filure. Howrd et l 1 observed tht more thn 7% of individuls receiving home PN survive longer thn 3 yers, nd there re severl necdotl reports of individuls who hve been receiving PN for more thn 3 yers. Complictions exist, but the longterm vibility of this therpy provides window for us to mend the intestinl deficit, while the ptient remins in wellnourished nd functioning stte. Contemporry strtegies for mending this deficit include intestinl trnsplnttion nd intestinl rehbilittion. Stimulting the process of intestinl dpttion is strtegy to increse the sur- (REPRINTED) ARCH SURG/ VOL 1 (NO. 6), JUNE 21 2 Downloded From: on 12/13/21 21 Americn Medicl Assocition. All rights reserved.

2 fce re nd functionl cpcity of the residul smll intestine following mssive smll-bowel resection. Most of us re fmilir with the mrked trophic effect tht enterl nutrients hve on smll intestinl mucos. Exmples of jejunoilel bypss from the dys when this ws used s method of britric surgery provide us with cler demonstrtion of the hypertrophied functioning intestine compred with the trophied bypssed segment. Observtions such s these led to n re of reserch tht focuses on wht hormones or fctors could be dded to PN to provoke the dptive responses observed in the intestine whereby enterl nutrients re processed. Among the mny stimuli tht hve been studied to dte, discussed herein re the effects provided by short-chin ftty cids (s) nd glucgonlike peptide 2 (GLP-2). Nordgrd et l 2 sought to understnd wht ttributes were importnt to mximize energy bsorption in individuls with intestinl filure by nlyzing the importnce of the following 2 fctors: (1) the presence of functionl colon nd (2) the consumption of highcrbohydrte diet. Among humns with short-bowel syndrome, they determined tht energy bsorption could be mximized by consuming high-crbohydrte diet; however, the benefit ws only chieved when functionl colon ws present. There ws no dvntge to high-fiber diet in ptients with jejunostomy. They theorized tht the colon cted s scvenging digestive orgn in sttes of mlbsorption owing to the presence of intestinl microbiot tht served to ferment mlbsorbed crbohydrte nd soluble fiber. This fermenttion process tht llowed for energy cpture from these substrtes ws termed crbohydrte slvge nd is dependent on the colonic epithelium to presumbly bsorb nd oxidize the s produced by fermenttion. The s re group of gstrointestinl-specific fuels tht re product of nerobic bcteril metbolism of dietry fiber nd resistnt crbohydrte. Acette, propionte, nd butyrte re produced intrluminlly in n lmost constnt molr rtio of 6:: nd ccount for pproximtely % of formed s. 3 Among their vrious properties, s stimulte sodium nd wter bsorption in the colon, re quickly bsorbed by intestinl mucos, re high in cloric content, re redily metbolized by intestinl epithelium nd liver, nd re trophic to the intestinl mucos. In rts, the ddition of s to PN hs been shown to prevent PN-ssocited mucosl trophy nd to enhnce structurl mrkers of dpttion to smll-bowel resection. 6,7 Confirming work by Korud et l, 6 study by Tppenden et l reveled tht systemic s increse nutrient uptke nd messenger RNA (mrna) bundnce of the bsolterl hexose trnsporter glucose trnsporter 2 (GLUT2) following intestinl resection in rts. These findings re unique becuse they indicte tht specific nutrient (ie, ) my modulte the gene expression nd trnsport cpcity of other nutrients (ie, glucose, glctose, nd fructose). Furthermore, the observed increse in nutrient uptke indictes tht systemic nutrients (ie, those provided to the bsolterl side of the enterocyte, s in totl PN) cn increse the trnsport of luminl substrtes (vi brush border trnsporters) provided by orl or enterl nutrition. The concept tht s cn be provided intrvenously to prepre the intestinl brush border for effective digestion nd bsorption of enterl nutrients is prticulrly ttrctive for ptients with intestinl filure. The most direct interprettion of the bility of the colon to hrvest energy from fermented crbohydrtes in the form of s implies certin dvntge to n individul unble to digest nd bsorb consumed nutrients in the smll intestine. However, we postulted tht these products of colonic fermenttion my be involved in the regultory process wherein the distl intestine initites humorl signls tht stimulte the dpttion to begin. In essence, feedbck mechnism whereby mlbsorbed substrtes reching the distl intestine initite the cscde tht prompts the proximte intestine to expnd its digestive nd bsorptive cpcity is powerful scenrio. Furthermore, literture citing complex crbohydrte diet s role in incresing energy bsorption of those with short-bowel syndrome were dults only, 2 nd the potentil effect in peditric intestine cptured our ttention given the mny children with intestinl filure. Finlly, only cocktils of s hd been shown to be intestotrophic to tht point, - nd given the tight correltion of butyrte with intestinl prolifertion, we postulted tht it ws the effective mong those commonly studied. In project funded by the Ntionl Institutes of Helth (Bethesd, Mrylnd), we sought to test the hypothesis tht totl PN supplemented with butyrte lone will rpidly increse the indexes of intestinl dpttion in the neonte nd tht these dptive responses will be ssocited with incresed plsm GLP-2 concentrtion. Neontl piglets (n=126) were obtined from locl swine producer within 2 hours of birth nd underwent superior ven cv cnnultion, swivel plcement, nd % proximl jejunoilel resection. Littermte piglets with similr body weights were rndomized to 1 of the following tretment groups: (1) stndrd PN, (2) stndrd PN plus 6mM s (3mM cette, 1 propionte, nd 9mM butyrte), (3) stndrd PN plus 9mM butyrte, or () stndrd PN plus 6mM butyrte. Within ech diet group, nimls were further rndomized (6 per group) to receive infusions t vrious time points fter surgery to llow for exmintion of short-term (, 12, or 2 hours) nd long-term (3 or 7 dys) dpttions. A criticl feture of this experimentl design ws the neontl piglet model of intestinl filure with nutritionl support. The neontl piglet is n excellent niml model for the humn infnt becuse of similr pthwys of nutrient digestion, bsorption, nd metbolism In ddition, the neontl piglet is commonly used model for the prenterlly fed infnt 13- nd is known to be suitble model for investigting therpeutic modlities for short-bowel syndrome in humns Heemskerk et l 1 vlidted the piglet intestinl filure model to ensure tht it resembled the complictions of short-bowel syndrome in humn neontes nd demonstrted tht the model induces impired body weight gin nd dpts the remining bowel t the tissue nd cellulr levels. In ddition, the neontl piglet experiences clinicl complictions comprble to those of the humn neonte receiving PN such s intestinl trophy, filure to thrive, nd ctheter sepsis. 21 Furthermore, the full-term neon- (REPRINTED) ARCH SURG/ VOL 1 (NO. 6), JUNE Downloded From: on 12/13/21 21 Americn Medicl Assocition. All rights reserved.

3 Villous Length, µm Control 9Bu 6Bu Ileum: Control < Tretments, P<.1 Figure 1. llel villous length ws incresed (*P.1) following tretment with control prenterl nutrition or supplementtion with short-chin ftty cid () cocktil, 9mM butyrte (9Bu), or 6mM butyrte (6Bu). Modified from Brtholome et l. 23 tl piglet hs body composition similr to tht of the premture humn (23-31 weeks gesttion), permitting more invsive methods of investigtion while mintining clinicl relevnce. 22 Wheres humn infnt doubles its birth weight by to 6 months, the piglet doubles its birth weight in the first 7 to 1 dys of life, providing rpid model of growth nd development for focused investigtions.,22 A fundmentl observtion clrified by this reserch is tht s enhnce structurl nd functionl ttributes of intestinl dpttion in the neontl intestine fter resection, s ws previously shown to occur in the dult rt intestine. 6 Intestinl dpttion ws observed using vrious structurl spects (intestinl weight or length, mucosl weight or composition, morphologic structure, nd epithelil kinetics) nd functionl spects (discchridse ctivity, ion nd nutrient trnsport, nd mrna nd protein bundnce of enterocytessocited nutrient trnsporters). These effects re detiled in the literture, 23 nd representtive dt demonstrting these dpttions re shown in Figure 1 nd Figure 2. Butyrte is the responsible for the increse in structurl nd functionl dpttions following intestinl resection in neontl piglets, s evidenced by lmost identicl effects of 3 s (36mM cette, 1 propionte, nd 9mM butyrte) compred with 9mM butyrte lone. Structurl nd functionl ttributes of intestinl dpttion reveled tht butyrte ws the responsible for the dptive results observed with the cocktil. This point is clerly shown in Figure 1, wherein ilel villous length ws incresed (P.1) in ll 3 -supplemented groups compred with the control PN group following mssive smll-bowel resection in neontl piglets. This expnsion of the villous epithelium ws due to n increse in epithelil prolifertion, s demonstrted by n incresed (P.1) number of prolifertion cell nucler ntigen stined cells per crypt (Figure 2), supported by similr increses (P=.) in mucosl DNA concentrtion. No difference ws observed between the cocktil-, 9mM butyrte-, or 6mM butyrte-treted groups in ny of the dependent vribles ssessed. Intestinl dpttion ws ffected t short- nd longterm time points by butyrte; however, structurl nd functionl dpttions did not occur in prllel. Exmintion of the results obtined in this study 23 reveled tht mny structurl ttributes of intestinl dpttion were ltered by butyrte, with increses (P.1) observed s erly s hours fter tretment (Figure 2). However, this observtion ws not widespred, reveling dichotomy between the structurl nd functionl dpttions ssessed. For exmple, ilel peptide trnsporter 1 (PepT1) trnsport ws pproximtely hlf tht of the control group fter 3 dys of butyrte tretment; by dy 7 of butyrte tretment, PepT1 ctivity ws incresed lmost -fold compred with tht of the control group (Figure 3). Dt such s these demonstrte tht the process of intestinl dpttion cn be ugmented within hours of stimultion; however, they underscore the concept tht structurl nd functionl dpttions re regulted by distinct signls nd likely represent lg ssocited with differentition of newly proliferted cells in the crypt to those expressing functionl proteins, such s PepT1 within the upper villous region. The use of time course to uncouple the short- nd long-term timing of the structurl nd functionl dpttions fter resection remins n importnt component of future work. Butyrte ffects intestinl function in short- nd longterm mnners. Despite the dt in Figure 3 showing tht some functionl ttributes (such s PepT1 ctivity) my require epithelil differentil nd time for the effects of butyrte to be fulfilled, other evidence reveled shortterm effects of butyrte on nutrient trnsport. 23 However, novel observtion in our lbortory demonstrted tht physiologic concentrtions of luminl butyrte (1mM) increse (P.) sodium-glucose cotrnsporter 1 ctivity more thn 2-fold within minutes of exposure (Figure ). 2 We re testing the hypothesis tht the mechnism whereby butyrte medites this response is vi fcilittion of recruitment of intrcellulr pools of SGLT-1 to the brush border membrne. Butyrte dministrtion increses GLP-2 plsm concentrtion, thereby reveling potentil regultory mechnism. At ll short- nd long-term time points studied fter intestinl resection in neontl piglets, plsm GLP-2 concentrtion ws incresed (P=.7) in the groups treted with supplementl totl PN (, 9mM butyrte, nd 6mM butyrte) compred with the control group (Figure ). 23 However, despite our initil hypothesis tht this increse in GLP-2 ws the mechnism whereby butyrte incresed intestinl dpttion, the dt we generted led us to postulte tht, lthough some of the effects observed with butyrte my hve been medited by GLP-2, others re likely due to the direct effects of butyrte. For exmple, our work studying the GLUT2 promoter found tht butyrte ctivted this promoter, wheres GLP-2 did not. Similrly, the cute effects of butyrte on SGLT-1 ctivity (Figure ) were not recpitulted with GLP-2 tretment. Finlly, using rt intestinl resection model, we determined tht inhibiting GLP-2 ctivity vi use of the truncted GLP-2 metbolite (3-33), shown to be receptor ntgonist, only prtilly inhibited specific structurl nd functionl ttributes of intestinl dpttion. 26 Butyrte lone is lso responsible for ctivtion of the GLUT2 promoter. The conclusion tht butyrte is the effective regrding intestinl dpttion ws sup- (REPRINTED) ARCH SURG/ VOL 1 (NO. 6), JUNE 21 3 Downloded From: on 12/13/21 21 Americn Medicl Assocition. All rights reserved.

4 2 Control PCNA-Stined Cells/Crypt Bu 6Bu Acute, h Chronic, d Ileum: Control < Tretments t h, 12 h, 2 h, 3 d, nd 7 d, P<.1 12 h 1 Figure 2. llel epithelil prolifertion ws incresed (*P.1) following tretment with control prenterl nutrition or supplementtion with short-chin ftty cid () cocktil, 9mM butyrte (9Bu), or 6mM butyrte (6Bu). PCNA indictes prolifertion cell nucler ntigen. Sections shown re from the 12th-hour time point nd visulized t 1 mgnifiction strength. Modified from Brtholome et l. 23 A Δ Isc/g/3 d (1mM Glysr) TPN 9Bu 6Bu Glucose Δ Isc, µa/cm b Luminl Butyrte Exposure (1mM), min B Δ Isc/g/7 d (1mM Glysr) TPN 9Bu 6Bu Figure 3. Activity of the ilel peptide trnsporter 1 following tretment with control totl prenterl nutrition (TPN) or supplementtion with 9mM butyrte (9Bu) or 6mM butyrte (6Bu) t 3 dys (top) nd 7 dys (bottom) following intestinl resection in piglets. *P., butyrte vs TPN or short-chin ftty cid () tretments. Glysr indictes glycylsrcosine; Isc, short-circuit current. Figure. Ilel sodium-glucose cotrnsporter 1 ctivity is upregulted (P.) within minutes of luminl exposure to physiologic concentrtions of butyrte (1mM), s mesured in modified Ussing chmbers. Brs with different letters re significntly different from ech other. Isc indictes short-circuit current. 2 Plsm GLP-2, pmol/l Control 9Bu 6Bu Control < Tretments, P =.7 Figure. Plsm glucgonlike peptide 2 (GLP-2) concentrtion is incresed (*P=.7) by ll short-chin ftty cid () supplements, including butyrte lone, following intestinl resection in neontl piglets. 9Bu indictes 9mM butyrte; 6Bu, 6mM butyrte. Modified from Brtholome et l. 23 ported by in vitro dt exmining upregultion of the humn GLUT2 promoter by butyrte using Cco2-BBe monolyers. In n in vitro system devoid of GLP-2, butyrte incresed GLUT2 mrna bundnce nd induced promoter ctivity in dose-dependent fshion (P.1 for both), wheres cette nd propionte did not (Figure 6). 27 As such, focused experiments re needed to identify the criticl components of intestinl dpttion nd to yield conclusions regrding the reltive contributions of butyrte nd GLP-2 during the vrious phses of this process. It is possible tht butyrte initites dpttion directly; however, it is more likely involved in cscde of dptive meditors, of which GLP-2 is strong cndidte. Indeed, experimentl evidence indictes tht there re likely seprte signls for short- vs long-term dpttion, 23 s there re for structurl vs functionl dpttion 23 ; therefore, understnding signling molecules during ech of these phses requires further study. In summry, the dt using relevnt preclinicl model of peditric short bowel syndrome indicte tht butyrte is the responsible for incresed structurl nd functionl indexes of dpttion nd tht these structurl nd functionl dpttions of the residul intestine re ltered t the short- ( hours) nd long-term (7 dys) time points studied. Armed with this knowledge, we seek to estblish cliniclly fesible methods for dministering butyrte to humn infnts with intestinl filure to stimulte structurl nd functionl dpttions of their smll (REPRINTED) ARCH SURG/ VOL 1 (NO. 6), JUNE Downloded From: on 12/13/21 21 Americn Medicl Assocition. All rights reserved.

5 Fold Increse in RLU/mg of Protein Control 1296/22 pgl3-luc /22 Empty pgl3-luc Acette intestine. We postulte tht the strtegic provision of prtil enterl nutrition, specificlly formulted to ugment butyrte production by the inclusion of prebiotics nd probiotics, will promote structurl nd functionl dpttions in neontl piglets with short bowel syndrome by enhncing mucosl surfce re nd nutrient processing cpcity, thereby prepring the residul smll intestine for proper digestion nd bsorption of enterl nutrients. Indeed, the dministrtion of butyrte directly to the intestinl mucos, compred with systemiclly s in our previous investigtions, my be even more efficcious. If the mechnisms by which butyrte stimultes intestinl dpttion re reveled using cliniclly fesible dministrtion strtegy, then the timing, route, nd composition of nutritionl support could be optimized to promote intestinl dpttion in children with intestinl filure nd to reduce their long-term dependence on PN. By enhncing the lives of children with intestinl filure, we honor the legcy of Stnley J. Dudrick, MD, wherein sustining their lives becme possible. Accepted for Publiction: September 2, 29. Correspondence: Kelly A. Tppenden, PhD, RD, Deprtment of Food Science nd Humn Nutrition, University of Illinois t Urbn Chmpign, 3 Bevier Hll, 9 S Goodwin Ave, Urbn, IL 6121 (tppende@illinois.edu). Finncil Disclosure: None reported. Funding/Support: This work ws supported in prt by grnt 762 from the Ntionl Institute of Dibetes nd Digestive nd Kidney Diseses. Previous Presenttion: Presented in prt t the Dudrick Symposium honoring Stnley J. Dudrick, MD; Mrch 2, 29; New Hven, Connecticut. REFERENCES Propionte 1. Howrd L, Hephey L, Fleming CR, Lininger L, Steiger E. Four yers of North Americn registry home prenterl nutrition outcome dt nd their implictions for ptient mngement. JPEN J Prenter Enterl Nutr. 1991;(): b Butyrte c 1 Figure 6. Response of the glucose trnsporter 2 promoter in Cco2-BBe cells to short-chin ftty cid () tretment. Cco2-BBe monolyers were treted with for hours before hrvest. Butyrte incresed (P.) promoter ctivtion compred with ll other tretments. Brs with different letters re significntly different from ech other. RLU indictes reltive light units. From Mngin nd Tppenden Nordgrd I, Hnsen BS, Mortensen PB. Colon s digestive orgn in ptients with short bowel. Lncet. 199;33(9): Cummings JH. Colonic bsorption: the importnce of short chin ftty cids in mn. Scnd J Gstroenterol Suppl. 19;93(suppl 7): Rombeu JL, Kripke SA. Metbolic nd intestinl effects of short chin ftty cids. JPEN J Prenter Enterl Nutr. 199;1()(suppl ):11S-1S.. Korud MJ, Rolndelli RH, Bliss DZ, Hstings J, Rombeu JL, Settle RG. Prenterl nutrition supplemented with short-chin ftty cids: effect on the smllbowel mucos in norml rts. Am J Clin Nutr. 199;1(): Korud MJ, Rolndelli RH, Settle RG, Zimmro DM, Rombeu JL. 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Supplementtion of totl prenterl nutrition with butyrte cutely increses structurl spects of intestinl dpttion fter n % jejunoilel resection in neontl piglets. JPEN J Prenter Enterl Nutr. 2;2(): Chung BM, Gilbert DZ, Tppenden KA. Luminl butyrte elicits rpid increse in ctive glucose trnsport in the rt ileum. JPEN J Prenter Enterl Nurtr. 2; 2(1):.. Thulesen J, Knudsen LB, Hrtmnn B, et l. The truncted metbolite GLP-2 (3-33) intercts with the GLP-2 receptor s prtil gonist. Regul Pept. 22; 13(1): Fust KL, Chung BM, Powell KL, Tppenden KA. The modest ddition of prebiotics to n elementl liquid diet llevites the intestinl compromise ssocited with wening syndrome in piglets [bstrct]. Gstroenterology. 26;13() (suppl 2):A Mngin HF, Tppenden KA. Butyrte increses GLUT2 mrna bundnce by inititing trnscription in Cco2-BBe cells. JPEN J Prenter Enterl Nutr. 29; 33(6): (REPRINTED) ARCH SURG/ VOL 1 (NO. 6), JUNE Downloded From: on 12/13/21 21 Americn Medicl Assocition. All rights reserved.