Effects of glucocorticoids combined with probiotics in treating Crohn's disease on inflammatory factors and intestinal microflora

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1 EXPERIMENTAL AND THERAPEUTIC MEDICINE 16: , 2018 Effects of glucocorticoids combined with probiotics in treting Crohn's disese on inflmmtory fctors nd intestinl microflor HUI SU, QIAN KANG, HAIHONG WANG, HUI YIN, LINGHUI DUAN, YULI LIU nd RUYING FAN Deprtment of Gstroenterology, PLA Army Generl Hospitl, Beijing , P.R. Chin Received Mrch 13, 2018; Accepted June 12, 2018 DOI: /etm Abstrct. This study investigted the effect of glucocorticoids combined with probiotics on inflmmtory fctors nd intestinl microflor in the tretment of Crohn's disese. Eighty-three ptients with Crohn's disese were selected from Mrch 2015 to December 2017 in PLA Army Generl Hospitl (Beijing, Chin). A totl of 83 ptients were rndomly divided into the control group nd tretment group. Ptients in the control group were treted with routine tretment of orl sulfslzine. Besides orl sulfslzine, ptients in the tretment group were treted with probiotics combined with glucocorticoids. At the sme time, totl of 40 helthy individuls were selected to serve s the helthy group (received no tretment). Clinicl efficcy, chnges of inflmmtory fctors, incidence of infection nd chnges of intestinl flor were compred between the different groups. After tretment, the levels of inflmmtory fctors in both groups significntly decresed, nd the reduction in the tretment group significntly incresed thn tht in the control group (P<0.05). The levels of inflmmtory cytokines in the tretment group reched the levels of tht in the helthy individuls fter tretment. After tretment, the levels of yest, enterococci nd peptococcus of the two groups of ptients were significntly decresed, while the level of lctobcillus ws significntly incresed, nd the chnges were more significnt in the tretment group thn those in the control group. After tretment, the number of intestinl flor in the tretment group reched tht of the helthy individuls. Tretment efficiency of the tretment group ws significntly higher thn tht of the control group, nd the infection rte of the control group ws significntly higher thn tht of the tretment group (P<0.05). The use of probiotics combined with glucocorticoid in the tretment of Crohn's disese cn improve clinicl curtive effect, reduce the secretion of inflmmtory fctors nd improve the level of intestinl flor, so s to chieve better outcomes compred with conventionl method. Correspondence to: Dr Ruying Fn, Deprtment of Gstroenterology, PLA Army Generl Hospitl, 5 Nnmencng, Beijing , P.R. Chin E-mil: scorpio81@sin.com Key words: Crohn's disese, probiotics, glucocorticoid, intestinl flor Introduction Crohn's disese is chronic gstrointestinl disese minly relted to eting hbits nd utoimmune function, nd clinicl sttisticl nlysis found tht the incidence of this disese in Chin is incresing (1-3). Crohn's disese cn cuse systemic symptoms, such s lesions in mouth, eyes, skin, nd gstrointestinl trct. Occurrence site of Crohn's disese is minly the gstrointestinl trct, nd highest incidence is found in ileum nd colon (4,5). Cliniclly, Crohn's disese is minly treted with ntibiotics, immunosuppressive gents nd other drugs (6-9). Antibiotics my cuse the development of intestinl flor resistnce, nd the immunosuppressive gents re not ffordble for most ptients. At present, probiotics nd glucocorticoid re incresingly widely used to tret this disese (2,10,11). In this study, probiotics combined with glucocorticoid therpy ws used to tret Crohn's disese. The clinicl tretment effects were observed nd compred. Ptients nd methods Mterils. A totl of 83 ptients with Crohn's disese were selected from Mrch 2015 to December 2017 in PLA Army Generl Hospitl (Beijing, Chin). Ptients were rndomly divided into the control group nd tretment group. The tretment group included 23 mles nd 20 femles, with n verge ge of 43.43±5.43 yers nd n verge disese durtion of 2.12±1.09 yers. The control group included 20 mles nd 20 femles, with n verge ge of 48.43±5.43 yers nd n verge disese durtion of 2.01±1.02 yers. The helthy group included 19 mles nd 21 femles, with n verge ge of 44.76±4.99 yers. There ws no significnt difference between the three groups in generl informtion such s ge, sex nd disese durtion. Inclusion criteri were: ptients who met the criteri for dignosis nd tretment of inflmmtory bowel disese ; ptients who were not suffering from hert, liver or other vitl orgn injuries; ptients without mentl diseses; ptients who could cooperte with the reserchers. Exclusion criteri were: ptients who were llergic to probiotics nd glucocorticoids; ptients who were pregnnt or in lcttion; ptients with other intestinl diseses. The study ws pproved by the Ethics Committee of PLA Army Generl Hospitl (Beijing, Chin). Ptients who prticipted in this study, signed n informed consent nd hd complete clinicl dt. Signed informed consents were obtined from the ptients or gurdins.

2 3000 SU et l: EFFECTS OF GLUCOCORTICOIDS COMBINED WITH PROBIOTICS IN CROHN'S DISEASE Tble I. Comprison of generl clinicl dt between two groups of ptients (n). Sex Lesion locliztion Lesion type Groups Cses Mle Femle Ilecolon Ileum Colon Stenosis Penetrtion type Non-penetrtion type Tretment Control Tble II. Comprison of inflmmtory cytokines between two groups of ptients (men ±SD). Groups Time-points CRP (ng/ml) TNF-α (ng/ml) IL-10 (pg/ml) Tretment Before tretment 13.39± ± ±1.67 After tretment 7.21± ± ±1.86 P vlue <0.001 <0.001 <0.001 Control Before tretment 13.51± ± ±1.45 After tretment 10.56± ± ±1.75 P vlue b <0.001 <0.001 <0.001 P vlue c <0.001 <0.001 <0.001 Helthy individuls 6.23± ± ±0.99 P vlue d <0.001 <0.001 <0.001 Comprison between before nd fter tretment in the tretment group; b Comprison between before nd fter tretment in the control group; c Comprison between fter tretment in the control group nd fter tretment in the tretment group; d Comprison between the helthy group nd fter tretment in the tretment group. Tble III. Comprison of intestinl flor between two groups of ptients nd helthy individuls (men ±SD). Groups Time-points Yest Enterococci Lctobcilli Peptococcus Tretment Before tretment 2.23± ± ± ±0.63 After tretment 1.03± ± ± ±0.32 Control Before tretment 2.42± ± ± ±0.61 After tretment 1.59±0.12,b 6.21±0.60,b 6.93±0.62,b 5.79±0.59,b Helthy individuls 0.92± ± ± ±0.34 P<0.05, compred with the pretretment level; b P<0.05, compred with the tretment group. Tble IV. Comprison of clinicl efficcy of two groups of ptients (n). Mrkedly Totl effective Groups Cses Recovery effective Effective Ineffective rte (%) Tretment (97.6) Control (85.3) P<0.05, compred with the tretment group. Methods. Ptients in the control group were treted with routine tretment of orl sulfslzine t dose of 1 g ech time, 4 times per dy. Besides orl sulfslzine, ptients in the tretment group were treted with probiotics combined with glucocorticoids. Probiotics: Bifidobcterium Lctobcillus triple tblets, t the dose of 4 x 500 mg per time, 2 times per dy. Glucocorticoids: prednisone, t the initil dose of mg/kg/dy nd grdully stopped in3-4 months.

3 EXPERIMENTAL AND THERAPEUTIC MEDICINE 16: , Tble V. Comprison of incidence of infection between two groups of ptients (n). Infectious bdominl Groups Cses distension nd dirrhe Abdominl bscess Pulmonry infection Sepsis Incidence (%) Tretment (51.1) Control (92.7) P<0.05, compred with the tretment group. Efficcy evlution nd observtion indictors. The levels of inflmmtory cytokines C-rective protein (CRP, TNF-α nd IL-10) were mesured before nd fter tretment. The inflmmtory cytokines were determined by using ELISA kit (Beyotime, Shnghi, Chin). Determintion of intestinl flor: fresh feces ws collected from ptients nd helthy individuls, nd yest, peptococcus, lctobcilli nd enterococci were isolted, cultured nd detected. Clinicl efficcy: recovery, clinicl symptoms nd signs disppered fter tretment, stool routine exmintion ws negtive, microscopic ulcer ws heled, mucosl recovery ws observed; mrkedly effective, clinicl symptoms nd signs disppered fter tretment, stool routine exmintion ws negtive, microscopic ulcer ws mostly heled; effective, clinicl symptoms nd signs disppered fter tretment, stool routine exmintion ws negtive nd mild inflmmtion ws observed by microscopic exmintion; ineffective, clinicl symptoms nd signs were not improved or ggregted. Totl effective rte = (recovered cses + pprent effective cses + effective cses)/totl number x100%. Sttisticl nlysis. Sttisticl softwre SPSS 17.0 (SPSS Inc., Chicgo, IL, USA) ws used to nlyze the dt. Enumertion dt were expressed s men ± stndrd devition. Enumertion dt were recorded s number. Comprison between multiple groups ws done using One-wy ANOVA test followed by post hoc test (Lest Significnt Difference). P<0.05 ws considered to indicte sttisticlly significnt difference. Results Comprison of generl clinicl dt between the two groups of ptients. There were 23 mles nd 20 femles in the tretment group, including 19 ptients with ileocolic, 17 ptients with ileum, 7 ptients with colon, nd 21 ptients with stenosis nd 15 ptients with penetrtion type nd 7 ptients with non penetrtion type. There were 20 mles nd 20 femles in the control group, including 15 ptients with ileocolic, 16 ptients with ileum, 9 ptients with colon, nd 19 ptients with stenosis nd 14 ptients with penetrtion type nd 7 ptients with non-penetrtion type. There ws no significnt difference in sex, lesion loction nd type of lesion between the two groups (Tble I). Comprison of inflmmtory cytokines between the two groups of ptients. Before tretment, the levels of CRP, TNF-α nd IL-10 in the tretment group were 13.39±0.93 ng/ml, 2.45±0.21 ng/ml nd 14.35±1.67 pg/ml, respectively. No significnt differences in the levels of CRP, TNF-α nd IL-10 were found between the two groups. After tretment, the levels of these inflmmtory fctors in both groups were significntly decresed, nd the levels of the inflmmtory fctors in the tretment group were significntly lower thn those in the control group (P<0.05). The levels of the inflmmtory fctors in the tretment group reched the levels of tht in the control group (Tble II). Comprison of intestinl flor between the groups of ptients nd helthy individuls. Before tretment, no significnt differences in number of yest, enterococci, lctobcilli nd peptococcus intestinl flor were found between the two groups. After tretment, the levels of yest, enterococci nd peptococcus of the groups of ptients were significntly decresed, while the level of lctobcillus ws significntly incresed in both groups, nd the chnges were more significnt in the tretment group thn those in the control group. After tretment, the number of intestinl flor in the tretment group reched tht of the helthy individuls (Tble III). Comprison of clinicl efficcy of the two groups of ptients. In the tretment group, 15 ptients recovered, 21 were mrke dly effective, 6 were effective, nd the totl effective rte ws 97.6%. In the control group, 8 ptients recovered, 15 were mrkedly effective, nd 11 ptients were effective, nd the totl effective rte ws 85.3%. Therpeutic efficiency of the the tretment group ws significntly higher thn tht of the control group (P<0.05) (Tble IV). Comprison of incidence of infection between the two groups of ptients. In the tretment group, 8 ptients developed infectious bdominl distension nd dirrhe, 9 ptients developed bdominl bscess, 4 ptients developed pulmonry infection, 1 ptient developed sepsis, nd the overll incidence ws 51.1%. In the control group, 12 ptients developed infectious bdominl distension nd dirrhe, 11 ptients developed bdominl bscess, 8 ptients developed pulmonry infection, 5 ptients developed sepsis, nd the overll incidence ws 92.7%. The infection rte of the control group ws significntly higher thn tht of the tretment group (P<0.05) (Tble V). Discussion Crohn's disese is n inflmmtory bowel disese tht cn cuse serious complictions of infection. Antibiotics re generlly used in the tretment of Crohn's disese, while long-term

4 3002 SU et l: EFFECTS OF GLUCOCORTICOIDS COMBINED WITH PROBIOTICS IN CROHN'S DISEASE use of ntibiotics my led to the development of resistnce, which in turn my ffect tretment outcomes (12,13). In this study, probiotics combined with glucocorticoid ws used to tret Crohn's disese, so s to explore the clinicl efficcy of this tretment effect nd the impct on intestinl flor. Tretment with probiotics is sfe for the intestine, nd cn provide nutrients for the intestine, improve the level of intestinl flor nd mintin the blnce of flor (14,15). Glucocorticoids cn rpidly diffuse into the cytoplsm fter entering the body nd bind to hormone receptors in cells. Glucocorticoid cn bind to corresponding rectnts nd ctivte the expression of relevnt genes to exert nti-inflmmtory effects (16,17). TNF-α s the mjor inflmmtory nd immune function fctor in the body is minly produced by ctivted monocytes nd megkryocytes. When inflmmtion occurs, the level of TNF-α significntly increses, thereby inducing the secretion of vriety of inflmmtory fctors nd dhesion molecules. IL-10 s n importnt inflmmtory fctor in Crohn's disese is minly produced by ctivted monocytes. IL-10 inhibits the secretion of inflmmtory meditors by monocytes, nd hs strong nti-inflmmtory effect. In Crohn's disese, intestinl flor is imblnced minly due to the prolifertion of yest. At the sme time, the numbers of enterococcus nd peptococcus were significntly incresed, while the number of lctobcillus ws decresed, seriously ffecting the intestinl digestive function (18,19). This study showed tht the effective rte of the tretment group ws significntly higher thn tht of the control group (97.6 vs. 85.3%), indicting the use of probiotics combined with glucocorticoid tretment cn improve tretment effect nd effectively llevite clinicl symptoms. After tretment, the levels of inflmmtory fctors in the tretment group were significntly lower thn those in the control group. After entering the humn body, probiotics cn improve intestinl dmge, protect intestinl wll permebility, thereby reducing the levels of proinflmmtory substnces such s inflmmtory cytokines nd endotoxin in lmin propri, thereby inhibiting inflmmtion. Glucocorticoids reduce the secretion of rchidonic cid, which is proinflmmtory precursor in the body, thereby inhibiting the production nd secretion of inflmmtory cytokines. After tretment, intestinl flor ws improved, the levels of yest, enterococci nd peptococcus were significntly decresed, nd the level of lctobcillus ws incresed. The improvement is more significnt in the tretment group thn tht in the control group, indicting the probiotics combined with glucocorticoid tretment cn ply better role thn conventionl methods in protecting intestinl flor. Results lso showed tht probiotics combined with glucocorticoid tretment cn reduce the incidence of infection, bdominl distension, dirrhe nd other side effects. In conclusion, the use of probiotics combined with glucocorticoid in the tretment of Crohn's disese cn improve clinicl efficcy, reduce infection rte, improve the protective effect of intestinl flor, nd effectively control the production nd secretion of inflmmtory cytokines. Therefore, this tretment should be populrized in clinicl prctice. Acknowledgements Not pplicble. Funding This study ws supported by Ntionl Science nd Technology Support Progrm (2014BAI09B05) nd The Specil Fund of Cpitl Helth Reserch nd Development (strting fund no ). Avilbility of dt nd mterils The dtsets used nd/or nlyzed during the present study re vilble from the corresponding uthor on resonble request. Authors' contributions HS, QK nd RF conceived nd designed the experiments, nd performed the sttisticl nlysis. HS, QK nd HW performed most of the experiments. HS contributed to the writing of the mnuscript. QK nd HW helped to drft the mnuscript. HY, LD nd YL contributed to the cquisition of dt. All the uthors hve red nd pproved the finl version of this study. Ethics pprovl nd consent to prticipte The study ws pproved by the Ethics Committee of PLA Army Generl Hospitl (Beijing, Chin). Ptients who prticipted in this study, signed n informed consent nd hd complete clinicl dt. Signed informed consents were obtined from the ptients or gurdins. Ptient consent for publiction Not pplicble. Competing interests The uthors declre tht they hve no competing interests. References 1. Sostegni R, Dperno M, Scglione N, Lvgn A, Rocc R nd Per A: Review rticle: Crohn's disese: monitoring disese ctivity. Aliment Phrmcol Ther 17 (Suppl 2): 11-17, Steinhrt H: Mintennce therpy in Crohn's disese. 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