Shared Immune Associations Between COVID-19 and Inflammatory Bowel Disease: A Cross-Sectional Observational Study in Shanghai, China.

Purpose: The rapid global spread of the SARS-CoV-2 Omicron variant introduces a novel complication: the emergence of IBD (inflammatory bowel disease)-like ulcers in certain patients. This research delves into this new challenge by juxtaposing the clinical manifestations and genetic expression patterns of individuals affected by the Omicron variant of COVID-19 with those diagnosed with IBD. It aims to decode the link between these conditions, potentially shedding light on previously unexplored facets of COVID-19 pathophysiology. This investigation emphasizes gene expression analysis as a key tool to identify wider disease correlations and innovative therapeutic avenues. Patients and Methods: From March to December 2022, patients with SARS-CoV-2 Omicron infection and inflammatory bowel disease and healthy controls were recruited in Shanghai East Hospital, Shanghai, China. The epidemiological and clinical characteristics of the patients were compared. Four RNA sequencing datasets (GSE205244, GSE201530, GSE174159, and GSE186507) were extracted from the Gene Expression Omnibus database to detect mutually differentially expressed genes and common pathways in patients with SARS-CoV-2 infection and inflammatory bowel disease. Results: Compared to patients with active inflammatory bowel disease, patients with SARS-CoV-2 infection were more likely to have elevated interferon-α levels and an increased lymphocyte count and less likely to have high interleukin-6, tumor necrosis factor-α, and C-reactive protein levels and an elevated neutrophil count. A total of 51 common differentially expressed genes were identified in the four RNA-sequencing datasets. Enrichment analysis suggested that these genes were related to inflammation and the immune response, especially the innate immune response and nucleotide oligomerization domain-like receptor signaling pathway. Conclusion: The inflammation and immune-response pathways in COVID-19 and inflammatory bowel disease have several similarities and some differences. The study identifies the NLR signaling pathway's key role in both COVID-19 and IBD, suggesting its potential as a target for therapeutic intervention and vaccine development.

hUC-MSCs therapy for Crohn's disease: efficacy in TNBS-induced colitis in rats and pilot clinical study.

BACKGROUND: The use of mesenchymal stem cells (MSCs) has recently emerged as a promising new therapeutic strategy for many diseases including perianal fistulizing Crohn's disease (CD). Whether hUC-MSCs can promote the healing of luminal ulcer in CD has not been studied so far. METHODS: The model of TNBS-induced colitis in rats was used to confirm the efficacy of hUC-MSCs in the treatment of CD. Then, seventeen CD patients refractory to or unsuitable for currently available therapies were enrolled and received once submucosal local injection through colonoscopy combined with once intravenous drip on the next day. All patients received a 24-week follow-up. Clinical and laboratory assessments were monitored at baseline, week 4, 8, 12, and 24. Endoscopic evaluations were conducted at baseline and week 12. Mucosal specimens were obtained at the margin of lesions by endoscopy biopsies and used for RNA sequencing. Two hUC-MSCs co-culture systems were established in vitro, one with the mucosa specimens and the other with M1 macrophages induced from THP1. The expressions of genes representing inflammation (TNFα, IL-6, and IL-1ß) and intestinal barrier function (ZO1, CLAUDIN1, and CDH1) were tested by RT-PCR. FINDINGS: hUC-MSCs treatment increased body weight and decreased disease activity index (DAI), colon macroscopic damage index (CMDI), and histopathological score (HPS) of rats with TNBS-induced colitis. The results of the clinical study also showed that this mode of hUC-MSCs application was associated with regression of intestinal ulceration. Eight patients (47%) got endoscopic responses (SES-CD improvement of ≥50% from baseline) and three patients (17.65%) got mucosal healing (SES-CD is zero), with a parallel improvement of clinical and laboratory parameters without serious adverse events. RNA sequencing showed hUC-MSCs therapy was associated with an upregulation of transcripts linked to intestinal epithelial barrier integrity and a downregulation of inflammatory signaling pathways in the intestinal mucosa, especially the TNF signaling pathway, IL-17 signaling pathway, and TLR signaling pathway. RNA expression of intestinal epithelial tight junction protein (ZO1, CLAUDIN1, and CDH1), and the RNA expression of major intestinal inflammatory factors in CD (IL-1ß, IL-6, and TNFα, p < 0.001 for all) were improved significantly. Moreover, hUC-MSCs could attenuate the polarization of M1 macrophage induced from THP1, thereby decreasing the mRNA expression of IL-1ß, IL-6, and TNFα significantly (p < 0.05 for all). TSG-6 expression was evaluated in hUC-MSCs culture supernatant after treatment with TNFα, IFNγ, and LPS for 48 h. And hUC-MSCs could inhibit the phosphorylation of JAK/STAT1 in the intestinal mucosa of CD patients. INTERPRETATION: hUC-MSCs transplantation alleviated TNBS-induced colitis in rats. In this pilot clinical study, preliminary data suggested that this approach to administering hUC-MSCs might have potential for clinical efficacy and manageable safety in treating refractory CD, potentially providing hope for better outcomes. No serious adverse events were observed. FUNDING: This work was funded by General Program of National Natural Science Foundation of China (Grant No. 82270639), the Scientific research project of Shanghai Municipal Health Committee (Grant No. 202240001), Specialty Feature Construction Project of Shanghai Pudong New Area Health Commission (Grant No. PWZzb2022-05), Shanghai East Hospital Youth Research and Cultivation Foundation program (Grant No. DFPY2022015), Peak Disciplines (Type IV) of Institutions of Higher Learning in Shanghai, Technology Development Project of Pudong Science, Technology and Economic Commission of Shanghai (Grant No. PKJ2021-Y08), Key Disciplines Group Construction Project of Shanghai Pudong New Area Health Commission (Grant No. PWZxq2022-06), Medical discipline Construction Project of Pudong Health Committee of Shanghai (Grant No. PWYgf2021-02) and National Natural Science Foundation of China (Grant No. 82300604).

Circulating Bone morphogenetic protein 9 (BMP9) as a new biomarker for noninvasive stratification of nonalcoholic fatty liver disease and metabolic syndrome.

Nonalcoholic fatty liver disease (NAFLD) is closely related to metabolic syndrome (MetS). Bone morphogenetic protein 9 (BMP9) is an essential factor in glucose, lipid and energy metabolism. This study aims to investigate whether BMP9 can serve as a serological marker for the severity of NAFLD or MetS. Blood samples, clinical data and FibroTouch test were collected from consecutively recruited 263 individuals in Shanghai East hospital. All the participants were divided into three groups: the healthy controls, nonalcoholic fatty liver (NAFL) group and nonalcoholic steatohepatitis (NASH) at-risk group according to the results of FibroTouch test and liver function. Serum BMP9 levels were measured by enzyme-linked immunosorbent assay. Serum BMP9 levels were positively correlated with transaminase, triglyceride, fasting plasma glucose, glycated hemoglobin (HbA1c) and uric acid while it showed a downward trend as the increasing number of MetS components. Furthermore, it differentiated NASH at-risk (58.13 ± 2.82 ng/L) from the other groups: healthy control (70.32 ± 3.70 ng/L) and NAFL (64.34 ± 4.76 ng/L) (p < 0.0001). Controlled attenuation parameter of liver fat and liver stiffness measurement were negatively correlated with BMP9 levels, while high-density lipoprotein levels were positively correlated. The risk of developing NAFLD increased along with elevated serum BMP9 and BMI, and a significantly higher risk was observed in men compared to women. BMP9 should be considered a protective factor for the onset and development of NAFLD, as well as a promising biomarker for the severity of the NAFLD and MetS.

Human umbilical cord mesenchymal stem cells attenuate diet-induced obesity and NASH-related fibrosis in mice.

Non-alcoholic steatohepatitis (NASH) is a progressive form of non-alcoholic fatty liver disease (NAFLD) that may progress to cirrhosis and hepatocellular carcinoma but has no available treatment. Mesenchymal stem cells (MSCs) have become increasingly prominent in cell therapy. Human umbilical cord MSCs (hUC-MSCs) are considered superior to other MSCs due to their strong immunomodulatory ability, ease of collection, low immune rejection, and no tumorigenicity. Though hUC-MSCs have received increasing attention in research, they have been rarely applied in any investigations or treatments of NASH and associated fibrosis. Therefore, this study evaluated the therapeutic efficacy of hUC-MSCs in C57BL/6 mice with diet-induced NASH. At week 32, mice were randomized into two groups: phosphate-buffered saline and MSCs, which were injected into the tail vein. At week 40, glucose metabolism was evaluated using glucose and insulin tolerance tests. NASH-related indicators were examined using various biological methods. hUC-MSC administration alleviated obesity, glucose metabolism, hepatic steatosis, inflammation, and fibrosis. Liver RNA-seq showed that the expression of the acyl-CoA thioesterase (ACOT) family members Acot1, Acot2, and Acot3 involved in fatty acid metabolism were altered. The cytochrome P450 (CYP) members Cyp4a10 and Cyp4a14, which are involved in the peroxisome proliferator-activator receptor (PPAR) signaling pathway, were significantly downregulated after hUC-MSC treatment. In conclusion, hUC-MSCs effectively reduced Western diet-induced obesity, NASH, and fibrosis in mice, partly by regulating lipid metabolism and the PPAR signaling pathway.

Development and external validation of prognostic scoring models for portal vein thrombosis: a multicenter retrospective study.

BACKGROUND: Portal vein thrombosis is a common complication of liver cirrhosis and hepatocellular carcinoma; however, few studies have reported its long-term clinical prognosis. This study aimed to establish and validate easy-to-use nomograms for predicting gastrointestinal bleeding, portal vein thrombosis resolution, and mortality of patients with portal vein thrombosis. METHODS: This multicenter retrospective cohort study included 425 patients with portal vein thrombosis who were divided into training (n = 334) and validation (n = 91) sets. Prediction models were developed using multivariate Cox regression analysis and evaluated using the consistency index and calibration plots. RESULTS: Predictors of gastrointestinal bleeding included a history of gastrointestinal bleeding, superior mesenteric vein thrombosis, red color sign observed during endoscopy, and hepatic encephalopathy. Meanwhile, predictors of resolution of portal vein thrombosis included a history of abdominal infection, C-reactive protein and hemoglobin levels, and intake of thrombolytics. Predictors of death included abdominal infection, abdominal surgery, aspartate aminotransferase level, hepatic encephalopathy, and ascites. All models had good discriminatory power and consistency. Anticoagulation therapy significantly increased the probability of thrombotic resolution without increasing the risk of bleeding or death. CONCLUSIONS: We successfully developed and validated three prediction models that can aid in the early evaluation and treatment of portal vein thrombosis.

A Novel Multiparameter Scoring Model for Noninvasive Early Prediction of Ischemic Colitis: A Multicenter, Retrospective, and Real-World Study.

INTRODUCTION: Ischemic colitis (IC) is a common gastrointestinal ischemic disease caused by hypoperfusion or reperfusion injury. However, there are few studies on risk factors associated with poor prognoses of the disease. This study aimed to determine the predictors of poor prognoses in patients with IC and establish a prognostic scoring method with good internal and external validity for identifying severe cases in an early stage. METHODS: We established a prognosis model by conducting a multicenter, retrospective study of patients hospitalized with IC between November 2008 and May 2020. Predictive power was tested using 5-fold internal cross-validation and external validation. RESULTS: The following 6 factors were included in the prognostic model: neutrophil count, D-dimer level, ischemia of the distal ileum, ischemia of the hepatic flexure, ulceration, and luminal stenosis. The area under the receiver-operating characteristic curve for internal cross-validation of the prediction model was 86%, and that for external validation was 95%. During internal validation, our model correctly identified 88.08% of the patients. It was further found that patients younger than 65 years with a higher neutrophil-to-lymphocyte ratio and higher heart rate had poor prognoses. Patients aged 65 years and older with ischemia of terminal ileum, hepatic flexure, splenic flexure, and intestinal stenosis had poor prognoses. DISCUSSION: Patients with ischemia in the hepatic flexure and the distal ileum, endoscopic evidence of ulcer or stenosis, higher neutrophil counts, and higher D-dimer levels have worse prognoses. This information could aid in the selection of timely and appropriate treatment.

Targeting p300/CBP Attenuates Hepatocellular Carcinoma Progression through Epigenetic Regulation of Metabolism.

Targeting epigenetics in cancer has emerged as a promising anticancer strategy. p300/CBP is a central regulator of epigenetics and plays an important role in hepatocellular carcinoma (HCC) progression. Tumor-associated metabolic alterations contribute to the establishment and maintenance of the tumorigenic state. In this study, we used a novel p300 inhibitor, B029-2, to investigate the effect of targeting p300/CBP in HCC and tumor metabolism. p300/CBP-mediated acetylation of H3K18 and H3K27 increased in HCC tissues compared with surrounding noncancerous tissues. Conversely, treatment with B029-2 specifically decreased H3K18Ac and H3K27Ac and displayed significant antitumor effects in HCC cells in vitro and in vivo. Importantly, ATAC-seq and RNA-seq integrated analysis revealed that B029-2 disturbed metabolic reprogramming in HCC cells. Moreover, B029-2 decreased glycolytic function and nucleotide synthesis in Huh7 cells by reducing H3K18Ac and H3K27Ac levels at the promoter regions of amino acid metabolism and nucleotide synthesis enzyme genes, including PSPH, PSAT1, ALDH18A1, TALDO1, ATIC, and DTYMK. Overexpression of PSPH and DTYMK partially reversed the inhibitory effect of B029-2 on HCC cells. These findings suggested that p300/CBP epigenetically regulates the expression of glycolysis-related metabolic enzymes through modulation of histone acetylation in HCC and highlights the value of targeting the histone acetyltransferase activity of p300/CBP for HCC therapy. SIGNIFICANCE: This study demonstrates p300/CBP as a critical epigenetic regulator of glycolysis-related metabolic enzymes in HCC and identifies the p300/CBP inhibitor B029-2 as a potential therapeutic strategy in this disease.

The Role of Bone Morphogenetic Protein 9 in Nonalcoholic Fatty Liver Disease in Mice.

Background and Aims: It's reported that bone morphogenetic protein 9 (BMP9) played an important role in lipid and glucose metabolism, but the role of BMP9 in nonalcoholic fatty liver disease (NAFLD) is unclear. Here, we evaluated the therapeutic efficacy of recombined BMP9 in NAFLD mice and investigated the potential mechanism. Methods: The effects of recombinant BMP9 on NAFLD were assessed in HFD-induced NAFLD mice. C57BL/6 mice were administrated with high-fat diet (HFD) for 12 weeks. In the last 4 weeks, mice were treated with PBS or recombined BMP9 once daily. Insulin sensitivity was evaluated by glucose tolerance test (GTT) and insulin tolerance test (ITT) at the end of the 12th week. Then NAFLD related indicators were assessed by a variety of biological methods, including histology, western blotting, real-time PCR, RNA-seq and assay for transposase-accessible chromatin using sequencing (ATAC-seq) analyses. Results: BMP9 reduced obesity, improved glucose metabolism, alleviated hepatic steatosis and decreased liver macrophages infiltration in HFD mice. RNA-seq showed that Cers6, Cidea, Fabp4 involved in lipid and glucose metabolism and Fos, Ccl2, Tlr1 involved in inflammatory response downregulated significantly after BMP9 treatment in HFD mouse liver. ATAC-seq showed that chromatin accessibility on promoters of Cers6, Fabp4, Ccl2 and Fos decreased after BMP9 treatment in HFD mouse liver. KEGG pathway analysis of dysregulated genes in RNA-seq and integration of RNA-seq and ATAC-seq showed that TNF signaling pathway and Toll-like receptor signaling pathway decreased in BMP9 treated HFD mouse liver. Conclusion: Our data revealed that BMP9 might alleviate NAFLD via improving glucose and lipid metabolism, decreasing inflammatory response and reshaping chromatin accessibility in HFD mouse liver. BMP9 downregulate genes related to lipid metabolism, glucose metabolism and inflammation expression, at least partially via decreasing promoter chromatin accessibility of Cers6, Fabp4, Fos and Tlr1. BMP9 may also reduce the expression of liver Ccl2, thereby changing the number or composition of liver macrophages, and ultimately reducing liver inflammation. The effect of BMP9 on NAFLD might be all-round, and not limit to lipid and glucose metabolism. Therefore, the underlying mechanism needs to be studied in detail further.

Effect of fluoroquinolone resistance on 14-day levofloxacin triple and triple plus bismuth quadruple therapy.

OBJECTIVE: Levofloxacin has been proposed to replace clarithromycin for Helicobacter pylori treatment. Seven- and 10-day fluoroquinolone triple therapies have generally failed to achieve cure rates of ≥90%, whereas 14-day therapy has achieved 95% success. The aim was to assess the efficacy and effect of fluoroquinolone resistance on 14-day levofloxacin-containing triple therapy with or without the addition of bismuth. DESIGN: Helicobacter pylori-positive patients with functional dyspepsia or healed peptic ulcers were randomized to receive lansoprazole 30 mg b.i.d., amoxicillin 1000 mg b.i.d., and levofloxacin 500 mg daily with (B-LAL) or without (LAL) bismuth potassium citrate 220 mg b.i.d. for 14 days. Eradication was assessed by ¹³C-urea breath testing 4 weeks after completing treatment. Antimicrobial susceptibility was by the agar dilution method. Success was defined as PP success ≥90%. RESULTS: A total of 152 of 161 patients (81 LAL and 80 B-LAL) enrolled completed treatment. The PP rates were 94.6% (70/74; 95% CI, 86.9-97.9%) with B-LAL and 85.9% (95% CI, 76.5-91.9%) with LAL (p = .07); the ITT eradication rates were 87.5% (95% CI, 78.5-93.1%) with B-LAL and 82.7% (95% CI, 73-89.4%) with LAL (p = .39). Levofloxacin resistance was present in 30.3%. Treatment success was excellent with susceptible strains (97.5%) versus resistant strains (70.6%) for B-LAL and 97.3% versus 37.5% for LAL, respectively. CONCLUSIONS: Fourteen-day fluoroquinolone therapy was highly effective when fluoroquinolone resistance rates are <12%. The addition of bismuth maintained effectiveness with fluoroquinolone resistance as high as 25%.

Efficacy of bismuth-containing quadruple therapies for clarithromycin-, metronidazole-, and fluoroquinolone-resistant Helicobacter pylori infections in a prospective study.

BACKGROUND & AIMS: We assessed the efficacy and safety of 4 bismuth-containing quadruple regimens as empiric therapies for Helicobacter pylori infections in patients who did not respond to previous treatment. METHODS: We performed a prospective single-center study of 424 patients with H pylori infection that was not eradicated by previous therapies. Patients were assigned randomly to groups given lansoprazole (30 mg twice daily) and bismuth potassium citrate (220 mg twice daily), along with 500 mg tetracycline and 400 mg metronidazole 4 times daily (LBTM), 500 mg tetracycline and 100 mg furazolidone 3 times daily (LBTF), 1000 mg amoxicillin 3 times and 500 mg tetracycline 4 times daily (LBAT), or 1000 mg amoxicillin and 100 mg furazolidone 3 times daily (LBAF). Eradication was assessed by a (13)C-urea breath test. Antimicrobial susceptibility was assessed in 188 patients by the agar dilution method. RESULTS: Per-protocol rates of H pylori eradication were greater than 90% for all regimens: 93.1% for LBTM (95% confidence interval [CI], 88.1%-98.0%), 96.1% for LBTF (95% CI, 92.4%-99.8%), 94.6% for LBAT (95% CI, 90.0%-99.2%), and 99.0% for LBAF (95% CI, 97.0%-100%). The intention-to-treat response rates were 87.9% for LBTM (95% CI, 81.7%-94.0%), 91.7% for LBTF (95% CI, 87.1%-96.3%), 83.8% for LBAT (95% CI, 76.8%-90.9%), and 95.2% for LBAF (95% CI, 91.1%-99.3%). Significantly more patients had infections eradicated by furazolidone-containing regimens than nonfurazolidone regimens (P = .01). Side effects occurred in 33.6% of subjects and occurred significantly more frequently in the LBTM group than the other 3 groups (vs LBTF, P = .006; vs LBAT, P = .003; vs LBAF, P = .02). Metronidazole resistance was 96.8%; no isolates were resistant to amoxicillin, tetracycline, or furazolidone. CONCLUSIONS: Four bismuth-containing quadruple therapies achieved greater than 90% eradication of H pylori in patients who did not respond to previous treatment, including patients with metronidazole resistance. For patients allergic to penicillin, tetracycline and either metronidazole- or furazolidone-containing regimens are recommended. ClincialTrials.gov number, NCT01668927.

Resistance of Helicobacter pylori to antibiotics from 2000 to 2009 in Shanghai.

AIM: To investigate the resistance of Helicobacter pylori (H. pylori) to 6 commonly used antibiotics from 2000 to 2009 in Shanghai. METHODS: A total of 293 H. pylori strains were collected from 2000 to 2009 in Shanghai and tested for their susceptibility to metronidazole, clarithromycin, amoxicillin, furazolidone, levofloxacin and tetracycline using agar dilution. RESULTS: The resistant rates of H. pylori to clarithromycin (8.6%, 9.0% and 20.7%) and levofloxacin (10.3%, 24.0% and 32.5%) increased from 2000 to 2009 in Shanghai. The resistant rate of H. pylori to metronidazole remained stable (40%-50%). Only one strain of H. pylori isolated in 2005 was resistant to tetracycline. All strains were sensitive to amoxicillin and furazolidone. The resistant rate of H. pylori to antibiotics was not related with the sex, age and clinical outcome of patients. CONCLUSION: Resistance of H. pylori to antibiotics plays an important role in making treatment strategies against H. pylori-associated diseases.

High efficacy of 14-day triple therapy-based, bismuth-containing quadruple therapy for initial Helicobacter pylori eradication.

BACKGROUND: The success rate of currently recommended 7-day triple therapy with a PPI plus amoxicillin and clarithromycin has fallen into the unacceptable range. It is urgent to look for a new strategy to treat the infection of Helicobacter pylori. AIMS: To observe the efficacy of triple therapy-based, bismuth-containing quadruple therapy for H. pylori treatment. METHODS: A total of 160 patients with functional dyspepsia who were Hp+ were randomly assigned into two groups. Regimen: Omeprazole 20 mg, Amoxicillin 1.0 g, Clarithromycin 500 mg and Bismuth Potassium Citrate 220 mg, twice a day. Eighty patients received 7-day quadruple therapy and 80 patients received the same therapy for 14 days. Six weeks after treatment, H. pylori eradication was assessed by (13)C-urea breath test. Minimal inhibitory concentrations of metronidazole, clarithromycin and amoxicillin of clinical isolates were determined by the twofold agar dilution method. RESULTS: Fourteen-day therapy led to a significant increase of H. pylori eradication success when compared to 7-day therapy in the intention-to-treat analysis (93.7 vs 80.0%; p = .01), and the per-protocol analysis (97.4 vs 82.0%; p = .0016). The H. pylori resistance rates to metronidazole, clarithromycin and amoxicillin were 42.1, 18.0 and 0%. Fourteen-day therapy was significantly more effective in patients with clarithromycin-resistant strains. Incidences of adverse events were comparable. CONCLUSIONS: Addition bismuth and prolonging treatment duration can overcome H. pylori resistance to clarithromycin and decrease the bacterial load. Fourteen-day triple therapy-based, bismuth-containing quadruple therapy achieved ITT success rate 93% and could be recommended as the first line eradication regimen.