Effect of probiotic supplementation in nonalcoholic steatohepatitis patients: PROBILIVER TRIAL protocol

Amanda Souza Silva-Sperb, Helena Abadie Moraes, Bruna Concheski de Moura, Bruna Cherubini Alves, Juliana Paula Bruch-Bertani, Vittoria Zambon Azevedo, Valesca Dall'Alba, Amanda Souza Silva-Sperb, Helena Abadie Moraes, Bruna Concheski de Moura, Bruna Cherubini Alves, Juliana Paula Bruch-Bertani, Vittoria Zambon Azevedo, Valesca Dall'Alba

Abstract

Background: Recently factors in the relationship between gut microbiota, obesity, diabetes and the metabolic syndrome have been suggested in the development and progression of nonalcoholic steatohepatitis (NASH). In this sense, this work aims to evaluate the effects of probiotic supplementation on intestinal microbiota modulation, degree of hepatic steatosis and fibrosis, inflammation, gut permeability, and body composition.

Methods: This double-blind, randomized clinical trial will include adult outpatients with a diagnosis of NASH confirmed by biopsy with or without transient elastography. All patients will undergo a complete anamnesis to investigate their alcohol consumption, previous history, medications, nutritional assessment (dietary intake and body composition), sarcopenia, physical activity level and physical and functional capacity, cardiovascular risk, biochemical parameters for assessment of inflammatory status, lipid profile, hepatic function, gut permeability, and assessment of microbiota. These procedures will be performed at baseline and repeated after 24 weeks (at the end of the study). Through the process of randomization, patients will be allocated to receive treatment A or treatment B. Both patients and researchers involved will be blinded (double-blind study). The intervention consists of treatment with a probiotic mix (Lactobacillus acidophillus + Bifidobacterium lactis + Lactobacillus rhamnosus + Lactobacillus paracasei, 1 x 109 CFU for each) and the placebo which is identical in all its characteristics and packaging. Patients will be instructed to consume two sachets/day during 24 weeks and to report any symptoms or side effects related to the use of the sachets. Adherence control will be carried out through the patient's notes on a form provided, and also by checking the number of sachets used.

Discussion: The final results of study will be analyzed and disseminated in 2020.

Trial registration: ClinicalTrials.gov, ID: NCT03467282 . Registered on 15 March 2018.

Keywords: Inflammation; Microbiota; Non-alcoholic fatty-liver disease; Permeability; Probiotic; Sarcopenia.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Schedule of enrollment, interventions, and assessments

References

    1. Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018;67(1):328–357. doi: 10.1002/hep.29367.
    1. Puchakayala BK, Verma S, Kanwar P, Hart J, Sanivarapu RR, Mohanty SR. Histopathological differences utilizing the nonalcoholic fatty liver disease activity score criteria in diabetic (type 2 diabetes mellitus) and non-diabetic patients with nonalcoholic fatty liver disease. World J Hepatol. 2015;7(25):2610–2618. doi: 10.4254/wjh.v7.i25.2610.
    1. Sanyal AJ, Chalasani N. Trials and tribulations in drug development for nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol. 2014;12:2104–2105. doi: 10.1016/j.cgh.2014.08.005.
    1. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease—Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64(1):73–84. doi: 10.1002/hep.28431.
    1. Chu H, Williams B, Schnabl B. Gut microbiota, fatty liver disease, and hepatocellular carcinoma. Liver Res. 2018;2(1):43–51. doi: 10.1016/j.livres.2017.11.005.
    1. Fukui H. Increased intestinal permeability and decreased barrier function: does it really influence the risk of inflammation? Inflamm Intest Dis. 2016;1(3):135–145. doi: 10.1159/000447252.
    1. Bluemel S, Williams B, Knight R, Schnabl B. Precision medicine in alcoholic and nonalcoholic fatty liver disease via modulating the gut microbiota. Am J Physiol Gastrointest Liver Physiol. 2016;311(6):G1018–G1036. doi: 10.1152/ajpgi.00245.2016.
    1. Poeta M, Pierri L, Vajro P. Gut-liver axis derangement in non-alcoholic fatty liver disease. Children (Basel) 2017;4(8):E66.
    1. Roh YS, Seki E. Toll-like receptors in alcoholic liver disease, non-alcoholic steatohepatitis and carcinogenesis. J Gastroenterol Hepatol. 2013;28(Suppl 1):38–42. doi: 10.1111/jgh.12019.
    1. Thuy S, Ladurner R, Volynets V, Wagner S, Strahl S, Königsrainer A, et al. Nonalcoholic fatty liver disease in humans is associated with increased plasma endotoxin and plasminogen activator inhibitor 1 concentrations and with fructose intake. J Nutr. 2008;138(8):1452–1455. doi: 10.1093/jn/138.8.1452.
    1. Arab J, Arrese M, Trauner M. Recent insights into the pathogenesis of nonalcoholic fatty liver disease. Annu Rev Pathol. 2018;13:321–350. doi: 10.1146/annurev-pathol-020117-043617.
    1. Ferolla SM, Couto CA, Costa-Silva L, Armiliato GN, Pereira CA, Martins FS, et al. Beneficial effect of synbiotic supplementation on hepatic steatosis and anthropometric parameters, but not on gut permeability in a population with nonalcoholic steatohepatitis. Nutrients. 2016;8(7):E397. doi: 10.3390/nu8070397.
    1. Luther J, Garber JJ, Khalili H, Dave M, Bale SS, Jindal R, et al. Hepatic injury in nonalcoholic steatohepatitis contributes to altered intestinal permeability. Cell Mol Gastroenterol Hepatol. 2015;1(2):222–232. doi: 10.1016/j.jcmgh.2015.01.001.
    1. Miele L, Valenza V, La Torre G, Montalto M, Cammarota G, Ricci R, et al. Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology. 2009;49(6):1877–1887. doi: 10.1002/hep.22848.
    1. Moschen AR, Kaser S, Tilg H. Non-alcoholic steatohepatitis: a microbiota-driven disease. Trends Endocrinol Metab. 2013;24(11):537–545. doi: 10.1016/j.tem.2013.05.009.
    1. Schneider AC, Machado AB, de Assis AM, Hermes DM, Schaefer PG, Guizzo R, et al. Effects of Lactobacillus rhamnosus GG on hepatic and serum lipid profiles in zebrafish exposed to ethanol. Zebrafish. 2014;11(4):371–378. doi: 10.1089/zeb.2013.0968.
    1. 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 diseases patients: a double blind randomized clinical trial. Eur Rev Med Pharmacol Sci. 2011;15(9):1090–1095.
    1. Shavakhi A, Minakari M, Firouzian H, Assali R, Hekmatdoost A, Ferns G. Effect of a probiotic and metformin on liver aminotransferases in non-alcoholic steatohepatitis: a double blind randomized clinical trial. Int J Prev Med. 2013;4(5):531–537.
    1. Wong VW, Won GL, Chim AM, Chu WC, Yeung DK, Li KC, Chan HL, et al. Treatment of nonalcoholic steatohepatitis with probiotics. A proof-of-concept study. Ann Hepatol. 2013;12(2):256–262. doi: 10.1016/S1665-2681(19)31364-X.
    1. Kobyliak N, Abenavoli L, Mykhalchyshyn G, Kononenko L, Boccuto L, Kyriienko D, et al. A multi-strain probiotic reduces the Fatty Liver Index, cytokines and aminotransferase levels in NAFLD patients: evidence from a randomized clinical trial. J Gastrointestin Liver Dis. 2018;27(1):41–49.
    1. Javadi L, Ghavami M, Khoshbaten M, Safaiyan A, Barzegari A, Gargari BP. The potential role of probiotics or/and prebiotic on serum lipid profile and insulin resistance in alcoholic fatty liver disease: a double blind randomized clinical trial. Crescent J Med Biol Sci. 2017;4(3):131–138.
    1. Hong HC, Hwang SY, Choi HY, Yoo HJ, Seo JA, Kim SG, et al. Relationship between sarcopenia and nonalcoholic fatty liver disease: the Korean Sarcopenic Obesity Study. Hepatology. 2014;59(5):1772–1778. doi: 10.1002/hep.26716.
    1. Guichelaar MM, Charlton MR. Decreased muscle mass in nonalcoholic fatty liver disease: new evidence of a link between growth hormone and fatty liver disease? Hepatology. 2014;59(5):1668–1670. doi: 10.1002/hep.27058.
    1. Lee YH, Kim SU, Song K, Park JY, Kim DY, Ahn SH, et al. Sarcopenia is associated with significant liver fibrosis independently of obesity and insulin resistance in nonalcoholic fatty liver disease: Nationwide surveys (KNHANES 2008–2011) Hepatology. 2016;63(3):776–786. doi: 10.1002/hep.28376.
    1. Cederholm T, Barazzoni R, Austin P, Ballmer P, Biolo G, Bischoff SC, et al. ESPEN guidelines on definitions and terminology of clinical nutrition. Clin Nutr. 2017;36(1):49–64. doi: 10.1016/j.clnu.2016.09.004.
    1. Wijarnpreecha K, Panjawatanan P, Thongprayoon C, Jaruvongvanich V, Ungprasert P. Sarcopenia and risk of nonalcoholic fatty liver disease: a meta-analysis. Saudi J Gastroenterol. 2018;24(1):12–17. doi: 10.4103/sjg.SJG_237_17.
    1. Bindels LB, Beck R, Schakman O, Martin JC, De Backer F, Sohet FM, et al. Restoring specific lactobacilli levels decreases inflammation and muscle atrophy markers in an acute leukemia mouse model. PLoS One. 2012;7(6):e37971. doi: 10.1371/journal.pone.0037971.
    1. Chan AW, Tetzlaff JM, Altman DG, Laupacis A, Gøtzsche PC, Krleža-Jerić K, et al. SPIRIT 2013 Statement: defining standard protocol items for clinical trials. Ann Intern Med. 2013;158(3):200–207. doi: 10.7326/0003-4819-158-3-201302050-00583.
    1. 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(3):535–542. doi: 10.3945/ajcn.113.068890.
    1. Castera L, Forns X, Alberti A. Non-invasive evaluation of liver fibrosis using transient elastography. J Hepatol. 2008;48(5):835–847. doi: 10.1016/j.jhep.2008.02.008.
    1. Angulo P, Hui JM, Marchesini G, Bugianesi E, George J, Farrell GC, et al. The NAFLD Fibrosis Score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology. 2007;45(4):846–854. doi: 10.1002/hep.21496.
    1. Kruger FC, Daniels CR, Kidd M, Swart G, Brundyn K, van Rensburg C, et al. APRI: a simple bedside marker for advanced fibrosis that can avoid liver biopsy in patients with NAFLD/NASH. S Afr Med J. 2011;101(7):477–480.
    1. Bedogni G, Bellentani S, Miglioli L, Masutti F, Passalacqua M, Castiglione A, et al. The Fatty Liver Index: a simple and accurate predictor of hepatic steatosis in the general population. BMC Gastroenterol. 2006;6:33. doi: 10.1186/1471-230X-6-33.
    1. Silva TR, Spritzer PM. Skeletal muscle mass is associated with higher dietary protein intake and lower body fat in postmenopausal women. Menopause. 2017;24(5):502–509. doi: 10.1097/GME.0000000000000793.
    1. Slinde F, Rossander-Hulthén L. Bioelectrical impedance: effect of 3 identical meals on diurnal impedance variation and calculation of body composition. Am J Clin Nutr. 2001;74(4):474–478. doi: 10.1093/ajcn/74.4.474.
    1. Schlüssel MM, dos Anjos LA, de Vasconcellos MT, Kac G. A dinamometria manual e seu uso na avaliação nutricional. (Reference values of handgrip dynamometry of healthy adults: a population-based study) Clin Nutr. 2008;27(4):601–607. doi: 10.1016/j.clnu.2008.04.004.
    1. Cesari M, Kritchevsky SB, Newman AB, Simonsick EM, Harris TB, Penninx BW, et al. Added value of physical performance measures in predicting adverse health related events: results from the Health, Aging and Body Composition Study. J Am Geriatr Soc. 2009;57(2):251–259. doi: 10.1111/j.1532-5415.2008.02126.x.
    1. Graham JE, Ostir GV, Fisher SR, Ottenbacher KJ. Assessing walk speed in clinical research: a systematic review. J Eval Clin Pract. 2008;14(4):552–562. doi: 10.1111/j.1365-2753.2007.00917.x.
    1. Cruz-Jentoft AJ, Baeyens JP, Bauer JM, Boirie Y, Cederholm T, Landi F, et al. Sarcopenia: European consensus on definition and diagnosis: Report of the European Working Group on Sarcopenia in Older People. Age Ageing. 2010;39(4):412–423. doi: 10.1093/ageing/afq034.
    1. Lauretani F, Russo CR, Bandinelli S, Bartali B, Cavazzini C, Di Iorio A, et al. Age-associated changes in skeletal muscles and their effect on mobility: an operational diagnosis of sarcopenia. J Appl Physiol (1985) 2003;95(5):1851–1860. doi: 10.1152/japplphysiol.00246.2003.
    1. Gustafson AS, Noaksson L, Kronhed AC, Möller M, Möller C. Changes in balance performance in physically active elderly people aged 73-80. Scand J Reab Med. 2000;32(4):168–172. doi: 10.1080/003655000750060913.
    1. D'Agostino RB, Sr, Vasan RS, Pencina MJ, Wolf PA, Cobain M, Massaro JM, et al. General cardiovascular risk profile for use in primary care: the Framingham Heart Study. Circulation. 2008;117(6):743–753. doi: 10.1161/CIRCULATIONAHA.107.699579.
    1. Goff DC, Jr, Lloyd-Jones DM, Bennett G, Coady S, D’Agostino RB, Raymond G, et al. 2013 ACC/AHA Cardiovascular Risk Guideline. Circulation. 2013;129:S49–S73. doi: 10.1161/01.cir.0000437741.48606.98.
    1. Schakel S, Sievert YA, Buzzard IM. Dietary fiber values for common foods. In: Spiller GA, editor. CRC handbook of dietary fiber in human nutrition. 3. Boca Raton: CRC Press; 2001. pp. 614–648.
    1. 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(6):740–743. doi: 10.1097/MPG.0b013e31821f9b85.

Source: PubMed

Sponsorer og samarbeidspartnere

Medisinsk tilstand

Legemiddelintervensjoner

3
Abonnere