To Evaluate the Beneficial Effect of Probiotics on NAFLD Patients and the Role of Gut Microbiota Modulation

To Evaluate the Clinical Efficacy of Probiotic in Patients With NAFLD

In this study, the improvement of the clinical status of early-stage non-alcoholic fatty liver disease (NAFLD) patients after the probiotic intervention will be assessed. And the mechanism of probiotics to prevent the progression of illness would be investigated. The chronic inflammation status, systemic oxidative stress, metabolism of carbohydrates and lipid, and gut microbiota of NAFLD patients will also be analyzed.

Study Overview

• Status: Completed
• Conditions: Non-Alcoholic Fatty Liver Disease
• Intervention / Treatment: Other: Placebo; Dietary supplement: Probiotics

Detailed Description

Uncontrolled NAFLD evolves in Non-Alcoholic SteatoHepatitis (NASH), cirrhosis and liver cancer. Early intervention to prevent the progression of illness of NAFLD is very important. From 2005 to 2018, 15 clinical trials concluded that multiple-strain probiotics significantly reduced the liver inflammation index and blood lipids in NAFLD patients. Many reports indicated that NAFLD-associated risk factors, such as chronic inflammation, oxidative stress, insulin resistance, dyslipidemia, and obesity are closely correlated with gut microbiota. Some substances (such as endotoxin and alcohol) produced by harmful gut bacteria caused the progression of the illness of NAFLD.

Three strains are Genmont® Normal Lactobacillus (GMNL) which were divided from natural environments, included Lactobacillus reuteri GMNL-263 (heat-killed) and GMNL-89 (alive) and Lactobacillus rhamnosus GMNL-74 ( alive). They are all isolated from the gastrointestinal tract of healthy Taiwanese and were known as common food material worldwide. The previous clinical research on probiotic consumption in type 2 Diabetes mellitus patients under normal drug treatment was conducted in Changhua Christian Hospital. Results showed that L. reuteri GMNL-263 was able to stabilize the weight and blood pressure of patients. L. reuteri GMNL-89 had a stable effect on glycated hemoglobin. There was no adverse reaction when probiotics combining with type 2 diabetes drugs. Meanwhile, L. rhamnosus GMNL-74 was observed to reduce weight gain in obese mice. In this clinical study, The anti-liver inflammation effect of consumption of Lactobacillus sachet in NAFLD patients will be demonstrated at baseline, 3 months and 6 months. In this clinical study, the anti-liver inflammation effect of consumption of Lactobacillus sachet in NAFLD patients will be demonstrated at baseline, 3 months and 6 months to understand the impact of the probiotics on NAFLD. Since the treatment of fatty liver should focus on controlling weight, blood sugar, and blood fat, the relevant clinical indexes will also be investigated.

• Study Type: Interventional
• Enrollment (Actual): 70
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Taiwan
  • New Taipei City, Taiwan
    • Fu Jen Catholic University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosis of Nonalcoholic fatty liver disease (NALFD) by ultrasound.
• The range of Alanine aminotransferase (ALT) blood test is 60-300 U/L

Exclusion Criteria:

• Alcoholic consumption (Female ≥ 10g/day or Male ≥ 20g/per)
• Patients with liver diseases, HBV(hepatitis B virus), HCV(hepatitis C virus), Primary Biliary Cholangitis.
• Autoimmune system disease
• Wilson's disease
• Hereditary hemochromatosis
• Patients with uncontrolled malignancy
• The subject had previously received weight reduction surgery
• Taking Antibiotics, probiotics, or any other drugs that affect NAFLD or glucose and lipid metabolism in past 2 months
• Pregnant or lactating female patients
• Patient who have severe allergy to soybeans or peanuts

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo group; Subjects received two placebo sachets per day	Other: Placebo; Same Additives to Probiotic group but replace probiotics with Corn starch and Maltodextrin.; Other Names: Control group
Experimental: Probiotic group; Subjects received two probiotic sachets per day	Dietary supplement: Probiotics; Multi-strain probiotic supplement includes Lactobacillus reuteri GMNL-263 (heat-killed) and GMNL-89 (alive) and Lactobacillus rhamnosus GMNL-74 ( alive).; Other Names: Test group

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum ALT (Alanine Aminotransferase) level at baseline	The number of patients will be enrolled with the concentration of ALT (Alanine Aminotransferase) ranging from 60 to 300 U/mL in serum.	baseline
Change from baseline in Serum ALT (Alanine Aminotransferase) level at 3-months	Fasting blood samples will be collected to examine the variation of ALT (Alanine Aminotransferase).	3-months
Change from baseline in Serum ALT (Alanine Aminotransferase) level at 6-months	Fasting blood samples will be collected to examine the variation of ALT (Alanine Aminotransferase).	6-months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in BMI (Body Mass index) at 3-months	BMI will be calculated with weight and height combined in kg/m^2, the weight will be measured in kilograms and the height will be recorded in centimeters.	3-months
Change from baseline in BMI (Body Mass index) at 6-months	BMI will be calculated with weight and height combined in kg/m^2, the weight will be measured in kilograms and the height will be recorded in centimeters.	6-months
Change from baseline in Waist and hip circumference at 3-months	Waist and hip circumference will take down in centimeters.	3-months
Change from baseline in Waist and hip circumference at 6-months	Waist and hip circumference will take down in centimeters.	6-months
Change from baseline in blood pressure at 3-months	The unit of measurement of blood pressure is mmHg. Both systolic and diastolic blood pressure will be measured.	3-months
Change from baseline in blood pressure at 6-months	The unit of measurement of blood pressure is mmHg. Both systolic and diastolic blood pressure will be measured.	6-months
Change from baseline in the progress of the non-alcoholic fatty liver disease at 3-months	Utilizing abdominal ultrasound to detect the progress of Non-alcoholic fatty liver disease (NAFLD).	3-months
Change from baseline in the progress of the non-alcoholic fatty liver disease at 6-months	Utilizing abdominal ultrasound to detect the progress of Non-alcoholic fatty liver disease (NAFLD).	6-months
Change from baseline in levels of AST(Aspartate Aminotransferase) at 3-months	Fasting blood samples will be collected to examine changes from baseline in AST(Aspartate Aminotransferase) in IU/L at 3-months.	3-months
Change from baseline in levels of AST(Aspartate Aminotransferase) at 6-months	Fasting blood samples will be collected to examine changes from baseline in AST(Aspartate Aminotransferase) in IU/L at 6-months.	6-months
Change from baseline in the level of γ-GT (γ-Glutamyl Transpeptidase) at 3-months	Fasting blood samples will be collected to examine changes from baseline in γ-GT (γ-Glutamyl Transpeptidase) in IU/L at 3-months.	3-months
Change from baseline in the level of γ-GT (γ-Glutamyl Transpeptidase) at 6-months	Fasting blood samples will be collected to examine changes from baseline in γ-GT (γ-Glutamyl Transpeptidase) in IU/L at 6-months.	6-months
Change from baseline in the level of BUN (Blood Urea Nitrogen) at 3-months	Fasting blood samples will be collected to examine changes in BUN(Blood Urea Nitrogen) from baseline in mg/dL at 3-months.	3-months
Change from baseline in the level of BUN (Blood Urea Nitrogen) at 6-months	Fasting blood samples will be collected to examine changes from baseline in BUN(Blood Urea Nitrogen) in mg/dL at 6-months.	6-months
Change from baseline in the level of CRE (Creatinine) at 3-months	Fasting blood samples will be collected to examine changes from baseline in CRE(Creatinine) in mg/dL at 3-months.	3-months
Change from baseline in the level of CRE (Creatinine) at 6-months	Fasting blood samples will be collected to examine changes from baseline in CRE(Creatinine) in mg/dL at 6-months.	6-months
Change from baseline in levels of FBS (Fasting Blood Sugar) at 3-months	Fasting blood samples will be collected to examine changes from baseline in FBS(Fasting Blood Sugar) in mg/dL at 6-months.	3-months
Change from baseline in the level of FBS (Fasting Blood Sugar) at 6-months	Fasting blood samples will be collected to examine changes from baseline in FBS(Fasting Blood Sugar) in mg/dL at 6-months.	6-months
Change from baseline in levels of HbA1c (Hemoglobin A1C) at 3-months	Fasting blood samples will be collected to investigate the levels of HbA1c(Hemoglobin A1C) in % from baseline at 3-months.	3-months
Change from baseline in levels of HbA1c (Hemoglobin A1C) at 6-months	Fasting blood samples will be collected to investigate the levels of HbA1c(Hemoglobin A1C) in % from baseline at 6-months.	6-months
Change from baseline in levels of serum insulin at baseline	Fasting blood samples will be collected to examine variation in serum insulin in uIU/mL from baseline at 3-months.	3-months
Change from 3-months in levels of serum insulin at baseline	Fasting blood samples will be collected to examine variation in serum insulin in uIU/mL from baseline at 6-months.	6-months
Change from Baseline in levels of HOMA-IR (Homeostatic Model Assessment for Insulin Resistance) at 3-months	HOMA-IR(Homeostatic Model Assessment for Insulin Resistance) will be calculated with insulin and glucose. (HOMA-IR=(insulin (mIU/L) and glucose (mg/dl))/405)	3-months
Change from baseline in levels of HOMA-IR (Homeostatic Model Assessment for Insulin Resistance) at 6-months	HOMA-IR(Homeostatic Model Assessment for Insulin Resistance) will be calculated with insulin and glucose. (HOMA-IR=(insulin (mIU/L) and glucose (mg/dl))/405)	6-months
Change from baseline in levels of TC (Total Cholesterol) at 3-months	Fasting blood samples will be collected to examine variation from baseline in (Total Cholesterol) in mg/dL at 3-months.	3-months
Change from baseline in levels of TC (Total Cholesterol) at 6-months	Fasting blood samples will be collected to examine variation from baseline in (Total Cholesterol) in mg/dL from baseline at 6-months.	6-months
Change from baseline in level of HDL (High density lipoprotein) at 3-months	Fasting blood samples will be collected to examine variation from baseline in HDL(High density lipoprotein) in mg/dL at 3-months.	3-months
Change from baseline in level of HDL (High density lipoprotein) at 6-months	Fasting blood samples will be collected to examine variation from baseline in HDL(High density lipoprotein) in mg/dL at 6-months.	6-months
Change from baseline in level of LDL (Low density lipoprotein) at 3-months	Fasting blood samples will be collected to examine variation from baseline in LDL(Low density lipoprotein) in mg/dL at 3-months.	3-months
Change from baseline in level of LDL (Low density lipoprotein) at 6-months	Fasting blood samples will be collected to examine variation from baseline in LDL(Low density lipoprotein) in mg/dL at 6-months.	6-months
Change from baseline in level of TG (Triglyceride) at 3-months	Fasting blood samples will be collected to examine variation from baseline in TG(Triglyceride) in mg/dL to 3-months.	3-months
Change from baseline in level of TG (Triglyceride) at 6-months	Fasting blood samples will be collected to examine variation from baseline in TG(Triglyceride) in mg/dL to 6-months.	6-months
Change from baseline in level of hs-CRP (high-sensitivity C-reactive protein) at 3-months	Blood samples will be collected to examine variation from baseline in hs-CRP(high-sensitivity C-reactive protein) in mg/dL at 3-months.	3-months
Change from baseline in level of hs-CRP (high-sensitivity C-reactive protein) at 6-months	Blood samples will be collected to examine variation from baseline in hs-CRP(high-sensitivity C-reactive protein) in mg/dL at 6-months.	6-months
Change from baseline in level of TNF-α (Tumor necrosis factor-α) at 3-months	Blood samples will be collected to examine variation from baseline in TNF-α (Tumor necrosis factor-α) in pg/mL at 3-months.	3-months
Change from baseline in level of TNF-α (Tumor necrosis factor-α) at 6-months	Blood samples will be collected to examine variation from baseline in TNF-α (Tumor necrosis factor-α) in pg/mL at 6-months.	6-months
Change from baseline in level of IL-1β (Interleukin-1 β) at 3-months	Blood samples will be collected to examine variation from baseline in IL-1β(Interleukin-1 β) in pg/mL at 3-months.	3-months
Change from baseline in level of IL-1β (Interleukin-1 β) at 6-months	Blood samples will be collected to examine variation from baseline in IL-1β(Interleukin-1 β) in pg/mL at 6-months.	6-months
Change from baseline in level of IL-6 (Interleukin-6) at 3-months	Blood samples will be collected to examine variation from baseline in IL-6(Interleukin-6) in pg/mL at 3-months.	3-months
Change from baseline in level of IL-6 (Interleukin-6) at 6-months	Blood samples will be collected to examine variation from baseline in IL-6(Interleukin-6) in pg/mL at 6-months.	6-months
Change from baseline in level of LPS (Lipopolysaccharides) at 3-months	Blood samples will be collected to examine variation from baseline in LPS(Lipopolysaccharides) in mg/dL at 3-months.	3-months
Change from baseline in level of LPS (Lipopolysaccharides) at 6-months	Blood samples will be collected to examine variation from baseline in LPS(Lipopolysaccharides) in mg/dL at 6-months.	6-months
Change from baseline in level of Leptin at 3-months	Blood samples will be collected to examine variation from baseline in Leptin in pg/mL at 3-months.	3-months
Change from baseline in level of Leptin at 6-months	Blood samples will be collected to examine variation from baseline in Leptin in pg/mL at 6-months.	6-months
Change from baseline in level of Adiponectin at 3-months	Blood samples will be collected to examine variation from baseline in Adiponectin in pg/mL at 3-months.	3-months
Change from baseline in level of Adiponectin at 6-months	Blood samples will be collected to examine variation from baseline in Adiponectin in pg/mL at 6-months.	6-months
Change from baseline in the level of SCFA (Short Chain Fatty Acids) at 6-months	Blood samples will be collected to examine variation from baseline in SCFA (Short Chain Fatty Acids) in ug/mL at 6-months.	6-months
Change from baseline in the level of TMAO (Trimethylamine N-oxide) at 6-months	Blood samples will be collected to examine variation from baseline in TMAO (Trimethylamine N-oxide) in μmol/L at 6-months.	6-months
Change from baseline in Self-questionnaire of Diet and lifestyle assessments at 6-months	The questionnaire will record dietary/drink preferences and other habits by the subject himself /herself, the content of the questionnaire includes vegetarian or not, the frequency if intake of tea, dairy, coffee or yakult intake, smoking habits, betel nuts intake and alcohol consumption.	6-months
Change from baseline in self-record of the International physical activity questionary (IPAQ) in physical assessment at 6-months	The questionnaire will be finished to record the laborious activity by the subject himself /herself before and after the treatment.	6-months
Change from baseline in gut microbiota at 6-months	The analysis of Gut microbiota will utilize DNA sequencing to investigate the intestinal microbiota through stool samples in subjects with NAFLD at 6-months.	6-months

Collaborators and Investigators

• Sponsor: GenMont Biotech Incorporation
• Collaborators: Fu Jen Catholic University Hospital
• Investigators: Principal Investigator: Chi-Yang Chang, PhD, Fu Jen Catholic University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): July 14, 2022
• Primary Completion (Actual): May 31, 2024
• Study Completion (Actual): May 31, 2024

Study Registration Dates

• First Submitted: May 5, 2022
• First Submitted That Met QC Criteria: May 31, 2022
• First Posted (Actual): June 2, 2022

Study Record Updates

• Last Update Posted (Actual): July 5, 2024
• Last Update Submitted That Met QC Criteria: July 2, 2024
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Probiotic; gut microbiota; Non-Alcoholic Fatty Liver Disease
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease
• Other Study ID Numbers: NAFLD2022

Drug and device information, study documents

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