Histological improvement of non-alcoholic steatohepatitis with a prebiotic: a pilot clinical trial
- 469 Downloads
In obesity and diabetes the liver is highly susceptible to abnormal uptake and storage of fat. In certain individuals hepatic steatosis predisposes to the development of non-alcoholic steatohepatitis (NASH), a disease marked by hepatic inflammation and fibrosis. Although the precise pathophysiology of NASH is unknown, it is believed that the gut microbiota-liver axis influences the development of this disease. With few treatment strategies available for NASH, exploration of gut microbiota-targeted interventions is warranted. We investigated the therapeutic potential of a prebiotic supplement to improve histological parameters of NASH.
In a placebo-controlled, randomized pilot trial, 14 individuals with liver-biopsy-confirmed NASH [non-alcoholic fatty liver activity score (NAS) ≥ 5] were randomized to receive oligofructose (8 g/day for 12 weeks followed by 16 g/day for 24 weeks) or isocaloric placebo for 9 months. The primary outcome measure was the change in liver biopsy NAS score and the secondary outcomes included changes in body weight, body composition, glucose tolerance, inflammatory markers, and gut microbiota.
Independent of weight loss, oligofructose improved liver steatosis relative to placebo and improved overall NAS score (P = 0.016). Bifidobacterium was enhanced by oligofructose, whereas bacteria within Clostridium cluster XI and I were reduced with oligofructose (P < 0.05). There were no adverse side effects that deterred individuals from consuming oligofructose for treatment of this disease.
Independent of other lifestyle changes, prebiotic supplementation reduced histologically-confirmed steatosis in patients with NASH. Larger follow-up studies are warranted.
This trial was registered at Clinicaltrials.com as NCT03184376.
KeywordsNon-alcoholic steatohepatitis Gut microbiota Prebiotic Oligofructose
The authors would like to thank all of the individuals who volunteered their time to participate and contribute to this study. The authors also thank Matt Workentine, Faculty of Veterinary Medicine, University of Calgary, for his technical assistance with 16S sequencing analysis.
MRB executed the study, collected data, analyzed data, and prepared the manuscript; JAP designed the study and obtained funding; HRR analyzed 16S gut microbiota sequencing data; PC collected data; KPR, SJ, and MR designed the study, collected data, and recruited participants; CSP performed VOC analysis; RAR designed the study, obtained funding and had final responsibility for the study. All authors had access to the study data and reviewed and approved the final manuscript.
This work was supported by a research grant from the Canadian Institutes of Health Research (MOP-136889) and a University of Calgary Seed Grant. MRB was supported by Alberta Innovates Health Solutions (AIHS) and an Honorary Izaak Walton Killam Doctoral Scholarship.
Compliance with ethical standards
Conflict of interest
MRB, JAP, HRR, PC, KPR, CSP, SJ, and MR declare no conflict of interest. RAR previously held a research grant from Beneo-Orafti, Inc., manufacturer of Orafti P95, for a project unrelated to this study.
- 4.Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, Torres-Gonzalez A, Gra-Oramas B, Gonzalez-Fabian L, Friedman SL, Diago M, Romero-Gomez M (2015) Weight loss through lifestyle modification significantly reduces features of non-alcoholic steatohepatitis. Gastroenterology 149(2):367–378.e365. https://doi.org/10.1053/j.gastro.2015.04.005 CrossRefGoogle Scholar
- 5.Dudekula A, Rachakonda V, Shaik B, Behari J (2014) Weight loss in non-alcoholic fatty liver disease patients in an ambulatory care setting is largely unsuccessful but correlates with frequency of clinic visits. PLoS One 9(11):e111808. https://doi.org/10.1371/journal.pone.0111808 CrossRefGoogle Scholar
- 10.Le Roy T, Llopis M, Lepage P, Bruneau A, Rabot S, Bevilacqua C, Martin P, Philippe C, Walker F, Bado A, Perlemuter G, Cassard-Doulcier AM, Gerard P (2013) Intestinal microbiota determines development of non-alcoholic fatty liver disease in mice. Gut 62(12):1787–1794. https://doi.org/10.1136/gutjnl-2012-303816 CrossRefGoogle Scholar
- 12.Gibson GR, Hutkins R, Sanders ME, Prescott SL, Reimer RA, Salminen SJ, Scott K, Stanton C, Swanson KS, Cani PD, Verbeke K, Reid G (2017) Expert consensus document: the International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics. Nat Rev Gastroenterol Hepatol 14(8):491–502. https://doi.org/10.1038/nrgastro.2017.75 CrossRefGoogle Scholar
- 16.Dewulf EM, Cani PD, Claus SP, Fuentes S, Puylaert PG, Neyrinck AM, Bindels LB, de Vos WM, Gibson GR, Thissen JP, Delzenne NM (2013) Insight into the prebiotic concept: lessons from an exploratory, double blind intervention study with inulin-type fructans in obese women. Gut 62(8):1112–1121. https://doi.org/10.1136/gutjnl-2012-303304 CrossRefGoogle Scholar
- 19.Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, Ferrell LD, Liu YC, Torbenson MS, Unalp-Arida A, Yeh M, McCullough AJ, Sanyal AJ, Non-alcoholic Steatohepatitis Clinical Research N (2005) Design and validation of a histological scoring system for non-alcoholic fatty liver disease. Hepatology 41(6):1313–1321. https://doi.org/10.1002/hep.20701 CrossRefGoogle Scholar
- 21.Godin G, Shephard RJ (1985) A simple method to assess exercise behavior in the community. Can J Appl Sport Sci 10(3):141–146Google Scholar
- 29.Malaguarnera M, Vacante M, Antic T, Giordano M, Chisari G, Acquaviva R, Mastrojeni S, Malaguarnera G, Mistretta A, Li Volti G, Galvano F (2012) Bifidobacterium longum with fructo-oligosaccharides in patients with non alcoholic steatohepatitis. Dig Dis Sci 57(2):545–553. https://doi.org/10.1007/s10620-011-1887-4 CrossRefGoogle Scholar
- 30.Eslamparast T, Poustchi H, Zamani F, Sharafkhah M, Malekzadeh R, Hekmatdoost A (2014) Synbiotic supplementation in non-alcoholic fatty liver disease: a randomized, double-blind, placebo-controlled pilot study. Am J Clin Nutr 99(3):535–542. https://doi.org/10.3945/ajcn.113.068890 CrossRefGoogle Scholar
- 31.Aller R, De Luis DA, Izaola O, Conde R, Gonzalez Sagrado M, Primo D, De La Fuente B, Gonzalez J (2011) Effect of a probiotic on liver aminotransferases in non-alcoholic fatty liver disease patients: a double blind randomized clinical trial. Eur Rev Med Pharmacol Sci 15(9):1090–1095Google Scholar
- 32.Vajro P, Mandato C, Licenziati MR, Franzese A, Vitale DF, Lenta S, Caropreso M, Vallone G, Meli R (2011) Effects of Lactobacillus rhamnosus strain GG in pediatric obesity-related liver disease. J Ped Gastroenterol Nutr 52(6):740–743. https://doi.org/10.1097/MPG.0b013e31821f9b85 CrossRefGoogle Scholar
- 33.Wong VW, Won GL, Chim AM, Chu WC, Yeung DK, Li KC, Chan HL (2013) Treatment of non-alcoholic steatohepatitis with probiotics. A proof-of-concept study. Ann Hepatol 12(2):256–262Google Scholar
- 34.Bomhof MR, Saha DC, Reid DT, Paul HA, Reimer RA (2014) Combined effects of oligofructose and Bifidobacterium animalis on gut microbiota and glycemia in obese rats. Obesity 22(3):763–771. https://doi.org/10.1002/oby.20632;10.1002/oby.20632 CrossRefGoogle Scholar
- 38.Daud NM, Ismail NA, Thomas EL, Fitzpatrick JA, Bell JD, Swann JR, Costabile A, Childs CE, Pedersen C, Goldstone AP, Frost GS (2014) The impact of oligofructose on stimulation of gut hormones, appetite regulation and adiposity. Obesity 22(6):1430–1438. https://doi.org/10.1002/oby.20754 CrossRefGoogle Scholar
- 39.Ryan MC, Itsiopoulos C, Thodis T, Ward G, Trost N, Hofferberth S, O’Dea K, Desmond PV, Johnson NA, Wilson AM (2013) The Mediterranean diet improves hepatic steatosis and insulin sensitivity in individuals with non-alcoholic fatty liver disease. J Hepatol 59(1):138–143. https://doi.org/10.1016/j.jhep.2013.02.012 CrossRefGoogle Scholar