PO Box 2345, Beijing 100023, Chin World J Gstroenterol 2007 Februry 7; 13(5): 748-753 World Journl of Gstroenterology ISSN 1007-9327 wjg@wjgnet.com 2007 The WJG Press. All rights reserved. CLINICAL RESEARCH Chios mstic tretment of ptients with ctive Crohn s disese Andrin C Klior, Mri G Stthopoulou, John K Trintfillidis, George VZ Dedoussis, Nikolos K Andrikopoulos Andrin C Klior, Mri G Stthopoulou, George VZ Dedoussis, Nikolos K Andrikopoulos, Deprtment of Science of Dietetics-Nutrition, Hrokopio University, Athens, Greece John K Trintfillidis, Deprtment of Gstroenterology, Sint Pnteleimon Generl Stte Hospitl, Nice, Athens, Greece Supported by grnt from the Chios Gum Mstic Growers Assocition Correspondence to: Dr. Andrin C Klior, Deprtment of Science of Dietetics-Nutrition, Hrokopio University of Athens, 70 El. Venizelou ve., Kllithe 17671, Athens, Greece. klior@hu.gr Telephone: +30-210-9549303 Received: 2006-11-02 Accepted: 2006-12-21 Key words: Chios mstic; Crohn s disese; C-rective protein; Cytokines; Antioxidnt potentil; Conservtive tretment Klior AC, Stthopoulou MG, Trintfillidis JK, Dedoussis GVZ, Andrikopoulos NK. Chios mstic tretment of ptients with ctive Crohn s disese. World J Gstroenterol 2007; 13(5): 748-753 http:///1007-9327/13/748.sp Abstrct AIM: To evlute the effectiveness of mstic dministrtion on the clinicl course nd plsm inflmmtory meditors of ptients with ctive Crohn s disese (CD). METHODS: This pilot study ws conducted in ptients with estblished mild to modertely ctive CD, ttending the outptient clinics of the hospitl, nd in helthy controls. Ten ptients nd 8 controls were recruited for 4-wk tretment with mstic cps (6 cps/d, 0.37 g/cp). All ptients successfully completed the protocol. CD Activity Index (CDAI), Nutritionl Risk Index (NRI), C-rective protein (CRP), interleukin-6 (IL-6), tumor necrosis fctor-lph (TNF-α), monocyte chemotctic protein-1 (MCP-1), nd totl ntioxidnt potentil (TAP) were evluted in the plsm t bseline nd t the end of the tretment period. Results were expressed s men vlues ± SE nd P < 0.05 ws considered to indicte sttisticl significnce. RESULTS: Ptients exhibited significnt reduction of CDAI (222.9 ± 18.7 vs 136.3 ± 12.3, P = 0.05) s compred to pretrement vlues. Plsm IL-6 ws significntly decresed (21.2 ± 9.3 pg/ml vs 7.2 ± 2.8 pg/ ml, P = 0.027), nd so did CRP (40.3 ± 13.1 mg/ml vs 19.7 ± 5.5, P = 0.028). TAP ws significntly incresed (0.15 ± 0.09 vs 0.57 ± 0.15 mmol/l uric cid, P = 0.036). No ptient or control exhibited ny kind of side effects. CONCLUSION: The results suggest tht mstic significntly decresed the ctivity index nd the plsm levels of IL-6 nd CRP in ptients with mildly to modertely ctive CD. Further double-blind, plcebo-controlled studies in lrger number of ptients re required to clrify the role of this nturl product in the tretment of ptients with CD. 2007 The WJG Press. All rights reserved. INTRODUCTION Crohn s disese (CD) is chronic inflmmtory disese of unknown etiology tht my ffect ny level of the gstrointestinl trct [1-3]. It is well estblished tht immunologicl mechnisms re involved in the pthogenesis of the disese. Inflmmtory cytokines, such s interleukin-6 (IL-6) nd tumor necrosis fctor-lph (TNF-α), hve pivotl role in induction nd mplifiction of the inflmmtory cscde. Prticulrly, IL-6 stimultes T-cell nd B-cell prolifertion nd differentition [4], while it medites the heptic expression of cute phse proteins [5]. Incresed concentrtion of TNF-α nd monocyte chemottrctnt protein-1 (MCP-1) hve been reported in ptients with CD [6]. Additionlly, during chronic inflmmtion, when sustined production of rective oxygen nd nitrogen species occurs, ntioxidnt defenses my weken, resulting in sitution termed oxidtive stress [7]. Thus, in ptients with CD, elevted oxidized lowdensity lipoprotein levels hve been reported compred to helthy controls [6]. Despite the lrge number of therpeutic gents vilble tody, none cn be considered s completely stisfctory either due to resistnt cses or becuse of significnt side effects. To our knowledge, there re only scttered reports of nturl compounds tht potentilly reverse relpse in CD. Trebble nd co-workers [8] demonstrted n nti-inflmmtory ctivity of fish oil nd ntioxidnt supplementtion evluted in mononucler cells of CD ptients, while Lvy et l [9] demonstrted the effectiveness of the ntioxidnt β-crotene in rt model s prophylctic dietry mesure in reducing the effects of cid induced enteritis, thus rising the possibility tht ptients with CD my benefit from the consumption of nturl β-crotene. Also the flvonoid rutin, wellestblished ntioxidnt compound, hs been suggested s therpeutic gent in CD. Rutin hs been shown to ttenute pro-inflmmtory cytokine production in both colonic
Klior AC et l. Chios mstic in Crohn s disese 749 mucos nd peritonel mcrophges of experimentl nimls [10]. Tretment with food phytochemicls hs been shown to be sfe, sustinble nd prcticl nd chnges of dietry hbits hve been dvocted in the therpy of CD [11]. Pistci lentiscus vr. Chi (Ancrdicee), well known s Chios mstic gum, is n evergreen shrub widely distributed in the Mediterrnen region. Mny ncient Greek uthors, including Dioscurides nd Theophrstus, mentioned Chios mstic for its heling properties in intestines, stomch nd liver. Mstic hs lso been reported to possess ntioxidnt [12] nd ntibcteril [13] ctivity. With reference to gstrointestinl disorders, the effectiveness of the resin ginst peptic ulcers is evident [14] in most studies, while only in two reports there is no effect on H pylori erdiction in vivo [15,16]. Furthermore, regrding gstric mucos, the plnt hs been shown to be heptoprotective in tetrchloride-intoxicted rts [17] nd to suppress the extent of iron-induced lipid peroxidtion in rt liver homogentes [18], without ny toxic effect. A mjor constituent of mstic, nmely olenolic cid, is mong the best-known triterpenes with biologicl properties ginst chemiclly induced liver injury in lbortory nimls, exerting nti-inflmmtory nd ntitumor-promotion effects [19]. This bckground informtion led us to exmine the effects of supplementtion with mstic in ptients with ctive CD. This study is the first ever reported to evlute mstic for possible clinicl effectiveness in ptients with CD. MATERIALS AND METHODS Study popultion Ten consecutive ptients with estblished CD nd eight helthy controls were recruited to prticipte in the tril. All ptients were ttending the outptient clinic of the Deprtment of Gstroenterology, Sint Pnteleimon Generl Stte Hospitl in Nice, Athens. Clinicl evidence of mild to moderte Crohn s disese excerbtion ws defined by score of CD Activity Index (CDAI) higher thn 150. Ptients with clinicl evidence of recurrence nd CDAI higher thn 400 were excluded from the study. Ptients receiving meslzine or ntibiotics during the time of relpse were sked to continue tretment. None ws receiving elementl diet or prenterl nutrition or ntioxidnt/minerl supplements nd none ws under tretment with immunosuppressives, immunomodultors nd/or corticosteroids. Eight helthy volunteers with norml serum concentrtions of C-rective protein (CRP) (< 5 mg/l) nd lbumin (> 40 g/l) served s controls. Assessed by Medicl History questionnires, controls included in the study were helthy persons without chronic inflmmtory disorder. Exclusion criteri for control recruitment were body mss index (BMI) higher thn 30 nd nti-inflmmtory drug tretment or ntioxidnt vitmin/minerl supplementtion prior to tril. All volunteers gve written consent fter hving received thourough informtion bout the ims nd procedure of the study. The Ethicl Committees of both Hrokopio University nd Sint Pnteleimon Generl Stte Hospitl pproved the protocol. Tble 1 shows some demogrphic Tble 1 Demogrphic chrcteristics nd medictions of ptients with CD nd controls Chrcteristic Ptients Controls Age (yr) Men 36.9 31.5 Rnge 18-73 25-45 Sex Femle 5 4 Mle 5 4 Durtion of disese (yr) 6.4 (± 3.9) - Concomitnt mediction - None 3 Meslzine 3 - Metronidzole 2 Azthioprine 2 Loction of Crohn s disese - Smll bowel 4 - Smll nd lrge bowel 6 - Fistulizing disese 3 - chrcteristics of ptients nd controls. Preprtion of mstic cps A UV source device (Jost/B-ro, Type FDLT 250/-80 2500) ws used for steriliztion of the Chios Mstic resin. Then, the sterilized mstic grnules were milled to fine powder (prticle size < 400 μm) by using Hosokw Alpine Mill (Fine Impct Mill 100 UP2). The encpsultion of powder ws performed using the Profill Cpsule filling System (Torpc Inc.). Cpsule cells (cpsugel, V cps, size 0) were mde of Hpromellose (hydroxypropyl methylcellulose) nd ech contined 0.37 (± 0.02) g of mstic powder. Intervention tril protocol Dissolution time ws mesured ccording to stndrd methods [20] nd ws found to lst pproximtely 7 min. Ptients nd helthy controls were subjected to 4-wk supplementtion with mstic cps (6 cps/d, 2.2 g in totl) over period from June 2005 to Jnury 2006. Dietry ssessment ws ccomplished pplying Food Frequency Questionnire (FFQ) nd 24 h reclls. Dietry instructions were given to both helthy controls nd ptients s to mintin consumption of food rich in nti-inflmmtory nd ntioxidnt ingredients s poor s initilly ssessed by FFQ nd 24 h recll interviews. Assessment of complince during the tril ws tested pplying 24 h reclls twice week. Mstic, either in the form of gum or s sweet or bred ingredient, nd fish oil, either crude or in the form of supplement, ws not llowed in either group. The dily energy intke ws evluted by mens of 24 h reclls. Blood smples were obtined for plsm isoltion nd subjected to CRP nd lbumin mesurements prior nd fter the tril. At the sme time points, plsm cytokine nd ntioxidnt potentil mesurements were performed. Body weight ws mesured using electronic scles initilly nd t the end of the tril. Disese ctivity index evlution The Crohn s Disese ctivity ws evluted by mens
750 ISSN 1007-9327 CN 14-1219/R World J Gstroenterol Februry 7, 2007 Volume 13 Number 5 of the CDAI [21]. The CDAI incorportes eight relted vribles: the number of liquid or very soft stools per dy, the severity of bdominl pin or crmping, generl well being, the presence or bsence of extrintestinl mnifesttions of CD, the presence or bsence of n bdominl mss, the use of ntidirrhel drugs, hemtocrit, nd body weight. Scores rnge from 0 to 600 with higher scores indicting more severe disese ctivity. A score of 151 to 200 corresponds with mild disese ctivity; moderte disese hs score of 201 to 400, nd scores of 401 or greter represent severe disese ctivity. CDAI 300 250 200 150 100 50 Biochemicl mesurements CRP concentrtions were nlyzed immunoturbidimetriclly on Beckmn Synchron CX5 fully utomted chemistry nlyzer. Albumin ws mesured by mens of the bromocresol green method on the sme nlyzer. Cytokine ssys Plsm cytokines from ptients with CD nd controls were ssessed by quntittive enzyme-linked immunosorbent ssys (ELISA) (R & D Systems Abingdon, UK) ccording to the mnufcturer s instructions. Sensitivity limits of TNF-α, IL-6, nd MCP-1 ELISAs re, respectively, 1.6 pg/ml, 0.70 pg/ml nd 5.0 pg/ml. Plsm cytokines from ptients with CD nd controls were ssessed in duplicte. Plsm totl ntioxidnt potentil ssy Totl ntioxidnt potentil (TAP) in plsm ws ssessed by colorimetric, quntittive ssy for TAP in queous smples (OxisReserch Portlnd, USA) ccording to the mnufcturer s instructions. The results of the ssy were expressed s mmol/l of uric cid equivlents. The sensitivity of the ssy is 30 μmol/l uric cid equivlents. Sttisticl nlysis Results were expressed s men ± SE. The Mnn-Whitney Test ws used for compring differences between ptients nd controls prior the intervention. Differences reported primrily nd t the end of the study within individul groups, were tested for significnce by the Wilcoxon signed rnks test. Clculted P < 0.05 ws considered to indicte sttisticl significnce. RESULTS Altertions of CDAI nd induction of remission The CDAI score ws ssessed t bseline nd fter the 4 wk tretment with mstic. All ptients receiving mstic showed reduction of the CDAI s compred to pretretment vlues. The reduction of the men CDAI vlue ws sttisticlly significnt (from 222.9 ± 18.7 to 136.3 ± 12.3, P = 0.05) (Figure 1). The two min elements of CDAI showing the most striking improvement were the number of liquid stools per dy nd the score of generl well being. Nutritionl risk index One of the cliniclly useful mesures of nutritionl sttus in CD is the Nutritionl Risk Index (NRI), which is 0 Figure 1 Crohn s disese ctivity index (CDAI) ws decresed in ptients with ctive Crohn s disese (n = 10) fter 4-wk tretment with mstic cps ( P < 0.05). Horizontl brs represent the men vlue (± SE). clculted bsed on serum lbumin levels nd body weight using the following eqution: NRI = [1.519 lbumin (g/l)] + [0.417 (current weight/usul weight) 100]. A NRI > 100 denotes bsence of nutritionl risk. NRI vlues between 97.5 nd 99.9 correspond to mild nutritionl risk, NRI vlues from 83.5 to 97.5 to moderte nutritionl risk, nd NRI vlues lower thn 83.5 to severe nutritionl risk. The ptients usul weight ws the body weight t the time of remission, s reported in medicl records t the hospitl nd confirmed by ech single ptient. NRI of helthy controls ws norml t the strt of the study nd remined unchnged fter the mstic supplementtion (dt not shown). The men NRI vlue of CD ptients incresed from 87.5 ± 3.7 before tretment to 91.5 ± 3.2 t the end of tretment (P = 0.059). This increse ws evident t the end of the second week of mstic supplementtion nd remined constnt therefter until the end of the tril. CRP Prior to mstic tretment, CRP levels were significntly higher in CD ptients (40.3 ± 13.1 mg/ml) thn in helthy controls (2.4 ± 0.7 mg/l) (P = 0.002). Tretment with mstic cps of helthy controls resulted in no modifictions in CRP vlues (2.3 ± 0.6 mg/l), which remined t concentrtions 5.0 mg/ml in ll individuls. In CD ptients, men CRP levels were significntly decresed fter tretment (from 40.3 ± 13.1 mg/ml to 19.7 ± 5.5, P = 0.028) (Figure 2). IL-6 plsm concentrtion IL-6 ws below detection in helthy controls prior to therpy, while in ptients it ws significntly elevted compred to controls (P = 0.034). As with CRP, IL-6 in controls remined unltered, while in ptients it decresed significntly (from 21.2 ± 9.3 pg/ml to 7.2 ± 2.8 pg/ml, P = 0.027) (Figure 3). TNF-α plsm concentrtion Ptients with ctive CD hd TNF-α plsm concentrtions 10-fold higher compred to controls before therpy (27.1 ± 9.7 pg/ml vs 2.6 ± 1.5 pg/ml, P = 0.009). After
Klior AC et l. Chios mstic in Crohn s disese 751 60 30 25 45 CRP (mg/l) 30 15 IL-6 (pg/ml) 20 15 10 5 0 0 Figure 2 C-rective protein (CRP) concentrtions in ptients with ctive Crohn s disese (n = 10) before nd fter 4-wk tretment with mstic cps ( P < 0.05). Horizontl brs represent the men vlue (± SE). Figure 3 Plsm concentrtions of interleukin-6 (IL-6) were suppressed in ptients with ctive Crohn s disese (n = 10) fter 4-wk tretment with mstic cps ( P < 0.05). Horizontl brs represent the men vlue (± SE). tretment, plsm TNF-α decresed in ptients, lthough this decrese did not rech sttisticl significnce (27.1 ± 9.7 pg/ml to 16.4 ± 4.7 pg/ml, P = 0.114). MCP-1 plsm concentrtion In the cse of MCP-1, ptients with ctive CD hd MCP-1 plsm concentrtions 2.5-fold higher compred to controls (140.7 ± 43.9 pg/ml vs 57.5 ± 11.8 pg/ml, P = 0.368). Although not sttisticlly significnt, decrese ws observed in MCP-1 in CD ptients t the end of the tril (76.6 ± 20.9 pg/ ml, P = 0.074). TAP (mmol uric cid) 0.8 0.6 0.4 0.2 Plsm TAP TAP ws significntly different between the two groups before mstic tretment (helthy controls, 0.4 ± 0.06 vs CD ptients, 0.15 ± 0.09 mmol/l uric cid, P = 0.003). As shown in Figure 4, TAP ws significntly incresed in individul groups fter mstic tretment (controls, 0.4 ± 0.06 vs 0.5 ± 0.05 mmol/l uric cid, P = 0.025; CD ptients, 0.15 ± 0.09 vs 0.57 ± 0.15 mmol/l uric cid, P = 0.036). Side-effects No ptient exhibited ny side effects. However, during the third dy of tretment, one femle ptient with CD of the smll nd lrge bowel reported n brupt onset of constiption. She ws dvised to reduce the dose for two dys. After tht, she continued tretment without further complints. No other untowrd effect ws reported. DISCUSSION Chios mstic hs been previously shown to exert vrious biologicl properties in vitro [12], in experimentl niml models [18] nd in humns [14]. In the current study, we demonstrted tht mstic ws effective in the regultion of inflmmtion, evluted by CRP, IL-6, TNF-α nd MCP-1 in plsm, s well s in the regultion of oxidtive stress, evluted by TAP. In more detils, mstic tretment significntly decresed the CDAI, which probbly occurred through decrese of the pro-inflmmtory IL-6, inducing remission in seven out of ten ptients. Another importnt 0.0 Figure 4 Plsm totl ntioxidnt potentil (TAP) ws upregulted in ptients with ctive Crohn s disese (n = 10) fter 4-wk tretment with mstic cps ( P < 0.05), indicting bsorption of ntioxidnts nd n improved in vivo ntioxidnt sttus. Horizontl brs represent the men vlue (± SE). observtion ws tht mstic resulted in improvement of the nutritionl sttus, s shown by NRI. Nutritionl support in ptients with CD hs primry role in inducing remission nd mlnutrition is very common in CD. While severl fctors, such s mlbsorption nd incresed resting energy expenditure in underweight ptients, my contribute to mlnutrition [22], decresed orl intke is the primry cuse. The methods used to support ptients with CD re enterl nd prenterl nutrition, in terms of protein-clorie intke. NRI is one of the most useful mesures of nutritionl sttus nd points out severely mlnourished ptients when less thn 83.5 [23]. Hereby we show tht NRI in ptients supplemented with mstic ws incresed, however not significntly, perhps due to the limited number of subjects. Prticulrly, NRI ws incresed in nine out of ten ptients supplemented with mstic, two of whom experienced no nutritionl risk (dt not shown). The min element of NRI showing improvement ws body weight gin. Bsed upon the fct tht dily energy intke ws unchnged during the tril (dt not shown), increse in body weight nd in NRI is due to the fct tht mstic tretment resulted in decrese of liquid stools nd therefore improvement in nutrient bsorption.
752 ISSN 1007-9327 CN 14-1219/R World J Gstroenterol Februry 7, 2007 Volume 13 Number 5 The observed decrese in NRI in one of the ptients ws due to body weight loss, despite the fct tht the number of liquid stools decresed. The dily energy intke of this young ptient ws grdully reduced nd, ccording to her sttement long fter the end of the protocol, she ws on diet for weight loss. The importnce of IL-6 in ptients with CD hs been well documented. In ptients with ctive CD, mrna for IL-6 is overexpressed in the inflmed mucos [24] nd IL-6 is thought to ply crucil role in the pthogenesis of CD. Elevted IL-6 in plsm of ptients with CD hs been previously described [25]. Accordingly, we report tht in ptients with CD plsm concentrtion of IL-6 ws significntly higher versus the control group. Significnt decrese in IL-6 with mstic tretment ws observed in ptients following decrese in plsm CRP (Figure 2). Becuse IL-6 is the min cytokine fctor responsible for heptic induction of cute phse proteins in CD, respective decrement in CRP is resonble. In view of the fct tht (1) oleoresins consist of triterpenes [26] with estblished nti-inflmmtory nd ntioxidnt effects [19,27] nd (2) mstic contins ntioxidnt phenolic compounds [28], it is more likely tht the plsm IL-6 decrese observed in CD ptients ws due to these compounds. TNF-α showed n unsignificnt (P = 0.114) 1.6-fold decrese in CD ptients. On the other hnd, the difference in TNF-α concentrtions between ptients nd controls t bseline ws significnt. The dt reported bout TNF-α in CD re somewht contrdictory. Wheres some groups were ble to demonstrte incresed concentrtions of TNF-α in CD compred to helthy controls [29], others were not [30]. Becuse TNF-α induces MCP-1 secretion vi the ctivtion of nucler fctor-kpp B [31], it is likely tht the slight decrese in MCP-1 ws due to the lower ctivtion of the nucler fctor-kpp B pthwy secondry to the decrese in TNF-α. Oxidtive stress hs been proven to upregulte IL-6 gene expression [32]. We show tht mstic tretment resulted in increse of plsm TAP in CD ptients (Figure 4) s well s in controls. Plsm is heterogenous solution of diverse ntioxidnts nd n increse in the ntioxidnt cpcity indictes bsorption of ntioxidnts nd n improved in vivo ntioxidnt sttus [33]. Whether the ntioxidnt triterpenes nd phenolics contined in mstic [12] re bsorbed or ct on the exposed gstrointestinl mucos, remins uncertin. Generlly, our knowledge on the bsorption nd biovilbility of polyphenols is still limited, nd the few studies in humns show tht some re well bsorbed nd others hrdly bsorbed [34]. The unbsorbed my remin in the lumen nd become vilble for fermenttion in the colon. A substntil proportion of the gstrointestinl mucos is therefore exposed to these compounds, or to their bcteril nd systemic metbolites [35]. However, phenolic compounds do not seem to be bsorbed s well s vitmins C nd E, nd hence their concentrtions cn be much higher in the lumen of the gstrointestinl trct thn re ever chieved in plsm or other body tissues, mking the ction in the gstrointestinl trct more likely. Even less re the dt on the bsorption of triterpenes. Glycyrrhetinic cid, the triterpene derivtive of glycyrrhizin, hs been shown to be bioctive in experimentl gstric lesion models [36] nd hs lso been detected in the serum of experimentl nimls [37]. In conclusion, subjecting CD ptients with mild to moderte ctivity to mstic tretment seems to improve the clinicl fetures of the disese nd to regulte inflmmtion nd ntioxidnt sttus. The use of nturl products s primry tretment in CD should ttrct wider support nd reserch, with incresing wreness of the hrm of the long-term use of corticosteroids. Whether it is time for gstroenterologists to embrce the concept tht nturl products, such s mstic, my be beneficil to CD needs further reserch in lrger cohorts. ACKNOWLEDGMENTS We wish to thnk the Chios Mstic Growers Assocition, especilly Dr. Christos Krtlis, for the production nd kind dontion of Chios mstic cps, exclusively for the needs of the tril. REFERENCES 1 Trintfillidis JK, Emmnouilidis A, Mnousos O, Nicolkis D, Kogevins M. Clinicl ptterns of Crohn's disese in Greece: follow-up study of 155 cses. Digestion 2000; 61: 121-128 2 Trintfillidis JK, Emmnouilidis A, Nicolkis D, Ifntis T, Cherckis P, Meriks EG. Crohn's disese in the elderly: clinicl fetures nd long-term outcome of 19 Greek ptients. 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