CBS-derived H2S facilitates host colonization of Vibrio cholerae by promoting the iron-dependent catalase activity of KatB.

Sensing and resisting oxidative stress is critical for Vibrio cholerae to survive in either the aquatic environment or the gastrointestinal tract. Previous studies mainly focused on the mechanisms of oxidative stress response regulation that rely on enzymatic antioxidant systems, while functions of non-enzymatic antioxidants are rarely discussed in V. cholerae. For the first time, we investigated the role of hydrogen sulfide (H2S), the simplest thiol compound, in protecting V. cholerae against oxidative stress. We found that degradation of L-cysteine by putative cystathionine ß-synthase (CBS) is the major source of endogenous H2S in V. cholerae. Our results indicate that intracellular H2S level has a positive correlation with cbs expression, while the enhanced H2S production can render V. cholerae cells less susceptible to H2O2 in vitro. Using proteome analysis and real-time qPCR assay, we found that cbs expression could stimulate the expression of several enzymatic antioxidants, including reactive oxygen species (ROS) detoxifying enzymes SodB, KatG and AhpC, the DNA protective protein DPS and the protein redox regulator Trx1. Assays of ROS detoxification capacities revealed that CBS-derived H2S could promote catalase activity at the post-translational level, especially for KatB, which serves as an important way that endogenous H2S participates in H2O2 detoxification. The enhancement of catalase activity by H2S is achieved through facilitating the uptake of iron. Adult mice experiments showed that cbs mutant has colonization defect, while either complementation of cbs or exogenous supplement of N-Acetyl-L-Cysteine restores its fitness in the host environment. Herein, we proposed that V. cholerae regulates CBS-dependent H2S production for better survival and proliferation under ROS stress.

T-cell activation Rho GTPase-activating protein maintains intestinal homeostasis by regulating intestinal T helper cells differentiation through the gut microbiota.

Common variants of the T-cell activation Rho GTPase-activating protein (TAGAP) are associated with the susceptibility to human inflammatory bowel diseases (IBDs); however, the underlying mechanisms are still unknown. Here, we show that TAGAP deficiency or TAGAP expression downregulation caused by TAGAP gene polymorphism leads to decreased production of antimicrobial peptides (AMPs), such as reg3g, which subsequently causes dysregulation of the gut microbiota, which includes Akkermansia muciniphila and Bacteroides acidifaciens strains. These two strains can polarize T helper cell differentiation in the gut, and aggravate systemic disease associated with the dextran sodium sulfate-induced (DSS) disease's phenotype in mice. More importantly, we demonstrated that recombinant reg3g protein or anti-p40 monoclonal antibody exerted therapeutic effects for the treatment of DSS-induced colitis in wild-type and TAGAP-deficient mice, suggesting that they are potential medicines for human IBD treatment, and they may also have a therapeutic effect for the patients who carry the common variant of TAGAP rs212388.

Combining IL-2-based immunotherapy with commensal probiotics produces enhanced antitumor immune response and tumor clearance.

BACKGROUND: Interleukin-2 (IL-2) serves as a pioneer of immunotherapeutic agent in cancer treatment. However, there is a considerable proportion of patients who cannot benefit from this therapy due to the limited clinical responses and dose-limiting toxicities. Mounting evidence indicates that commensal microbiota shapes the outcome of cancer immunotherapies. In this study, we aim to investigate the enhancing effect of Akkermansia muciniphila (AKK), a beneficial commensal microbe receiving considerable attentions, on the antitumor efficacy of IL-2 and explore the underlying molecular mechanism. METHODS: Colorectal carcinoma patient-derived tumor tissues were used to evaluate the therapeutic efficacy of combination treatment. AKK was orally delivered to B16F10 and CT26 tumor-bearing mice along with systemic IL-2 treatment. Flow cytometry was carried out to analyze the tumor immune microenvironment. The molecular mechanism of the enhanced therapeutic efficacy was explored by RNA-seq and then verified in tumor-bearing mice. RESULTS: Combined treatment with IL-2 and AKK showed a stronger antitumor efficacy in colorectal cancer patient-derived tumor tissues. Meanwhile, the therapeutic outcome of IL-2 was significantly potentiated by oral administration of AKK in subcutaneous melanoma and colorectal tumor-bearing mice, resulting from the strengthened antitumor immune surveillance. Mechanistically, the antitumor immune response elicited by AKK was partially mediated by Amuc, derived from the outer membrane protein of AKK, through activating toll-like receptor 2 (TLR2) signaling pathway. Besides, oral supplementation with AKK protected gut barrier function and maintained mucosal homeostasis under systemic IL-2 treatment. CONCLUSION: These findings propose that IL-2 combined with AKK is a novel therapeutic strategy with prospecting application for cancer treatment in clinical practice.

[Comparative study of right anterolateral minithoracotomy and median sternotomy in the repair of atrial septal defects].

OBJECTIVE: To compare the effect of right anterolateral minithoractomy and median sternotomy for atrial septal defect closure. METHODS: In this study, 82 patients, whose age ranged from 4 to 46 years with a mean of 15.7+/-8.6 years, underwent surgical repair of the atrial septal defects on the beating heart through right anterolateral minithoractomy. Ten of these cases were complicated by moderate to severe pulmonary hypertension, and 3 by partial anomalous pulmonary venous connection. Another 67 patients with an age range of 3 to 49 years (mean 17.0+/-12.5 years) underwent surgical repair of the atrial septal defects through full-length median sternotomy with the heart beat arrested, and complication of moderate to severe pulmonary hypertension was identified in 11 cases and partial anomalous venous connection in 5. Comparisons were performed between the 2 groups in terms of the length of skin incision, cardiopulmonary bypass (CPB) time, postoperative mechanical ventilation time, intensive care unit stay, postoperative hospital stay, and the volume of postoperative drainage. RESULTS: There was no operative mortality in either of the 2 groups. In the former group, the CPB time (35.2+/-14.1 min), postoperative mechanical ventilation time (6.5+/-2.5 h), postoperative drainage volume (237.6+/-172.5 ml), postoperative hospital stay (7.4+/-1.2 d) and skin incision length (6.5+/-0.9 cm) were all significantly less than those of the latter group of patients, whose CPB time was 42.7+/-11.8 min, postoperative mechanical ventilation time 7.9+/-3.8 h, postoperative drainage volume 304.3+/-192.4 ml, postoperative hospital stay 9.0+/-2.9 d and skin incision length 15.9+/-1.7 cm (P < 0.01). The intensive care unit stay did not differ significantly between the 2 groups (35.1+/-16.2 h vs 32.3+/-24.1 h, P > 0.05). CONCLUSION: A right anterolateral minithoracotomy for repairs of atrial septal defects is a safe, effective and simple technique to ensure minimal surgical invasion with shorter postoperative hospital stay. Minithoracotomy can be performed to replace median sternotomy in the correction of atrial septal defects, including those complicated by partial anomalous pulmonary venous connection.