>>Project 1(AELC-Study)

Effect of aerobic exercise and low carbohydrate diet on pre-diabetic non-alcoholic fatty liver disease in postmenopausal women and middle aged men: study protocol for the AELC randomized controlled trial.

PI: Professor Sulin Cheng

Research team: Professors Dajiang Lu, Jianqing Sun, Renwei Wang, Wuyi Liu, Jun Zou. Drs: Jun Ge, Qing Gu, Zhengchang Xia, Junjun Liu, Wenbin Liu, Xuebo Chen, Rei Li. Researchers: Xiaobo Zhang, Yifan Yang, Shenglong Le, Na Wu, Xiao Tan, Eveliina Munukka, Petri Wiklund

Background

Both pre-diabetes and non-alcoholic fatty liver disease (NAFLD) are associated with an unhealthy lifestyle and pose extremely high costs to the healthcare system. In this study, we aim to explore whether aerobic exercise (AEx) and low carbohydrate diet (LCh) affect liver fat content in pre-diabetes via modification of gut microbiota composition and other post-interventional effects.

Objectives and hypothesis

Previous studies have shown that inflammation of the intestinal mucosa is linked to immune dysfunction and dysbiotic gut microbiota composition, which may lead to a“leaky” gut and introduction of bacterial components, including endotoxins, into the blood stream. These endotoxins induce chronic inflammation disrupting normal lipid movement through the cell membrane and increasing lipid synthesis, causing accumulation of lipids that leads to further metabolic disturbances and hepatic fat accumulation.

The gut microbiota composition can be modified by exercise and diet. Therefore, changes in the level of physical activity and composition of diet may result in favorable changes in microbiota composition which could, in turn, be accompanied by reductions in liver fat content, thus improving glucose and lipid metabolism and insulin sensitivity. A six-month exercise and diet intervention is enough to induce repatterning of microbiota composition. However, stabilization of “healthy” gut microbiota composition needs persistent exercise and balanced diet. Subjects may relapse to an “unhealthy” gut microbiota composition after cessation of exercise and balanced diet.

Therefore, the purpose of this study is to investigate the gut microbiota composition of postmenopausal women and middle aged men with pre-diabetic NAFLD compared to healthy controls, and whether chronic but latent bacterial infections are more frequent in NAFLD subjects than in healthy subjects. In addition, we will determine whether aerobic exercise and low carbohydrate diet reduce liver fat content via modification of gut microbiota composition in postmenopausal women and middle aged men.

Methods/Design

A 6-month randomized intervention with 6-month follow-up is conducted from January 2013 to December 2015. The target sample size for intervention is 200 postmenopausal women and middle-aged men aged 50-65 year-old with pre-diabetes and NAFLD defined by clinical values from outpatient registration of Yangpu District Health Care Service Centres, Shanghai, China. The qualified subjects are randomized into 4 groups with 50 subjects in each group: 1=AEx, 2=LCh, 3=AEx+LCh, and 4=control. In addition, two age-matched reference groups (5=pre-diabetes without NAFLD (n=50) and 6=Healthy without pre-diabetes or NAFLD (n=50)) are included. The exercise program consists of progressive and variable aerobic exercise (mainly Nordic walking with intensity of 60 to 75% of initial fitness level, 3-5 times/week and 30-60 min/time). The diet program includes dietary consultation plus supplementation with a special lunch meal (40% of total energy intake/day) which aims to reduce the amount of carbohydrate consumption (progressive and variable reduction to 30%). The control and reference groups are advised to maintain their habitual habits during the intervention.

Primary outcome

The primary outcome measures are liver fat content, glucose and lipid metabolism and gut microbiota composition at baseline, after 6-month intervention and additional 6-month follow-up. The secondary outcome measures include body composition, blood pressure, hormones, cytokines and serum metabonomics. In addition, assessments of socio-psychological aspects, quality of life, social support, physical activity and diet will be performed by means of questionnaire and interview.

This research using specific lifestyle interventions offers a novel approach for liver fat reduction and diabetes intervention via modification of the gut microbiota composition, and explores the importance of incorporating fitness assessment and exercise in the management of patients with pre-diabetes and fatty liver disorders. If our program is shown to be effective, it will open new strategies to combat these chronic diseases.

Trial registration

Current Controlled Trials ISRCTN42622771.

>>Project 2 (Health SJTU)