Metabolic Flexibility, Gut Microbiota, Healthy Diet and Exercise in NAFLD on Genetics Base

Body Composition, Adiposity Phenotype, Metabolic Flexibility, and Gut Microbiota in PNPLA3 and TM6SF2 Gene Variant Carriers and Non-carriers With Nonalcoholic Fatty Liver Disease. Effects of a Nutritional Intervention Combined to Exercise

Nonalcoholic fatty liver disease (NAFLD) is associated to obesity, metabolic syndrome and genetic predisposition: specific variants of the genes PNPLA3 and TM6SF2 are the most involved. Also biochemical mechanisms that affect the "metabolic flexibility" need to be better clarified.

It is known that a dietary intervention, accompanied by a physical personalized training, reduce either the hepatic fat content either insulin resistance.

Therefore, the aim of the study is to evaluate "metabolic flexibility" in obese NAFLD subjects taking in account the presence or absence of PNPLA3 and TM6SF2 polymorphism and the histopathological diagnosis of either simple steatosis or nonalcoholic steatohepatitis (NASH). The composition of gut microbiota will be also evaluated.

Finally, two distinct healthy dietary profiles accompanied by a personalized physical training, will be tested to comprehend whether and how "healthy diets" could operate in the clinical treatment of NAFLD and related conditions.

Study Overview

• Status: Completed
• Conditions: Obesity; Non-alcoholic Fatty Liver Disease
• Intervention / Treatment: Dietary supplement: Mediterranean diet; Other: Aerobic exercise; Dietary supplement: Low fat diet

Detailed Description

Nonalcoholic fatty liver disease (NAFLD) is frequently associated to obesity and metabolic syndrome. In NAFLD, a heritable component to disease susceptibility has been demonstrated: the variants of the genes PNPLA3 and TM6SF2 are the most involved genetic determinants.

To date, biochemical mechanisms that affect the "metabolic flexibility" in obese NAFLD subjects, in presence or absence of genetic susceptibility, need to be better clarified.

Different studies demonstrated that a dietary intervention, accompanied by a physical personalized training, significantly reduce either the hepatic fat content either insulin resistance in overweight and obese subjects, independently of weight loss.

On these bases, the aim of the study is to evaluate "metabolic flexibility" in obese NAFLD subjects taking in account their genetics (presence or absence of PNPLA3 and TM6SF2 polymorphisms) and the histopathological diagnosis of either simple steatosis or nonalcoholic steatohepatitis (NASH). In addition, the composition of gut microbiota will be evaluated.

Finally, in this study, two distinct healthy dietary profiles accompanied by a personalized physical training, will be tested in order to comprehend whether and how "healthy diets" could be effective not only in the prevention, but also in the clinical treatment of NAFLD and other related conditions.

• Study Type: Interventional
• Enrollment (Actual): 120
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Italy
  • Rome, Italy, 00185
    • Department of Translational and Precision Medicine, Sapienza University of Rome, Umberto I Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• body mass index (BMI) > 30 Kg/m2 and < 40 Kg/m2;
• Caucasian Italian subjects
• hepatic steatosis according with ultrasonographic Hamaguchi's criteria and/or hypertransaminasemia (ALT >30 IU/L in men and >20 IU/L in women)

Exclusion Criteria:

• any malignant disease during the last 5 years;
• any inflammatory or autoimmune disease;
• corticosteroids for systemic use;
• renal failure (GFR<90 ml/min);
• heart failure (NYHA classes II-IV);
• history of viral or autoimmune liver disease;
• any cause cirrhosis;
• excessive alcohol intake (>140g/week for men and 70g/week for women);
• participation in a reducing-weight program in the last 3 months;
• level of physical activity higher than 3 METs;
• therapy with antibiotics during the last 3 months;
• bile salts, cholestyramine during the last 6 months before enrollment;
• previous cholecystectomy;
• gallbladder disease

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Mediterranean diet; Hypocaloric Mediterranean diet for a 4-month period; Aerobic exercise training for a 4-month period;	Dietary supplement: Mediterranean diet; In the Mediterranean diet fat intake will be equal to 35% of the total energy intake minus carbohydrate and protein energy carbohydrate as 65% of total calorie intake, dietary cholesterol <300 mg/day, dietary fiber 25 g/day.; Other: Aerobic exercise; A personalized program of aerobic exercise will be prescribed to the participants of both arms, following the "FITT" principles (frequency, intensity, time and type).
EXPERIMENTAL: Low fat diet; Hypocaloric low fat diet supplemented by branched and essential amino acids considering the total protein intake for a 4- month period; Aerobic exercise training for a 4- month period;	Other: Aerobic exercise; A personalized program of aerobic exercise will be prescribed to the participants of both arms, following the "FITT" principles (frequency, intensity, time and type).; Dietary supplement: Low fat diet; In the hypocaloric low fat diet, fat will represent less than 25% of the total energy intake. Branched and essential amino acids will be administered taking into account the total protein intake.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cholesterol assessment	total cholesterol, HDL- cholesterol, LDL- cholesterol levels reported as mg/dl	baseline
Cholesterol assessment	total cholesterol, HDL- cholesterol, LDL- cholesterol levels reported as mg/dl	18 weeks after baseline
triglycerides assessment	tryglicerides levels reported as mg/dl	baseline
triglycerides assessment	tryglicerides levels reported as mg/dl	18 weeks after baseline
metabolic flexibility variation in liver function;	alanine aminotransferase (ALT) [U/L] , aspartate aminotransferase (AST) [UI/L]	baseline
metabolic flexibility variation in liver function;	alanine aminotransferase (ALT) [U/L] , aspartate aminotransferase (AST) [UI/L]	18 weeks after baseline
Waist circumference measurements;	waist circumference reported as cm	baseline
Waist circumference measurements;	waist circumference reported as cm	18 weeks after baseline
anthropometric measurements;	Body mass index reported as kg/m^2	baseline
anthropometric measurements;	Body mass index reported as kg/m^2	18 weeks after baseline
Ultrasonographic examination;	Liver ultrasonography according with criteria by Hamaguchi	baseline
Ultrasonographic examination;	Liver ultrasonography according with criteria by Hamaguchi	18 weeks after baseline
Glucidic profile	fasting glucose reported as mg/dl	baseline
Glucidic profile	fasting glucose reported as mg/dl	18 weeks after baseline
Insulinemia	insulin reported as µU/mL	baseline
Insulinemia	insulin reported as µU/mL	18 weeks after baseline

Collaborators and Investigators

• Sponsor: University of Roma La Sapienza
• Collaborators: Göteborg University; Bambino Gesù Hospital and Research Institute; Università degli studi di Roma Foro Italico
• Investigators: Principal Investigator: Stefano Ginanni Corradini, MD, PhD, Department Translational and Precision Medicine, Sapienza University of Rome

Study record dates

Study Major Dates

• Study Start (ACTUAL): October 1, 2016
• Primary Completion (ACTUAL): September 1, 2021
• Study Completion (ACTUAL): February 1, 2022

Study Registration Dates

• First Submitted: October 26, 2016
• First Submitted That Met QC Criteria: October 28, 2016
• First Posted (ESTIMATE): November 1, 2016

Study Record Updates

• Last Update Posted (ACTUAL): May 27, 2022
• Last Update Submitted That Met QC Criteria: May 26, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease
• Other Study ID Numbers: RIF.CE:4119

Plan for Individual participant data (IPD)

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