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Background & Aims: Intestinal fibrosis is a significant complication of Crohn's disease (CD). Gut microbiota reactive Th17 cells are crucial in the pathogenesis of CD; however, how Th17 cells induce intestinal fibrosis is still not completely understood., Methods: In this study, T-cell transfer model with wild-type (WT) and Areg -/- Th17 cells and dextran sulfate sodium (DSS)-induced chronic colitis model in WT and Areg -/- mice were used. CD4 + T-cell expression of AREG was determined by quantitative reverse-transcriptase polymerase chain reaction and enzyme-linked immunosorbent assay. The effect of AREG on proliferation/migration/collagen expression in human intestinal myofibroblasts was determined. AREG expression was assessed in healthy controls and patients with CD with or without intestinal fibrosis., Results: Although Th1 and Th17 cells induced intestinal inflammation at similar levels when transferred into Tcrβxδ -/- mice, Th17 cells induced more severe intestinal fibrosis. Th17 cells expressed higher levels of AREG than Th1 cells. Areg -/- mice developed less severe intestinal fibrosis compared with WT mice on DSS insults. Transfer of Areg -/- Th17 cells induced less severe fibrosis in Tcrβxδ -/- mice compared with WT Th17 cells. Interleukin (IL)6 and IL21 promoted AREG expression in Th17 cells by activating Stat3. Stat3 inhibitor suppressed Th17-induced intestinal fibrosis. AREG promoted human intestinal myofibroblast proliferation, motility, and collagen I expression, which was mediated by activating mammalian target of rapamycin and MEK. AREG expression was increased in intestinal CD4 + T cells in fibrotic sites compared with nonfibrotic sites from patients with CD., Conclusions: These findings reveal that Th17-derived AREG promotes intestinal fibrotic responses in experimental colitis and human patients with CD. Thereby, AREG might serve as a potential therapeutic target for fibrosis in CD., (Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Gut bacteria-derived short-chain fatty acids (SCFAs) play crucial roles in the maintenance of intestinal homeostasis. However, how SCFAs regulate epithelial turnover and tissue repair remain incompletely understood. In this study, we investigated how the SCFA propionate regulates cell migration to promote epithelial renewal and repair., Methods: Mouse small intestinal epithelial cells (MSIE) and human Caco-2 cells were used to determine the effects of SCFAs on gene expression, proliferation, migration, and cell spreading in vitro. Video microscopy and single cell tracking were used to assess cell migration kinetically. 5-bromo-2'-deoxyuridine (BrdU) and hydroxyurea were used to assess the effects of SCFAs on migration in vivo. Lastly, an acute colitis model using dextran sulfate sodium (DSS) was used to examine the effects of SCFAs in vivo., Results: Using video microscopy and single cell tracking, we found that propionate promoted intestinal epithelial cell migration by enhancing cell spreading and polarization, which led to increases in both cell speed and persistence. This novel function of propionate was dependent on inhibition of class I histone deacetylases (HDAC) and GPR43 and required signal transducer and activator of transcription 3 (STAT3). Furthermore, using 5-bromo-2'-deoxyuridine (BrdU) and hydroxyurea in vivo, we found that propionate enhanced cell migration up the crypt-villus axis under homeostatic conditions, while also protecting against ulcer formation in experimental colitis., Conclusion: Our results demonstrate a mechanism by which propionate stimulates cell migration in an HDAC inhibition, GPR43, and STAT3 dependent manner, and suggest that propionate plays an important role in epithelial migration independent of proliferation., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Stimulator of interferon genes (STING) has been shown to play a critical role in orchestrating immune responses to various pathogens through sensing cyclic dinucleotides. However, how STING regulates intestinal homeostasis is still not completely understood. In this study, we found that STING -/- mice were more susceptible to enteric infection with Citrobacter rodentium compared to wild-type (WT) mice evidenced by more severe intestinal inflammation and impaired bacterial clearance. STING -/- mice demonstrated lower expression of REG3γ but not β-defensins and Cramp in IECs. Consistently, STING -/- IECs showed reduced capacity to inhibit bacterial growth. STING agonists, both 10-carboxymethyl-9-acridanone (CMA) and 5,6-dimethylxanthenone-4-acetic acid (DMXAA), promoted REG3γ expression IECs. Furthermore, STING agonists promoted WT but not REG3γ-deficient IEC bacterial killing. Mechanistically, STING agonists activated STAT3 and promoted glycolysis in IECs. Inhibition of STAT3 pathway and glycolysis suppressed STING-induced REG3γ production in IECs, and abrogated STING-mediated IEC killing of C. rodentium. Additionally, treatment with the STING ligand, 2,3-cGAMP, inhibited C. rodentium-induced colitis in vivo. Overall, STING promotes IEC REG3γ expression to inhibit enteric infection and intestinal inflammation, thus, maintaining the intestinal homeostasis., (© 2020 Federation of American Societies for Experimental Biology.)

Inflammatory macrophages in colonic mucosa are the leading drivers of the pathology associated with inflammatory bowel disease (IBD). Here we examined whether gadolinium chloride (GdCl3), a macrophage selective inhibitor, would improve the course of 2,4,6-trinitro benzene sulfonic acid (TNBS) and dextran sodium sulfate (DSS)-induced colitis in mice and the potential mechanisms were investigated. By giving GdCl3 to colitis mice through intravenous or intrarectal route, we found that GdCl3 markedly ameliorated the colitis severity, including less weight loss, decreased disease activity index scores, and improved mucosal damage. To investigate the potential mechanisms, flow-cytometric analysis was performed to detect the proportion of mucosal macrophages in colon. The results showed that GdCl3 had no macrophage depletion effect in colonic mucosa, but significantly suppressed TNBS and DSS-induced TNFα, IL-1β and IL-6 secretions. Also, Western blotting analysis indicated that NF-κB p65 expression was significantly attenuated in the mucosa in colitis mice with GdCl3 treatment. Then, the anti-inflammatory activity of GdCl3 was confirmed in LPS-stimulated RAW 264.7 cells that GdCl3 might down-regulate the production of proinflammatory cytokines by macrophages through inhibition of the NF-κB signaling pathway. Therefore, intervention with mucosal inflammatory macrophages may be a promising therapeutic target in IBD.

Unlabelled: Previous studies suggested that brain-derived neurotrophic factor (BDNF) might act as an important modulator in chronic pain states. However, no systematic study has used knock-out mice to clarify its effect on visceral sensitivity. In the present study, 2,4,6-trinitrobenzene sulfonic acid (TNBS) was administered to heterozygous (BDNF(+/-)) knock-out and wild-type (BDNF(+/+)) mice to induce colitis. Visceral response to colorectal distension (CRD) and bladder reactivity were recorded. Results demonstrated that in normal state, BDNF(+/-) and BDNF(+/+) mice did not differ in the visceral response to CRD at <60 mm Hg pressure and the bladder reactivity; however, with 60 mm Hg pressure, BDNF(+/-) mice showed a weaker visceral response to CRD. In inflammatory state of colitis, TNBS induced upregulation of BDNF in dorsal root ganglia of both genotypes while BDNF(+/-) mice showing significantly lower sensitivity in the colon at 30 mm Hg and lower sensitivity in bladder than BDNF(+/+) mice. The two genotypes showed no significant difference in inflammatory severity. Thus, BDNF deficiency results in developmental changes in colonic nociception in both control and inflammatory states, which are more significant in inflammatory state. For bladder reactivity, BDNF deficiency leads to lower sensitization in inflammatory state but has no effect in control state., Perspective: This article highlights the role of BDNF in colonic and referred bladder hyperalgesia in mice. The findings might help in determining novel pharmaceutical interventions targeted at BDNF to relieve abdominal pain., (Copyright (c) 2009 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved.)

Transient receptor potential ankyrin-1 (TRPA1) is an important receptor that contributes to inflammatory pain. However, previous studies were mainly concerned with its function in somatic hyperalgesia while few referred to visceral, especially colonic inflammatory hyperalgesia. The present study was aimed to investigate the role of TRPA1 in visceral hyperalgesia after trinitrobenzene sulfonic acid (TNBS)-induced colitis. Results indicate that TNBS induced a significant increase in visceral sensitivity to colonic distension and chemical irritation accompanied by up-regulation of TRPA1 in colonic afferent dorsal root ganglia (DRG). Intrathecal administration of TRPA1 antisense (AS) oligodeoxynucleotide (ODN) reduced the TRPA1 expression in DRG as well as suppressed the colitis-induced hyperalgesia to nociceptive colonic distension and intracolonic allyl isothiocyanate (AITC). Meanwhile the TRPA1 antisense ODN had no effect on transient receptor potential vanilloid-1 (TRPV1) expression, which was proposed to highly co-express with TRPA1, and no effect on the response to TRPV1 agonist, capsaicin. These data suggest an apparent role of TRPA1 in visceral hyperalgesia following colitis that might provide a novel therapeutic target for the relief of pain.