Hydrochlorothiazide-induced glucose metabolism disorder is mediated by the gut microbiota via LPS-TLR4-related macrophage polarization

Jian-Quan Luo; Huan Ren; Man-Yun Chen; Qing Zhao; Nian Yang; Qian Liu; Yong-Chao Gao; Hong-Hao Zhou; Wei-Hua Huang; Wei Zhang

doi:10.1016/j.isci.2023.107130

Hydrochlorothiazide-induced glucose metabolism disorder is mediated by the gut microbiota via LPS-TLR4-related macrophage polarization

iScience. 2023 Jun 15;26(7):107130. doi: 10.1016/j.isci.2023.107130. eCollection 2023 Jul 21.

Authors

Jian-Quan Luo^{1

2

3

4}, Huan Ren^{1

2

3

5}, Man-Yun Chen^{1

2

3}, Qing Zhao^{1

2

3}, Nian Yang^{1

2

3}, Qian Liu^{1

2

3}, Yong-Chao Gao^{1

2

3}, Hong-Hao Zhou^{1

2

3}, Wei-Hua Huang^{1

2

3}, Wei Zhang^{1

2

3}

Affiliations

¹ Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha 410008, P. R. China.
² Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, 110 Xiangya Road, Changsha 410078, P. R. China.
³ National Clinical Research Center for Geriatric Disorders, 87 Xiangya Road, Changsha 410008, Hunan, P.R. China.
⁴ Department of Pharmacy, the Second Xiangya Hospital, Central South University, Changsha, China.
⁵ Department of Pharmacy, Hunan Provincial People's Hospital, the First Affiliated Hospital of Hunan Normal University, No.61 Western Jiefang Road, Changsha, Hunan, China.

Abstract

Hydrochlorothiazide (HCTZ) is reported to impair glucose tolerance and may induce new onset of diabetes, but the pharmacomicrobiomics of the adverse effect for HCTZ remains unknown. Mice-fed HCTZ exhibited insulin resistance and impaired glucose tolerance. By using FMT and antibiotic cocktail models, we found that HCTZ-induced metabolic disorder was mediated by commensal microbiota. HCTZ consumption disturbed the structure of the intestinal microbiota, causing abnormal elevation of Gram-negative Enterobacteriaceae and lipopolysaccharide (LPS) then leading to intestinal barrier dysfunction. Additionally, HCTZ activated TLR4 signaling and induced macrophage polarization and inflammation in the liver. Furthermore, HCTZ-induced macrophage polarization and metabolic disorder were abrogated by blocking TLR4 signaling. HCTZ consumption caused a significant increase in Gram-negative Enterobacteriaceae, which elevated the levels of LPS, thereby activating LPS/TLR4 pathway, promoting inflammation and macrophage polarization, and resulting in metabolic disorders. These findings revealed that the gut microbiome is the key medium underlying HCTZ-induced metabolic disorder.

Keywords: Biological sciences; Cell biology; Immunology; Molecular physiology.