Untargeted and targeted metabolomics reveal bile acid profile changes in rats with ethylene glycol-induced calcium oxalate nephrolithiasis

Zijian Zhou; Dexiang Feng; Donghui Shi; Peng Gao; Lujia Wang; Zhong Wu

doi:10.1016/j.cbi.2023.110570

Untargeted and targeted metabolomics reveal bile acid profile changes in rats with ethylene glycol-induced calcium oxalate nephrolithiasis

Chem Biol Interact. 2023 Aug 25:381:110570. doi: 10.1016/j.cbi.2023.110570. Epub 2023 May 25.

Authors

Zijian Zhou¹, Dexiang Feng², Donghui Shi³, Peng Gao⁴, Lujia Wang⁵, Zhong Wu⁶

Affiliations

¹ Department of Urology, Huashan Hospital, Fudan University, Shanghai, 200040, PR China.
² Department of Urology, Dushu Lake Hospital Affiliated to Soochow University, Medical Center of Soochow University, Suzhou Dushu Lake Hospital, Suzhou, 215123, PR China.
³ Department of Urology, Suzhou Wu Zhong People's Hospital, Suzhou, 215100, PR China.
⁴ Department of Urology, Huashan Hospital, Fudan University, Shanghai, 200040, PR China; Clinical Research Center of Urolithiasis, Shanghai Medical College, Fudan University, Shanghai, 200040, PR China.
⁵ Department of Urology, Huashan Hospital, Fudan University, Shanghai, 200040, PR China; Clinical Research Center of Urolithiasis, Shanghai Medical College, Fudan University, Shanghai, 200040, PR China. Electronic address: lukewang2006@126.com.
⁶ Department of Urology, Huashan Hospital, Fudan University, Shanghai, 200040, PR China; Clinical Research Center of Urolithiasis, Shanghai Medical College, Fudan University, Shanghai, 200040, PR China. Electronic address: drzhongwu1964@126.com.

PMID: 37244400
DOI: 10.1016/j.cbi.2023.110570

Abstract

Calcium oxalate (CaOx) nephrolithiasis is a prevalent disorder linked to metabolism. Examining metabolic alterations could potentially give an initial understanding of the origins of CaOx nephrolithiasis. This study aims to determine gut metabolic biomarkers differentiating CaOx nephrolithiasis utilizing untargeted and targeted metabolomics. CaOx nephrolithiasis model rats were built by 1% ethylene glycol administration. Histologic staining and renal function measurement revealed the presence of crystals in the lumen of the renal tubules, the renal injury and interstitial fibrosis in CaOx rats, demonstrating that the models of CaOx were established successfully. Hematoxylin & eosin (H&E) staining showed that CaOx group had inflammation and damage in the ileal tissue. Immunofluorescence and PCR results displayed that the tight junction proteins, ZO-1 and Occludin levels were decreased in the ileal tissues of the CaOx group. The untargeted metabolomic analysis revealed that 269 gut metabolites were differentially expressed between the CaOx group and the control group. Meanwhile, bile secretion, the main metabolic pathway in CaOx nephrolithiasis, was identified. Following, five significant bile acid metabolites were selected utilizing the targeted bile acid metabolomics, including Hyodeoxycholic acid (HDCA), Glycohyodeoxycholic acid (GHDCA), Nor-Deoxycholic Acid, omega-muricholic acid, and Taurolithocholic acid. Among these metabolites, HDCA and GHDCA presented the highest predictive accuracy with AUC = 1 to distinguish the CaOx group from the control group. As a result of network pharmacology, target genes of HDCA and GHDCA in CaOx nephrolithiasis were enriched in oxidative stress and apoptosis pathways. Conclusively, our study provides insight into bile acids metabolic changes related to CaOx nephrolithiasis. Although alterations in biochemical pathways indicate a complex pathology in CaOx rats, bile acid changes may serve as biomarkers of CaOx nephrolithiasis.

Keywords: Bile acid; Biomarker; Calcium oxalate; Ethylene glycol; Metabolomics; Nephrolithiasis.

MeSH terms

Animals
Bile Acids and Salts / metabolism
Calcium Oxalate* / metabolism
Ethylene Glycol / metabolism
Ethylene Glycol / toxicity
Kidney / metabolism
Kidney Calculi* / metabolism
Metabolomics
Rats

Substances

Calcium Oxalate
Ethylene Glycol
Bile Acids and Salts

Supplementary concepts

Nephrolithiasis, Calcium Oxalate