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Stress-Induced Corticotropin-Releasing Hormone-Mediated NLRP6 Inflammasome Inhibition and Transmissible Enteritis in Mice
Open accessAbstract
Background & aims Stress alters brain-gut interactions and could exacerbate intestinal disorders, including irritable bowel syndrome. Alterations in the intestinal microbiota have been associated with irritable bowel syndrome. Maintenance of healthy microbiota requires nucleotide-binding oligomerization domain protein-like receptors, pyrin-domain containing (NLRP)-6 inflammasomes. We investigated the involvement of NLRP6 in water-avoidance stress (WAS)-induced intestinal disorders in mice.Methods B57BL6 mice were subjected to WAS for 1 hour each day for 10 days; body weights and intestinal inflammation and permeability were analyzed. We investigated signaling via the NLRP3 and NLRP6 inflammasomes, and the role of corticotropin-releasing hormone (CRH) in WAS-associated inflammation and NLRP6 inhibition. Mice that were not exposed to stress were co-housed with mice subjected to WAS to determine the effects of WAS-induced dysbiosis, measured by sequencing bacterial 16S ribosomal RNA. We also assessed the effects of a peroxisome proliferator-activated receptor-γ agonist and probiotics.Results WAS-induced small-bowel inflammation (enteritis) was associated with inhibition of NLRP6, but not NLRP3, and was prevented by a peroxisome proliferator-activated receptor-γ agonist, which induced epithelial expression of NLRP6. CRH was released during WAS and inhibited NLRP6 expression. WAS induced alterations in the gut microbiota of mice; co-housed nonstressed mice developed enteritis associated with increased CRH and decreased levels of NLRP6. Probiotic therapy reduced intestinal inflammation in mice with WAS-induced enteritis.Conclusions Exposure of mice to stress inhibits NLRP6 and alters the composition of the gut microbiota, leading to intestinal inflammation. These findings might explain the benefits of probiotics for patients with stress-associated gastrointestinal disorders.
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In the citing paper
“Published data from animal and clinical studies indicate that stress causes dysbiosis.”
From Stress triggers flare of inflammatory bowel disease in children and adults (2019) · cites this paper as [45]
Experimental — accuracy not yet measuredIn the citing paper
“acute stress in mice induced the release of intestinal CRF independently of the HPA axis [131].”
From Anxiety, depression, and the microbiome: A role for gut peptides (2018) · cites this paper as [131]
In the citing paper
“Animal models of chronic stress demonstrate altered intestinal physiology and GM composition, with an increased secretory state and permeability (352–355).”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [354]
In the citing paper
“A study showed that exposure to stress inhibits the NOD-like receptor, pyrin domain containing (NLRP)-6 inflammasome, altering the constitution of the gut flora, thus leading to inflammation of the intestine.”
From Stress triggers flare of inflammatory bowel disease in children and adults (2019) · cites this paper as [45]
In the citing paper
“Leukocytic infiltration, intestinal hyperpermeability, increased serum TNF-α, and upregulated IL-17 and IL-6 expression in mucosa have also been discovered during stress (45).”
From Stress triggers flare of inflammatory bowel disease in children and adults (2019) · cites this paper as [45]
In the citing paper
“Animals exposed to WAS developed acute small intestinal inflammation as evaluated by histological scores in an experimental study.”
From Stress triggers flare of inflammatory bowel disease in children and adults (2019) · cites this paper as [45]
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Metadata
- Authors
- Sun, Y., Zhang, M., Chen, C., Gillilland, M., Sun, X., El–Zaatari, M., Huffnagle, G. B., Young, V. B., Zhang, J., Hong, S., Chang, Y., Gumucio, D. L., Owyang, C., & Kao, J. Y.
- Affiliations
- Shandong University (CN)
- University of Michigan (US)
- Corresponding author
- Kao, John Y.
- ORCID
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2013-06
- Volume
- 144
- Issue
- 7
- Pages
- 1478-1487.e8
- ISSN
- 0016-5085 (ISSN-L)
- PMC
- PMC3777426
- OpenAlex
- W2056707130
- Cited by
- 157
- References
- 33
- Citations by year
- 2026: 7 · 2025: 12 · 2024: 14 · 2023: 10 · 2022: 15 · 2021: 13 · 2020: 15 · 2019: 14 · 2018: 8 · 2017: 12 · 2016: 8 · 2015: 6 · 2014: 15 · 2013: 8
- FWCI
- 5.53
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases
- National Institute of Diabetes and Digestive and Kidney Diseases (R21 AI087869, U19 090871)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Keywords
- NLRP6 inflammasome, corticotropin-releasing factor, water avoidance stress, intestinal inflammation, gut dysbiosis, NLRP3 inflammasome, peroxisome proliferator-activated receptor gamma agonists, probiotics, gut-brain axis, irritable bowel syndrome, intestinal permeability
- MeSH terms
- Animals, Corticotropin-Releasing Hormone, Disease Models, Animal, Enteritis, Female, Mice, Inbred C57BL, Receptors, Cell Surface, Stress, Psychological, Probiotics, Irritable Bowel Syndrome, PPAR gamma, Mice, Metagenome, Inflammasomes
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