The latest medical research on Gastroenterology

The research magnet gathers the latest research from around the web, based on your specialty area. Below you will find a sample of some of the most recent articles from reputable medical journals about gastroenterology gathered by our medical AI research bot.

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Uphill battle: Innovation of thiopurine therapy in global inflammatory bowel disease care.

Indian Journal of Gastroenterology

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract that encompasses two major conditions: Crohn's di...

Another renaissance for bile acid gastrointestinal microbiology.

Nat Rev Gastroenterol

The field of bile acid microbiology in the gastrointestinal tract is going through a current rebirth after a peak of activity in the late 1970s and...

Impending hepatocellular carcinoma diagnosis in cirrhotic patients after HCV cure features a natural killer cell signature.


The risk of developing hepatocellular carcinoma (HCC) in chronically infected hepatitis C virus (HCV) patients with liver cirrhosis is significantly elevated. This risk remains high even after a sustained virological response (SVR) with direct acting antivirals (DAA). To date, disease-associated signatures of natural killer (NK) cells indicating HCC development are unclear. This study investigated NK cell signatures and functions in eight cohorts covering the time span of HCC development, diagnosis, and onset. In-depth analysis of NK cell profiles from cirrhotic patients that developed HCC (HCV-HCC) post SVR compared to those who remained tumor-free (HCV-noHCC) revealed increasingly dissimilar NK cell signatures over time. We identified expression patterns with persistently high frequencies of TIM-3 and CD38 on NK cells that was largely absent in healthy controls and was associated with a high probability of HCC development. Functional assays revealed that the NK cells had potent cytotoxic features. In contrast to HCV-HCC, the signature of HCV-noHCC converged with the signature found in healthy controls over time. Regarding tissue-distribution, single-cell-sequencing showed high frequencies of these cells in liver tissue and the invasive margin, but markedly lower frequencies in tumors.

We show that HCV-related HCC development has profound effects on the imprint of NK cells. Persistent co-expression of TIM-3hi and CD38+ on NK cells is an early indicator for HCV-related HCC development. We propose profiling of NK cells may be a rapid and valuable tool to assess the risk of HCC development in a timely manner in cirrhotic patients after HCV cure.

Genome-wide association study identifies high-impact susceptibility loci for hepatocellular carcinoma in North America.


Despite the substantial impact of environmental factors, individuals with a family history of liver cancer have increased risk for hepatocellular carcinoma (HCC). However, genetic factors have not been studied systematically by genome-wide approaches in large numbers of individuals from European-descent populations (EDP).

We conducted a two-stage genome-wide association study (GWAS) on HCC not affected by hepatitis B virus infections. A total of 1872 HCC cases and 2907 controls were included in the discovery stage and 1200 HCC cases and 1832 controls in the validation. We analyzed the discovery and validation samples separately and then conducted meta-analysis. All analyses were conducted in the presence and absence of hepatitis C virus (HCV). The liability-scale heritability was 24.4% for overall HCC. Five regions with significant ORs (95% CI) were identified for non-viral HCC: 3p22.1, MOBP, rs9842969, [0.51, (0.40-0.65)]; 5p15.33, TERT, rs2242652, [0.70, (0.62-0.79)]; 19q13.11, TM6SF2, rs58542926, [1.49, (1.29-1.72)]; 19p13.11 MAU2, rs58489806, [1.53, (1.33-1.75)]; and 22q13.31, PNPLA3, rs738409, [1.66, (1.51-1.83)]. One region was identified for HCV-induced HCC: 6p21.31, HLA-DQB1, rs9275224, [0.79, (0.74-0.84)]. A combination of homozygous variants of PNPLA3 and TERT showing a 6.5-fold higher risk for non-viral-related HCC compared to individuals lacking these genotypes. This observation suggests that gene-gene interactions may identify individuals at elevated risk for developing HCC.

Our GWAS highlights novel genetic susceptibility of non-viral HCC among EDP from North America with substantial heritability. Selected genetic influences were observed for HCV-positive HCC. Our findings indicate the importance of genetic susceptibility to HCC development.

Full adherence to cirrhosis quality indicators is associated with lower mortality in acute variceal bleeding: Nationwide audit.


Acute variceal bleeding (AVB) is a major complication in cirrhosis patients. Using a nationwide AVB audit, we performed a nested cohort study to determine whether full adherence to the AVB quality indicator (QI) improves clinical outcomes in patients with cirrhosis and AVB.

We assessed real-world adherence to AVB QI among patients with cirrhosis admitted for AVB in all public hospitals in Singapore between January 2015 and December 2020. Full adherence was considered when all five QIs were fulfilled: prophylactic antibiotics, vasoactive agents, timely endoscopy, endoscopic hemostasis during index endoscopy, and nonselective beta-blockers after AVB. We compare 6-weeks mortality between the full adherence and suboptimal adherence groups using a propensity-matched cohort.

A total of 989 patients with AVB were included. Full adherence to all AVB QI was suboptimal (56.5%). Analysis of the propensity-matched cohort with comparable baseline characteristics showed that full adherence was associated with a lower risk of early infection (20.0% vs. 26.9%), early rebleeding (5.2% vs. 10.2%), and mortality at 6-week (8.2% vs. 19.7%) and 1 year (21.3% vs. 35.4%) (p<0.05 for all). While full adherence was associated with a lower 6-week mortality regardless of the MELD score, non-adherence was associated with a higher 6-week mortality despite a lower predicted risk of 6-week mortality. Despite high adherence with the recommended process measures, patients with CTP-C remain at a higher risk of rebleeding, 6-week and 1-year mortality.

Full adherence to the AVB QI should be the target for quality improvement in patients with cirrhosis.

Enhanced SLC35B2/SAV1 sulfation axis promotes tumor growth through inhibiting Hippo signaling in hepatocellular carcinoma.


Protein tyrosine sulfation (PTS) is a common post-translational modification that regulates a variety of physiological and pathological processes. However, the role of PTS in cancer remains poorly understood. The goal of this study was to determine whether and how PTS plays a role in HCC progression.

By mass spectrometry and bioinformatics analysis, we identified SAV1 as a novel substrate of PTS in hepatocellular carcinoma (HCC). Oxidative stress upregulates the transcription of SLC35B2, a Golgi-resident transporter of sulfate donor 3'-phosphoadenosine 5'-phosphosulfate, leading to increased sulfation of SAV1. Sulfation of SAV1 disrupts the formation of SAV1-MST1 complex, resulting in a decrease of MST1 phosphorylation and subsequent inactivation of Hippo signaling. These molecular events ultimately foster the growth of HCC cells both in vivo and in vitro. Moreover, SLC35B2 is a novel transcription target gene of the Hippo pathway, constituting a positive feedback loop that facilitates HCC progression under oxidative stress.

Our findings reveal a regulatory mechanism of SLC35B2/SAV1 sulfation axis in response to oxidative stress, highlighting its potential as a promising therapeutic target for HCC.

ASK1/p38 axis inhibition blocks the release of mitochondrial "danger signals" from hepatocytes and suppresses progression to cirrhosis and liver cancer.


Apoptosis Signal-regulating Kinase 1 (ASK1) is activated by various pathological stimuli and induce cell apoptosis via downstream p38 activation. We studied the effect of pharmacological ASK1 inhibition on cirrhosis and its sequalae using comprehensive preclinical in vivo and in vitro systems.

Short- (4-6 wk) and long-term (24-44 wk) ASK1 inhibition using small molecule GS-444217 was tested in thioacetamide-induced and BALB/c.Mdr2-/- murine models of cirrhosis and hepatocellular carcinoma (HCC), and in vitro using primary hepatocyte cell death assays. Short-term GS-444217 therapy in both models strongly reduced phosphorylated p38, hepatocyte death, and fibrosis by up to 50%. Profibrogenic release of mitochondrial DAMP mtDNA from dying hepatocytes was blocked by ASK1 or p38 inhibition. Long-term (24 wk) therapy in BALBc.Mdr2-/- model resulted in moderate 25% reduction in bridging fibrosis, but not in net collagen deposition. Despite this, development of cirrhosis was effectively prevented, with strongly reduced p21+ hepatocyte staining (by 72%), serum ammonia levels (by 46%) and portal pressure (average 6.07 vs 8.53 mmHg in controls). Extended ASK1 inhibition for 44 wk in aged BALB/c.Mdr2-/- mice resulted in markedly reduced tumor number and size by ~50% compared to control group.

ASK1 inhibition suppresses profibrogenic release of mtDNA from dying hepatocytes in p38-dependent manner and protects from liver fibrosis. Long-term ASK1 targeting resulted in diminished net antifibrotic effect, but the progression to liver cirrhosis and cancer in BALBc/Mdr2-/- mice was effectively inhibited. These data support the clinical evaluation of ASK1 inhibitors in fibrotic liver diseases.

Oleic acid-PPARγ-FABP4 loop fuels cholangiocarcinoma colonization in lymph node metastases microenvironment.


Lymph node metastasis is a significant risk factor for cholangiocarcinoma patients, but the mechanisms underlying cholangiocarcinoma colonization in the lymph node microenvironment remain unclear. We aimed to determine whether metabolic reprogramming fueled the adaptation and remodeling of cholangiocarcinoma cells to the lymph node microenvironment.

Here, we applied single-cell RNA sequencing (scRNA-seq) of primary tumor lesions and paired lymph node metastases from cholangiocarcinoma patients and revealed significantly reduced inter-tumor heterogeneity and syntropic lipid metabolic reprogramming of cholangiocarcinoma after metastasis to lymph nodes, which was verified by pan-cancer scRNA-seq analysis, highlighting the essential role of lipid metabolism in tumor colonization in lymph nodes. Metabolomics and in vivo CRISPR/Cas9 screening identified PPARγ as a crucial regulator in fueling cholangiocarcinoma colonization in lymph node through the oleic acid-PPARγ-FABP4 positive feedback loop by up-regulating fatty acid uptake and oxidation. Patient-derived organoids and animal models have demonstrated that blocking this loop impairs cholangiocarcinoma proliferation and colonization in the lymph node microenvironment and is superior to systemic inhibition of fatty acid oxidation. PPARγ-regulated fatty acid metabolic reprogramming in cholangiocarcinoma also contributes to the immune-suppressive niche in lymph node metastases by producing kynurenine, and was found to be associated with tumor relapse, immune-suppressive lymph node microenvironment, and poor immune checkpoint blockade response.

Our results reveal the role of the oleic acid-PPARγ-FABP4 loop in fueling cholangiocarcinoma colonization in lymph nodes, and demonstrate that PPARγ-regulated lipid metabolic reprogramming is a promising therapeutic target for relieving cholangiocarcinoma lymph node metastasis burden and reducing further progression.

Serum aryl hydrocarbon receptor activity is associated with survival in patients with alcohol-associated hepatitis.


Patients with alcohol-associated hepatitis (AH) have an altered fecal metabolome, including reduced microbiota-derived tryptophan metabolites which function as ligands for aryl hydrocarbon receptor (AhR). The aim of this study was to assess serum AhR ligand activity in AH patients.

The study included 74 controls without alcohol use disorder (AUD), 97 patients with AUD and 330 AH patients from two different multicenter cohorts (InTeam: 134, AlcHepNet: 196). Serum AhR activity was evaluated using an AhR reporter assay with HepG2-Lucia cells incubated with serum for 24 hours.

Serum AhR activity was significantly higher in patients with AH compared with both controls (1.59 vs. 0.96-fold change, p<0.001) and patients with AUD (1.59 vs. 0.93, p<0.001). In both AH cohorts, patients with AhR activity ≥ 2.09 had significantly lower cumulative survival rates at 30, 60, 90, and 180 days compared to those with AhR activity<2.09. When serum AhR activity was used to further stratify patients with severe AH, the cumulative 30, 60, 90, and 180-day survival rates for patients with severe AH and the AhR activity ≥ 2.09 group were all significantly lower than those with an AhR activity<2.09 group.

Serum AhR activity was significantly higher in patients with AH compared with controls and individuals with AUD, and this increased activity was associated with higher mortality. Consequently, serum AhR activity holds potential as a prognostic marker.

Antibiotics for inflammatory bowel disease: Current status.

Indian Journal of Gastroenterology

There is abundant literature reporting about the use of antibiotics in inflammatory bowel disease (IBD), but their role in the management of IBD is...

Gut bacteriome in inflammatory bowel disease: An update on recent advances.

Indian Journal of Gastroenterology

Inflammatory bowel diseases (IBD) are chronic inflammatory gut disorders, majorly classified as ulcerative colitis and Crohn's disease. The complex...

Stellate cell-specific adhesion molecule protocadherin 7 regulates sinusoidal contraction.


Sustained inflammation and hepatocyte injury in chronic liver disease activate hepatic stellate cells (HSCs) to transdifferentiate into fibrogenic, contractile myofibroblasts. We investigated the role of protocadherin 7 (PCDH7), a cadherin family member not previously characterized in liver, whose expression is restricted to HSCs.

We created a PCDH7fl/fl mouse line, which was crossed to LRAT-Cre mice to generate HSC-specific PCDH7 knockout animals. HSC contraction in vivo was tested in response to the HSC-selective vasoconstrictor endothelin-1 (ET-1) using intravital multiphoton microscopy. To establish a PCDH7 null HSC line, cells were isolated from PCDH7fl/fl mice and infected with adenovirus expressing Cre. Hepatic expression of PCDH7 was strictly restricted to HSCs. Knockout of PCDH7 in vivo abrogated HSC-mediated sinusoidal contraction in response to ET-1. In cultured HSCs, loss of PCDH7 markedly attenuated contractility within collagen gels and led to altered gene expression in pathways governing adhesion and vasoregulation. Loss of contractility in PCDH7 KO cells was impaired Rho-GTPase signaling, as demonstrated by altered gene expression, reduced assembly of F-actin fibers and loss of focal adhesions.

The stellate cell-specific cadherin, PCDH7 is a novel regulator of HSC contractility whose loss leads to cytoskeletal remodeling and sinusoidal relaxation.