Gut microbial metabolism is linked to variations in circulating non-high density lipoprotein cholesterol

Shiyi Zhou; Ludi Liu; Bingqi Ye; Yingxi Xu; Yi You; Shanshan Zhu; Jingmeng Ju; Jialu Yang; Wenkang Li; Min Xia; Yan Liu

doi:10.1016/j.ebiom.2024.105150

Gut microbial metabolism is linked to variations in circulating non-high density lipoprotein cholesterol

EBioMedicine. 2024 May 9:104:105150. doi: 10.1016/j.ebiom.2024.105150. Online ahead of print.

Authors

Shiyi Zhou¹, Ludi Liu², Bingqi Ye², Yingxi Xu², Yi You¹, Shanshan Zhu¹, Jingmeng Ju¹, Jialu Yang¹, Wenkang Li¹, Min Xia³, Yan Liu⁴

Affiliations

¹ Guangdong Provincial Key Laboratory of Food, Nutrition and Health, PR China; Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou, PR China.
² Guangdong Provincial Key Laboratory of Food, Nutrition and Health, PR China; Department of Statistics and Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou, PR China.
³ Guangdong Provincial Key Laboratory of Food, Nutrition and Health, PR China; Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou, PR China. Electronic address: xiamin@mail.sysu.edu.cn.
⁴ Guangdong Provincial Key Laboratory of Food, Nutrition and Health, PR China; Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou, PR China. Electronic address: liuyan215@mail.sysu.edu.cn.

Abstract

Background: Non-high-density lipoprotein cholesterol (non-HDL-c) was a strong risk factor for incident cardiovascular diseases and proved to be a better target of lipid-lowering therapies. Recently, gut microbiota has been implicated in the regulation of host metabolism. However, its causal role in the variation of non-HDL-c remains unclear.

Methods: Microbial species and metabolic capacities were assessed with fecal metagenomics, and their associations with non-HDL-c were evaluated by Spearman correlation, followed by LASSO and linear regression adjusted for established cardiovascular risk factors. Moreover, integrative analysis with plasma metabolomics were performed to determine the key molecules linking microbial metabolism and variation of non-HDL-c. Furthermore, bi-directional mendelian randomization analysis was performed to determine the potential causal associations of selected species and metabolites with non-HDL-c.

Findings: Decreased Eubacterium rectale but increased Clostridium sp CAG_299 were causally linked to a higher level of non-HDL-c. A total of 16 microbial capacities were found to be independently associated with non-HDL-c after correcting for age, sex, demographics, lifestyles and comorbidities, with the strongest association observed for tricarboxylic acid (TCA) cycle. Furthermore, decreased 3-indolepropionic acid and N-methyltryptamine, resulting from suppressed capacities for microbial reductive TCA cycle, functioned as major microbial effectors to the elevation of circulating non-HDL-c.

Interpretation: Overall, our findings provided insight into the causal effects of gut microbes on non-HDL-c and uncovered a novel link between non-HDL-c and microbial metabolism, highlighting the possibility of regulating non-HDL-c by microbiota-modifying interventions.

Funding: A full list of funding bodies can be found in the Sources of funding section.

Keywords: 3-Indolepropionic acid; Gut microbiota; Mendelian randomization; N-methyltryptamine; Non-high-density lipoprotein cholesterol.