TRIP6 promotes inflammatory damage via the activation of TRAF6 signaling in a murine model of DSS-induced colitis

Background TRIP6 is a zyxin family member that serves as an adaptor protein to regulate diverse biological processes. In prior reports, TRIP6 was shown to play a role in regulating inflammation. However, its in vivo roles and mechanistic importance in colitis remain largely elusive. Herein, we therefore employed TRIP6-deficient (TRIP6−/−) mice in order to explore the mechanistic importance of TRIP6 in a dextran sodium sulfate (DSS)-induced model of murine colitis. Findings Wild-type (TRIP6+/+) mice developed more severe colitis following DSS-mediated disease induction relative to TRIP6−/− mice, as evidenced by more severe colonic inflammation and associated crypt damage. TRIP6 expression in wild-type mice was significantly elevated following DSS treatment. Mechanistically, TRIP6 binds to TRAF6 and enhances oligomerization and autoubiquitination of TRAF6. This leads to the activation of NF-κB signaling and the expression of pro-inflammatory cytokines such as TNFα and IL-6, in the in vivo mouse model of colitis. Conclusions These in vivo data demonstrate that TRIP6 serves as a positive regulator of DSS-induced colitis through interactions with TRAF6 resulting in the activation of inflammatory TRAF6 signaling, highlighting its therapeutic promise as a protein that theoretically can be targeted to prevent or treat colitis.

Sustained Post-Developmental T-Bet Expression Is Critical for the Maintenance of Type One Innate Lymphoid Cells In Vivo

Innate lymphoid cells (ILC) play a significant role in the intestinal immune response and T-bet+ CD127+ group 1 cells (ILC1) have been linked to the pathogenesis of human inflammatory bowel disease (IBD). However, the functional importance of ILC1 in the context of an intact adaptive immune response has been controversial. In this report we demonstrate that induced depletion of T-bet using a Rosa26-Cre-ERT2 model resulted in the loss of intestinal ILC1, pointing to a post-developmental requirement of T-bet expression for these cells. In contrast, neither colonic lamina propria (cLP) ILC2 nor cLP ILC3 abundance were altered upon induced deletion of T-bet. Mechanistically, we report that STAT1 or STAT4 are not required for intestinal ILC1 development and maintenance. Mice with induced deletion of T-bet and subsequent loss of ILC1 were protected from the induction of severe colitis in vivo. Hence, this study provides support for the clinical development of an IBD treatment based on ILC1 depletion via targeting T-bet or its downstream transcriptional targets.

Akkermansia muciniphila Protects Against Psychological Disorder-Induced Gut Microbiota-Mediated Colonic Mucosal Barrier Damage and Aggravation of Colitis

Psychological disorders are associated with increased risk of severe inflammatory bowel disease (IBD) by causing gut microbiota dysbiosis and colonic mucosal barrier damage. However, the interaction between chronic restraint stress (CRS), gut microbiota composition, and colonic mucus remains unclear. We demonstrated that mice under CRS conditions exhibited alterations in microbiota composition, disruption of colonic mucus, and aggravation of colitis. In addition, the abundance of Akkermansia muciniphila was significantly decreased in mice under CRS and UC patients with depression, and positively associated with the expression of MUC2. After antibiotic treatment, the recipient mice colonized with CRS microbiota showed barrier defects and severe colitis. Administration of Akkermansia muciniphila was found to restore colonic mucus and modify the gut microbiota. We confirm that CRS-mediated gut microbiota dysbiosis results in colonic mucosal barrier damage and aggravation of colitis. Our results suggest that A. muciniphila is expected to be a potential probiotic to protect and treat colonic mucus that is involved in IBD with psychological disorders.

EP.TU.688The fate of the rectal stump following subtotal colectomy for acute colitis

Aims Acute severe colitis requires surgery in approximately thirty percent of cases. Subtotal colectomy with end ileostomy is the standard procedure with distinct advantages to a laparoscopic approach. Controversy surrounds the optimal short and long-term management of the distal rectal stump. This study reviews the clinical outcomes and the fate of the rectal stump in this patient cohort. Methods Analysis of prospective data of patients who underwent emergency subtotal colectomy for severe acute colitis between 2010 and 2020 in a tertiary referral centre. Results Sixty-six patients underwent subtotal colectomy (median age, 40years; M:F, 1.3:1). Subtotal colectomy was performed for failure of medical therapy during an acute episode of severe colitis (56%), for fulminant colitis (40%), or for colonic strictures (4%). In 98% percent of patients the rectal stump was closed at the level of the recto-sigmoid junction and in 2% a mucous fistula was formed. 73% of patients opted for no further surgery, but 27% underwent a completion proctectomy, most commonly performed because of rectal stump bleeding. The median follow-up was 6.25years, during which 17% of those with a completion proctectomy underwent an ileo-pouch anal anastomosis (IPAA). Conclusions Subtotal colectomy with closed rectal intra-peritoneal stump and end ileostomy is the procedure of choice in severe acute colitis refractory to maximal medical therapy or fulminant colitis. Given the patient dissatisfaction and morbidity associated with mucous fistula, this procedure should be abandoned. Pelvic dissection should not be performed at the time of the emergency subtotal colectomy given the risk of morbidity.

Lactobacillus Alleviates Colitis Caused by Chemotherapy Via Biofilm Formation

Background: Severe colitis is a common side effect of chemotherapy in cancer patients. A widely consumed probiotic, Lactobacillus, has been reported to alleviate colitis. However, the gastric acid has a powerful bactericidal effect, which restricts to clinical trial success. In this study, we attempted to enhance the viability of probiotics in a gastric acid environment and improve the colitis induced by dextran sulfate sodium (DSS) and chemotherapeutic docetaxel.Methods: We purified Lactobacillus from diverse brands of yogurt and estimated their growth at pH 6.8 and pH 2.0. In the further investigation, the bacterial biofilm formation was used to define the mechanism by which administration of LGG via oral gavage alleviates the colitis and intestine permeability of the mice induced by DSS and docetaxel. The potential benefit of probiotics on the treatment of breast cancer metastasis has been assessed as well.Results: Lactobacillus growth was unexpectedly faster in the pH 2.0 than in the neutral pH medium during the first hour. However, its growth was greatly reduced after the first hour in the pH 2.0 medium but was maintained at neutral pH. As expected, Escherichia coli (E. coli) could not grow well in an acidic medium. Lactobacillus rhamnosus (LGG) administered in the fasting state via oral gavage significantly improved the preventive effect in the colitis caused by DSS and docetaxel. Further mechanistic investigations suggested that LGG reduced the permeability of the intestine and decreased the expression of proinflammatory cytokines, TNFα, IL-1β, and IL-6, in colitis by biofilm formation. We examined the chemotherapeutic effect of docetaxel in a breast cancer model and found that increasing the docetaxel dose may reduce tumor growth and metastasis in the lung but did not benefit survival due to severe colitis. However, the LGG supplement significantly improved the survival of tumor-bearing mice following a high dose of docetaxel treatment. Conclusions: Our findings provide new insights into the potential mechanism of probiotic protection of the intestine and provide a novel therapeutic strategy to augment the chemotherapeutic treatment of tumors.