Yang Wang's research while affiliated with Peking University People's Hospital and other places

Background & Aims Gut–vascular barrier (GVB) dysfunction has been shown to be a prerequisite for nonalcoholic fatty liver disease (NAFLD) development. However, the causes of GVB disruption and the underlying mechanisms are still elusive. Here, we explored whether and how Escherichia coli ( E. coli ) NF73‐1, a pathogenic E. coli strain isolated from nonalcoholic steatohepatitis patients, contributes to NAFLD by modulating the GVB. Methods C57BL/6J mice were fed with high‐fat diet (HFD) or normal diet in the presence or absence of E. coli NF73‐1 for the indicated time periods. Intestinal barrier function and infiltration of immune cells were evaluated in these mice. Endothelial cells were exposed to E. coli NF73‐1 for barrier integrity analysis. Results HFD‐induced GVB disruption preceded the damage of intestinal epithelial barrier (IEB) as well as intestinal and hepatic inflammatory changes and can be reversed by vascular endothelial growth factor A blockade. Antibiotic treatment prevented mice from HFD‐induced liver steatosis by restoration of the GVB. Notably, E. coli NF73‐1 caused a more conspicuous damage of GVB than that of the IEB and contributed to NAFLD development. Mechanistically, E. coli NF73‐1 dismantled the GVB by inhibiting the Wnt/β‐catenin signalling pathway. Activation of Wnt/β‐catenin improved the GVB and impeded the translocation of E. coli NF73‐1 into the liver in vitro and in vivo. Conclusions E. coli NF73‐1 disrupts GVB and aggravates NAFLD via inhibiting the Wnt/β‐catenin signalling pathway. Targeting E. coli NF73‐1 or selectively enhancing the GVB may act as potential avenues for the prevention and treatment of NAFLD.

Background Clinically, a large part of inflammatory bowel disease (IBD) patients is complicated by oral lesions. Although previous studies proved oral microbial dysbiosis in IBD patients, the bacterial community in the gastrointestinal (GI) tract of those IBD patients combined with oral ulcers has not been profiled yet. Methods In this study, we enrolled four groups of subjects, including healthy controls (CON), oral ulcer patients (OU), and ulcerative colitis patients with (UC_OU) and without (UC) oral ulcers. Bio-samples from three GI niches containing salivary, buccal, and fecal samples, were collected for 16S rRNA V3-V4 region sequencing. Bacterial abundance and related bio-functions were compared, and data showed that the fecal microbiota was more potent than salivary and buccal microbes in shaping the host immune system. ~ 22 UC and 10 UC_OU 5-aminosalicylate (5-ASA) routine treated patients were followed-up for six months; according to their treatment response (a decrease in the endoscopic Mayo score), they were further sub-grouped as responding and non-responding patients. Results We found those UC patients complicated with oral ulcers presented weaker treatment response, and three oral bacterial genera, i.e., Fusobacterium, Oribacterium, and Campylobacter, might be connected with treatment responding. Additionally, the salivary microbiome could be an indicator of treatment responding in 5-ASA routine treatment rather than buccal or fecal ones. Conclusions The fecal microbiota had a strong effect on the host’s immune indices, while the oral bacterial microbiota could help stratification for ulcerative colitis patients with oral ulcers. Additionally, the oral microbiota had the potential role in reflecting the treatment response of UC patients. Three oral bacteria genera (Fusobacterium, Oribacterium, and Campylobacter) might be involved in UC patients with oral ulcers lacking treatment responses, and monitoring oral microbiota may be meaningful in assessing the therapeutic response in UC patients.

Background: There has been emerging evidence that liver sinusoidal endothelial cells (LSECs) play an important role in the pathogenesis of nonalcoholic steatohepatitis (NASH). This study aims to figure out the signature of the gene expression profile of LSECs in NASH and to explore potential biomarkers related to damaged LSECs in NASH. Methods and materials: Animal experiments were performed to demonstrate the significant structural damage of LSECs in the NASH model. To further understand the functional changes of these damaged LSECs in NASH, we used the public GEO database that contained microarray data for the gene expression of LSECs in NASH and normal mouse liver. Differentially expressed genes (DEGs) were analyzed, and further Gene Ontology (GO) enrichment analysis was performed to understand the functional changes. The hub genes were then identified and validated via external GEO databases. Results: There was significant structural damage to LSECs in the NASH model, accompanied by remarkable functional changes of LSECs with 174 DEGs (156 upregulated and 18 downregulated genes). The functions of these DEGs were mainly enriched in the inflammatory reactions and immune responses. Nine specifically expressed hub genes were identified. Among them, CCL4 and ITGAX showed the most significant correlation with NASH, with AUROC of 0.77 and 0.86, respectively. The protein–protein interaction network, mRNA–miRNA interaction network, and ceRNA network were further predicted. Conclusion: LSECs show significant structural damage and functional changes in NASH. The LSEC-related DEGs, such as CCL4 and ITGAX, might be promising biomarkers as well as potential treatment targets for NASH.

Although post-cholecystectomy (PC) patients usually have gastrointestinal complications and a higher risk of colorectal cancer, previous studies undetected a heightened risk of inflammatory bowel disease. Thus, we tried to investigate cholecystectomy’s impact and pathophysiological mechanism on murine colitis models and clarify the association among fecal bile acids (BAs), mucosal bacterial microbiota, and immune cells in the PC patients. One month or three months after cholecystectomy, mice have induced colitis and tested BAs and fecal microbiota analysis. Next, mice were treated with various cholecystectomy-accumulated bile acids in drinking water for three months before inducing colitis. All 14 paired PC patients and healthy subjects were enrolled for BAs and mucosal microbiota analysis. Cholecystectomy ameliorated DSS-induced murine colitis, accelerated mucosal repair, and induced a significant shifting of fecal microbiota and BAs profiles under colitis status, which featured a higher relative abundance of species involved in BAs metabolism and increased secondary BAs concentrations. Cholecystectomy-associated secondary BAs (LCA, DCA, and HDCA) also ameliorated DSS-induced colitis and accelerated mucosal repair in mice. Cholecystectomy and specific secondary BAs treatments inhibited monocytes/macrophages recruitment in colitis mice. In vitro, cholecystectomy-associated secondary BAs also downregulated monocytes chemokines in the THP-1 derived macrophages through activation of the LXRα-linked signaling pathway. The alterations of mucosal microbiota and fecal BAs profiles were found in the PC patients, characterized as increased species with potential immuno-modulating effects and secondary BAs, which were negatively associated with peripheral monocytes levels. Cholecystectomy-induced secondary bile acids accumulation ameliorated colitis through inhibiting monocyte/macrophage recruitment, which might be mediated by the LXRα-related signaling pathway. Cholecystectomy, after 3 months follow-up, has an immune-regulatory role in murine colitis, preliminarily explaining that no increased risk of IBD had been reported in the PC patients, which still warrants further studies.

Background : Nonalcoholic fatty liver disease (NAFLD) is an independent risk factor for severe acute pancreatitis (AP). The underlying mechanism remains unclear. We sought to determine how bacterial translocation and cholesterol metabolism in the liver and pancreas affect the severity of AP in NAFLD mice. Methods : C57BL/6N mice were fed on a high-fat diet (HFD) to generate the NAFLD model, and mice in the control group were provided with a normal diet (ND). After being anesthetized with ketamine/xylazine, mice got a retrograde infusion of taurocholic acid sodium into the pancreatic duct to induce AP, and sham operation (SO) was used as control. Serum amylase and Schmidt's pathological score system were used to evaluate AP severity. Bacterial loads, total cholesterol level, and cholesterol metabolic-associated molecules [low-density lipoprotein receptor (LDLR) and ATP-binding cassette transporter A1 (ABCA1)] were analyzed in the liver and pancreas. Results : Compared with the ND-AP group, mice in the HFD-AP group had severer pancreatitis, manifested with higher serum amylase levels and higher AP pathologic scores, especially the inflammation and hemorrhage scores. Compared with the HFD-SO group and ND-AP group, bacterial loads in the liver and pancreas were significantly higher in the HFD-AP group. Mice in the HFD-AP group showed a decreased LDLR expression and an increased ABCA1 expression in the pancreas, although there was no significant difference in pancreas total cholesterol between the HFD-AP group and the ND-AP group. Conclusions : NAFLD aggravates AP via increasing bacterial translocation in the liver and pancreas and affecting pancreas cholesterol metabolism in mice.

Background Gastrointestinal symptoms have been reported in patients with COVID-19. Several clinical investigations suggested that gastrointestinal symptoms were associated with disease severity of COVID-19. However, the relevance of gastrointestinal symptoms and mortality of COVID-19 remains largely unknown. We aim to investigate the relationship between gastrointestinal symptoms and COVID-19 mortality. Methods We searched the PubMed, Embase, Web of science and Cochrane for studies published between Dec 1, 2019 and May 1, 2021, that had data on gastrointestinal symptoms in COVID-19 patients. Additional literatures were obtained by screening the citations of included studies and recent reviews. Only studies that reported the mortality of COVID-19 patients with/without gastrointestinal symptoms were included. Raw data were pooled to calculate OR (Odds Ratio). The mortality was compared between patients with and without gastrointestinal symptoms, as well as between patients with and without individual symptoms (diarrhea, nausea/vomiting, abdominal pain). Results Fifty-three literatures with 55,245 COVID-19 patients (4955 non-survivors and 50,290 survivors) were included. The presence of GI symptoms was not associated with the mortality of COVID-19 patients (OR=0.88; 95% CI 0.71–1.09; P=0.23). As for individual symptoms, diarrhea (OR=1.01; 95% CI 0.72–1.41; P=0.96), nausea/vomiting (OR=1.16; 95% CI 0.78–1.71; P=0.46) and abdominal pain (OR=1.55; 95% CI 0.68–3.54; P=0.3) also showed non-relevance with the death of COVID-19 patients. Conclusions Gastrointestinal symptoms are not associated with higher mortality of COVID-19 patients. The prognostic value of gastrointestinal symptoms in COVID-19 requires further investigation.

Background: Methotrexate is well-known in treating inflammatory bowel disease (IBD), rheumatoid arthritis (RA), psoriasis (Ps), and psoriatic arthritis (PsA). Several reports have indicated a higher incidence of methotrexate (MTX)-related liver adverse events in patients with IBD. We aim to investigate the risk of liver injury in patients with IBD and those with non-IBD diseases treated with MTX. Methods: We searched PubMed, Embase, and the Cochrane Library for articles that reported liver adverse events in patients with IBD, RA, and Ps/PsA, receiving MTX therapy. Additional articles were obtained by screening the references of recent meta-analysis and reviews. Raw data from included articles were pooled to calculate the cumulative incidence of total liver injury (TLI), MTX discontinuation (MTX-D), and liver fibrosis (LF). RR (relative risk) was calculated to compare the difference between patients with IBD and those with non-IBD diseases. Results: A total of 326 articles with 128,876 patients were included. The patients with IBD had higher incidence of TLI [11.2 vs. 9.2%; relative risk (RR) = 1.22; P = 0.224] and MTX-D (2.6 vs. 1.8%; RR, 1.48; P = 0.089) than patients with non-IBD diseases. Due to the publication bias, trim-and-fill was performed. Afterwards, the patients with IBD showed significantly higher risk of TLI (11.2 vs. 3%; RR = 3.76; p < 0.001), MTX-D (3.3 vs. 0.7%; RR = 5; p < 0.001) and LF (3.1 vs. 0.1%; RR = 38.62; P = 0.001) compared with patients with non-IBD diseases. Conclusion: IBD is associated with a higher risk of MTX-related liver injury. The mechanism of MTX-induced hepatotoxicity might be different in IBD and non-IBD diseases, and needs to be verified in future research.

Neutrophils are the most abundant type of leukocytes with diverse functions in immune defense including production of reactive oxygen species, bacteriocidal proteins, neutrophil extracellular traps, and pro-inflammatory mediators. However, aberrant accumulation of neutrophils in host tissues and excessive release of bacteriocidal compounds can lead to unexpected injury to host organs. Neutrophil-mediated liver injury has been reported in various types of liver diseases including liver ischemia/reperfusion injury, nonalcoholic fatty liver disease, endotoxin-induced liver injury, alcoholic liver disease, and drug-induced liver injury. Yet the mechanisms of neutrophil-induced hepatotoxicity in different liver diseases are complicated. Current knowledge of these mechanisms are summarized in this review. In addition, a substantial body of evidence has emerged showing that liver sinusoidal endothelial cells (LSECs) participate in several key steps of neutrophil-mediated liver injury including neutrophil recruitment, adhesion, transmigration, and activation. This review also highlights the current understanding of the interactions between LSECs and neutrophils in liver injury. The future challenge is to explore new targets for selectively interfering neutrophil-induced liver injury without impairing host defense function against microbial infection. Further understanding the role of LSECs in neutrophil-induced hepatotoxicity would aid in developing more selective therapeutic approaches for liver disease.

Background Based on the gut–liver axis theory, a leaky gut can aggravate liver injury. However, clinical studies suggest that although gut mucosa damage is commonly observed in inflammatory bowel disease (IBD), it seldom leads to severe liver injury. We hypothesize that there is a hepatic barrier in the gut–liver axis, which protects the liver against gut-derived invasive factors. Methods Colitis was induced by dextran sulfate sodium (DSS) in eight different liver injury models in Sprague–Dawley rats. Liver sinusoidal endothelial cell (LSEC) injury was evaluated by a scanning and transmission electron microscope. Neutrophils were depleted by injection of anti-rat polymorphonuclear serum. Two pneumonia models were also induced to investigate the mechanism of neutrophil recruitment and activation. LSECs isolated from rat liver were used to investigate the effect on neutrophil recruitment and activation. Results Among eight liver injury models, DSS colitis had no effect on liver injury in three models with normal LSECs. In the other five models with LSEC rupture, liver injury was significantly exacerbated by colitis, and increased hepatic neutrophil accumulation was observed. When neutrophils were depleted, colitis-induced liver injury was significantly attenuated. In pneumonia, liver injury, and colitis models, the level of CXCL1 correlated with the recruitment of neutrophils in different tissues, while DSS colitis and LSEC injury synergistically contributed to increased CXCL1 expression in the liver. In colitis-induced liver injury, neutrophils were activated in the liver. Injured LSECs showed both structural and functional changes, with significantly increased expression of CXCL1 and TNF-α under the stimulation of lipopolysaccharide (LPS). The combination of gut-derived LPS and LSEC-derived TNF-α led to the activation of neutrophils, characterized by enhanced production of reactive oxygen species, pro-inflammatory cytokines, and the formation of neutrophil extracellular traps. Conclusion LSECs constitute a vitally important barrier in the gut–liver axis, defending the liver against colitis-induced injury. When LSECs are damaged, they can turn into a pro-inflammatory pattern under the stimulation of LPS. LSEC injury and colitis-derived LPS synergistically contribute to the recruitment and activation of hepatic neutrophils. Neutrophils play a pivotal role as a downstream effector in colitis-induced liver injury.

Liver diseases are associated with the leaky gut via the gut‐liver‐axis. Previous studies have paid much attention to the effect of gut barrier damage. Notably, clinical observations and basic research reveal that the gut barrier damage seldom leads to liver injury independently, but aggravates pre‐existing liver diseases such as nonalcoholic fatty liver disease and drug‐induced liver injury. These evidences suggest that there is a hepatic barrier in the gut‐liver‐axis, protecting the liver against gut‐derived pathogenic factors. However, it has never been investigated which type of liver cell plays the role of hepatic barrier. Under physiological conditions, liver sinusoidal endothelial cell (LSEC) can take up and eliminate virus, bacteriophage, microbial products and metabolic wastes. LSEC also keeps the homeostasis of liver immune environment via tolerance‐inducing and anti‐inflammatory functions. In contrast, under pathological conditions, the clearance function of LSEC is impaired, and LSEC turns into a pro‐inflammatory pattern. Given its anatomical position and physiological functions, LSEC is proposed as the hepatic barrier in the gut‐liver‐axis. In this review, we aim to further understand the role of LSEC as the hepatic barrier. Future studies are warranted to seek effective treatments to improve LSEC health, which appears to be a promising approach to prevent gut‐derived liver injury.