The Effect of Probiotics on the Clinical Outcomes and Gut Microenvironment in Patients With Fatty Liver

Study of the Effect of Probiotics on the Clinical Outcomes and Gut Microenvironment in Patients With Non-alcoholic Fatty Liver Disease: a Randomised Controlled Trial

Fatty liver has been associated with high risk of progression to inflammation of the liver, liver cirrhosis (hardening of the liver), and eventually can lead to liver cancer. So far, the treatment for this condition involves controlling the cholesterol level in the body by practicing low fat diet and daily exercise. However, recently there has been evidence that alteration of the normal population of various types of bacteria that lives in the intestines may contributes to the development of fatty liver.

Probiotics is a dietary supplement containing live bacteria that is formulated to change the composition and population of the bacteria in the intestines. It is postulated that by taking specifically formulated probiotics, the alteration of the intestinal bacteria may lead to improvement of the fatty liver, leading to better daily liver function.

In this 6-month study, investigators would like to investigate the effectiveness of the probiotics in improving the liver function and in the treatment of the fatty liver. It will compare the fatty liver of patients who took the probiotics supplements compared to those who did not took it and see if there is any improvement.

Study Overview

• Status: Unknown
• Conditions: Non-Alcoholic Fatty Liver Disease
• Intervention / Treatment: Dietary supplement: (Microbial cell preparation) Probiotics; Other: Placebo

Detailed Description

Non-alcoholic fatty liver disease (NAFLD) is one of the common causes of chronic liver disease nowadays. NAFLD is considered as the hepatic manifestation of metabolic syndrome. In Malaysia, the prevalence of metabolic disorders such as diabetes mellitus, obesity and dyslipidemia are increasing with time. Despite the disease burden, treatments for NAFLD are currently limited due to the ongoing evolving theory of its pathogenesis.

One of the proposed mechanisms is via gut-liver axis (GLA), whereby the role of gut microbiota has been implicated. Two main components of GLA are gut microbiota and gut barrier. A change in gut microbiota composition will predispose to gut barrier dysfunction, which subsequently leads to bacterial by-products translocation into the portal circulation. Eventually, these by-products reach the liver and trigger the cascades of hepatic inflammation, leading to fatty liver and its disease progression.

The aim of this study is to investigate the role of probiotics in modulating the gut microenvironment - namely gut microbiota composition, gut barrier function and local gut inflammation, as well as its effect on the clinical outcomes in NAFLD patients.

Investigators propose a randomised, double-blind, placebo-controlled trial of 6-month duration. Investigators aim to recruit 48 NALFD patients, with either treated with probiotics or placebo. Small intestinal microbiota will be determined by 16S-rRNA sequencing and immunoreactivity of zona occludens-1 (tight junction protein in the gut barrier) and cytokines mRNA level will be measured. The degree of liver steatosis and stiffness will be assessed by using transient elastography and biochemical blood tests. All these variables will be determined pre- and post-intervention with probiotics/placebo.

This study will provide a valuable knowledge on the role of probiotics as the gut microenvironment modulator and strengthen the hypothesis of GLA involvement in the NAFLD development. Hence, probiotics can be strongly considered as one of the treatment options for non-alcoholic fatty liver disease.

• Study Type: Interventional
• Enrollment (Anticipated): 48
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Khairul Najmi Muhammad Nawawi, MBBCh BAO; Phone Number: +60183734807; Email: khairulnajmi84@gmail.com

Study Locations

• Malaysia
  • Kuala Lumpur
    • Cheras, Kuala Lumpur, Malaysia, 56000
      • Recruiting
      • The University of Malaysia Medical Centre
      • Contact: Khairul Najmi Muhammad Nawawi, MBBCh BAO; Phone Number: 0060183734807; Email: khairulnajmi84@gmail.com
      • Sub-Investigator: Mohamad Hizami Mohamad Nor, MBBCh BAO
      • Sub-Investigator: Nurainina Ayob, MSc
      • Sub-Investigator: Raja Affendi Raja Ali, FRCP
      • Sub-Investigator: Norfilza Mohd Mokhtar, PhD
      • Sub-Investigator: Geok Chin Tan, PhD
      • Sub-Investigator: Zhiqin Wong, FRCP

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age 18 and above 2. Diagnosis of NAFLD is confirmed by the presence of fatty liver detected by abdominal ultrasound and controlled attenuation parameter (CAP) score from FibroScan® of >263 3. Raised ALT level (above upper limit of normal): > 35IU/L for males and > 25 IU/L for females

Exclusion Criteria:

1. Evidence of other chronic liver diseases (as determined by clinical and standard investigations) - e.g. Hepatitis B, C infections, autoimmune hepatic disorders.
2. Evidence of acute disorders that affecting the liver - e.g. drug induced liver injury, non-Hepatitis B, C viral infection.
3. Biliary disease.
4. Liver cancer - primary hepatocellular carcinoma or liver metastasis.
5. Evidence of liver cirrhosis.
6. Alcohol intake > 20g/day for males and >10g/day for females.
7. Use of steatogenic medications within the past one months - e.g. systemic steroids, methotrexate.
8. History of bariatric surgery
9. Intake of antibiotics and/or probiotic and proton pump inhibitor within one month before the start of the study or during the study period.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Group A; Patients will be given Lactobacillus & Bifidobacterium containing probiotics [Lactobacillus acidophilus (107mg), Lactobacillus casei subsp (107mg), Lactobacillus lactis (107mg), Bifidobacterium bifidum (107mg), Bifidobacterium infantis (107mg) and Bifidobacterium longum (107mg], to be taken 1 sachet twice daily for 6 months.	Dietary supplement: (Microbial cell preparation) Probiotics; Lactobacillus acidophilus (107mg), Lactobacillus casei subsp (107mg), Lactobacillus lactis (107mg), Bifidobacterium bifidum (107mg), Bifidobacterium infantis (107mg) and Bifidobacterium longum (107mg); Other Names: Hexbio
Placebo Comparator: Group B; Patients will be given placebo sachet (exactly the same packaging as active comparator) to be taken 1 sachet twice daily for 6 months.	Other: Placebo; Placebo sachet with no microbial cell preparation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean difference in hepatic steatosis score	as measured by Controlled Attenuated Parameter score from Transient Elastography (Fibroscan)	6-7 months post supplementation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean difference in hepatic fibrosis score	as measured by liver stiffness score from Transient Elastography (Fibroscan)	6-7 months post supplementation
Mean difference in hepatic steatosis, inflammation and fibrosis scores	as measured by 10 serum biomarkers (LiverFASt)	6-7 months post supplementation
Microbiota composition of small intestine	assessed by 16rRNA Amplicon Sequencing	6-7 months post supplementation
Mean difference of immunoreactivity score of zona occludens-1 (ZO-1: indicator of intestinal permeability) and CD4+,CD8+, IL-8 (indicator of intestinal mucosal immune system).	Immunohistochemistry	6-7 months post supplementation
Mean difference in mRNA expression of genes related to inflammation (IL-6, TNF-alpha, IFN-gamma)	Measured by serum qPCR	6-7 months post supplementation

Collaborators and Investigators

• Sponsor: Universiti Kebangsaan Malaysia Medical Centre
• Collaborators: Ministry of Education, Malaysia; B-Crobes Laboratory Sdn. Bhd; Fibronostics Pte. Ltd
• Investigators: Principal Investigator: Khairul Najmi Muhammad Nawawi, MBBCh BAO, The University of Malaysia Medical Centre, Kuala Lumpur, Malaysia

Study record dates

Study Major Dates

• Study Start (Actual): August 30, 2019
• Primary Completion (Anticipated): July 1, 2020
• Study Completion (Anticipated): December 1, 2020

Study Registration Dates

• First Submitted: August 29, 2019
• First Submitted That Met QC Criteria: August 29, 2019
• First Posted (Actual): August 30, 2019

Study Record Updates

• Last Update Posted (Actual): September 4, 2019
• Last Update Submitted That Met QC Criteria: August 29, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Keywords: Probiotics; Gut Liver Axis
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease
• Other Study ID Numbers: FRGS/1/2018/SKK02/UKM/03/2

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No