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Gut Enterochromaffin Cells are Critical Drivers of Visceral Pain and Anxiety

James R. Bayrer, Joel Castro, Archana Venkataraman, Kouki K. Touhara, Nathan D. Rossen, Ryan D. Morrie, Aenea Hendry, Jessica Madden, Kristina N. Braverman, Gudrun Schober, Mariana Brizuela, Carla Bueno Silva, Holly A. Ingraham, Stuart M. Brierley, David Julius
doi: https://doi.org/10.1101/2022.04.04.486775
James R. Bayrer
1Department of Pediatrics, UCSF, Mission Bay, San Francisco, CA, 94143, USA
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Joel Castro
2College of Medicine, Flinders Health and Medical Research Institute, Adelaide, SA 5042, AUSTRALIA
3Hopwood Centre for Neurobiology, South Australian Health & Medical Research Institute, North Terrace, Adelaide, SA 5000, AUSTRALIA
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Archana Venkataraman
4Department of Cellular and Molecular Pharmacology, UCSF, MIssion Bay, San Francisco, CA 94143, USA
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Kouki K. Touhara
5Department of Physiology, UCSF, Mission Bay, San Francisco, CA 94143, USA
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Nathan D. Rossen
5Department of Physiology, UCSF, Mission Bay, San Francisco, CA 94143, USA
6Tetrad Graduate Program, UCSF, Mission Bay, San Francisco, CA 94143, USA
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Ryan D. Morrie
5Department of Physiology, UCSF, Mission Bay, San Francisco, CA 94143, USA
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Aenea Hendry
2College of Medicine, Flinders Health and Medical Research Institute, Adelaide, SA 5042, AUSTRALIA
3Hopwood Centre for Neurobiology, South Australian Health & Medical Research Institute, North Terrace, Adelaide, SA 5000, AUSTRALIA
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Jessica Madden
2College of Medicine, Flinders Health and Medical Research Institute, Adelaide, SA 5042, AUSTRALIA
3Hopwood Centre for Neurobiology, South Australian Health & Medical Research Institute, North Terrace, Adelaide, SA 5000, AUSTRALIA
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Kristina N. Braverman
1Department of Pediatrics, UCSF, Mission Bay, San Francisco, CA, 94143, USA
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Gudrun Schober
2College of Medicine, Flinders Health and Medical Research Institute, Adelaide, SA 5042, AUSTRALIA
3Hopwood Centre for Neurobiology, South Australian Health & Medical Research Institute, North Terrace, Adelaide, SA 5000, AUSTRALIA
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Mariana Brizuela
2College of Medicine, Flinders Health and Medical Research Institute, Adelaide, SA 5042, AUSTRALIA
3Hopwood Centre for Neurobiology, South Australian Health & Medical Research Institute, North Terrace, Adelaide, SA 5000, AUSTRALIA
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Carla Bueno Silva
1Department of Pediatrics, UCSF, Mission Bay, San Francisco, CA, 94143, USA
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Holly A. Ingraham
4Department of Cellular and Molecular Pharmacology, UCSF, MIssion Bay, San Francisco, CA 94143, USA
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Stuart M. Brierley
2College of Medicine, Flinders Health and Medical Research Institute, Adelaide, SA 5042, AUSTRALIA
3Hopwood Centre for Neurobiology, South Australian Health & Medical Research Institute, North Terrace, Adelaide, SA 5000, AUSTRALIA
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  • For correspondence: david.julius@ucsf.edu stuart.brierley@flinders.edu.au
David Julius
5Department of Physiology, UCSF, Mission Bay, San Francisco, CA 94143, USA
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  • For correspondence: david.julius@ucsf.edu stuart.brierley@flinders.edu.au
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ABSTRACT

Gastrointestinal (GI) discomfort is a hallmark of most gut disorders and represents a significant component of chronic visceral pain 1. For the growing population afflicted by irritable bowel syndrome (IBS), GI hypersensitivity and pain persist long after signs of tissue injury have resolved 2. IBS also exhibits a strong sex bias afflicting women three-fold more than men 1. Identifying the molecules, cells, and circuits that mediate both the acute and persistent phases of visceral pain is a critical first step in understanding how environmental and endogenous factors produce long-term changes in the nervous system or associated tissues to engender chronic pain syndromes 3,4. Enterochromaffin (EC) cells within the gut epithelium are exceedingly rare sensory neuroendocrine cells that detect and transduce noxious stimuli to nearby nerve endings via serotonin. Here, we manipulate murine EC cell activity using genetic strategies to ascertain their contributions to visceral pain. We show that acute EC cell activation is sufficient to elicit hypersensitivity to gut distension and necessary for the sensitizing actions of isovalerate, a bacterially derived short-chain fatty acid irritant associated with inflammatory GI disorders. Remarkably, prolonged EC cell activation by itself is sufficient to produce persistent visceral hypersensitivity, even in the absence of an instigating inflammatory episode. Perturbing the activity of these rare EC cells led to a marked increase in anxiety-like behaviors that normalized after blocking serotonergic signaling. Sex differences were also observed accross a range of assays indicating that females have a higher baseline visceral sensitivity. Our findings validate a critical role for EC cell-mucosal afferent signaling in acute and persistent GI pain while highlighting mechanistically defined genetic models for studying visceral hypersensitivity, sex differences, and associated behaviors.

Competing Interest Statement

The authors have declared no competing interest.

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Posted April 05, 2022.
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Gut Enterochromaffin Cells are Critical Drivers of Visceral Pain and Anxiety
James R. Bayrer, Joel Castro, Archana Venkataraman, Kouki K. Touhara, Nathan D. Rossen, Ryan D. Morrie, Aenea Hendry, Jessica Madden, Kristina N. Braverman, Gudrun Schober, Mariana Brizuela, Carla Bueno Silva, Holly A. Ingraham, Stuart M. Brierley, David Julius
bioRxiv 2022.04.04.486775; doi: https://doi.org/10.1101/2022.04.04.486775
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Gut Enterochromaffin Cells are Critical Drivers of Visceral Pain and Anxiety
James R. Bayrer, Joel Castro, Archana Venkataraman, Kouki K. Touhara, Nathan D. Rossen, Ryan D. Morrie, Aenea Hendry, Jessica Madden, Kristina N. Braverman, Gudrun Schober, Mariana Brizuela, Carla Bueno Silva, Holly A. Ingraham, Stuart M. Brierley, David Julius
bioRxiv 2022.04.04.486775; doi: https://doi.org/10.1101/2022.04.04.486775

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