The Role of Microbiome Reprogramming on Liver Fat Accumulation

NCT03914495 | Terminated

• 1 other identifier: 1312439
• Study Type: interventional
• Target: 57
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to investigate whether reprogramming the microbiome via soluble fiber supplementation will decrease liver fat in obese individuals.

Conditions

NAFLD

Keywords

inulin; microbiome; hepatic steatosis; obesity

Outcome Measures

Primary Outcomes (1)

• Absolute Change in Liver Fat

  Liver fat changes will be assessed by MRI-PDFF

  28 days

Study Arms (2)

Placebo

PLACEBO COMPARATOR

Participants will receive powdered maltodextrin to provide equivalent calories and macronutrients without any fiber.

Dietary Supplement: Placebo

Inulin

ACTIVE COMPARATOR

Participants will receive inulin, 10 grams TID for 28 days with titration as follows: 10 grams QD for 3 days, 20 grams BID for 4 days with the remaining 21 days at 10 g TID.

Dietary Supplement: Inulin

Interventions

Inulin DIETARY_SUPPLEMENT

Powdered inulin will be provided in pre-weighed portions for consumption in a 1 week titration to reduce GI side effects with a 21 day intervention at full dose.

Inulin

Placebo DIETARY_SUPPLEMENT

Powdered maltodextrin will be provided in pre-weighed portions for consumption in a 1 week titration with a 21 day intervention at full dose.

Placebo

Eligibility Criteria

• Age: 35 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 35-65 years
• Magnetic Resonance Imaging Proton Density Fat Fraction (MRI-PDFF) 5%-30% (+0.5%)
• Liver stiffness \<3.5 kPa by Magnetic Resonance Elastography (MRE)
• Body mass index (BMI) 27.5-45 kg/m2
• Weight stable (weight change of no more than 3 kg +0.5 kg) during the 6 months prior to enrollment
• For individuals with type 2 diabetes: HbA1c ≥6.5 - \<9.5%. If taking allowable diabetes medications, HbA1c can be below 6.5%.
• Fasting triglycerides 400 mg/dL (4.5 mmol/L)
• Able to speak and understand written and spoken English
• Understands the procedures and agrees to participate by giving written informed consent
• Willing and able to comply with scheduled study days, laboratory tests, and other study procedures

You may not qualify if:

• Acute or chronic medical conditions or medication that would contraindicate the participation in the research testing or could potentially affect metabolic function including, but not limited to:
• Diagnosis of type 1 diabetes mellitus
• Insulin use
• Change within 3 months of screening of any medication used to treat insulin resistance or type 2 diabetes
• History of regular alcohol consumption exceeding 14 drinks/week for females or 21 drinks/week for males within the previous 6 months (1 drink = 5 ounces \[150 mL\] of wine, 12 ounces \[360 mL\] of beer, or 1.5 ounces \[45 mL\] of hard liquor)
• A total score of 8 on the Alcohol Use Disorders Identification Test (AUDIT) questionnaire, indicating harmful or hazardous alcohol consumption
• Clinical evidence of hepatic decompensation, including, but not limited to esophageal varices, ascites, or hepatic encephalopathy
• Evidence of other forms of chronic liver disease (including laboratory tests and confirmed with a single repeat, if needed):
• Hepatitis B virus: defined by presence of hepatitis B surface antigen
• Hepatitis C virus: As defined by a clinical history of previous diagnosis of Hepatitis C (treated or untreated) or a positive Hepatitis C antibody.
• Known diagnosis of primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune hepatitis, or overlap syndrome
• Alcoholic liver disease
• Known diagnosis of hemochromatosis
• Prior known drug-induced liver injury
• Known or suspected hepatocellular carcinoma or other liver cancer

Sponsors & Collaborators

• AdventHealth Translational Research Institute: lead

Study Sites (1)

Translational Research Institute for Metabolism and Diabetes

Orlando, Florida, 32804, United States

Location

Related Publications (20)

• Estes C, Razavi H, Loomba R, Younossi Z, Sanyal AJ. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology. 2018 Jan;67(1):123-133. doi: 10.1002/hep.29466. Epub 2017 Dec 1.

  PMID: 28802062 BACKGROUND

• Rinella ME. Nonalcoholic fatty liver disease: a systematic review. JAMA. 2015 Jun 9;313(22):2263-73. doi: 10.1001/jama.2015.5370.

  PMID: 26057287 BACKGROUND

• Cohen JC, Horton JD, Hobbs HH. Human fatty liver disease: old questions and new insights. Science. 2011 Jun 24;332(6037):1519-23. doi: 10.1126/science.1204265.

  PMID: 21700865 BACKGROUND

• Stefan N, Haring HU, Cusi K. Non-alcoholic fatty liver disease: causes, diagnosis, cardiometabolic consequences, and treatment strategies. Lancet Diabetes Endocrinol. 2019 Apr;7(4):313-324. doi: 10.1016/S2213-8587(18)30154-2. Epub 2018 Aug 30.

  PMID: 30174213 BACKGROUND

• Caputo T, Gilardi F, Desvergne B. From chronic overnutrition to metaflammation and insulin resistance: adipose tissue and liver contributions. FEBS Lett. 2017 Oct;591(19):3061-3088. doi: 10.1002/1873-3468.12742. Epub 2017 Jul 25.

  PMID: 28677122 BACKGROUND

• Younossi Z, Anstee QM, Marietti M, Hardy T, Henry L, Eslam M, George J, Bugianesi E. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol. 2018 Jan;15(1):11-20. doi: 10.1038/nrgastro.2017.109. Epub 2017 Sep 20.

  PMID: 28930295 BACKGROUND

• Valbusa F, Agnoletti D, Scala L, Grillo C, Arduini P, Bonapace S, Calabria S, Scaturro G, Mantovani A, Zoppini G, Turcato E, Maggioni AP, Arcaro G, Targher G. Non-alcoholic fatty liver disease and increased risk of all-cause mortality in elderly patients admitted for acute heart failure. Int J Cardiol. 2018 Aug 15;265:162-168. doi: 10.1016/j.ijcard.2018.04.129. Epub 2018 May 2.

  PMID: 29739707 BACKGROUND

• Adams LA, Harmsen S, St Sauver JL, Charatcharoenwitthaya P, Enders FB, Therneau T, Angulo P. Nonalcoholic fatty liver disease increases risk of death among patients with diabetes: a community-based cohort study. Am J Gastroenterol. 2010 Jul;105(7):1567-73. doi: 10.1038/ajg.2010.18. Epub 2010 Feb 9.

  PMID: 20145609 BACKGROUND

• Fabbrini E, Magkos F, Mohammed BS, Pietka T, Abumrad NA, Patterson BW, Okunade A, Klein S. Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesity. Proc Natl Acad Sci U S A. 2009 Sep 8;106(36):15430-5. doi: 10.1073/pnas.0904944106. Epub 2009 Aug 24.

  PMID: 19706383 BACKGROUND

• Lonardo A, Sookoian S, Pirola CJ, Targher G. Non-alcoholic fatty liver disease and risk of cardiovascular disease. Metabolism. 2016 Aug;65(8):1136-50. doi: 10.1016/j.metabol.2015.09.017. Epub 2015 Sep 25.

  PMID: 26477269 BACKGROUND

• Loomba R, Sanyal AJ, Kowdley KV, Terrault N, Chalasani NP, Abdelmalek MF, McCullough AJ, Shringarpure R, Ferguson B, Lee L, Chen J, Liberman A, Shapiro D, Neuschwander-Tetri BA. Factors Associated With Histologic Response in Adult Patients With Nonalcoholic Steatohepatitis. Gastroenterology. 2019 Jan;156(1):88-95.e5. doi: 10.1053/j.gastro.2018.09.021. Epub 2018 Sep 15.

  PMID: 30222962 BACKGROUND

• Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, Harrison SA, Brunt EM, Sanyal AJ. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018 Jan;67(1):328-357. doi: 10.1002/hep.29367. Epub 2017 Sep 29. No abstract available.

  PMID: 28714183 BACKGROUND

• Dumas ME, Barton RH, Toye A, Cloarec O, Blancher C, Rothwell A, Fearnside J, Tatoud R, Blanc V, Lindon JC, Mitchell SC, Holmes E, McCarthy MI, Scott J, Gauguier D, Nicholson JK. Metabolic profiling reveals a contribution of gut microbiota to fatty liver phenotype in insulin-resistant mice. Proc Natl Acad Sci U S A. 2006 Aug 15;103(33):12511-6. doi: 10.1073/pnas.0601056103. Epub 2006 Aug 8.

  PMID: 16895997 BACKGROUND

• Zhou D, Pan Q, Shen F, Cao HX, Ding WJ, Chen YW, Fan JG. Total fecal microbiota transplantation alleviates high-fat diet-induced steatohepatitis in mice via beneficial regulation of gut microbiota. Sci Rep. 2017 May 8;7(1):1529. doi: 10.1038/s41598-017-01751-y.

  PMID: 28484247 BACKGROUND

• 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. Intestinal microbiota determines development of non-alcoholic fatty liver disease in mice. Gut. 2013 Dec;62(12):1787-94. doi: 10.1136/gutjnl-2012-303816. Epub 2012 Nov 29.

  PMID: 23197411 BACKGROUND

• Kaden-Volynets V, Basic M, Neumann U, Pretz D, Rings A, Bleich A, Bischoff SC. Lack of liver steatosis in germ-free mice following hypercaloric diets. Eur J Nutr. 2019 Aug;58(5):1933-1945. doi: 10.1007/s00394-018-1748-4. Epub 2018 Jun 20.

  PMID: 29926176 BACKGROUND

• De Minicis S, Rychlicki C, Agostinelli L, Saccomanno S, Candelaresi C, Trozzi L, Mingarelli E, Facinelli B, Magi G, Palmieri C, Marzioni M, Benedetti A, Svegliati-Baroni G. Dysbiosis contributes to fibrogenesis in the course of chronic liver injury in mice. Hepatology. 2014 May;59(5):1738-49. doi: 10.1002/hep.26695. Epub 2014 Feb 25.

  PMID: 23959503 BACKGROUND

• Kang DJ, Betrapally NS, Ghosh SA, Sartor RB, Hylemon PB, Gillevet PM, Sanyal AJ, Heuman DM, Carl D, Zhou H, Liu R, Wang X, Yang J, Jiao C, Herzog J, Lippman HR, Sikaroodi M, Brown RR, Bajaj JS. Gut microbiota drive the development of neuroinflammatory response in cirrhosis in mice. Hepatology. 2016 Oct;64(4):1232-48. doi: 10.1002/hep.28696. Epub 2016 Jul 29.

  PMID: 27339732 BACKGROUND

• Mazagova M, Wang L, Anfora AT, Wissmueller M, Lesley SA, Miyamoto Y, Eckmann L, Dhungana S, Pathmasiri W, Sumner S, Westwater C, Brenner DA, Schnabl B. Commensal microbiota is hepatoprotective and prevents liver fibrosis in mice. FASEB J. 2015 Mar;29(3):1043-55. doi: 10.1096/fj.14-259515. Epub 2014 Dec 2.

  PMID: 25466902 BACKGROUND

• Henao-Mejia J, Elinav E, Jin C, Hao L, Mehal WZ, Strowig T, Thaiss CA, Kau AL, Eisenbarth SC, Jurczak MJ, Camporez JP, Shulman GI, Gordon JI, Hoffman HM, Flavell RA. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature. 2012 Feb 1;482(7384):179-85. doi: 10.1038/nature10809.

  PMID: 22297845 BACKGROUND

Related Links

• Webpage for Translational Research Institute for Metabolism and Diabetes

MeSH Terms

Conditions

Non-alcoholic Fatty Liver Disease; Fatty Liver; Obesity

Interventions

Inulin

Condition Hierarchy (Ancestors)

Liver Diseases; Digestive System Diseases; Overweight; Overnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Starch; Glucans; Biopolymers; Polymers; Macromolecular Substances; Dietary Carbohydrates; Carbohydrates; Fructans; Polysaccharides

Study Officials

• Karen Corbin, PhD

  Study Principal Investigator

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 11, 2019
• First Posted: April 16, 2019
• Study Start: May 21, 2019
• Primary Completion: June 2, 2021
• Study Completion: June 9, 2021
• Last Updated: February 13, 2023

Record last verified: 2023-02

Locations

US (1)