Bile acid-dependent transcription factors and chromatin accessibility determine regional heterogeneity of intestinal antimicrobial peptides

Yue Wang; Yanbo Yu; Lixiang Li; Mengqi Zheng; Jiawei Zhou; Haifan Gong; Bingcheng Feng; Xiao Wang; Xuanlin Meng; Yanyan Cui; Yanan Xia; Shuzheng Chu; Lin Lin; Huijun Chang; Ruchen Zhou; Mingjun Ma; Zhen Li; Rui Ji; Ming Lu; Xiaoyun Yang; Xiuli Zuo; Shiyang Li; Yanqing Li

doi:10.1038/s41467-023-40565-7

Bile acid-dependent transcription factors and chromatin accessibility determine regional heterogeneity of intestinal antimicrobial peptides

Nat Commun. 2023 Aug 22;14(1):5093. doi: 10.1038/s41467-023-40565-7.

Authors

Yue Wang^#¹, Yanbo Yu^#^{1

2

3}, Lixiang Li^#^{1

2

3}, Mengqi Zheng^#¹, Jiawei Zhou¹, Haifan Gong⁴, Bingcheng Feng¹, Xiao Wang⁵, Xuanlin Meng⁶, Yanyan Cui⁷, Yanan Xia¹, Shuzheng Chu⁷, Lin Lin¹, Huijun Chang¹, Ruchen Zhou¹, Mingjun Ma¹, Zhen Li^{1

2

3}, Rui Ji^{1

2

3}, Ming Lu⁸, Xiaoyun Yang^{1

2

3}, Xiuli Zuo^{9

10

11}, Shiyang Li^{12

13

14}, Yanqing Li^{15

16

17}

Affiliations

¹ Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan, China.
² Laboratory of Translational Gastroenterology, Qilu Hospital of Shandong University, Jinan, China.
³ Shandong Provincial Clinical Research Center for digestive disease, Jinan, China.
⁴ School of Computer Science and Engineering, Sun Yat-sen University, Guangzhou, China.
⁵ Department of Pathology, Qilu Hospital of Shandong University, Jinan, China.
⁶ State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic and Developmental Sciences, and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
⁷ Advanced Medical Research Institute, Shandong University, Jinan, China.
⁸ Clinical Epidemiology Unit, Qilu Hospital of Shandong University, Jinan, China.
⁹ Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan, China. zuoxiuli@sdu.edu.cn.
¹⁰ Laboratory of Translational Gastroenterology, Qilu Hospital of Shandong University, Jinan, China. zuoxiuli@sdu.edu.cn.
¹¹ Shandong Provincial Clinical Research Center for digestive disease, Jinan, China. zuoxiuli@sdu.edu.cn.
¹² Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan, China. lishiyang@sdu.edu.cn.
¹³ Advanced Medical Research Institute, Shandong University, Jinan, China. lishiyang@sdu.edu.cn.
¹⁴ Key Laboratory for Experimental Teratology of Ministry of Education, Shandong University, Jinan, China. lishiyang@sdu.edu.cn.
¹⁵ Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan, China. liyanqing@sdu.edu.cn.
¹⁶ Laboratory of Translational Gastroenterology, Qilu Hospital of Shandong University, Jinan, China. liyanqing@sdu.edu.cn.
¹⁷ Shandong Provincial Clinical Research Center for digestive disease, Jinan, China. liyanqing@sdu.edu.cn.

^# Contributed equally.

Abstract

Antimicrobial peptides (AMPs) are important mediators of intestinal immune surveillance. However, the regional heterogeneity of AMPs and its regulatory mechanisms remain obscure. Here, we clarified the regional heterogeneity of intestinal AMPs at the single-cell level, and revealed a cross-lineages AMP regulation mechanism that bile acid dependent transcription factors (BATFs), NR1H4, NR1H3 and VDR, regulate AMPs through a ligand-independent manner. Bile acids regulate AMPs by perturbing cell differentiation rather than activating BATFs signaling. Chromatin accessibility determines the potential of BATFs to regulate AMPs at the pre-transcriptional level, thus shaping the regional heterogeneity of AMPs. The BATFs-AMPs axis also participates in the establishment of intestinal antimicrobial barriers of fetuses and the defects of antibacterial ability during Crohn's disease. Overall, BATFs and chromatin accessibility play essential roles in shaping the regional heterogeneity of AMPs at pre- and postnatal stages, as well as in maintenance of antimicrobial immunity during homeostasis and disease.

Publication types

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

MeSH terms

Antimicrobial Peptides
Bile Acids and Salts
Chromatin* / genetics
Intestines*
Transcription Factors / genetics

Substances

Chromatin
Antimicrobial Peptides
Bile Acids and Salts
Transcription Factors