酒精性肝病与肠道微生态的研究进展
|
摘要
酒精性肝病(alcoholic liver disease, ALD)是由于长期大量饮酒所致的肝损害,以肝细胞脂肪变性和脂肪贮积为主要特征,疾病谱包括脂肪肝、酒精性肝炎、酒精性肝纤维化和酒精性肝硬化,其中脂肪肝及早期酒精性肝炎在戒酒后可逆转. ALD的发病机制尚未完全明了,研究认为,肠道微生态失衡与ALD的发生发展密切相关.慢性酒精摄入可通过影响肠道黏膜通透性、肠道菌群失调、细菌移位等方式引起肠道微生态失衡,进而激活机体免疫应答,诱导肝脏产生炎性反应而造成肝损伤.基于此,临床可通过补充益生菌或益生元、合理应用抗生素及粪菌移植等方式调节肠道菌群失调,从而达到治疗的目的,此外,针对肠道微生态失衡的靶向治疗亦成为目前的研究热点.
Alcoholic liver disease(ALD) is damage to the liver that occurs after excessive alcohol use over a long period of time, which is mainly characterized by hepatocyte steatosis and fat storage, and the disease spectrum includes steatosis, steatohepatitis, alcoholic fibrosis, and cirrhosis. Steatosis and early steatohepatitis are reversible after cessation of alcohol use. Although the pathogenesis of ALD is not yet fully understood, many studies have shown that the intestinal microecological dysbiosis is closely related to the occurrence and development of ALD. Chronic alcohol use may cause intestinal microecological dysbiosis by leading to increased intestinal mucosal permeability, intestinal flora imbalance, and bacterial translocation, which can then activate immune response, induce an inflammatory response in the liver, and thus lead to liver damage. Based on this situation, we can adjust the intestinal flora imbalance to achieve the goal of treating ALD by using various methods such as supplementing probiotics or prebiotics, properly using antibiotics, and performing fecal microbiota transplantation. In addition, targeted therapy for intestinal bacterial imbalance has also become a hotspot in current research.
Alcoholic liver disease(ALD) is damage to the liver that occurs after excessive alcohol use over a long period of time, which is mainly characterized by hepatocyte steatosis and fat storage, and the disease spectrum includes steatosis, steatohepatitis, alcoholic fibrosis, and cirrhosis. Steatosis and early steatohepatitis are reversible after cessation of alcohol use. Although the pathogenesis of ALD is not yet fully understood, many studies have shown that the intestinal microecological dysbiosis is closely related to the occurrence and development of ALD. Chronic alcohol use may cause intestinal microecological dysbiosis by leading to increased intestinal mucosal permeability, intestinal flora imbalance, and bacterial translocation, which can then activate immune response, induce an inflammatory response in the liver, and thus lead to liver damage. Based on this situation, we can adjust the intestinal flora imbalance to achieve the goal of treating ALD by using various methods such as supplementing probiotics or prebiotics, properly using antibiotics, and performing fecal microbiota transplantation. In addition, targeted therapy for intestinal bacterial imbalance has also become a hotspot in current research.
引文
1 Fung P,Pyrsopoulos N.Emerging concepts in alcoholic hepatitis.World J Hepatol 2017;9:567-585[PMID:28515843DOI:10.4254/wjh.v9.i12.567]
2 McLoughlin RM,Mills KH.Influence of gastrointestinal commensal bacteria on the immune responses that mediate allergy and asthma.J Allergy Clin Immunol 2011;127:1097-1097;quiz 1108-1109[PMID:21420159 DOI:10.1016/j.jaci.2011.02.012]
3 Baraona E,Julkunen R,Tannenbaum L,Lieber CS.Role of intestinal bacterial overgrowth in ethanol production and metabolism in rats.Gastroenterology 1986;90:103-110[PMID:3940238 DOI:10.1016/0016-5085(86)90081-8]
4 Bode JC,Bode C,Heidelbach R,Dürr HK,Martini GA.Jejunal microflora in patients with chronic alcohol abuse.Hepatogastroenterology 1984;31:30-34[PMID:6698486]
5 Casafont Morencos F,de las Heras Casta?o G,Martín Ramos L,López Arias MJ,Ledesma F,Pons Romero F.Small bowel bacterial overgrowth in patients with alcoholic cirrhosis.Dig Dis Sci 1996;41:552-556[PMID:8617135 DOI:10.1007/BF02282340]
6 Hartmann P,Chen P,Wang HJ,Wang L,McCole DF,Brandl K,St?rkel P,Belzer C,Hellerbrand C,Tsukamoto H,Ho SB,Schnabl B.Deficiency of intestinal mucin-2 ameliorates experimental alcoholic liver disease in mice.Hepatology 2013;58:108-119[PMID:23408358 DOI:10.1002/hep.26321]
7 Yan AW,Fouts DE,Brandl J,St?rkel P,Torralba M,Schott E,Tsukamoto H,Nelson KE,Brenner DA,Schnabl B.Enteric dysbiosis associated with a mouse model of alcoholic liver disease.Hepatology 2011;53:96-105[PMID:21254165 DOI:10.1002/hep.24018]
8 Bauer TM,Schwacha H,Steinbrückner B,Brinkmann FE,Ditzen AK,Kist M,Blum HE.Diagnosis of small intestinal bacterial overgrowth in patients with cirrhosis of the liver:poor performance of the glucose breath hydrogen test.JHepatol 2000;33:382-386[PMID:11019993 DOI:10.1016/S0168-8278(00)80273-1]
9 Simrén M,Stotzer PO.Use and abuse of hydrogen breath tests.Gut 2006;55:297-303[PMID:16474100 DOI:10.1136/gut.2005.075127]
10 Kerlin P,Wong L.Breath hydrogen testing in bacterial overgrowth of the small intestine.Gastroenterology 1988;95:982-988[PMID:3410238 DOI:10.1016/0016-5085(88)90173-4]
11 Guarner C,Runyon BA,Young S,Heck M,Sheikh MY.Intestinal bacterial overgrowth and bacterial translocation in cirrhotic rats with ascites.J Hepatol 1997;26:1372-1378[PMID:9210626 DOI:10.1016/S0168-8278(97)80474-6]
12 Sánchez E,Casafont F,Guerra A,de Benito I,Pons-Romero F.Role of intestinal bacterial overgrowth and intestinal motility in bacterial translocation in experimental cirrhosis.Rev Esp Enferm Dig 2005;97:805-814[PMID:16438624 DOI:10.4321/S1130-01082005001100005]
13 Morencos FC,de las Heras Casta?o G,Martín Ramos L,López Arias MJ,Ledesma F,Pons Romero F.Small bowel bacterial overgrowth in patients with alcoholic cirrhosis.Dig Dis Sci 1995;40:1252-1256[PMID:7781442 DOI:10.1007/BF02065533]
14 Gabbard SL,Lacy BE,Levine GM,Crowell MD.The impact of alcohol consumption and cholecystectomy on small intestinal bacterial overgrowth.Dig Dis Sci 2014;59:638-644[PMID:24323179 DOI:10.1007/s10620-013-2960-y]
15 Bajaj JS,Heuman DM,Hylemon PB,Sanyal AJ,White MB,Monteith P,Noble NA,Unser AB,Daita K,Fisher AR,Sikaroodi M,Gillevet PM.Altered profile of human gut microbiome is associated with cirrhosis and its complications.J Hepatol 2014;60:940-947[PMID:24374295 DOI:10.1016/j.jhep.2013.12.019]
16 Bajaj JS,Ridlon JM,Hylemon PB,Thacker LR,Heuman DM,Smith S,Sikaroodi M,Gillevet PM.Linkage of gut microbiome with cognition in hepatic encephalopathy.Am JPhysiol Gastrointest Liver Physiol 2012;302:G168-G175[PMID:21940902 DOI:10.1152/ajpgi.00190.2011]
17 Chen Y,Yang F,Lu H,Wang B,Chen Y,Lei D,Wang Y,Zhu B,Li L.Characterization of fecal microbial communities in patients with liver cirrhosis.Hepatology 2011;54:562-572[PMID:21574172 DOI:10.1002/hep.24423]
18 Kakiyama G,Pandak WM,Gillevet PM,Hylemon PB,Heuman DM,Daita K,Takei H,Muto A,Nittono H,Ridlon JM,White MB,Noble NA,Monteith P,Fuchs M,Thacker LR,Sikaroodi M,Bajaj JS.Modulation of the fecal bile acid profile by gut microbiota in cirrhosis.J Hepatol 2013;58:949-955[PMID:23333527 DOI:10.1016/j.jhep.2013.01.003]
19 Kakiyama G,Hylemon PB,Zhou H,Pandak WM,Heuman DM,Kang DJ,Takei H,Nittono H,Ridlon JM,Fuchs M,Gurley EC,Wang Y,Liu R,Sanyal AJ,Gillevet PM,Bajaj JS.Colonic inflammation and secondary bile acids in alcoholic cirrhosis.Am J Physiol Gastrointest Liver Physiol 2014;306:G929-G937[PMID:24699327 DOI:10.1152/ajpgi.00315.2013]
20 Mutlu EA,Gillevet PM,Rangwala H,Sikaroodi M,Naqvi A,Engen PA,Kwasny M,Lau CK,Keshavarzian A.Colonic microbiome is altered in alcoholism.Am J Physiol Gastrointest Liver Physiol 2012;302:G966-G978[PMID:22241860 DOI:10.1152/ajpgi.00380.2011]
21 Bajaj JS,Heuman DM,Hylemon PB,Sanyal AJ,Puri P,Sterling RK,Luketic V,Stravitz RT,Siddiqui MS,Fuchs M,Thacker LR,Wade JB,Daita K,Sistrun S,White MB,Noble NA,Thorpe C,Kakiyama G,Pandak WM,Sikaroodi M,Gillevet PM.Randomised clinical trial:Lactobacillus GGmodulates gut microbiome,metabolome and endotoxemia in patients with cirrhosis.Aliment Pharmacol Ther 2014;39:1113-1125[PMID:24628464 DOI:10.1111/apt.12695]
22 Bajaj JS,Hylemon PB,Ridlon JM,Heuman DM,Daita K,White MB,Monteith P,Noble NA,Sikaroodi M,Gillevet PM.Colonic mucosal microbiome differs from stool microbiome in cirrhosis and hepatic encephalopathy and is linked to cognition and inflammation.Am J Physiol Gastrointest Liver Physiol 2012;303:G675-G685[PMID:22821944 DOI:10.1152/ajpgi.00152.2012]
23 Zhao HY,Wang HJ,Lu Z,Xu SZ.Intestinal microflora in patients with liver cirrhosis.Chin J Dig Dis 2004;5:64-67[PMID:15612659]
24 Liu Q,Duan ZP,Ha DK,Bengmark S,Kurtovic J,Riordan SM.Synbiotic modulation of gut flora:effect on minimal hepatic encephalopathy in patients with cirrhosis.Hepatology 2004;39:1441-1449[PMID:15122774 DOI:10.1002/hep.20194]
25 Kirpich IA,Solovieva NV,Leikhter SN,Shidakova NA,Lebedeva OV,Sidorov PI,Bazhukova TA,Soloviev AG,Barve SS,McClain CJ,Cave M.Probiotics restore bowel flora and improve liver enzymes in human alcohol-induced liver injury:a pilot study.Alcohol 2008;42:675-682[PMID:19038698 DOI:10.1016/j.alcohol.2008.08.006]
26 Petrasek J,Mandrekar P,Szabo G.Toll-like receptors in the pathogenesis of alcoholic liver disease.Gastroenterol R e s P r a c t 2010;2010:710381[P M I D:20827314 D O I:10.1155/2010/710381]
27 Lieber CS.Alcoholic fatty liver:its pathogenesis and mechanism of progression to inflammation and fibrosis.Alcohol 2004;34:9-19[PMID:15670660 DOI:10.1016/j.alcohol.2004.07.008]
28 Cederbaum AI,Lu Y,Wu D.Role of oxidative stress in alcohol-induced liver injury.Arch Toxicol 2009;83:519-548[PMID:19448996 DOI:10.1007/s00204-009-0432-0]
29 Leung TM,Nieto N.CYP2E1 and oxidant stress in alcoholic and non-alcoholic fatty liver disease.J Hepatol 2013;58:395-398[PMID:22940046 DOI:10.1016/j.jhep.2012.08.018]
30 Dolganiuc A,Thomes PG,Ding WX,Lemasters JJ,Donohue TM Jr.Autophagy in alcohol-induced liver diseases.Alcohol Clin Exp Res 2012;36:1301-1308[PMID:22551004 DOI:10.1111/j.1530-0277.2012.01742.x]
31 Nassir F,Ibdah JA.Role of mitochondria in alcoholic liver disease.World J Gastroenterol 2014;20:2136-2142[PMID:24605012 DOI:10.3748/wjg.v20.i9.2136]
32 Fernández-Checa JC,Kaplowitz N,García-Ruiz C,Colell A.Mitochondrial glutathione:importance and transport.Semin Liver Dis 1998;18:389-401[PMID:9875556]
33 Wheeler MD,Kono H,Yin M,Nakagami M,Uesugi T,Arteel GE,G?bele E,Rusyn I,Yamashina S,Froh M,Adachi Y,Iimuro Y,Bradford BU,Smutney OM,Connor HD,Mason RP,Goyert SM,Peters JM,Gonzalez FJ,Samulski RJ,Thurman RG.The role of Kupffer cell oxidant production in early ethanol-induced liver disease.Free Radic Biol Med 2001;31:1544-1549[PMID:11744328]
34 Enomoto N,Ikejima K,Bradford BU,Rivera CA,Kono H,Goto M,Yamashina S,Schemmer P,Kitamura T,Oide H,Takei Y,Hirose M,Shimizu H,Miyazaki A,Brenner DA,Sato N,Thurman RG.Role of Kupffer cells and gut-derived endotoxins in alcoholic liver injury.J Gastroenterol Hepatol2000;15 Suppl:D20-D25[PMID:10759216]
35 Schnabl B,Brenner DA.Interactions between the intestinal microbiome and liver diseases.Gastroenterology 2014;146:1513-1524[PMID:24440671 DOI:10.1053/j.gastro.2014.01.020]
36 Rao R.Endotoxemia and gut barrier dysfunction in alcoholic liver disease.Hepatology 2009;50:638-644[PMID:19575462DOI:10.1002/hep.23009]
37 Wood S,Pithadia R,Rehman T,Zhang L,Plichta J,Radek KA,Forsyth C,Keshavarzian A,Shafikhani SH.Chronic alcohol exposure renders epithelial cells vulnerable to bacterial infection.PLoS One 2013;8:e54646[PMID:23358457 DOI:10.1371/journal.pone.0054646]
38 O’Shea RS,Dasarathy S,Mc Cullough AJ;Practice Guideline Committee of the American Association for the Study of Liver Diseases;Practice Parameters Committee of the American College of Gastroenterology.Alcoholic liver disease.Hepatology 2010;51:307-328[PMID:20034030 DOI:10.1002/hep.23258]
39 Sato N,Lindros KO,Baraona E,Ikejima K,Mezey E,J?rvel?inen HA,Ramchandani VA.Sex difference in alcoholrelated organ injury.Alcohol Clin Exp Res 2001;25:40S-45S[PMID:11391047]
40 Monzoni A,Masutti F,Saccoccio G,Bellentani S,Tiribelli C,Giacca M.Genetic determinants of ethanol-induced liver damage.Mol Med 2001;7:255-262[PMID:11471570]
41 Tian C,Stokowski RP,Kershenobich D,Ballinger DG,Hinds DA.Variant in PNPLA3 is associated with alcoholic liver disease.Nat Genet 2010;42:21-23[PMID:19946271 DOI:10.1038/ng.488]
42 Goodrich JK,Waters JL,Poole AC,Sutter JL,Koren O,Blekhman R,Beaumont M,Van Treuren W,Knight R,Bell JT,Spector TD,Clark AG,Ley RE.Human genetics shape the gut microbiome.Cell 2014;159:789-799[PMID:25417156 DOI:10.1016/j.cell.2014.09.053]
43 Addolorato G,Montalto M,Capristo E,Certo M,Fedeli G,Gentiloni N,Stefanini GF,Gasbarrini G.Influence of alcohol on gastrointestinal motility:lactulose breath hydrogen testing in orocecal transit time in chronic alcoholics,social drinkers and teetotaler subjects.Hepatogastroenterology 1997;44:1076-1081[PMID:9261602]
44 Gupta A,Dhiman RK,Kumari S,Rana S,Agarwal R,Duseja A,Chawla Y.Role of small intestinal bacterial overgrowth and delayed gastrointestinal transit time in cirrhotic patients with minimal hepatic encephalopathy.J Hepatol 2010;53:849-855[PMID:20675008 DOI:10.1016/j.jhep.2010.05.017]
45 Madrid AM,Hurtado C,Venegas M,Cumsille F,Defilippi C.Long-Term treatment with cisapride and antibiotics in liver cirrhosis:effect on small intestinal motility,bacterial overgrowth,and liver function.Am J Gastroenterol2001;96:1251-1255[P M I D:11316178 D O I:10.1111/j.1572-0241.2001.03636.x]
46 Chari S,Teyssen S,Singer MV.Alcohol and gastric acid secretion in humans.Gut 1993;34:843-847[PMID:8314520]
47 Dinoso VP Jr,Chey WY,Braverman SP,Rosen AP,Ottenberg D,Lorber SH.Gastric secretion and gastric mucosal morphology in chronic alcoholics.Arch Intern Med 1972;130:715-719[PMID:5083414]
48 Shindo K,Machida M,Miyakawa K,Fukumura M.Asyndrome of cirrhosis,achlorhydria,small intestinal bacterial overgrowth,and fat malabsorption.Am J Gastroenterol 1993;88:2084-2091[PMID:8249977]
49 Raedsch R,Stiehl A,Gundert-Remy U,Walker S,Sieg A,Czygan P,Kommerell B.Hepatic secretion of bilirubin and biliary lipids in patients with alcoholic cirrhosis of the liver.Digestion 1983;26:80-88[PMID:6840409 DOI:10.1159/000198872]
50 Inagaki T,Moschetta A,Lee YK,Peng L,Zhao G,Downes M,Yu RT,Shelton JM,Richardson JA,Repa JJ,Mangelsdorf DJ,Kliewer SA.Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor.Proc Natl Acad Sci USA 2006;103:3920-3925[PMID:16473946 DOI:10.1073/pnas.0509592103]
51 Lorenzo-Zú?iga V,BartolíR,Planas R,Hofmann AF,Vi?ado B,Hagey LR,Hernández JM,Ma?éJ,Alvarez MA,Ausina V,Gassull MA.Oral bile acids reduce bacterial overgrowth,bacterial translocation,and endotoxemia in cirrhotic rats.Hepatology 2003;37:551-557[PMID:12601352 DOI:10.1053/jhep.2003.50116]
52 Scott KP,Gratz SW,Sheridan PO,Flint HJ,Duncan SH.The influence of diet on the gut microbiota.Pharmacol Res 2013;69:52-60[PMID:23147033 DOI:10.1016/j.phrs.2012.10.020]
53 Gao B,Bataller R.Alcoholic liver disease:pathogenesis and new therapeutic targets.Gastroenterology 2011;141:1572-1585[PMID:21920463 DOI:10.1053/j.gastro.2011.09.002]
54 Michelena J,Altamirano J,Abraldes JG,AffòS,MoralesIbanez O,Sancho-Bru P,Dominguez M,García-Pagán JC,Fernández J,Arroyo V,Ginès P,Louvet A,Mathurin P,Mehal WZ,Caballería J,Bataller R.Systemic inflammatory response and serum lipopolysaccharide levels predict multiple organ failure and death in alcoholic hepatitis.Hepatology 2015;62:762-772[PMID:25761863 DOI:10.1002/hep.27779]
55 Bautista AP.Impact of alcohol on the ability of Kupffer cells to produce chemokines and its role in alcoholic liver disease.JGastroenterol Hepatol 2000;15:349-356[PMID:10824877]
56 Louvet A,Mathurin P.Alcoholic liver disease:mechanisms of injury and targeted treatment.Nat Rev Gastroenterol Hepatol 2015;12:231-242[PMID:25782093 DOI:10.1038/nrgastro.2015.35]
57 Mandrekar P,Ambade A,Lim A,Szabo G,Catalano D.An essential role for monocyte chemoattractant protein-1in alcoholic liver injury:regulation of proinflammatory cytokines and hepatic steatosis in mice.Hepatology 2011;54:2185-2197[PMID:21826694 DOI:10.1002/hep.24599]
58 Zhong W,McClain CJ,Cave M,Kang YJ,Zhou Z.The role of zinc deficiency in alcohol-induced intestinal barrier dysfunction.Am J Physiol Gastrointest Liver Physiol2010;298:G625-G633[PMID:20167873 DOI:10.1152/ajpgi.00350.2009]
59 Zhong W,Zhao Y,Sun X,Song Z,McClain CJ,Zhou Z.Dietary zinc deficiency exaggerates ethanol-induced liver injury in mice:involvement of intrahepatic and extrahepatic factors.PLoS One 2013;8:e76522[PMID:24155903 DOI:10.1371/journal.pone.0076522]
60 Chang B,Sang L,Wang Y,Tong J,Zhang D,Wang B.The protective effect of VSL#3 on intestinal permeability in a rat model of alcoholic intestinal injury.BMC Gastroenterol 2013;13:151[PMID:24138544 DOI:10.1186/1471-230X-13-151]
61 Lunia MK,Sharma BC,Sharma P,Sachdeva S,Srivastava S.Probiotics prevent hepatic encephalopathy in patients with cirrhosis:a randomized controlled trial.Clin Gastroenterol Hepatol 2014;12:1003-1008.e1[PMID:24246768 DOI:10.1016/j.cgh.2013.11.006]
62 Bull-Otterson L,Feng W,Kirpich I,Wang Y,Qin X,Liu Y,Gobejishvili L,Joshi-Barve S,Ayvaz T,Petrosino J,Kong M,Barker D,McClain C,Barve S.Metagenomic analyses of alcohol induced pathogenic alterations in the intestinal microbiome and the effect of Lactobacillus rhamnosus GGtreatment.PLoS One 2013;8:e53028[PMID:23326376 DOI:10.1371/journal.pone.0053028]
63 Ritze Y,Bárdos G,Claus A,Ehrmann V,Bergheim I,Schwiertz A,Bischoff SC.Lactobacillus rhamnosus GGprotects against non-alcoholic fatty liver disease in mice.PLo SOne 2014;9:e80169[PMID:24475018 DOI:10.1371/journal.pone.0080169]
64 Cicenia A,Scirocco A,Carabotti M,Pallotta L,Marignani M,Severi C.Postbiotic activities of lactobacilli-derived factors.JClin Gastroenterol 2014;48 Suppl 1:S18-S22[PMID:25291118DOI:10.1097/MCG.0000000000000231]
65 Hartmann P,Chen WC,Schnabl B.The intestinal microbiome and the leaky gut as therapeutic targets in alcoholic liver disease.Front Physiol 2012;3:402[PMID:23087650 DOI:10.3389/fphys.2012.00402]
66 Adachi Y,Moore LE,Bradford BU,Gao W,Thurman RG.Antibiotics prevent liver injury in rats following long-term exposure to ethanol.Gastroenterology 1995;108:218-224[PMID:7806045]
67 Chen P,St?rkel P,Turner JR,Ho SB,Schnabl B.Dysbiosisinduced intestinal inflammation activates tumor necrosis factor receptor I and mediates alcoholic liver disease in mice.Hepatology 2015;61:883-894[PMID:25251280 DOI:10.1002/hep.27489]
68 Bajaj JS,Heuman DM,Sanyal AJ,Hylemon PB,Sterling RK,Stravitz RT,Fuchs M,Ridlon JM,Daita K,Monteith P,Noble NA,White MB,Fisher A,Sikaroodi M,Rangwala H,Gillevet PM.Modulation of the metabiome by rifaximin in patients with cirrhosis and minimal hepatic encephalopathy.PLoSOne 2013;8:e60042[PMID:23565181 DOI:10.1371/journal.pone.0060042]
69 Woodhouse CA,Patel VC,Singanayagam A,Shawcross DL.Review article:the gut microbiome as a therapeutic target in the pathogenesis and treatment of chronic liver disease.Aliment Pharmacol Ther 2018;47:192-202[PMID:29083037DOI:10.1111/apt.14397]
70 El Feghaly RE,Bangar H,Haslam DB.The molecular basis of Clostridium difficile disease and host response.Curr Opin Gastroenterol 2015;31:24-29[PMID:25394235 DOI:10.1097/MOG.0000000000000131]
71 Zhang F,Luo W,Shi Y,Fan Z,Ji G.Should we standardize the 1,700-year-old fecal microbiota transplantation?Am JGastroenterol 2012;107:1755-1756[PMID:23160295 DOI:10.1038/ajg.2012.251]
72 Eiseman B,Silen W,Bascom GS,Kauvar AJ.Fecal enema as an adjunct in the treatment of pseudomembranous enterocolitis.Surgery 1958;44:854-859[PMID:13592638]
73 Armstrong MJ,Pathmakanthan S,Iqbal TH.Fecal microbiota transplantation for Clostridium difficile infection.JAMA 2015;313:725-726[PMID:25688787 DOI:10.1001/jama.2014.18617]
74 van Nood E,Vrieze A,Nieuwdorp M,Fuentes S,Zoetendal EG,de Vos WM,Visser CE,Kuijper EJ,Bartelsman JF,Tijssen JG,Speelman P,Dijkgraaf MG,Keller JJ.Duodenal infusion of donor feces for recurrent Clostridium difficile.N Engl J Med 2013;368:407-415[PMID:23323867 DOI:10.1056/NEJMoa1205037]
75 K?nig J,Siebenhaar A,H?genauer C,Arkkila P,Nieuwdorp M,Norén T,Ponsioen CY,Rosien U,Rossen NG,Satokari R,Stallmach A,de Vos W,Keller J,Brummer RJ.Consensus report:faecal microbiota transfer-clinical applications and procedures.Aliment Pharmacol Ther 2017;45:222-239[PMID:27891639 DOI:10.1111/apt.13868]
76 Zhong W,McClain CJ,Cave M,Kang YJ,Zhou Z.The role of zinc deficiency in alcohol-induced intestinal barrier dysfunction.Am J Physiol Gastrointest Liver Physiol 2010;298:G625-G633[PMID:20167873 DOI:10.1152/ajpgi.00350.2009]
77 Ge X,Lu Y,Leung TM,S?rensen ES,Nieto N.Milk osteopontin,a nutritional approach to prevent alcoholinduced liver injury.Am J Physiol Gastrointest Liver Physiol2013;304:G929-G939[PMID:23518682 DOI:10.1152/ajpgi.00014.2013]
78 Alwahsh SM,Gebhardt R.Dietary fructose as a risk factor for non-alcoholic fatty liver disease(NAFLD).Arch Toxicol 2017;91:1545-1563[PMID:27995280 DOI:10.1007/s00204-016-1892-7]
79 Lippai D,Bala S,Catalano D,Kodys K,Szabo G.MicroRNA-155 deficiency prevents alcohol-induced serum endotoxin increase and small bowel inflammation in mice.Alcohol Clin Exp Res 2014;38:2217-2224[PMID:25156614DOI:10.1111/acer.12483]
2 McLoughlin RM,Mills KH.Influence of gastrointestinal commensal bacteria on the immune responses that mediate allergy and asthma.J Allergy Clin Immunol 2011;127:1097-1097;quiz 1108-1109[PMID:21420159 DOI:10.1016/j.jaci.2011.02.012]
3 Baraona E,Julkunen R,Tannenbaum L,Lieber CS.Role of intestinal bacterial overgrowth in ethanol production and metabolism in rats.Gastroenterology 1986;90:103-110[PMID:3940238 DOI:10.1016/0016-5085(86)90081-8]
4 Bode JC,Bode C,Heidelbach R,Dürr HK,Martini GA.Jejunal microflora in patients with chronic alcohol abuse.Hepatogastroenterology 1984;31:30-34[PMID:6698486]
5 Casafont Morencos F,de las Heras Casta?o G,Martín Ramos L,López Arias MJ,Ledesma F,Pons Romero F.Small bowel bacterial overgrowth in patients with alcoholic cirrhosis.Dig Dis Sci 1996;41:552-556[PMID:8617135 DOI:10.1007/BF02282340]
6 Hartmann P,Chen P,Wang HJ,Wang L,McCole DF,Brandl K,St?rkel P,Belzer C,Hellerbrand C,Tsukamoto H,Ho SB,Schnabl B.Deficiency of intestinal mucin-2 ameliorates experimental alcoholic liver disease in mice.Hepatology 2013;58:108-119[PMID:23408358 DOI:10.1002/hep.26321]
7 Yan AW,Fouts DE,Brandl J,St?rkel P,Torralba M,Schott E,Tsukamoto H,Nelson KE,Brenner DA,Schnabl B.Enteric dysbiosis associated with a mouse model of alcoholic liver disease.Hepatology 2011;53:96-105[PMID:21254165 DOI:10.1002/hep.24018]
8 Bauer TM,Schwacha H,Steinbrückner B,Brinkmann FE,Ditzen AK,Kist M,Blum HE.Diagnosis of small intestinal bacterial overgrowth in patients with cirrhosis of the liver:poor performance of the glucose breath hydrogen test.JHepatol 2000;33:382-386[PMID:11019993 DOI:10.1016/S0168-8278(00)80273-1]
9 Simrén M,Stotzer PO.Use and abuse of hydrogen breath tests.Gut 2006;55:297-303[PMID:16474100 DOI:10.1136/gut.2005.075127]
10 Kerlin P,Wong L.Breath hydrogen testing in bacterial overgrowth of the small intestine.Gastroenterology 1988;95:982-988[PMID:3410238 DOI:10.1016/0016-5085(88)90173-4]
11 Guarner C,Runyon BA,Young S,Heck M,Sheikh MY.Intestinal bacterial overgrowth and bacterial translocation in cirrhotic rats with ascites.J Hepatol 1997;26:1372-1378[PMID:9210626 DOI:10.1016/S0168-8278(97)80474-6]
12 Sánchez E,Casafont F,Guerra A,de Benito I,Pons-Romero F.Role of intestinal bacterial overgrowth and intestinal motility in bacterial translocation in experimental cirrhosis.Rev Esp Enferm Dig 2005;97:805-814[PMID:16438624 DOI:10.4321/S1130-01082005001100005]
13 Morencos FC,de las Heras Casta?o G,Martín Ramos L,López Arias MJ,Ledesma F,Pons Romero F.Small bowel bacterial overgrowth in patients with alcoholic cirrhosis.Dig Dis Sci 1995;40:1252-1256[PMID:7781442 DOI:10.1007/BF02065533]
14 Gabbard SL,Lacy BE,Levine GM,Crowell MD.The impact of alcohol consumption and cholecystectomy on small intestinal bacterial overgrowth.Dig Dis Sci 2014;59:638-644[PMID:24323179 DOI:10.1007/s10620-013-2960-y]
15 Bajaj JS,Heuman DM,Hylemon PB,Sanyal AJ,White MB,Monteith P,Noble NA,Unser AB,Daita K,Fisher AR,Sikaroodi M,Gillevet PM.Altered profile of human gut microbiome is associated with cirrhosis and its complications.J Hepatol 2014;60:940-947[PMID:24374295 DOI:10.1016/j.jhep.2013.12.019]
16 Bajaj JS,Ridlon JM,Hylemon PB,Thacker LR,Heuman DM,Smith S,Sikaroodi M,Gillevet PM.Linkage of gut microbiome with cognition in hepatic encephalopathy.Am JPhysiol Gastrointest Liver Physiol 2012;302:G168-G175[PMID:21940902 DOI:10.1152/ajpgi.00190.2011]
17 Chen Y,Yang F,Lu H,Wang B,Chen Y,Lei D,Wang Y,Zhu B,Li L.Characterization of fecal microbial communities in patients with liver cirrhosis.Hepatology 2011;54:562-572[PMID:21574172 DOI:10.1002/hep.24423]
18 Kakiyama G,Pandak WM,Gillevet PM,Hylemon PB,Heuman DM,Daita K,Takei H,Muto A,Nittono H,Ridlon JM,White MB,Noble NA,Monteith P,Fuchs M,Thacker LR,Sikaroodi M,Bajaj JS.Modulation of the fecal bile acid profile by gut microbiota in cirrhosis.J Hepatol 2013;58:949-955[PMID:23333527 DOI:10.1016/j.jhep.2013.01.003]
19 Kakiyama G,Hylemon PB,Zhou H,Pandak WM,Heuman DM,Kang DJ,Takei H,Nittono H,Ridlon JM,Fuchs M,Gurley EC,Wang Y,Liu R,Sanyal AJ,Gillevet PM,Bajaj JS.Colonic inflammation and secondary bile acids in alcoholic cirrhosis.Am J Physiol Gastrointest Liver Physiol 2014;306:G929-G937[PMID:24699327 DOI:10.1152/ajpgi.00315.2013]
20 Mutlu EA,Gillevet PM,Rangwala H,Sikaroodi M,Naqvi A,Engen PA,Kwasny M,Lau CK,Keshavarzian A.Colonic microbiome is altered in alcoholism.Am J Physiol Gastrointest Liver Physiol 2012;302:G966-G978[PMID:22241860 DOI:10.1152/ajpgi.00380.2011]
21 Bajaj JS,Heuman DM,Hylemon PB,Sanyal AJ,Puri P,Sterling RK,Luketic V,Stravitz RT,Siddiqui MS,Fuchs M,Thacker LR,Wade JB,Daita K,Sistrun S,White MB,Noble NA,Thorpe C,Kakiyama G,Pandak WM,Sikaroodi M,Gillevet PM.Randomised clinical trial:Lactobacillus GGmodulates gut microbiome,metabolome and endotoxemia in patients with cirrhosis.Aliment Pharmacol Ther 2014;39:1113-1125[PMID:24628464 DOI:10.1111/apt.12695]
22 Bajaj JS,Hylemon PB,Ridlon JM,Heuman DM,Daita K,White MB,Monteith P,Noble NA,Sikaroodi M,Gillevet PM.Colonic mucosal microbiome differs from stool microbiome in cirrhosis and hepatic encephalopathy and is linked to cognition and inflammation.Am J Physiol Gastrointest Liver Physiol 2012;303:G675-G685[PMID:22821944 DOI:10.1152/ajpgi.00152.2012]
23 Zhao HY,Wang HJ,Lu Z,Xu SZ.Intestinal microflora in patients with liver cirrhosis.Chin J Dig Dis 2004;5:64-67[PMID:15612659]
24 Liu Q,Duan ZP,Ha DK,Bengmark S,Kurtovic J,Riordan SM.Synbiotic modulation of gut flora:effect on minimal hepatic encephalopathy in patients with cirrhosis.Hepatology 2004;39:1441-1449[PMID:15122774 DOI:10.1002/hep.20194]
25 Kirpich IA,Solovieva NV,Leikhter SN,Shidakova NA,Lebedeva OV,Sidorov PI,Bazhukova TA,Soloviev AG,Barve SS,McClain CJ,Cave M.Probiotics restore bowel flora and improve liver enzymes in human alcohol-induced liver injury:a pilot study.Alcohol 2008;42:675-682[PMID:19038698 DOI:10.1016/j.alcohol.2008.08.006]
26 Petrasek J,Mandrekar P,Szabo G.Toll-like receptors in the pathogenesis of alcoholic liver disease.Gastroenterol R e s P r a c t 2010;2010:710381[P M I D:20827314 D O I:10.1155/2010/710381]
27 Lieber CS.Alcoholic fatty liver:its pathogenesis and mechanism of progression to inflammation and fibrosis.Alcohol 2004;34:9-19[PMID:15670660 DOI:10.1016/j.alcohol.2004.07.008]
28 Cederbaum AI,Lu Y,Wu D.Role of oxidative stress in alcohol-induced liver injury.Arch Toxicol 2009;83:519-548[PMID:19448996 DOI:10.1007/s00204-009-0432-0]
29 Leung TM,Nieto N.CYP2E1 and oxidant stress in alcoholic and non-alcoholic fatty liver disease.J Hepatol 2013;58:395-398[PMID:22940046 DOI:10.1016/j.jhep.2012.08.018]
30 Dolganiuc A,Thomes PG,Ding WX,Lemasters JJ,Donohue TM Jr.Autophagy in alcohol-induced liver diseases.Alcohol Clin Exp Res 2012;36:1301-1308[PMID:22551004 DOI:10.1111/j.1530-0277.2012.01742.x]
31 Nassir F,Ibdah JA.Role of mitochondria in alcoholic liver disease.World J Gastroenterol 2014;20:2136-2142[PMID:24605012 DOI:10.3748/wjg.v20.i9.2136]
32 Fernández-Checa JC,Kaplowitz N,García-Ruiz C,Colell A.Mitochondrial glutathione:importance and transport.Semin Liver Dis 1998;18:389-401[PMID:9875556]
33 Wheeler MD,Kono H,Yin M,Nakagami M,Uesugi T,Arteel GE,G?bele E,Rusyn I,Yamashina S,Froh M,Adachi Y,Iimuro Y,Bradford BU,Smutney OM,Connor HD,Mason RP,Goyert SM,Peters JM,Gonzalez FJ,Samulski RJ,Thurman RG.The role of Kupffer cell oxidant production in early ethanol-induced liver disease.Free Radic Biol Med 2001;31:1544-1549[PMID:11744328]
34 Enomoto N,Ikejima K,Bradford BU,Rivera CA,Kono H,Goto M,Yamashina S,Schemmer P,Kitamura T,Oide H,Takei Y,Hirose M,Shimizu H,Miyazaki A,Brenner DA,Sato N,Thurman RG.Role of Kupffer cells and gut-derived endotoxins in alcoholic liver injury.J Gastroenterol Hepatol2000;15 Suppl:D20-D25[PMID:10759216]
35 Schnabl B,Brenner DA.Interactions between the intestinal microbiome and liver diseases.Gastroenterology 2014;146:1513-1524[PMID:24440671 DOI:10.1053/j.gastro.2014.01.020]
36 Rao R.Endotoxemia and gut barrier dysfunction in alcoholic liver disease.Hepatology 2009;50:638-644[PMID:19575462DOI:10.1002/hep.23009]
37 Wood S,Pithadia R,Rehman T,Zhang L,Plichta J,Radek KA,Forsyth C,Keshavarzian A,Shafikhani SH.Chronic alcohol exposure renders epithelial cells vulnerable to bacterial infection.PLoS One 2013;8:e54646[PMID:23358457 DOI:10.1371/journal.pone.0054646]
38 O’Shea RS,Dasarathy S,Mc Cullough AJ;Practice Guideline Committee of the American Association for the Study of Liver Diseases;Practice Parameters Committee of the American College of Gastroenterology.Alcoholic liver disease.Hepatology 2010;51:307-328[PMID:20034030 DOI:10.1002/hep.23258]
39 Sato N,Lindros KO,Baraona E,Ikejima K,Mezey E,J?rvel?inen HA,Ramchandani VA.Sex difference in alcoholrelated organ injury.Alcohol Clin Exp Res 2001;25:40S-45S[PMID:11391047]
40 Monzoni A,Masutti F,Saccoccio G,Bellentani S,Tiribelli C,Giacca M.Genetic determinants of ethanol-induced liver damage.Mol Med 2001;7:255-262[PMID:11471570]
41 Tian C,Stokowski RP,Kershenobich D,Ballinger DG,Hinds DA.Variant in PNPLA3 is associated with alcoholic liver disease.Nat Genet 2010;42:21-23[PMID:19946271 DOI:10.1038/ng.488]
42 Goodrich JK,Waters JL,Poole AC,Sutter JL,Koren O,Blekhman R,Beaumont M,Van Treuren W,Knight R,Bell JT,Spector TD,Clark AG,Ley RE.Human genetics shape the gut microbiome.Cell 2014;159:789-799[PMID:25417156 DOI:10.1016/j.cell.2014.09.053]
43 Addolorato G,Montalto M,Capristo E,Certo M,Fedeli G,Gentiloni N,Stefanini GF,Gasbarrini G.Influence of alcohol on gastrointestinal motility:lactulose breath hydrogen testing in orocecal transit time in chronic alcoholics,social drinkers and teetotaler subjects.Hepatogastroenterology 1997;44:1076-1081[PMID:9261602]
44 Gupta A,Dhiman RK,Kumari S,Rana S,Agarwal R,Duseja A,Chawla Y.Role of small intestinal bacterial overgrowth and delayed gastrointestinal transit time in cirrhotic patients with minimal hepatic encephalopathy.J Hepatol 2010;53:849-855[PMID:20675008 DOI:10.1016/j.jhep.2010.05.017]
45 Madrid AM,Hurtado C,Venegas M,Cumsille F,Defilippi C.Long-Term treatment with cisapride and antibiotics in liver cirrhosis:effect on small intestinal motility,bacterial overgrowth,and liver function.Am J Gastroenterol2001;96:1251-1255[P M I D:11316178 D O I:10.1111/j.1572-0241.2001.03636.x]
46 Chari S,Teyssen S,Singer MV.Alcohol and gastric acid secretion in humans.Gut 1993;34:843-847[PMID:8314520]
47 Dinoso VP Jr,Chey WY,Braverman SP,Rosen AP,Ottenberg D,Lorber SH.Gastric secretion and gastric mucosal morphology in chronic alcoholics.Arch Intern Med 1972;130:715-719[PMID:5083414]
48 Shindo K,Machida M,Miyakawa K,Fukumura M.Asyndrome of cirrhosis,achlorhydria,small intestinal bacterial overgrowth,and fat malabsorption.Am J Gastroenterol 1993;88:2084-2091[PMID:8249977]
49 Raedsch R,Stiehl A,Gundert-Remy U,Walker S,Sieg A,Czygan P,Kommerell B.Hepatic secretion of bilirubin and biliary lipids in patients with alcoholic cirrhosis of the liver.Digestion 1983;26:80-88[PMID:6840409 DOI:10.1159/000198872]
50 Inagaki T,Moschetta A,Lee YK,Peng L,Zhao G,Downes M,Yu RT,Shelton JM,Richardson JA,Repa JJ,Mangelsdorf DJ,Kliewer SA.Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor.Proc Natl Acad Sci USA 2006;103:3920-3925[PMID:16473946 DOI:10.1073/pnas.0509592103]
51 Lorenzo-Zú?iga V,BartolíR,Planas R,Hofmann AF,Vi?ado B,Hagey LR,Hernández JM,Ma?éJ,Alvarez MA,Ausina V,Gassull MA.Oral bile acids reduce bacterial overgrowth,bacterial translocation,and endotoxemia in cirrhotic rats.Hepatology 2003;37:551-557[PMID:12601352 DOI:10.1053/jhep.2003.50116]
52 Scott KP,Gratz SW,Sheridan PO,Flint HJ,Duncan SH.The influence of diet on the gut microbiota.Pharmacol Res 2013;69:52-60[PMID:23147033 DOI:10.1016/j.phrs.2012.10.020]
53 Gao B,Bataller R.Alcoholic liver disease:pathogenesis and new therapeutic targets.Gastroenterology 2011;141:1572-1585[PMID:21920463 DOI:10.1053/j.gastro.2011.09.002]
54 Michelena J,Altamirano J,Abraldes JG,AffòS,MoralesIbanez O,Sancho-Bru P,Dominguez M,García-Pagán JC,Fernández J,Arroyo V,Ginès P,Louvet A,Mathurin P,Mehal WZ,Caballería J,Bataller R.Systemic inflammatory response and serum lipopolysaccharide levels predict multiple organ failure and death in alcoholic hepatitis.Hepatology 2015;62:762-772[PMID:25761863 DOI:10.1002/hep.27779]
55 Bautista AP.Impact of alcohol on the ability of Kupffer cells to produce chemokines and its role in alcoholic liver disease.JGastroenterol Hepatol 2000;15:349-356[PMID:10824877]
56 Louvet A,Mathurin P.Alcoholic liver disease:mechanisms of injury and targeted treatment.Nat Rev Gastroenterol Hepatol 2015;12:231-242[PMID:25782093 DOI:10.1038/nrgastro.2015.35]
57 Mandrekar P,Ambade A,Lim A,Szabo G,Catalano D.An essential role for monocyte chemoattractant protein-1in alcoholic liver injury:regulation of proinflammatory cytokines and hepatic steatosis in mice.Hepatology 2011;54:2185-2197[PMID:21826694 DOI:10.1002/hep.24599]
58 Zhong W,McClain CJ,Cave M,Kang YJ,Zhou Z.The role of zinc deficiency in alcohol-induced intestinal barrier dysfunction.Am J Physiol Gastrointest Liver Physiol2010;298:G625-G633[PMID:20167873 DOI:10.1152/ajpgi.00350.2009]
59 Zhong W,Zhao Y,Sun X,Song Z,McClain CJ,Zhou Z.Dietary zinc deficiency exaggerates ethanol-induced liver injury in mice:involvement of intrahepatic and extrahepatic factors.PLoS One 2013;8:e76522[PMID:24155903 DOI:10.1371/journal.pone.0076522]
60 Chang B,Sang L,Wang Y,Tong J,Zhang D,Wang B.The protective effect of VSL#3 on intestinal permeability in a rat model of alcoholic intestinal injury.BMC Gastroenterol 2013;13:151[PMID:24138544 DOI:10.1186/1471-230X-13-151]
61 Lunia MK,Sharma BC,Sharma P,Sachdeva S,Srivastava S.Probiotics prevent hepatic encephalopathy in patients with cirrhosis:a randomized controlled trial.Clin Gastroenterol Hepatol 2014;12:1003-1008.e1[PMID:24246768 DOI:10.1016/j.cgh.2013.11.006]
62 Bull-Otterson L,Feng W,Kirpich I,Wang Y,Qin X,Liu Y,Gobejishvili L,Joshi-Barve S,Ayvaz T,Petrosino J,Kong M,Barker D,McClain C,Barve S.Metagenomic analyses of alcohol induced pathogenic alterations in the intestinal microbiome and the effect of Lactobacillus rhamnosus GGtreatment.PLoS One 2013;8:e53028[PMID:23326376 DOI:10.1371/journal.pone.0053028]
63 Ritze Y,Bárdos G,Claus A,Ehrmann V,Bergheim I,Schwiertz A,Bischoff SC.Lactobacillus rhamnosus GGprotects against non-alcoholic fatty liver disease in mice.PLo SOne 2014;9:e80169[PMID:24475018 DOI:10.1371/journal.pone.0080169]
64 Cicenia A,Scirocco A,Carabotti M,Pallotta L,Marignani M,Severi C.Postbiotic activities of lactobacilli-derived factors.JClin Gastroenterol 2014;48 Suppl 1:S18-S22[PMID:25291118DOI:10.1097/MCG.0000000000000231]
65 Hartmann P,Chen WC,Schnabl B.The intestinal microbiome and the leaky gut as therapeutic targets in alcoholic liver disease.Front Physiol 2012;3:402[PMID:23087650 DOI:10.3389/fphys.2012.00402]
66 Adachi Y,Moore LE,Bradford BU,Gao W,Thurman RG.Antibiotics prevent liver injury in rats following long-term exposure to ethanol.Gastroenterology 1995;108:218-224[PMID:7806045]
67 Chen P,St?rkel P,Turner JR,Ho SB,Schnabl B.Dysbiosisinduced intestinal inflammation activates tumor necrosis factor receptor I and mediates alcoholic liver disease in mice.Hepatology 2015;61:883-894[PMID:25251280 DOI:10.1002/hep.27489]
68 Bajaj JS,Heuman DM,Sanyal AJ,Hylemon PB,Sterling RK,Stravitz RT,Fuchs M,Ridlon JM,Daita K,Monteith P,Noble NA,White MB,Fisher A,Sikaroodi M,Rangwala H,Gillevet PM.Modulation of the metabiome by rifaximin in patients with cirrhosis and minimal hepatic encephalopathy.PLoSOne 2013;8:e60042[PMID:23565181 DOI:10.1371/journal.pone.0060042]
69 Woodhouse CA,Patel VC,Singanayagam A,Shawcross DL.Review article:the gut microbiome as a therapeutic target in the pathogenesis and treatment of chronic liver disease.Aliment Pharmacol Ther 2018;47:192-202[PMID:29083037DOI:10.1111/apt.14397]
70 El Feghaly RE,Bangar H,Haslam DB.The molecular basis of Clostridium difficile disease and host response.Curr Opin Gastroenterol 2015;31:24-29[PMID:25394235 DOI:10.1097/MOG.0000000000000131]
71 Zhang F,Luo W,Shi Y,Fan Z,Ji G.Should we standardize the 1,700-year-old fecal microbiota transplantation?Am JGastroenterol 2012;107:1755-1756[PMID:23160295 DOI:10.1038/ajg.2012.251]
72 Eiseman B,Silen W,Bascom GS,Kauvar AJ.Fecal enema as an adjunct in the treatment of pseudomembranous enterocolitis.Surgery 1958;44:854-859[PMID:13592638]
73 Armstrong MJ,Pathmakanthan S,Iqbal TH.Fecal microbiota transplantation for Clostridium difficile infection.JAMA 2015;313:725-726[PMID:25688787 DOI:10.1001/jama.2014.18617]
74 van Nood E,Vrieze A,Nieuwdorp M,Fuentes S,Zoetendal EG,de Vos WM,Visser CE,Kuijper EJ,Bartelsman JF,Tijssen JG,Speelman P,Dijkgraaf MG,Keller JJ.Duodenal infusion of donor feces for recurrent Clostridium difficile.N Engl J Med 2013;368:407-415[PMID:23323867 DOI:10.1056/NEJMoa1205037]
75 K?nig J,Siebenhaar A,H?genauer C,Arkkila P,Nieuwdorp M,Norén T,Ponsioen CY,Rosien U,Rossen NG,Satokari R,Stallmach A,de Vos W,Keller J,Brummer RJ.Consensus report:faecal microbiota transfer-clinical applications and procedures.Aliment Pharmacol Ther 2017;45:222-239[PMID:27891639 DOI:10.1111/apt.13868]
76 Zhong W,McClain CJ,Cave M,Kang YJ,Zhou Z.The role of zinc deficiency in alcohol-induced intestinal barrier dysfunction.Am J Physiol Gastrointest Liver Physiol 2010;298:G625-G633[PMID:20167873 DOI:10.1152/ajpgi.00350.2009]
77 Ge X,Lu Y,Leung TM,S?rensen ES,Nieto N.Milk osteopontin,a nutritional approach to prevent alcoholinduced liver injury.Am J Physiol Gastrointest Liver Physiol2013;304:G929-G939[PMID:23518682 DOI:10.1152/ajpgi.00014.2013]
78 Alwahsh SM,Gebhardt R.Dietary fructose as a risk factor for non-alcoholic fatty liver disease(NAFLD).Arch Toxicol 2017;91:1545-1563[PMID:27995280 DOI:10.1007/s00204-016-1892-7]
79 Lippai D,Bala S,Catalano D,Kodys K,Szabo G.MicroRNA-155 deficiency prevents alcohol-induced serum endotoxin increase and small bowel inflammation in mice.Alcohol Clin Exp Res 2014;38:2217-2224[PMID:25156614DOI:10.1111/acer.12483]