Intestinal crypt microbiota modulates intestinal stem cell turnover and tumorigenesis via indole acetic acid

Shuning Zhang; Lihua Peng; Shyamal Goswami; Yuchen Li; Haiyue Dang; Shuli Xing; Panpan Feng; Giulia Nigro; Yingying Liu; Yingfei Ma; Tianhao Liu; Jiahua Yang; Tinglei Jiang; Yingnan Yang; Nick Barker; Philippe Sansonetti; Parag Kundu

doi:10.1038/s41564-025-01937-5

Intestinal crypt microbiota modulates intestinal stem cell turnover and tumorigenesis via indole acetic acid

Nat Microbiol. 2025 Mar;10(3):765-783. doi: 10.1038/s41564-025-01937-5. Epub 2025 Feb 19.

Authors

Shuning Zhang^#^{1

2}, Lihua Peng^#¹, Shyamal Goswami¹, Yuchen Li¹, Haiyue Dang^{1

2}, Shuli Xing¹, Panpan Feng¹, Giulia Nigro³, Yingying Liu⁴, Yingfei Ma⁵, Tianhao Liu⁶, Jiahua Yang⁷, Tinglei Jiang⁴, Yingnan Yang⁸, Nick Barker⁹, Philippe Sansonetti¹⁰, Parag Kundu^{11

12}

Affiliations

¹ Laboratory for Microbiota-Host Interactions, The Center for Microbes, Development and Health, Shanghai Institute of Immunity and Infection-Chinese Academy of Sciences, Shanghai, China.
² University of Chinese Academy of Sciences, Beijing, China.
³ Microenvironment and Immunity Unit, INSERM U1224, Institut Pasteur, Paris, France.
⁴ Jilin Provincial Key Laboratory of Animal Resource Conservation and Utilization, Northeast Normal University, Changchun, China.
⁵ Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
⁶ Affiliated Hospital of Jiangnan University and Wuxi Medical College, Jiangnan University, Wuxi, China.
⁷ Department of General Surgery, Putuo Hospital, Shanghai, China.
⁸ Luodian Hospital in Baoshan District, Shanghai, China.
⁹ Institute of Molecular and Cell Biology, Singapore and Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
¹⁰ Institut Pasteur, Paris, France.
¹¹ Laboratory for Microbiota-Host Interactions, The Center for Microbes, Development and Health, Shanghai Institute of Immunity and Infection-Chinese Academy of Sciences, Shanghai, China. parag7777@gmail.com.
¹² University of Chinese Academy of Sciences, Beijing, China. parag7777@gmail.com.

^# Contributed equally.

PMID: 39972061
DOI: 10.1038/s41564-025-01937-5

Abstract

Intestinal crypts harbour a specific microbiota but whether and how these bacteria regulate intestinal stem cells (ISCs) or influence colorectal cancer (CRC) development is unclear. Here we screened crypt-resident bacteria in organoids and found that indole acetic acid (IAA) secreted by Acinetobacter radioresistens inhibits ISC turnover. A. radioresistens inhibited cellular proliferation in tumour slices from CRC patients and inhibited intestinal tumorigenesis and spheroid initiation in APC^Min/+ mice. Targeted clearance of A. radioresistens from colonic crypts using bacteriophage increased EphB2 expression and consequently promoted cellular proliferation, ISC turnover and tumorigenesis in mouse models of CRC. The protective effects of A. radioresistens were abrogated upon deletion of trpC to prevent IAA production, or upon intestine-specific aryl hydrocarbon receptor (AhR) knockout, identifying an IAA-AhR-Wnt-β-catenin signalling axis that promotes ISC homeostasis. Our findings reveal a protective role for an intestinal crypt-resident microbiota member in tumorigenesis.

MeSH terms

Animals
Carcinogenesis* / metabolism
Cell Proliferation
Colorectal Neoplasms* / metabolism
Colorectal Neoplasms* / microbiology
Colorectal Neoplasms* / pathology
Gastrointestinal Microbiome* / physiology
Humans
Indoleacetic Acids* / metabolism
Intestinal Mucosa / microbiology
Mice
Mice, Inbred C57BL
Mice, Knockout
Organoids / microbiology
Receptors, Aryl Hydrocarbon / genetics
Receptors, Aryl Hydrocarbon / metabolism
Stem Cells* / metabolism
Stem Cells* / microbiology

Substances

Indoleacetic Acids
indoleacetic acid
Receptors, Aryl Hydrocarbon

Grants and funding

2019SHZDZX02/Science and Technology Commission of Shanghai Municipality (Shanghai Municipal Science and Technology Commission)