The causal relationship of cigarette smoking to metabolic disease risk and the possible mediating role of gut microbiota

Jingda Zhang; Lin Hou; Shanxiang Lei; Yan Li; Guogang Xu

doi:10.1016/j.ecoenv.2024.117522

The causal relationship of cigarette smoking to metabolic disease risk and the possible mediating role of gut microbiota

Ecotoxicol Environ Saf. 2024 Dec 21:290:117522. doi: 10.1016/j.ecoenv.2024.117522. Online ahead of print.

Authors

Jingda Zhang¹, Lin Hou², Shanxiang Lei¹, Yan Li³, Guogang Xu⁴

Affiliations

¹ The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing 100853, China.
² Department of Physiology, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing 100730, China.
³ Department of Occupational Health and Environmental Health, School of Public Health, Capital Medical University, Beijing 100069, China.
⁴ The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing 100853, China; State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital, Beijing 100853, China. Electronic address: gxu@301hospital.com.cn.

PMID: 39709709
DOI: 10.1016/j.ecoenv.2024.117522

Abstract

Background: Cigarette smoking is a leading cause of preventable death worldwide, with its associated diseases and conditions. Emerging evidence suggests that cigarette smoking contributes to a range of pathological metabolic injuries, including diabetes and nonalcoholic fatty liver disease (NAFLD). The impact of gut microbiota on metabolic health and diseases has been observed, but the causality remains uncertain.

Objective: To confirm the causal relationship between cigarette smoking and metabolic diseases, and to investigate the possible mediating effect of gut microbiota on these connections.

Methods: The relationships among cigarette smoking, metabolic diseases, and the gut microbiome were analyzed by Univariate Mendelian randomization (UVMR). Furthermore, to mitigate the impact of confounding factors, adjusted models were conducted via the multivariate Mendelian randomization (MVMR) method, aiming to improve the accuracy of prediction. Ultimately, the study evaluated the effect of the intermediary factor, gut microbiome, on the relationship between cigarette smoke and metabolic diseases.

Results: The phenomenon that a causal relationship between cigarette smoke (249752 individuals) and gut microbiota (7738 individuals), diabetes (406831 individuals), NAFLD (377998 individuals), hypercholesterolaemia (463010 individuals), and obesity (463010 individuals) was observed using UVMR. In the MVMR model, the genetic connection between cigarette smoking, gut microbiota, and type 2 diabetes remained significant. Of note, paraprevotella_clara served an important mediating role in the type 2 diabetes associated with cigarette smoke.

Conclusion: This work offered genetic evidence linking cigarette smoke to metabolic diseases, suggesting that the gut microbiota, particularly paraprevotella_clara, might be a crucial mediator in the development of type 2 diabetes caused by cigarette smoke. Our future studies should consider conducting other ethnic groups MR analyses, particularly with larger sample sizes. Still, more in vivo and in vitro work should be carried out to validate the precise effect and molecular mechanisms of the gut microbiome.

Keywords: Diabetes mellitus, Type 2; Mendelian randomization analysis; Metabolic diseases; Microbiota; Tobacco smoking.