TY - JOUR
T1 - Microbes exploit death-induced nutrient release by gut epithelial cells
AU - Anderson, Christopher J.
AU - Medina, Christopher B.
AU - Barron, Brady J.
AU - Karvelyte, Laura
AU - Aaes, Tania Løve
AU - Lambertz, Irina
AU - Perry, Justin S.A.
AU - Mehrotra, Parul
AU - Gonçalves, Amanda
AU - Lemeire, Kelly
AU - Blancke, Gillian
AU - Andries, Vanessa
AU - Ghazavi, Farzaneh
AU - Martens, Arne
AU - van Loo, Geert
AU - Vereecke, Lars
AU - Vandenabeele, Peter
AU - Ravichandran, Kodi S.
N1 - Funding Information:
Acknowledgements We thank members of the Ravichandran laboratory, M. Kendall and H. Agaisse for numerous discussions and input on this work and for critical reading of the manuscript. We thank H. Remaut for sharing the clinical E. coli isolates, A. Wullaert for Gsdmd knockout mice, and M. Bertrand for Ripk1 kinase-dead mice. We thank the Germ-Free and Gnotobiotic Mouse Facility (UGent/UZ Gent/VIB), VIB Protein Core, VIB Flow Cytometry Core, VIB Bioimaging Core, and VIB Nucleomics Core for their contributions. K.S.R. is supported by FWO (Odysseus grant G0F5716N, EOS DECODE 30837538), Special Research Fund UGent (iBOF BOF20/IBF/037), European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 835243), grants from NHLBI (P01HL120840), NIGMS (R35GM122542) and the Center for Cell Clearance/University of Virginia School of Medicine; grants to P.V. from the FWO (EOS MODEL-IDI, FWO Grant 30826052, G.0E04.16N, G.0C76.18N, G.0B71.18N, G.0B96.20N), Methusalem (BOF16/ MET_V/007), iBOF20/IBF/039 ATLANTIS, Foundation against Cancer (FAF-F/2016/865, F/2020/1505), CRIG and GIGG consortia, and VIB; grants to L.V. from Foundation against cancer (2020-091) and Ghent University (iBOF A21/TT/0612); and grants to G.V.L. from Foundation against Cancer (STK 2014-142 and STK 2018-093) and FWO (G020216N). Additional support was received through the FWO Postdoctoral Fellowship (1225421N to C.J.A., and 1227220N P.M.), NIH T32 Pharmacology Training Grant (T32GM007055 to C.B.M., and B.J.B.), and Ghent University BOF grant (01P02519 to T.L.A.).
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2021/8/12
Y1 - 2021/8/12
N2 - Regulated cell death is an integral part of life, and has broad effects on organism development and homeostasis1. Malfunctions within the regulated cell death process, including the clearance of dying cells, can manifest in diverse pathologies throughout various tissues including the gastrointestinal tract2. A long appreciated, yet elusively defined relationship exists between cell death and gastrointestinal pathologies with an underlying microbial component3–6, but the direct effect of dying mammalian cells on bacterial growth is unclear. Here we advance a concept that several Enterobacteriaceae, including patient-derived clinical isolates, have an efficient growth strategy to exploit soluble factors that are released from dying gut epithelial cells. Mammalian nutrients released after caspase-3/7-dependent apoptosis boosts the growth of multiple Enterobacteriaceae and is observed using primary mouse colonic tissue, mouse and human cell lines, several apoptotic triggers, and in conventional as well as germ-free mice in vivo. The mammalian cell death nutrients induce a core transcriptional response in pathogenic Salmonella, and we identify the pyruvate formate-lyase-encoding pflB gene as a key driver of bacterial colonization in three contexts: a foodborne infection model, a TNF- and A20-dependent cell death model, and a chemotherapy-induced mucositis model. These findings introduce a new layer to the complex host–pathogen interaction, in which death-induced nutrient release acts as a source of fuel for intestinal bacteria, with implications for gut inflammation and cytotoxic chemotherapy treatment.
AB - Regulated cell death is an integral part of life, and has broad effects on organism development and homeostasis1. Malfunctions within the regulated cell death process, including the clearance of dying cells, can manifest in diverse pathologies throughout various tissues including the gastrointestinal tract2. A long appreciated, yet elusively defined relationship exists between cell death and gastrointestinal pathologies with an underlying microbial component3–6, but the direct effect of dying mammalian cells on bacterial growth is unclear. Here we advance a concept that several Enterobacteriaceae, including patient-derived clinical isolates, have an efficient growth strategy to exploit soluble factors that are released from dying gut epithelial cells. Mammalian nutrients released after caspase-3/7-dependent apoptosis boosts the growth of multiple Enterobacteriaceae and is observed using primary mouse colonic tissue, mouse and human cell lines, several apoptotic triggers, and in conventional as well as germ-free mice in vivo. The mammalian cell death nutrients induce a core transcriptional response in pathogenic Salmonella, and we identify the pyruvate formate-lyase-encoding pflB gene as a key driver of bacterial colonization in three contexts: a foodborne infection model, a TNF- and A20-dependent cell death model, and a chemotherapy-induced mucositis model. These findings introduce a new layer to the complex host–pathogen interaction, in which death-induced nutrient release acts as a source of fuel for intestinal bacteria, with implications for gut inflammation and cytotoxic chemotherapy treatment.
UR - http://www.scopus.com/inward/record.url?scp=85111733423&partnerID=8YFLogxK
U2 - 10.1038/s41586-021-03785-9
DO - 10.1038/s41586-021-03785-9
M3 - Article
C2 - 34349263
AN - SCOPUS:85111733423
SN - 0028-0836
VL - 596
SP - 262
EP - 267
JO - Nature
JF - Nature
IS - 7871
ER -