Interaction effect between NAFLD severity and high carbohydrate diet on gut microbiome alteration and hepatic de novo lipogenesis
Hyena Kang,
Hyun Ju You,
Giljae Lee,
Seung Hyun Lee,
Taekyung Yoo,
Murim Choi,
Sae Kyung Joo,
Jeong Hwan Park,
Mee Soo Chang,
Dong Hyeon Lee,
Won Kim,
GwangPyo Ko
Affiliations
Hyena Kang
Department of Environmental Health Sciences, Graduate School of Public Health, Seoul National University, Republic of Korea
Hyun Ju You
Department of Environmental Health Sciences, Graduate School of Public Health, Seoul National University, Republic of Korea
Giljae Lee
Department of Environmental Health Sciences, Graduate School of Public Health, Seoul National University, Republic of Korea
Seung Hyun Lee
Department of Environmental Health Sciences, Graduate School of Public Health, Seoul National University, Republic of Korea
Taekyung Yoo
Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea
Murim Choi
Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea
Sae Kyung Joo
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Republic of Korea
Jeong Hwan Park
Department of Pathology, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Republic of Korea
Mee Soo Chang
Department of Pathology, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Republic of Korea
Dong Hyeon Lee
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Republic of Korea
Won Kim
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Republic of Korea
GwangPyo Ko
Department of Environmental Health Sciences, Graduate School of Public Health, Seoul National University, Republic of Korea
Nonalcoholic fatty liver disease (NAFLD) is associated with high carbohydrate (HC) intake. We investigated whether the relationship between carbohydrate intake and NAFLD is mediated by interactions between gut microbial modulation, impaired insulin response, and hepatic de novo lipogenesis (DNL). Stool samples were collected from 204 Korean subjects with biopsy-proven NAFLD (n = 129) and without NAFLD (n = 75). The gut microbiome profiles were analyzed using 16S rRNA amplicon sequencing. Study subjects were grouped by the NAFLD activity score (NAS) and percentage energy intake from dietary carbohydrate. Hepatic DNL-related transcripts were also analyzed (n = 90). Data from the Korean healthy twin cohort (n = 682), a large sample of individuals without NAFLD, were used for comparison and validation. A HC diet rather than a low carbohydrate diet was associated with the altered gut microbiome diversity according to the NAS. Unlike individuals from the twin cohort without NAFLD, the abundances of Enterobacteriaceae and Ruminococcaceae were significantly different among the NAS subgroups in NAFLD subjects who consumed an HC diet. The addition of these two microbial families, along with Veillonellaceae, significantly improved the diagnostic performance of the predictive model, which was based on the body mass index, age, and sex to predict nonalcoholic steatohepatitis in the HC group. In the HC group, two crucial regulators of DNL (SIRT1 and SREBF2) were differentially expressed among the NAS subgroups. In particular, kernel causality analysis revealed a causal effect of the abundance of Enterobacteriaceae on SREBF2 upregulation and of the surrogate markers of insulin resistance on NAFLD activity in the HC group. Consuming an HC diet is associated with alteration in the gut microbiome, impaired glucose homeostasis, and upregulation of hepatic DNL genes, altogether contributing to NAFLD pathogenesis.
