Featured
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| Open AccessIntestinal Atp8b1 dysfunction causes hepatic choline deficiency and steatohepatitis
Choline is an essential nutrient derived primarily from dietary phosphatidylcholine, and its deficiency causes steatohepatitis. Here, the authors show that intestinal Atp8b1 contributes to choline metabolism through lysoPC absorption and that its dysfunction causes choline deficiency and steatohepatitis.
- Ryutaro Tamura
- , Yusuke Sabu
- & Hisamitsu Hayashi
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Article
| Open AccessZHX2 emerges as a negative regulator of mitochondrial oxidative phosphorylation during acute liver injury
Mitochondria dysfunction contributes to acute liver injuries. Zhang et al. find that Zhx2 deletion enhances mitochondrial function by promoting electron transport chain gene expression via PGC-1α dependent and independent manner.
- Yankun Zhang
- , Yuchen Fan
- & Chunhong Ma
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Article
| Open AccessIndocyanine green fluorescence imaging-guided versus conventional laparoscopic lymphadenectomy for gastric cancer: long-term outcomes of a phase 3 randomised clinical trial
Due to high rate of metastasis, lymphadenectomy is a cornerstone of the surgical treatment of gastric cancer however the accurate dissection of lymph nodes (LN) can be challenging. Here, the authors present the long-term outcomes of a randomised control trial investigating indocyanine green fluorescence image-guided LN retrieval in gastric cancer patients undergoing laparoscopic gastrectomy.
- Qi-Yue Chen
- , Qing Zhong
- & Chang-Ming Huang
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Article
| Open AccessMicrobiome and metabolome features in inflammatory bowel disease via multi-omics integration analyses across cohorts
Gut microbiota play pivotal roles in IBD. Here, Ning et al. use a multi-omics approach to characterize gut microbiota and metabolites alterations, and potential pathogenic bacteria associated with IBD, with the aim to help develop more precise biomarkers for IBD diagnosis and drug targets
- Lijun Ning
- , Yi-Lu Zhou
- & Jie Hong
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Article
| Open AccessA randomised Phase IIa trial of amine oxidase copper-containing 3 (AOC3) inhibitor BI 1467335 in adults with non-alcoholic steatohepatitis
The authors report data from a Phase IIa randomised, double-blind trial in patients with NASH showing that BI 1467335 strongly and dose-dependently inhibited AOC3 activity (involved in hepatic inflammation) and was well tolerated at all tested doses.
- Philip N. Newsome
- , Arun J. Sanyal
- & Eric Lawitz
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Article
| Open AccessFarnesoid X receptor activation by bile acids suppresses lipid peroxidation and ferroptosis
Ferroptosis is a regulated form of cell death occurring upon lipid peroxidation. Here, the authors discovered that activation of the Farnesoid X receptor by bile acids suppresses ferroptosis through upregulation of anti-ferroptotic genes.
- Juliane Tschuck
- , Lea Theilacker
- & Kamyar Hadian
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Article
| Open AccessFood amyloid fibrils are safe nutrition ingredients based on in-vitro and in-vivo assessment
Food protein amyloid fibrils have superior properties but due to safety concerns, have not yet been used in foods. In-vitro and in-vivo studies here show that upon digestion they are safe and can be used as potential ingredients for human nutrition.
- Dan Xu
- , Jiangtao Zhou
- & Raffaele Mezzenga
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Article
| Open AccessBroad-spectrum kinome profiling identifies CDK6 upregulation as a driver of lenvatinib resistance in hepatocellular carcinoma
Acquired resistance to cancer therapies can develop due to kinase rewiring. Here, using a broad-spectrum chemical probe, the authors perform kinome screening and identify CDK6-mediated accumulation of cancer stem cells as a driver of lenvatinib (multitargeted tyrosine kinase inhibitor) resistance in hepatocellular carcinoma.
- Carmen Oi Ning Leung
- , Yang Yang
- & Terence Kin Wah Lee
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Article
| Open AccessThe mitochondrial fusion protein OPA1 is dispensable in the liver and its absence induces mitohormesis to protect liver from drug-induced injury
The role of the mitochondrial fusion protein OPA1 in liver function is unknown. Here, authors showed that OPA1 is dispensable in the liver, and that the mitohormesis induced by OPA1 deletion prevents liver injury and contributes to liver resiliency.
- Hakjoo Lee
- , Tae Jin Lee
- & Yisang Yoon
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Article
| Open AccessImmune checkpoint inhibitor-induced colitis is mediated by polyfunctional lymphocytes and is dependent on an IL23/IFNγ axis
Immune checkpoint inhibitors (CPI) could effectively target cancers that are resistant to traditional therapy but may initiate immune related adverse effects, such as colitis. Here, authors characterise the gut immune microenvironment during CPI-colitis by bulk RNA sequencing, single-cell RNA sequencing and flow cytometry, and find that interleukin 23 plays an important role in promoting inflammation via cytotoxic polyfunctional IFNγ-producing lymphocytes.
- Jonathan W. Lo
- , Domenico Cozzetto
- & Nick Powell
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Article
| Open AccessIntelligent surgical workflow recognition for endoscopic submucosal dissection with real-time animal study
AI-enabled cognitive assistance for therapeutic procedures has rarely been pre-clinically validated. Here, the authors propose an intelligent surgical workflow recognition suit AI-Endo for endoscopic submucosal dissection, extensively validated on external and animal trial datasets.
- Jianfeng Cao
- , Hon-Chi Yip
- & Qi Dou
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Article
| Open AccessPreservation versus resection of Denonvilliers’ fascia in total mesorectal excision for male rectal cancer: follow-up analysis of the randomized PUF-01 trial
Total mesorectal excision (TME) for rectal cancer can require partial resection of Denonvilliers’ fascia (DVF). Here the authors report the secondary outcomes of a randomized trial to evaluate the safety and effect of DVF preservation during laparoscopic TME on postoperative urogenital function and oncological safety in male patients with mid-low rectal cancer.
- Jiafeng Fang
- , Bo Wei
- & Hongbo Wei
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Article
| Open AccessLactylation of METTL16 promotes cuproptosis via m6A-modification on FDX1 mRNA in gastric cancer
Cuproptosis regulation in tumors is unclear. Here the authors find that copper promotes METTL16 lactylation, inducing cuproptosis via stabilizing FDX1 in gastric cancer. Targeting lactyl-METTL16 and cuproptosis offers a potential feasible strategy for cancer therapy.
- Lianhui Sun
- , Yuan Zhang
- & Chen Huang
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Article
| Open AccessRING finger protein 13 protects against nonalcoholic steatohepatitis by targeting STING-relayed signaling pathways
The STING-relayed inflammation response has been increasingly identified as one of the key drivers of NAFLD progression. Here the authors show that an E3 ubiquitin ligase, RNF13, can ameliorate NAFLD phenotypes by facilitating the TRIM29-mediated degradation of STING.
- Zhibin Lin
- , Peijun Yang
- & Lin Wang
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Article
| Open AccessSleeping Beauty transposon mutagenesis identified genes and pathways involved in inflammation-associated colon tumor development
Chronic inflammation promotes the development and progression of colorectal cancer (CRC) while the underlying mechanism remains to be elucidated. Here, the authors perform in vivo transposon mutagenesis screening to identify that TNFα-activated senescence signaling acts as selective pressure to drive mutation of Cdkn2a and other senescence-related genes in inflammation-accelerated CRC.
- Kana Shimomura
- , Naoko Hattori
- & Haruna Takeda
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Article
| Open AccessFibroblast growth factor 18 stimulates the proliferation of hepatic stellate cells, thereby inducing liver fibrosis
Fibroblast growth factor (FGF)18 plays pleiotropic roles, including bone development and carcinogenesis, however, its precise role in liver fibrosis remains incompletely understood. Here, the authors show that FGF18 promotes liver fibrosis by stimulating hepatic stellate cell proliferation, without concomitant upregulation of profibrotic genes.
- Yuichi Tsuchiya
- , Takao Seki
- & Hiroyasu Nakano
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Article
| Open AccessURI alleviates tyrosine kinase inhibitors-induced ferroptosis by reprogramming lipid metabolism in p53 wild-type liver cancers
Despite being a promising treatment for hepatocellular carcinoma (HCC), resistance to tyrosine kinase inhibitors (TKI) present a major obstacle. Here, the authors demonstrate that lipid metabolism reprogramming via URI mediated stearoyl-CoA desaturase 1 upregulation present a targetable driver of sorafenib resistance in HCC.
- Zhiwen Ding
- , Yufei Pan
- & Lu Wang
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Article
| Open AccessClaudin-23 reshapes epithelial tight junction architecture to regulate barrier function
Claudin family proteins are important for regulating epithelial barrier function. Here the authors show that claudin-23 controls paracellular flux by combining with other claudins to alter tight junction architecture and permeability.
- Arturo Raya-Sandino
- , Kristen M. Lozada-Soto
- & Asma Nusrat
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Article
| Open AccessGut microbiota aggravates neutrophil extracellular traps-induced pancreatic injury in hypertriglyceridemic pancreatitis
Given the association of gut microbiota dysbiosis with hypertriglyceridemic pancreatitis (HTGP), authors assess the gut microbial diversity of patients with HTGP, and provide immunological insight utilising a murine model.
- Guanqun Li
- , Liwei Liu
- & Bei Sun
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Article
| Open AccessHeat-inactivated Bifidobacterium adolescentis ameliorates colon senescence through Paneth-like-cell-mediated stem cell activation
Here, Wang et al. show that heat-inactivated Bifidobacterium adolescentis mediates maintenance of host intestinal barrier through intestinal stem cells activation, which can potentially have translational implications for alleviation of colon senescence and related diseases.
- Yadong Qi
- , Jiamin He
- & Liangjing Wang
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Article
| Open AccessIFNγ-Stat1 axis drives aging-associated loss of intestinal tissue homeostasis and regeneration
Omrani, Krepelova et al. report that aging-induced proinflammatory IFNγ/Stat1 signalling primes intestinal stem cells to a secretory fate and to antigen presenting cells impairing the regenerative capacity of the aging gut epithelium.
- Omid Omrani
- , Anna Krepelova
- & Francesco Neri
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Article
| Open AccessTHBS1-producing tumor-infiltrating monocyte-like cells contribute to immunosuppression and metastasis in colorectal cancer
Thrombospondin-1 (THBS1) is a matricellular protein highly expressed in inflammatory processes, including cancer. Here the authors show that bone-marrow derived monocyte-like cells are the primary source of THBS1 in colorectal cancer, associated with mesenchymal characteristics, immunosuppression and a poor prognosis.
- Mayuki Omatsu
- , Yuki Nakanishi
- & Hiroshi Seno
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Article
| Open AccessPhage-microbe dynamics after sterile faecal filtrate transplantation in individuals with metabolic syndrome: a double-blind, randomised, placebo-controlled clinical trial assessing efficacy and safety
Bacteriophages (phages) can modify the gut microbiome to benefit human health. Here, the authors report the results of a double blind, randomized, placebo-controlled trial, showing that faecal filtrate transplantation (FFT), containing phages from lean healthy donors, is safe and improves glycemic variability in patients with metabolic syndrome, while shifting the gut phage composition.
- Koen Wortelboer
- , Patrick A. de Jonge
- & Hilde Herrema
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Article
| Open AccessAryl hydrocarbon receptor utilises cellular zinc signals to maintain the gut epithelial barrier
Dietary zinc and plant-derived aryl hydrocarbon receptor (AHR) agonists are involved in maintaining intestinal epithelium integrity. The authors show that combined supplementation with AHR ligands and zinc might be effective in preventing inflammatory gut disorders.
- Xiuchuan (Lucas) Hu
- , Wenfeng Xiao
- & Christer Hogstrand
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Article
| Open AccessThe interplay between dietary fatty acids and gut microbiota influences host metabolism and hepatic steatosis
Here, Schoeler et al. investigate how interaction between dietary lipids and the gut microbiota affect hepatic steatosis and host metabolism, showing that dietary lipids impact the gut microbiota composition independent on fiber intake in humans and mice.
- Marc Schoeler
- , Sandrine Ellero-Simatos
- & Robert Caesar
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Article
| Open AccessPractical diagnosis of cirrhosis in non-alcoholic fatty liver disease using currently available non-invasive fibrosis tests
The practical rules for the early non-invasive diagnosis of cirrhosis in NAFLD are not well defined. Here, the authors develop and validate two diagnostic tools: a stepwise stratification algorithm including a cirrhosis group, and a risk prediction chart providing a personalized assessment of the individual probability of cirrhosis.
- Jérôme Boursier
- , Marine Roux
- & Philip N. Newsome
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Article
| Open AccessBile acid-dependent transcription factors and chromatin accessibility determine regional heterogeneity of intestinal antimicrobial peptides
Wang et al. clarify the regional heterogeneity of intestinal AMPs and identify that chromatin accessibility determines the potential of BATFs to regulate AMPs at the pre-transcriptional level, thus shaping the regional heterogeneity of AMPs.
- Yue Wang
- , Yanbo Yu
- & Yanqing Li
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Article
| Open AccessDesmoplastic stroma restricts T cell extravasation and mediates immune exclusion and immunosuppression in solid tumors
Tumor stroma is a key component of the immunosuppressive tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC). Here, in preclinical PDAC models, the authors show that depletion of FAP-expressing cancer associated fibroblasts with FAP-targeted CAR T cells results in a loss of the integrity of the desmoplastic matrix, rendering tumors more susceptible to sequential treatment with mesothelin-targeted CAR-T cells.
- Zebin Xiao
- , Leslie Todd
- & Ellen Puré
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Article
| Open Accessp21-activated kinase 4 suppresses fatty acid β-oxidation and ketogenesis by phosphorylating NCoR1
PPARα corepressor NCoR1 is a key regulator of fatty acid β-oxidation and ketogenesis. Here, the authors demonstrate that p21-activated kinase 4 phosphorylates NCoR1 at T1619/T2124, resulting in PPARα transrepression and ketone body reduction.
- Min Yan Shi
- , Hwang Chan Yu
- & Eun Ju Bae
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Article
| Open AccessGut microbiota-derived tryptamine and phenethylamine impair insulin sensitivity in metabolic syndrome and irritable bowel syndrome
Here, the authors show a causal role for gut bacteria-derived metabolites tryptamine and phenethylamine in contributing to insulin resistance and the development of metabolic syndrome in patients with irritable bowel syndrome and type 2 diabetes.
- Lixiang Zhai
- , Haitao Xiao
- & Zhao-Xiang Bian
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Article
| Open AccessNeoadjuvant sintilimab in combination with concurrent chemoradiotherapy for locally advanced gastric or gastroesophageal junction adenocarcinoma: a single-arm phase 2 trial
Neoadjuvant chemotherapy followed by gastrectomy is considered standard of care for locally advanced gastric and gastroesophageal junction (G/GEJ) cancers. Here the authors report the results of a phase 2 trial of neoadjuvant sintilimab (anti-PD1) plus chemoradiotherapy in patients with locally advanced G/GEJ tumors.
- Jia Wei
- , Xiaofeng Lu
- & Baorui Liu
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Article
| Open AccessLong-term ex situ normothermic perfusion of human split livers for more than 1 week
Long-term machine perfusion of human livers outside the body is an emerging field with tremendous potential for the assessment, recovery, and modification of organs prior to transplantation. Here, the authors report the long-term ex situ perfusion of human livers and demonstrate the ability to split and perfuse these organs using a standardised protocol.
- Ngee-Soon Lau
- , Mark Ly
- & Carlo Pulitano
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Article
| Open AccessA single-cell transcriptional landscape of immune cells shows disease-specific changes of T cell and macrophage populations in human achalasia
Achalasia is a rare motility disorder of the esophagus resulting from abnormal immune responses, but the immunologic mechanism is unclear. Here the authors use scRNA-seq of PBMC and esophageal lower sphincter tissue and find C1QC+ macrophages and tissue-resident memory T cells with expanded compositions and altered transcriptional profiles in achalasia.
- Zu-Qiang Liu
- , Hao Dai
- & Quan-Lin Li
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Article
| Open AccessSchwann cells regulate tumor cells and cancer-associated fibroblasts in the pancreatic ductal adenocarcinoma microenvironment
The effects of Schwann cells on the neuro-stroma niche in pancreatic ductal adenocarcinoma (PDAC) remain to be explored. Here, single-cell RNA-sequencing and spatial transcriptome analysis of PDAC tissues reveal that Schwann cells induce malignant subtypes of tumour cells and cancer associated fibroblasts.
- Meilin Xue
- , Youwei Zhu
- & Hao Chen
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Article
| Open AccessMacrophage and neutrophil heterogeneity at single-cell spatial resolution in human inflammatory bowel disease
Chronic intestinal inflammatory diseases including ulcerative colitis and Crohn’s disease display extensive heterogeneity in the immunopathology, disease manifestation and response to treatment. Here the authors apply single cell transcriptomic and spatial molecular imaging, and characterise macrophage and neutrophils in samples from patients with inflammatory bowel diseases.
- Alba Garrido-Trigo
- , Ana M. Corraliza
- & Azucena Salas
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| Open AccessA gut feeling for drugs that have metabolic benefits
Resveratrol (REV) is a natural polyphenol with anti-obesity effects. However, the mechanisms remain unclear due to its low bioavailability and the lack of defined membrane-bound or nuclear receptors. Pang and colleagues reported that REV intervention (REV-I) alters gut microbiota and bile acid profile, leading to the inhibition of farnesoid X receptor (FXR) and attenuation of scavenger receptor class B type 1 (SR-B1)-mediated chylomicron secretion. This highlights a therapeutic potential of targeting gut microbiome and intestinal SR-B1 for obesity and diabetes treatment.
- Eryun Zhang
- , Alon Agua
- & Wendong Huang
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Article
| Open AccessTET2 and TET3 loss disrupts small intestine differentiation and homeostasis
DNA demethylation is known to be critical for the development and function of many tissues. Here the authors show that it is also required for intestinal lineage differentiation, and that mice lacking DNA demethylases have altered microbiomes and a predisposition to inflammation.
- Ihab Ansari
- , Llorenç Solé-Boldo
- & Yehudit Bergman
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Article
| Open AccessNFIC regulates ribosomal biology and ER stress in pancreatic acinar cells and restrains PDAC initiation
Pancreatic acinar differentiation can be tumour suppressive for pancreatic ductal adenocarcinoma (PDAC). Here the authors identify nuclear factor I family of transcription factors NFIC as a regulator of pancreatic acinar cell function that restrains mutant KRas-driven pancreas cancer initiation in mice.
- Isidoro Cobo
- , Sumit Paliwal
- & Francisco X. Real
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Article
| Open AccessSelective oxidative protection leads to tissue topological changes orchestrated by macrophage during ulcerative colitis
Ulcerative colitis is associated with increased infiltration and cellularity, yet the precise tissue topology remains poorly understood. Here the authors employ imaging mass cytometry and single-cell RNA sequencing to characterise intestinal lesions in patients with ulcerative colitis, and show the architecture at the individual cell level which includes a decrease in the resident macrophage population.
- Juan Du
- , Junlei Zhang
- & Jianpeng Sheng
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Article
| Open AccessUSP25 regulates KEAP1-NRF2 anti-oxidation axis and its inactivation protects acetaminophen-induced liver injury in male mice
The redox status of a cell is regulated through a number of mechanisms, chief among these is the KEAP1-mediated ubiquitination and degradation of NRF2. Here the authors show that KEAP1 itself is ubiquitinated and degraded in a process that is opposed by the ubiquitin-specific protease USP25.
- Changzhou Cai
- , Huailu Ma
- & Jiewei Wang
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Article
| Open AccessTrans-Golgi protein TVP23B regulates host-microbe interactions via Paneth cell homeostasis and Goblet cell glycosylation
Increased susceptibility to gastrointestinal infections and colitis can be driven by a failure to maintain intestinal homeostasis. Here, using a forward genetic screen, Song et al. identify and characterise the role of TVP23B in Paneth cell and goblet cell function, and its impact on colitis.
- Ran Song
- , William McAlpine
- & Emre E. Turer
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Article
| Open AccessIn vivo PAR-CLIP (viP-CLIP) of liver TIAL1 unveils targets regulating cholesterol synthesis and secretion
Here the authors develop viP-CLIP, a technique allowing the identification of RNA binding proteins (RBP) targets in mouse tissues, and identify the RBP Tial1 as a regulator of cholesterol metabolism in the liver.
- Hasan Vatandaslar
- , Aitor Garzia
- & Markus Stoffel
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Article
| Open AccessA probiotic bi-functional peptidoglycan hydrolase sheds NOD2 ligands to regulate gut homeostasis in female mice
Lactobacillus-based probiotics have been reported to be beneficial for colitis through incompletely understood mechanisms. Here the authors identify an uncharacterized secreted enzyme named LPH from multiple probiotic Lactobacillus strains, which protects female mice from chemically induced colitis and colorectal cancer via NOD2 signalling.
- Jie Gao
- , Lei Wang
- & Xiaolong He
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Article
| Open AccessColitis ameliorates cholestatic liver disease via suppression of bile acid synthesis
The association between primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) has been known for decades, but mechanisms of gut-liver crosstalk are incompletely understood. Here, the authors show a colitis-triggered protective circuit suppressing cholestatic liver disease which encourages multi-organ treatment strategies for PSC.
- Wenfang Gui
- , Mikal Jacob Hole
- & Kai Markus Schneider
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Article
| Open AccessBacteriophage therapy against pathological Klebsiella pneumoniae ameliorates the course of primary sclerosing cholangitis
Patients with primary sclerosing cholangitis (PSC) harboring Klebsiella pneumoniae (Kp) exhibit poor clinical outcomes. Here, the authors show that administration of a phage cocktail targeting PSC-derived Kp reduces bacterial burden in Kp-colonized mice and alleviates liver injury.
- Masataka Ichikawa
- , Nobuhiro Nakamoto
- & Takanori Kanai
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Article
| Open AccessBacteriophage targeting microbiota alleviates non-alcoholic fatty liver disease induced by high alcohol-producing Klebsiella pneumoniae
Previous studies have shown that high alcohol-producing Klebsiella pneumoniae (HiAlc Kpn) in the intestinal microbiome could be one of the causes of non-alcoholic fatty liver disease (NAFLD). Here, the authors show the effectiveness of phage in mice with HiAlc Kpn-induced NAFLD indicating phage therapy targeting gut microbiota may be an alternative to antibiotics, with potential efficacy and safety.
- Lin Gan
- , Yanling Feng
- & Jing Yuan
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Article
| Open AccessGiardia hinders growth by disrupting nutrient metabolism independent of inflammatory enteropathy
Giardia lamblia intestinal infection is independently associated with faltering linear growth in children in low-middle income countries, yet the mechanistic pathway has not been clearly identified. Authors utilise the MAL-ED cohort, and a gnotobiotic murine model, to explain Giardia-induced effects on childhood growth.
- Natasa Giallourou
- , Jason Arnold
- & Luther A. Bartelt
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Article
| Open AccessMicrobiota-assisted iron uptake promotes immune tolerance in the intestine
Iron deficiencies are a common non intestinal symptom seen in patients with irritable bowel disease. Here the authors show an associative link between microbiota assisted uptake of nutrients including iron and the promotion of immune tolerance in the intestine.
- Lizhen Zhu
- , Geng Li
- & Xing Chang
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Article
| Open AccessRegorafenib inhibits EphA2 phosphorylation and leads to liver damage via the ERK/MDM2/p53 axis
The mechanism underlying regorafenib’s hepatotoxicity during anticancer therapy remains elusive. Here, the authors show regorafenib inhibits the phosphorylation of EphA2 at Ser897 resulting in the accumulation of p53 and contributes to hepatocytes apoptosis and the formation of hepatotoxicity.
- Hao Yan
- , Wentong Wu
- & Peihua Luo