Bile acid metabolomics identifies chenodeoxycholic acid as a therapeutic agent for pancreatic necrosis

Qingtian Zhu; Chenchen Yuan; Xiaowu Dong; Yaodong Wang; Baiqiang Li; Bo Tu; Weiwei Chen; Xingmeng Xu; Weijuan Gong; Weiming Xiao; Yanbing Ding; Lianghao Hu; Weiqin Li; Guotao Lu

doi:10.1016/j.xcrm.2023.101304

Bile acid metabolomics identifies chenodeoxycholic acid as a therapeutic agent for pancreatic necrosis

Cell Rep Med. 2023 Dec 19;4(12):101304. doi: 10.1016/j.xcrm.2023.101304. Epub 2023 Nov 29.

Authors

Qingtian Zhu¹, Chenchen Yuan¹, Xiaowu Dong¹, Yaodong Wang², Baiqiang Li³, Bo Tu⁴, Weiwei Chen⁵, Xingmeng Xu¹, Weijuan Gong¹, Weiming Xiao¹, Yanbing Ding¹, Lianghao Hu⁶, Weiqin Li⁷, Guotao Lu⁸

Affiliations

¹ Pancreatic Center, Department of Gastroenterology, Yangzhou Key Laboratory of Pancreatic Disease, Institute of Digestive Diseases, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China.
² Department of Gastroenterology, Kunshan Hospital of Traditional Chinese Medicine, Kunshan Affiliated Hospital of Nanjing University of Chinese Medicine, Kunshan, China.
³ Department of Critical Care Medicine, Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.
⁴ Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
⁵ Department of Gastroenterology, Clinical Medical College, Yangzhou University, Yangzhou, China.
⁶ Department of Gastroenterology, Changhai Hospital, The Second Military Medical University, Shanghai, China. Electronic address: lianghao-hu@hotmail.com.
⁷ Department of Critical Care Medicine, Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China. Electronic address: liweiqindr@nju.edu.cn.
⁸ Pancreatic Center, Department of Gastroenterology, Yangzhou Key Laboratory of Pancreatic Disease, Institute of Digestive Diseases, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China. Electronic address: gtlu@yzu.edu.cn.

Abstract

Bile acids are altered and associated with prognosis in patients with acute pancreatitis (AP). Here, we conduct targeted metabolomic analyses to detect bile acids changes in patients during the acute (n = 326) and the recovery (n = 133) phases of AP, as well as in healthy controls (n = 60). Chenodeoxycholic acid (CDCA) decreases in the acute phase, increases in the recovery phase, and is associated with pancreatic necrosis. CDCA and its derivative obeticholic acid exhibit a protective effect against acinar cell injury in vitro and pancreatic necrosis in murine models, and RNA sequencing reveals that the oxidative phosphorylation pathway is mainly involved. Moreover, we find that overexpression of farnesoid X receptor (FXR, CDCA receptor) inhibits pancreatic necrosis, and interfering expression of FXR exhibits an opposite phenotype in mice. Our results possibly suggest that targeting CDCA is a potential strategy for the treatment of acinar cell necrosis in AP, but further verification is needed.

Keywords: acinar cells; acute pancreatitis; bile acids metabolomics; chenodeoxycholic acid; farnesoid X receptor; obeticholic acid; oxidative phosphorylation; pancreatic necrosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acute Disease
Animals
Bile Acids and Salts*
Chenodeoxycholic Acid / pharmacology
Chenodeoxycholic Acid / therapeutic use
Humans
Mice
Pancreatitis, Acute Necrotizing* / drug therapy
Receptors, Cytoplasmic and Nuclear

Substances

Bile Acids and Salts
Receptors, Cytoplasmic and Nuclear
Chenodeoxycholic Acid