Associations between sex hormones, receptors, binding proteins and inflammatory bowel disease: a Mendelian randomization study.

Background: Gender differences existed in inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC). Observational studies have revealed associations between sex hormones and IBD, such as estrogen and testosterone. However, the exact relationship between these sex hormones and IBD is unclear. Method: Based on the genome-wide association studies data of eight sex hormones, two sex hormone receptors, sex hormone-binding globulin (SHBG), total IBD and its two subtypes, we performed a two-sample Mendelian randomization (MR) study to analyze their mutual relationship. For estradiol (E2), progesterone (PROG), bioavailable testosterone (BAT), total testosterone (TT) and SHBG, sex-stratified MR analyses were also performed. Inverse variance weighted method, MR-Egger regression and Weighted median method were used for causal analyses. Sensitivity analyses were conducted to test the stability of causal relationships. Besides, a reverse MR analysis was performed to estimate the reverse causation. Results: E2 (P=0.028) and TT (P=0.034) had protective effects on CD. Sex-stratified analyses revealed protective roles of E2 in males on total IBD (P=0.038) and CD (P=0.020). TT in females had protective effects on total IBD (P=0.025) and CD (P=0.029), and BAT in females decreased the risk of developing CD (P=0.047) and UC (P=0.036). Moreover, SHBG in males was also associated with a decreased risk of CD (P=0.021). The reversed MR analysis showed that CD was negatively correlated with estrogen receptor (P=0.046). UC was negatively correlated with PROG in females (P=0.015) and positively correlated with SHBG levels in males (P=0.046). Conclusion: Findings of this study revealed the mutual causal associations between sex hormones and the risk of developing IBD.

The role of sphingosine-1-phosphate in the gut mucosal microenvironment and inflammatory bowel diseases.

Sphingosine-1-phosphate (S1P), a type of bioactive sphingolipid, can regulate various cellular functions of distinct cell types in the human body. S1P is generated intracellularly by the catalysis of sphingosine kinase 1/2 (SphK1/2). S1P is transferred to the extracellular environment via the S1P transporter, binds to cellular S1P receptors (S1PRs) and subsequently activates S1P-S1PR downstream signaling. Dysbiosis of the intestinal microbiota, immune dysregulation and damage to epithelial barriers are associated with inflammatory bowel disease (IBD). Generally, S1P mainly exerts a proinflammatory effect by binding to S1PR1 on lymphocytes to facilitate lymphocyte migration to inflamed tissues, and increased S1P was found in the intestinal mucosa of IBD patients. Notably, there is an interaction between the distribution of gut bacteria and SphK-S1P signaling in the intestinal epithelium. S1P-S1PR signaling can also regulate the functions of intestinal epithelial cells (IECs) in mucosa, including cell proliferation and apoptosis. Additionally, increased S1P in immune cells of the lamina propria aggravates the inflammatory response by increasing the production of proinflammatory cytokines. Several novel drugs targeted at S1PRs have recently been used for IBD treatment. This review provides an overview of the S1P-S1PR signaling pathway and, in particular, summarizes the various roles of S1P in the gut mucosal microenvironment to deeply explore the function of S1P-S1PR signaling during intestinal inflammation and, more importantly, to identify potential therapeutic targets for IBD in the SphK-S1P-S1PR axis.

Alterations in the gut microbiota and the efficacy of adjuvant probiotic therapy in liver cirrhosis.

Background: Liver cirrhosis is the end stage of various chronic liver diseases (CLDs). The gut microbiota can impact the liver environment and trigger chronic liver inflammation through the gut-liver axis. Alteration of the gut microbiota has become an effective strategy in the biological treatment of cirrhosis. Methods: Twenty-eight patients with liver cirrhosis and 16 healthy individuals were included, and fresh stool samples were collected. We analyzed changes in the gut microbiota between groups by 16S rRNA sequencing and evaluated the association between microbiota alterations and hepatic function. Additionally, 102 cirrhotic patients were retrospectively enrolled and divided into a probiotic group (n=44) and a nonprobiotic group (n=58) in addition to standard treatment for cirrhosis. Patients were monitored for hematological parameters and hepatic function during the six-month follow-up. Results: The gut microbiota profile of patients with cirrhosis was greatly different from that of healthy individuals, presenting with significantly reduced α diversity and decreased abundance of representative SCFA-producing bacteria including Firmicutes, Coprococcus and Clostridium IV. The pathogenic bacteria Gammaproteobacteria, Veillonella, and Bacilli were greatly enriched in cirrhotic patients. Additionally, patients with decompensated cirrhosis (DCPC) had a significantly reduced abundance of Oscillibacter compared to compensated cirrhosis (CPC), which is also a SCFA-producing bacteria, and the lower Firmicutes to Bacteroidetes ratio and enhanced MDR values were also shown in DCPC patients compared to CPC patients. In addition, the abundance of Firmicutes was negatively related to hepatic function in cirrhotic patients, including the levels of ALT, AST, and DBIL. From the retrospective study, we found that biochemical improvements in alanine transaminase (ALT) and total bilirubin (TBIL) were obtained in DCPC patients who received oral probiotic therapy compared with the nonprobiotic group. Conclusion: Severe microbial dysbiosis existed in patients with liver cirrhosis, especially patients who reached the decompensatory stage. SCFA-producing bacteria were significantly reduced in cirrhosis. Altered gut microbiota cause changes in functional modules, which may contribute to cirrhosis progression and are associated with clinical prognosis. Adjuvant probiotic supplementation to enhance SCFA-producing bacteria can be a prospective therapy for patients with cirrhosis.

YAP Activates STAT3 Signalling to Promote Colonic Epithelial Cell Proliferation in DSS-Induced Colitis and Colitis Associated Cancer.

Background and Aims: Yes-associated protein (YAP) is a key transcriptional coactivator of cell proliferation and differentiation. In this study, we sought to identify the roles of YAP in colonic epithelial regeneration and tumourigenesis. Methods: Murine DSS-induced colitis and YAP overexpression models were constructed via lentiviral intraperitoneal injection. Stable YAP-overexpressing cells, protein immunoprecipitation, and ChIP were used to deeply explore the molecular mechanism. Results: We found that the expression of YAP was dramatically diminished in the colonic crypts during the acute colitis phase, while YAP was strikingly enhanced to initiate tissue repair after DSS withdrawal. Overexpressing YAP in mice drastically accelerated epithelial regeneration, presenting with more intact structural integrity and reduced inflammatory cell infiltration in the mucosa. Further mechanistic studies showed that the expression of YAP in the nucleus was significantly increased by 2 h post-DSS removal, accompanied by upregulated protein levels of activated STAT3. Overexpression of YAP (YAPWT) elevated the expression of activated STAT3 and its transcriptional targets and strengthened the proliferation and "wound healing" ability of colonic cells. However, these effects were reversed when STAT3 was silenced in YAPWT cells. Moreover, YAP could directly interact with STAT3 in the nucleus, and c-Myc and CyclinD1 were the transcriptional targets. Finally, during colitis-associated cancer (CAC), YAPWT promoted the progression of CAC, while the phosphomimetic YAP downregulated the expression of STAT3 and inhibited the development and progression of CAC. Conclusion: YAP activates STAT3 signalling to facilitate mucosal regeneration after DSS-induced colitis. However, excessive YAP activation in the colonic epithelium promotes CAC development.

The Hippo-YAP/TAZ Signaling Pathway in Intestinal Self-Renewal and Regeneration After Injury.

The Hippo pathway and its downstream effectors, the transcriptional coactivators Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), control stem cell fate and cell proliferation and differentiation and are essential for tissue self-renewal and regeneration. YAP/TAZ are the core components of the Hippo pathway and they coregulate transcription when localized in the nucleus. The intestinal epithelium undergoes well-regulated self-renewal and regeneration programs to maintain the structural and functional integrity of the epithelial barrier. This prevents luminal pathogen attack, and facilitates daily nutrient absorption and immune balance. Inflammatory bowel disease (IBD) is characterized by chronic relapsing inflammation of the entire digestive tract. Impaired mucosal healing is a prominent biological feature of IBD. Intestinal self-renewal is primarily dependent on functional intestinal stem cells (ISCs), especially Lgr5+ crypt base columnar (CBC) cells and transient-amplifying (TA) cells in the crypt base. However, intestinal wound healing is a complicated process that is often associated with epithelial cells, and mesenchymal and immune cells in the mucosal microenvironment. Upon intestinal injury, nonproliferative cells rapidly migrate towards the wound bed to reseal the damaged epithelium, which is followed by cell proliferation and differentiation. YAP is generally localized in the nucleus of Lgr5+ CBC cells, where it transcriptionally regulates the expression of the ISC marker Lgr5 and plays an important role in intestinal self-renewal. YAP/TAZ are the primary mechanical sensors of the cellular microenvironment. Their functions include expanding progenitor and stem cell populations, reprogramming differentiated cells into a primitive state, and mediating the regenerative function of reserve stem cells. Thus, YAP/TAZ play extremely crucial roles in epithelial repair after damage. This review provides an overview of the Hippo-YAP/TAZ signaling pathway and the processes of intestinal self-renewal and regeneration. In particular, we summarize the roles of YAP/TAZ in the phases of intestinal self-renewal and regeneration to suggest a potential strategy for IBD treatment.

The Role of Vitamin D in Immune System and Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is a nonspecific inflammatory disease that includes ulcerative colitis (UC) and Crohn's disease (CD). The pathogenesis of IBD is not fully understood but is most reported associated with immune dysregulation, dysbacteriosis, genetic susceptibility, and environmental risk factors. Vitamin D is an essential nutrient for the human body, and it not only regulates bone metabolism but also the immune system, the intestinal microbiota and barrier. Vitamin D insufficiency is common in IBD patients, and the abnormal low levels of vitamin D are highly correlated with disease activity, treatment response, and risk of relapse of IBD. Accumulating evidence supports the protective role of vitamin D in IBD through regulating the adaptive and innate immunity, maintaining the intestinal barrier and balancing the gut microbiota. This report aims to provide a broad overview of the role vitamin D in the immune system, especially in the pathogenesis and treatment of IBD, and its possible role in predicting relapse.

Anemia induced by hemangioma at the duodenal papilla, resected by endoscopic mucosal resection.

A 7-year-old ever healthy girl presented to our hospital with anemia for half-a-year, and her lowest hemoglobin level was 75g/L. She denied any hematemesis or melena, however her fecal occult blood test was positive. Computed tomography revealed an oval lesion in the descending duodenum.

Perianal and Luminal Relapse Following Perianal Surgical Intervention in Crohn's Disease.

BACKGROUND AND AIMS: Fistula relapse occurs in 20-30% of patients with perianal Crohn's disease (PCD) despite optimal medico-surgical management. We aimed in this study to assess the rate of perianal and luminal relapse after surgically induced remission and to determine factors associated with fistula relapse. METHODS: Consecutive perianal CD patients who achieved clinical remission after surgery for fistulising PCD from January 2013 to January 2019 were included. The cumulative probabilities of relapse-free survival were estimated using the Kaplan-Meier method. RESULTS: A total of 130 patients were included. Sixty-six of 130 patients received infliximab (IFX) therapy after perianal surgery. After a median follow-up of 62 months (interquartile range [IQR]: 28-117 months), perianal relapse occurred in 30 of 64 (46.9%) nonbiological medication-treated cases and in 14 of 66 (21.1%) cases in the IFX therapy group. The cumulative probabilities of perianal relapse-free survival in patients with nonbiological treatment were 77.1% at 1 year, 54.6% at 3 years, and 30% at 5 years. The rates of survival without perianal fistula relapse in the IFX-treated group were 91.6%, 69.2%, and 59.3% at 1, 3 and 5 years, respectively. In patients treated with IFX after perianal surgery, discontinuation of IFX therapy (odds ratio [OR]=2.43, p=0.036), a penetrating CD phenotype (OR=4.324, p=0.019), and a complex perianal fistula (OR=3.392, p=0.026) were independently associated with perianal relapse in multivariate analysis. CONCLUSION: Infliximab therapy reduced the risk of perianal relapse after surgical remission in PCD patients compared with nonbiological treatment. However, approximately 40% of patients using infliximab experienced perianal relapse at 5 years, and patients who discontinued use of IFX or experienced a penetrating phenotype or a complex perianal fistula were associated with increased relapse rate.

[Early-stage hemodynamic changes in dogs with gunshot wound in seawater].

OBJECTIVE: To investigate the hemodynamic changes in the early stages of gunshot wound of dogs in seawater for exploring early treatment protocol. METHOD: Fourteen conventional Beagles models undergoing gunshot wound in seawater were used along with another 2 dogs receiving the wound on land to serve as control. After the dogs were rescued from the seawater, the respiration (R), heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), central venous pressure (CVP), pulmonary arterial wedge pressure (PAWP), and cardiac output (CO) were measured continuously in the early stages of the wound (53.62+/-12.19 min following injury), followed by statistical analysis of the results. RESULTS: Compared with the control group, the hemodynamic disturbance of the dogs receiving the wound in seawater was relatively severe during the first 15 min of the wound. The mortality tended to descend relevant to the position of the wounds, in the order of the head, chest, abdomen and limbs. CONCLUSIONS: Gunshot wound in seawater may cause severe hemodynamic changes, resulting in progressive dysfunction of circulation and high mortality rate. Early treatment should be targeted at hemodynamic stabilization in accordance to the characteristic changes during the early stages of the wound.

[Quantitative study of bacteriological infections in dogs undergoing gunshot wound in seawater].

OBJECTIVE: To investigate the changes in bacterial proliferation and the time of infection occurrence in dogs wounded by gunshot in seawater. METHOD: Fourteen canine models of gunshot wound in seawater were established, with another 2 dogs receiving the wound without seawater immersion serving as control. Gross observation and quantitative bacterial analysis were performed at 0, 6, 12 and 24 h after the injury respectively, and two dynamic models for the bacterial growth were set up on the basis of statistical analysis of the results. RESULTS: Bacterial quantity in both of the two groups tended to increase with time, but at each time point after the injury, the seawater group had higher bacterial count than the other group. Within 6 h after the injury, the bacterial count reached the critical point for clinical infection in seawater group. The two bacterial growth dynamics models were (1) Y=9.12 x 10(3+0.247X) and (2) Y=1.35 x 10(3+0.227X) for the seawater group and land group respectively, with the variant X representing time after gunshot injury, and Y the bacterial count per gram tissue. Using the dynamic models, we found that to reach the same bacteria count, the land group needed 4 h more than the seawater group(4.2 h). CONCLUSIONS: Bacterial proliferation is accelerated in the wounds in seawater to result in earlier infection onset with more severity, suggesting that early debridement within 4 h after the injury, complete washing of the wound and early administration of the antibiotics are necessary for the wound management.