A transcriptional atlas of gut-innervating neurons reveals activation of interferon signaling and ferroptosis during intestinal inflammation
Enteric infections often cause long-term sequelae, including persistent gastrointestinal symptoms, such as pain, discomfort, or irritable bowel syndrome. The plethora of sensory symptoms indicates that gut-innervating neurons might be directly affected by inflammation. However, sequencing studies of neurons in the gastrointestinal tract are hampered by difficulties in purifying neurons, especially during inflammation. Activating a nuclear GFP tag selectively in neurons enabled sort purification of intrinsic and extrinsic neurons of the gastrointestinal tract in models of intestinal inflammation. Using bulk and single-nucleus RNA sequencing, we mapped the whole transcriptomic landscape and identified a conserved neuronal response to inflammation, which included the interferon signaling and ferroptosis pathway. Deletion of the interferon receptor 1 in neurons regulated ferroptosis, neuronal loss, and consequently gut-transit time. Collectively, this study offers a resource documenting neuronal adaptation to inflammatory conditions and exposes the interferon and ferroptosis pathways as signaling cascades activated in neurons during inflammation.
Authors
- Laura P. Bartel
- Sotiria Boulekou (ORCID: https://orcid.org/0000-0001-5520-4164)
- Nele Sterczyk
- Christoph S. N. Klose (ORCID: https://orcid.org/0000-0001-8803-2979)
- Dilmurat Yusuf (ORCID: https://orcid.org/0000-0001-8683-7845)
- Manuel O. Jakob (ORCID: https://orcid.org/0000-0003-3638-3114)
- Patricio Thieme
- Carl Weidinger (ORCID: https://orcid.org/0000-0002-9948-0088)
- Anja A. Kühl (ORCID: https://orcid.org/0000-0003-2293-5387)
- Catalina Cosovanu (ORCID: https://orcid.org/0000-0003-4412-4227)
- Mario Witkowski (ORCID: https://orcid.org/0000-0002-8791-5558)
- Miguel González-Acera (ORCID: https://orcid.org/0009-0008-9445-5650)
- Marvin Bubeck (ORCID: https://orcid.org/0000-0001-6612-1989)
- Heidi Limberger
- Yanjiang Luo (ORCID: https://orcid.org/0009-0003-0401-467X)
- Patrycja M. Forster
- Alexandra Polici
Institutions
- University of Freiburg (DE)
- Humboldt-Universität zu Berlin (DE)
- Universitätsklinikum Erlangen (DE)
- German Rheumatism Research Centre (DE)
Publication Details
- Journal
- Neuron
- Published
- 2025-03-17
- DOI
- https://doi.org/10.1016/j.neuron.2025.02.018
- Citations
- 14
- Primary Topic
- Cancer-related molecular mechanisms research
- Type
- article
- Field-Weighted Citation Impact
- 13.11
Funders
- Deutsche Forschungsgemeinschaft
- Volkswagen Foundation
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Interdisziplinäres Zentrum für Klinische Forschung, Universitätsklinikum Würzburg
- European Research Council