Stress-Induced Corticotropin-Releasing Hormone-Mediated NLRP6 Inflammasome Inhibition and Transmissible Enteritis in Mice

Abstract

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.

Psychological stress exacerbates NSAID-induced small bowel injury by inducing changes in intestinal microbiota and permeability via glucocorticoid receptor signaling

“…Stress-induced microbial shifts have been reported in previous studies [15,47]. A WASinduced microbial shift in rats was mainly analyzed using a sequencer [47].…”

“…A WASinduced microbial shift in rats was mainly analyzed using a sequencer [47]. In mice, stress changed the Lactobacillaceae and unclassified Clostridiales contents of the small intestine while decreasing its Lacnospiraceae and unclassified Bacteroidetes contents [15]. Some mechanisms for the microbial changes caused by stress have been proposed in previous works.…”

“…Intestinal permeability was measured in mice that were exposed to 8 days of WAS and sham stress as reported previously [15]. 4000 Da of fluorescein isothiocyanate (FITC)-dextran (Sigma-Aldrich, St. Louis, MO, USA) were dissolved in distilled water to 15 mM in shaded conditions.…”

The structures of the colonic mucosa-associated and luminal microbial communities are distinct and differentially affected by a prolonged murine stressor

“…22,39,40 Some studies suggest that changes to the microbiota could be involved in stressor-induced GI immune dysfunction, but stressor-induced changes in gut microbiota have not been well-characterized. 41,42 In this study, mice were exposed to a widely used and well-validated murine model of chronic stress to elucidate the effects of a long-term stressor upon the colonic microbiota. The data show that microbial communities associating with colonic tissue and found in the lumen of the colon have unique community structures that are differentially impacted by psychological stressor exposure.…”

Gut microbiota, the immune system, and diet influence the neonatal gut–brain axis

“…Characteristically, innate immune cells release interleukin-1, interleukin-18, and interleukin-33 (46); however, inhibitory signals from the inflammasome may also downregulate inflammation in the gut (47). For example, in a mouse model of murine enteritis, efferent vagal signaling via corticotropin-releasing hormone inhibits inflammasome-induced inflammation, thereby reducing intestinal enteritis (16,48). The GBA thereby can regulate inflammasome-mediated activation of innate immune cells in the gut through the action of the hypothalamic-pituitary axis, thereby abrogating inflammation in the intestine.…”