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Pre-, pro-, synbiotics in nonalcoholic fatty liver diseases 곽금연성균관대학교의과대학삼성서울병원소화기내과 Geum-Youn Gwak Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul,

1 Pre-, pro-, synbiotics in nonalcoholic fatty liver diseases 곽금연성균관대학교의과대학삼성서울병원소화기내과 Geum-Youn Gwak Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea Recent evidence suggests that the gut microbiota plays a key role in the development of insulin resistance, fatty liver, necro-inflammation and fibrosis through effects on caloric salvage, host energy metabolism, pro-inflammatory signaling and direct hepatotoxicity of bacterial products. In this respect, manipulating enteric flora may represent a potential therapeutic option in the treatment of nonalcoholic fatty liver diseases (NAFLD). Several studies reported that administration of prebiotics (oligosaccharides), probiotics (living microorganisms) and synbiotics (mixture of prebiotics and probiotics) modified the composition of intestinal flora and restored the microbial balance. This review presents a compilation of the scientific evidence found in the last years showing the results of interventions with prebiotics, probiotics or both in the treatment of NAFLD in animals and human. Keywords: Microbiota; Nonalcoholic fatty liver disease; Prebiotics; Probiotics; Synbiotics 서론 최근비알코올성지방간질환의병태생리학적기전중하나로 장 - 간축 (gut-liver axis) 이론이부각되 고있다. 1 이는장내미생물이인슐린저항성, 지방간, 괴사염증및간섬유화의발생에주요한역할을하 여비알코올성지방간질환발생을일으키는내인성요인이된다는내용으로, 2,3 이에발맞추어 prebiotics, probiotics 또는 synbiotics의투여를통해장내미생물의조성을변화시키고균형을복원하는방법이비알코올성지방간질환치료의한전략으로부상하고있다. Prebiotics란장내미생물의조성과활성도를변화시킴으로써숙주에유익한작용을하는비소화성당류를지칭하며, probiotics는적당한양으로투여되었을때숙주의건강에유익한작용을하는살아있는미생물을일컫는다. Synbiotics는 prebiotics와 probiotics의혼합물을말한다. 본강의에서는비알코올성지방간질환의치료에있어서그간이들을이용한대표적인전임상및임상연구결과들을정리하고향후이들의실전적용가능성을전망해보고자한다. 64 대한간학회 The Korean Association for study of the Liver

2 곽금연 Pre-, pro-, synbiotics in nonalcoholic fatty liver diseases 본론 1. 전임상연구 (Pre-clinical study) Li 등은, 4 비알코올성지방간질환의동물모델인 ob/ob 생쥐에게고지방식이와함께 Streptococcus, Bifidobacterium, Lactobacillus 세종류의미생물혼합물인 VSL#3를 4주간투여하였는데, VSL#3 투여군에서조직학적간내염증개선과혈중 ALT 감소가관찰되었다. 인슐린저항성을유발하는 Jun N-terminal kinase (JNK) 활성도는본래 ob/ob 생쥐의간에서증가되어있는데 VSL#3 투여로 JNK 활성도가감소되었으며, 인슐린저항성의또다른기전인 IKKβ의활성도를반영하는 nuclear factor κb (NF-κB) 의 DNA binding activity 또한감소되었다. VSL#3 투여군은인슐린저항성의개선으로인해 fatty acid β-oxidation 과 uncoupling protein (UCP)-2 발현이감소되었다. 이러한결과는장내미생물이간내인슐린저항성과비알코올성지방간질환의발생에병태적역할을담당하는내인성신호를조절한다는개념을지지한다. 또다른연구에서는, 5 C57BL6 생쥐에게고지방식이를투여하여간의 NKT 세포를줄이고인슐린저항성과간지방증을유도하였다. VSL#3 투여군에서는고지방식이투여로인한변화가개선되었는데, 이효과는 NKT 세포의존적이었으며 tumor necrosis factor (TNF)-α 감소와 IκB kinase 신호전달의감쇠에의한것이었다. Esposito 등의연구에서, 6 고지방식이로유도된지방간염모델쥐에게 VSL#3를투여하였을때지질과산화표지자 (malondialdehyde (MDA)), TNF-α, inducible nitric oxide synthase (inos), cyclooxygenase 2 (COX-2) 발현감소가초래되었다. 마찬가지로, VSL#3 투약은간과지방조직에서인슐린저항성을낮추어유전적이상지질혈증을가지는 ApoE(-/-) 생쥐에서지방간염과죽상동맥경화증을예방하였다. 7 또한 Ritze 등의연구에서는, 8 C57BL/J6 생쥐에게과당과함께체중 g 당 colony-forming units (cfu) 의농도로 Lactobacillus rhamnosus GG (LGG) 을보충함으로써비알코올성지방간질환을완화시켰다. LGG는투약종료후소장에서유익한세균을증가시켰을뿐만아니라십이지장 tight-junction 단백질농도를증가시키고문맥 LPS 농도를감소시켰다. 아울러 LGG를투여받은생쥐에서는간의 TNF-α, IL-8, IL-1β mrna 발현감소, 간지방축적감소, 그리고문맥 ALT 농도감소도관찰되었다. Lactobacillus casei strain Shirota (LcS) 를이용한연구에서는, 9 쥐에게 methionine-choline-deficient 식이 (MCD) 를먹이면대변내 Lactobacillus와 Bifidobacterium과같은젖산균이감소되는데이때 LcS를함께투여하면 LcS 뿐아니라다른젖산균들도증가되고, 동시에지방간염발생이억제됨을증명하였다. 2. 임상연구 (Clinical study) Loguercio 등은, 10 비알코올성지방간질환환자들에게 3개월간 VSL#3를투약하여지질과산화지표인혈중 malondialdehyde (MDA), 4-hydroxynonenal (4-HNE) 농도를감소시켰다. 이와함께간손상지표인 65

3 2016 대한간학회추계 Single Topic Symposium AST, ALT 농도와, 산화스트레스지표인 S-Nitrosothiols (S-NO) 도감소되었다. 그러나 TNF-a, IL-6, IL-10과같은염증성사이토카인의변화는관찰되지않았다. Vajro 등은소아를대상으로한무작위위약대조이중맹검연구에서, 11 Lactobacillus rhamnosus strain GG (12 billion CFU/ 일 ) 를 8주간투여하여체질량지수및복부지방량변화와무관하게소장내미생물과증식지표인 peptidoglycan-polysaccharide (PG-PS) IgA 항체와 ALT 농도를유의하게감소시켰다. Aller 등은조직학적으로확진된 30명의비알코올성지방간질환환자들에게 Lactobacillus bulgaricus와 Streptococcus thermophilus를 3개월간투여한무작위위약대조이중맹검연구에서, 12 위약군에서는투약전후 ALT, AST, GGT의감소가없었던반면 (ALT, 60.7 ± 32.1 vs ± 35.5 UI/L, P < 0.05: AST, 31.7 ± 13.1 vs ± 13.8 UI/L, P > 0.05: GGT, 82.1 ± 55.1 vs ± 65.3 UI/L, P > 0.05), 치료군에는세지표모두유의한개선을보임을증명하였다 (ALT, 67.7 ± 25.1 vs ± 30.4 UI/L, P < 0.05: AST: 41.3 ± 15.5 vs ± 10.4 UI/L, P < 0.05: GGT ± 63.1 vs ± 60.8 UI/L, P < 0.05). Wong 등은 13 조직학적으로확진된비알코올성지방간염환자에게 6개월간 probiotics (Lactobacillus plantarum, Lactobacillus deslbrueckii, Lactobacillus acidophilus, Lactobacillus rhamnosus, Bifidobacterium bifidum) 를투여하여간내중성지방량을투약전 22.6 ± 8.2% 에서투약후 14.9 ± 7.0% 로유의하게감소시켰다. (P = 0.034) Probiotics 투약군은혈중 AST, ALT 농도도치료전후에각각 -13 ± 31 IU/L, -26 ± 91 IU/L의변화를보였다. 반면체질량지수, 허리둘레, 혈당과지질농도의변화는없었다. Malaguarnera 등은 14 비알코올성지방간염환자에게 24주간 Bifidobacterium longum과 fructo-oligosaccharides (FOS)-FOS는장관내유익한세균인 bifidobacteria의성장을촉진하는 prebiotics이다-를동시투약한후대조군과비교하였는데투약전후 AST vs IU/mL (P < 0.05), LDL cholesterol vs mmol/l (P < 0.001), C-reactive protein (CRP) -2.9 vs mg/l (P < 0.05), TNF-α vs ng/ml (P < 0.001), homeostasis model assessment of insulin resistance (HOMA-IR) -1.1 vs (P < 0.001), 혈중 endotoxin 농도 vs pg/ml (P < 0.001) 로유의한차이를보였다. NASH activity index (P < 0.05) 역시시험군에서투약전후에 9.44 (range 6-10) 에서 3.22 (range 1-7) 로감소하였다. 상기네개의무작위대조연구들을 meta-analysis하였을때, 15 probiotics 투약군은 ALT, AST, total-cholesterol, high density lipoprotein (HDL), TNF-α, HOMA-IR이유의하게감소하였다. [ALT: weighted mean difference (WMD) , 95% CI: ~ , P < ; AST: WMD , 95% CI: ~ -7.00, P = 0.002; total-cholesterol: WMD -0.28, 95% CI: ~ -0.01, P = 0.04; HDL: WMD -0.09, 95% CI: ~ 0.01, P = 0.03; TNF-α: WMD -0.32, 95% CI: ~ -0.17, P < ; HOMA-IR: WMD -0.46, 95% CI: ~ -0.19, P = ]. 그러나 probiotics 투약군에서체질량지수, 혈당, LDL의변화는없었다 ( 체질량지수 : WMD 0.05, 95% CI: ~ 0.29, P = 0.64; 혈당 : WMD 0.05, 95% CI: ~ 0.35, P = 0.76; LDL: WMD -0.38, 95% CI: ~ 0.02, P = 0.06). 66 대한간학회 The Korean Association for study of the Liver

4 곽금연 Pre-, pro-, synbiotics in nonalcoholic fatty liver diseases Eslamparast 등은 명의비알코올성지방간질환환자에게식이요법및신체활동과더불어 synbiotics (7 strains of bacteria-lactobacillus casei, Lactobacillus rhamnosus, Streptococcus thermophilus, Bifidobacterium breve, Lactobacillus acidophilus, Bifidobacterium longum, Lactobacillus bulgaricus, plus prebiotic-fructooligosaccharide) 를 28일간투여하는무작위대조연구를수행하였는데 synbiotics를투여한군이대조군에비해 ALT [-25.1 (-26.2, -24) vs (-9.5, -5.1) IU/L; P < 0.001], AST [ (-32.1, -30.5) vs (-11.1, -4.8) IU/L; P < 0.001], GGT [ (-15.5, -14.7) vs (-6.6, -3.9) IU/L; P < 0.001], high-sensitivity CRP [-2.3 (-3, -1.5) vs (-1.5, -0.6) mmol/l; P < 0.05], TNF-α [-1.4 (-1.7, -1.1) vs (-0.8, -0.3) mmol/l; P < 0.001], total NFκB p65 [ (-0.022, ) vs (-0.004, ) mmol/l; P < 0.001], fibrosis score by transient elastography [-2.98 (-3.6, -2.37) vs (-1.32, -0.22) kpa; P < 0.001] 의유의한차이를보여주었다. 결론 현재까지비알코올성지방간질환의치료에있어서 prebiotics, probiotics, synbiotics의효능에대한연구는소규모로이루어져왔으며, 특히사람을대상으로한연구는매우빈약한실정이다. 하지만비알코올성지방간질환의발생과진행에있어서장내미생물들의역할에대한이론적, 실험적근거가견고한만큼, 이들이장기적인검증을거쳐가까운미래에비알코올성지방간질환의약물적치료의한축을담당할수있기를기대한다. REFERENCES 1. Kirpich IA, Marsano LS, McClain CJ. Gut-liver axis, nutrition, and non-alcoholic fatty liver disease. Clin. Biochem 2015;48: Eslamparast T, Eghtesad S, Hekmatdoost A, Poustchi H. Probiotics and nonalcoholic fatty liver disease. Middle East J Dig. Dis 2013;5: Farrell GC. Is bacterial ash the flash that ignites NASH? Gut 2001;48: Li Z, Yang S, Lin H, Huang J, Watkins PA, Moser AB, et al. Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease. Hepatology 2003;37: Ma X, Hu J, Li Z. Probiotics improve high fat diet-induced hepatic steatosis and insulin resistance by increasing hepatic NKT cells. J Hepatol 2008;49: Esposito E, Iacono A, Bianco G, Autore G, Cuzzocrea S, Vajro P, et al. Probiotics reduce the inflammatory response induced by a high-fat diet in the liver of young rats. J Nutr 2009;139: Mencarelli A, Cipriani S, Renga B, Bruno A, D'Amore C, Distrutti E, et al. VSL#3 resets insulin signaling and protects against NASH and atherosclerosis in a model of genetic dyslipidemia and intestinal inflammation. PLoS ONE 2012;7:e Ritze Y, Bárdos G, Claus A, Ehrmann V, Bergheim I, Schwiertz A, et al. Lactobacillus rhamnosus GG protects against 67

5 2016 대한간학회추계 Single Topic Symposium non-alcoholic fatty liver disease in mice. PLoS ONE 2014;9:e Okubo H, Sakoda H, Kushiyama A, Fujishiro M, Nakatsu Y, Fukushima T et al. Lactobacillus casei strain Shirota protects against nonalcoholic steatohepatitis development in a rodent model. Am J Physiol Gastrointest Liver Physiol 2013;305:G911-G Loguercio C, Federico A, Tuccillo C, Terracciano F, D Auria MV, De Simone C, et al. Beneficial effects of a probiotic VSL#3 on parameters of liver dysfunction in chronic liver diseases. J Clin Gastroenterol 2005;39: Vajro P, Mandato C, Licenziati MR, Franzese A, Vitale DF, Lenta S, et al. Effects of Lactobacillus rhamnosus strain GG in pediatric obesity-related liver disease. J Pediatr Gastroenterol Nutr 2011;52: Aller R, De Luis DA, Izaola O, Conde R, Gonzalez Sagrado M, Primo D, et al. Effect of a probiotic on liver aminotransferases in nonalcoholic fatty liver disease patients: A double blind randomized clinical trial. Eur Rev Med Pharmacol Sci 2011; 15: Wong VW, Won GL, Chim AM, Chu WC, Yeung DK, Li KC, et al. Treatment of nonalcoholic steatohepatitis with probiotics. A proof-of-concept study. Ann. Hepatol 2013;12: Malaguarnera M, Vacante M, Antic T, Giordano M, Chisari G, Acquaviva R, et al. Bifidobacterium longum with fructo-oligosaccharides in patients with non-alcoholic steatohepatitis. Dig Dis Sci 2012;57: Ma YY, Li L, Yu CH, Shen Z, Chen LH, Li YM. Effects of probiotics on nonalcoholic fatty liver disease: A meta-analysis. World J Gastroenterol 2013;19: Eslamparast T, Poustchi H, Zamani F, Sharafkhah M, Malekzadeh R, Hekmatdoost A. Synbiotic supplementation in nonalcoholic fatty liver disease: A randomized, double-blind, placebo-controlled pilot study. Am J Clin Nutr 2014:99: 대한간학회 The Korean Association for study of the Liver

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( )Kju269.hwp 만성세균성전립선염모델흰쥐에서 의항염효과 Anti-inflammatory Effect of Lycopene on Chronic Bacterial Prostatitis Rat Model Cho Hwan Yang, Dong Wan Sohn, Yong-Hyun Cho From the Department of Urology, The Catholic University