S-amlodipine induces liver inflammation and dysfunction through the alteration of intestinal microbiome in a rat model

ABSTRACT

S-amlodipine, a commonly prescribed antihypertensive agent, is widely used in clinical settings to treat hypertension. However, the potential adverse effects of long-term S-amlodipine treatment on the liver remain uncertain, given the cautionary recommendations from clinicians regarding its administration in individuals with impaired liver function. To address this, we conducted a study using an eight-week-old male rat model and administered a daily dose of 0.6 ~ 5 mg/kg of S-amlodipine for 7 weeks. Our findings demonstrated that 1.2 ~ 5 mg/kg of S-amlodipine treatment induced liver inflammation and associated dysfunction in rats, further in vitro experiments revealed that the observed liver inflammation and dysfunction were not attributable to direct effects of S-amlodipine on the liver. Metagenome sequencing analysis revealed that S-amlodipine treatment led to alterations in the gut microbiome of rats, with the bloom of E. coli (4.5 ~ 6.6-fold increase) and a decrease in A. muciniphila (1,613.4 ~ 2,000-fold decrease) and B. uniformis (20.6 ~ 202.7-fold decrease), subsequently causing an increase in the gut bacterial lipopolysaccharide (LPS) content (1.4 ~ 1.5-fold increase in feces). S-amlodipine treatment also induced damage to the intestinal barrier and increased intestinal permeability, as confirmed by elevated levels of fecal albumin; furthermore, the flux of gut bacterial LPS into the bloodstream through the portal vein resulted in an increase in serum LPS content (3.3 ~ 4-fold increase). LPS induces liver inflammation and subsequent dysfunction in rats by activating the TLR4 pathway. This study is the first to show that S-amlodipine induces liver inflammation and dysfunction by perturbing the rat gut microbiome. These results indicate the adverse effects of S-amlodipine on the liver and provide a rich understanding of the safety of long-term S-amlodipine administration.

KEYWORDS:

• S-amlodipine
• liver dysfunction
• gut microbiome
• LPS
• intestinal barrier damage
• inflammatory response

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions

D. M. and Y. L. conceived and designed the study, and X. L. wrote the manuscript. X. L., H. F., L. P., H. G., and C. Y. performed the experiments, and X. L. performed fecal metagenome sequencing. X. L., P. Z., and H. L. collected and analyzed the data. D. M. and Y. L. supervised the study and edited the manuscript.

Data availability statement

The clean sequencing datasets of fecal metagenome sequencing have been deposited in the CNCB Genome Sequence Archive (GSA) under the BioProject accession number PRJCA005398. The RNA sequence datasets of the liver were accessible under the BioProject accession number PRJCA005400.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2024.2316923

Additional information

Funding

This work was supported by the Key Projects of the National Natural Science Foundation of China (41831287), National Key R&D Program of China (2020YFC1806904), National Natural Science Foundation of China (31870351, 42107456), and China Postdoctoral Science Foundation (2021M691662).