Xiaojian Zhang,1– 3,* Yanbin Cheng,4,* Qingyu Wei,5 Lixuan Sang,1,2 Quansheng Li5 

1Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110022, People’s Republic of China; 2College of Exercise and Health, Shenyang Sport University, Shenyang, Liaoning, 110102, People’s Republic of China; 3Rehabilitation Hospital of Weifang High-tech Zone, Weifang, Shandong, 261205, People’s Republic of China; 4Department of Cardiovascular Ultrasound, the First Hospital of China Medical University, Shenyang, Liaoning, 110001, People’s Republic of China; 5Department of Allergy, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110022, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Lixuan Sang, Email sanglixuan2008@163.com; Quansheng Li, Email li_quan_sheng@126.com

Background: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a global concern. The gut microbiota and hepatic fatty acid beta-oxidation have been shown to be important factors in the development of MAFLD. Independently, exercise and berberine can significantly ameliorate symptoms of MAFLD, although the specific mechanism is not clear; moreover, it is not known whether the combination of exercise and berberine produces a better therapeutic effect.
Methods: Over an experimental period of 17 weeks, the effects of exercise, berberine, and a combined (exercise/berberine) intervention on the composition of the gut microbiota and the expression of hepatic fatty acid beta-oxidation related proteins were examined. The mice were divided into five treatment groups: CON (control group, n = 10), HFD (high-fat diet, n = 10), HFE (high-fat diet + exercise, n = 10), HFB (high-fat diet + berberine, n = 10), and HBE (high-fat-diet + exercise + berberine, n = 10). The dose of BBR administered for oral gavage was 300 mg/kg, once per day, for 8 weeks. Mice were subjected to treadmill exercise, 5 days per week for 8 weeks, and the intensity was increased gradually.
Results: Serological and histopathological results showed that exercise, berberine and a combined (exercise/berberine) intervention effectively improved liver lipid accumulation caused by a high-fat diet. Analysis of 16S rRNA showed that the three interventions restored the species and number of gut microbiota in MAFLD mice. The functional prediction of gut microbiota revealed significant differences in beta-oxidation-related units among groups. Simultaneously, exercise and berberine intervention regulated the expression of hepatic fatty acid beta-oxidation-related proteins ACOX1, HMGCS2, and CPT-1α, with the combined intervention having a more significant effect than each intervention alone.
Conclusion: Our findings indicate that exercise and berberine ameliorate MAFLD by regulating the gut microbiota and hepatic fatty acid beta-oxidation, suggesting that their combination may be a potential therapy for MALFD.

Keywords: metabolic dysfunction-associated fatty liver disease, gut microbiota, fatty acid beta-oxidation, exercise, berberine