Featured
-
-
Matters Arising
| Open AccessReply to ‘Hypothermic machine perfusion before viability testing of previously discarded human livers’
- Hynek Mergental
- , Richard W. Laing
- & Darius F. Mirza
-
Article
| Open AccessSprouty2 limits intestinal tuft and goblet cell numbers through GSK3β-mediated restriction of epithelial IL-33
Dynamic regulation of colonic secretory cell numbers is a critical component of the response to intestinal injury and inflammation. Here, the authors show that loss of the intracellular signalling regulator Sprouty2 in the intestinal epithelial cells is a protective response to injury that leads to increased secretory cell numbers, thus limiting colitis severity.
- Michael A. Schumacher
- , Jonathan J. Hsieh
- & Mark R. Frey
-
Article
| Open AccessClostridioides difficile exploits toxin-mediated inflammation to alter the host nutritional landscape and exclude competitors from the gut microbiota
The effects of antibiotics on the gut microbiota can lead to enhanced colonization of Clostridioides difficile (C. difficile) and toxin-mediated pathogenesis. Here, using defined toxin-mutant strains and a murine model, the authors provide insights into how toxin-induced inflammation alters C. difficile metabolism, host tissue gene expression and gut microbiota, together influencing a beneficial niche for infection.
- Joshua R. Fletcher
- , Colleen M. Pike
- & Casey M. Theriot
-
Article
| Open AccessInduced organoids derived from patients with ulcerative colitis recapitulate colitic reactivity
Although ulcerative colitis (UC) is a major type of inflammatory bowel disease, attempts to model it fully have fallen short. Here the authors use patient-derived iPS cells to develop a UC organoid model that recapitulates disease histological and functional features, and confirm the role of CXCL8/CXCR1 in pathogenesis.
- Samaneh K. Sarvestani
- , Steven Signs
- & Emina H. Huang
-
Article
| Open AccessNOD2 deficiency increases retrograde transport of secretory IgA complexes in Crohn’s disease
Trafficking of IgA/commensal complex in the gut has been implicated in inflammatory bowel diseases such as Crohn’s disease, but molecular insights are still lacking. Here the authors show, using mouse model or human cells, that NOD2 mutation increases IgA transport, potentially by altering gut microfold cells from the gut, to impact gut inflammation.
- Nicolas Rochereau
- , Xavier Roblin
- & Stéphane Paul
-
Article
| Open AccessA diet-microbial metabolism feedforward loop modulates intestinal stem cell renewal in the stressed gut
Here, using a mouse model of chronic stress, the authors investigate how diet impacts stress and gut microbial structure and epithelial integrity and show that dietary raffinose metabolism to fructose couples stress-induced gut microbial remodeling to intestinal stem cell renewal and epithelial homeostasis.
- Yuanlong Hou
- , Wei Wei
- & Haiping Hao
-
Article
| Open AccessNeoadjuvant FLOT versus SOX phase II randomized clinical trial for patients with locally advanced gastric cancer
Neoadjuvant FLOT regimen has shown promising results for the treatment of locally advanced gastric cancer, however SOX regimen remains the preferred chemotherapy in Eastern countries. Here the authors report that the two therapies result in similar outcomes, measured as clinical downstaging and pathological response, in a phase II randomized clinical trial.
- Birendra Kumar Sah
- , Benyan Zhang
- & Zhenggang Zhu
-
Article
| Open AccessFAM3D is essential for colon homeostasis and host defense against inflammation associated carcinogenesis
The cytokine like protein FAM3D (Fam3D in mice) is highly expressed in the digestive tract with unknown role in colon pathophysiology. Here, by using gene deficient mice, the authors show that Fam3D is critically involved in colon homeostasis, host defense against colitis-associated carcinogenesis, and the balance of microbiota.
- Weiwei Liang
- , Xinjian Peng
- & Ying Wang
-
Article
| Open AccessCharacterization of the pathoimmunology of necrotizing enterocolitis reveals novel therapeutic opportunities
Necrotizing Enterocolitis (NEC) is an untreatable intestinal disease in infants. Here the authors show that human and experimental mouse NEC is associated with altered toll-like receptor expression in the intestine, enhanced Th17/type 3 polarization in adaptive immune and innate lymphoid cells, dysregulated microbiota, and reduced interleukin-37 signaling.
- Steven X. Cho
- , Ina Rudloff
- & Marcel F. Nold
-
Article
| Open AccessDistinct signatures of gut microbiome and metabolites associated with significant fibrosis in non-obese NAFLD
Nonalcoholic fatty liver disease (NAFLD) is associated with obesity but also found in individuals without obesity. Here, gut microbiome analysis using a biopsy-proven NAFLD cohort reveal distinct signatures of microbiome-metabolites associated with significant fibrosis in patients with NAFLD without obesity.
- Giljae Lee
- , Hyun Ju You
- & GwangPyo Ko
-
Article
| Open AccessRemote ischemic conditioning counteracts the intestinal damage of necrotizing enterocolitis by improving intestinal microcirculation
Necrotizing enterocolitis (NEC) is one of the most lethal gastrointestinal emergencies in neonates needing precision treatment. Here the authors show that remote ischemic conditioning is a non-invasive therapeutic method that enhances blood flow in the intestine, reduces damage, and improves NEC outcome.
- Yuhki Koike
- , Bo Li
- & Agostino Pierro
-
Article
| Open AccessPhase I clinical trial repurposing all-trans retinoic acid as a stromal targeting agent for pancreatic cancer
All-trans retinoic acid - ATRA- is known to remodulate the stroma of pancreatic cancer in mice. Here, the authors carried out a Phase Ib trial in pancreatic patients and show that ATRA in combination with chemotherapy is a safe potential treatment for patients with advanced pancreatic cancer, and demonstrate a stromal modulatory effect.
- Hemant M. Kocher
- , Bristi Basu
- & David J. Propper
-
Article
| Open AccessTelomere dysfunction activates YAP1 to drive tissue inflammation
How telomere dysfunction is directly linked to inflammation in humans is currently unclear. Here the authors reveal that telomere dysfunction drives activation of the YAP1 transcription factor, up-regulating the pro inflammatory factor, pro-IL-18 thus revealing a link between telomere dysfunction and initiation of intestinal inflammation.
- Deepavali Chakravarti
- , Baoli Hu
- & Ronald A. DePinho
-
Article
| Open AccessFaecal microbiota transplantation for the treatment of diarrhoea induced by tyrosine-kinase inhibitors in patients with metastatic renal cell carcinoma
Tyrosine kinase inhibitors (TKIs) have improved the clinical outcomes of patients with metastatic renal cell carcinoma (mRCC), however TKI-related diarrhoea is a common and serious adverse effect. Here the authors show in a randomized clinical trial that faecal microbiota transplantation from healthy donors can improve TKI-induced diarrhoea in patients with mRCC.
- Gianluca Ianiro
- , Ernesto Rossi
- & Giovanni Cammarota
-
Article
| Open AccessElucidating the fundamental fibrotic processes driving abdominal adhesion formation
Abdominal adhesions are a common cause of bowel obstruction, but knowledge regarding adhesion biology and anti-adhesion therapies remains limited. Here the authors report a systematic analysis of mouse and human adhesion tissues demonstrating that visceral fibroblast JUN and associated PDGFRA expression promote adhesions, and JUN suppression can prevent adhesion formation.
- Deshka S. Foster
- , Clement D. Marshall
- & Michael T. Longaker
-
Article
| Open AccessGut microbial co-abundance networks show specificity in inflammatory bowel disease and obesity
Gut microbiome alterations have been linked to inflammatory bowel disease (IBD) and obesity. Here, the authors characterize the metagenomes of four large human cohorts and perform co-abundance network analysis showing that dysbiosis in disease is marked by the altered co-abundance relationships, suggesting that pathway coabundance networks are more heterogeneous than species network.
- Lianmin Chen
- , Valerie Collij
- & Jingyuan Fu
-
Matters Arising
| Open AccessReply to “Acid inhibitors and allergy: comorbidity, causation and confusion”
- Erika Jensen-Jarolim
- , Michael Kundi
- & Galateja Jordakieva
-
Article
| Open AccessPatients with immune-mediated inflammatory diseases receiving cytokine inhibitors have low prevalence of SARS-CoV-2 seroconversion
Cytokine storm seems to be a common feature of severe COVID-19 pathology. Here, the authors show a reduced rate of SARS-CoV2 positivity in a large population of patients with immune-mediated inflammatory diseases if they are already being treated with cytokine or JAK inhibitors, indicating these treatments are safe to continue and are possibly protective against COVID19.
- David Simon
- , Koray Tascilar
- & Georg Schett
-
Article
| Open AccessHuman norovirus targets enteroendocrine epithelial cells in the small intestine
Human norovirus pathogenesis is incompletely understood due to a lack of appropriate animal disease models. Here, Green et al. show norovirus replication in chromogranin A-positive enteroendocrine cells and other epithelial cells in tissue from a pediatric intestinal transplant recipient with severe gastroenteritis.
- Kim Y. Green
- , Stuart S. Kaufman
- & Stanislav V. Sosnovtsev
-
Article
| Open AccessHepatocyte mitochondria-derived danger signals directly activate hepatic stellate cells and drive progression of liver fibrosis
Progressive fibrosis is a driver of morbidity and mortality in many chronic liver diseases, but the underlying mechanisms are incompletely understood. Here, the authors show that mitochondria-derived damage-associated molecular patterns are released from injured hepatocytes and can trigger fibrogenic activation of hepatic stellate cells.
- Ping An
- , Lin-Lin Wei
- & Yury V. Popov
-
Article
| Open AccessProimmunogenic impact of MEK inhibition synergizes with agonist anti-CD40 immunostimulatory antibodies in tumor therapy
Immune checkpoint inhibitors have limited efficacy in tumors with lower mutational burden and non-permissive microenvironment. Here, the authors show that combining MEK inhibition with an agonist anti-CD40 immunostimulatory antibody improves antitumor treatment by inducing immunogenic changes in the tumor microenvironment.
- Daniel Baumann
- , Tanja Hägele
- & Rienk Offringa
-
Article
| Open AccessCytokines regulate the antigen-presenting characteristics of human circulating and tissue-resident intestinal ILCs
Murine ILCs can modulate T cell responses in MHCII-dependent manner. Here the authors show that human ILCs process and present antigens and induce T-cell responses upon exposure to IL-1-family cytokines; along with the article by Lehmann et al, this work elucidates how cytokines set context specificity of ILC-T cell crosstalk by regulating ILC antigen presentation.
- Anna Rao
- , Otto Strauss
- & Jenny Mjösberg
-
Article
| Open AccessDietary lipids fuel GPX4-restricted enteritis resembling Crohn’s disease
Dietary lipids are linked to the development of inflammatory bowel diseases through unclear mechanisms. Here, the authors report that dietary polyunsaturated fatty acids trigger intestinal inflammation resembling aspects of Crohn’s disease, which is restricted by glutathione peroxidase 4 in the intestinal epithelium.
- Lisa Mayr
- , Felix Grabherr
- & Timon E. Adolph
-
Article
| Open AccessPrimary tumors release ITGBL1-rich extracellular vesicles to promote distal metastatic tumor growth through fibroblast-niche formation
Mechanisms regulating the formation of pre-metastatic niches remain poorly understood. Here, the authors show that ITGBL1-containing extracellular vesicles derived from primary colorectal cancer cells activate the production of inflammatory cytokines by resident fibroblasts in distant organs, promoting metastatic cancer growth.
- Qing Ji
- , Lihong Zhou
- & Qi Li
-
Article
| Open AccessPlasmid-mediated metronidazole resistance in Clostridioides difficile
Cases of C. difficile (CD) resistant to metronidazole have been reported but the mechanism remains enigmatic. Here the authors identify a plasmid, which correlates with metronidazole resistance status in a large international collection of CD isolates, and demonstrate that the plasmid can confer metronidazole resistance.
- Ilse M. Boekhoud
- , Bastian V. H. Hornung
- & Wiep Klaas Smits
-
Article
| Open AccessNon-canonical Wnt signalling regulates scarring in biliary disease via the planar cell polarity receptors
In fibrotic biliary disease, portal fibroblasts promote both biliary scarring and bile duct regeneration. Here, the authors report that the non-canonical Wnt-PCP signalling promotes bile duct scarring in mice, and inhibition of Wnt-ligands reduces the scarring without impairing regeneration.
- D. H. Wilson
- , E. J. Jarman
- & L. Boulter
-
Article
| Open AccessGene therapy for progressive familial intrahepatic cholestasis type 3 in a clinically relevant mouse model
Progressive familial intrahepatic cholestasis type 3 is a disease caused by mutations in the gene encoding the multidrug resistance protein 3, and has limited treatment options. Here they show that adeno-associated virus mediated gene therapy prevents disease progression in a mouse disease model.
- Nicholas D. Weber
- , Leticia Odriozola
- & Cristian Smerdou
-
Article
| Open AccessFlagellin-elicited adaptive immunity suppresses flagellated microbiota and vaccinates against chronic inflammatory diseases
Gut microbiota alterations, including enrichment of flagellated bacteria, are associated with metabolic syndrome and chronic inflammatory diseases. Here, Tran et al. show, in mice, that elicitation of mucosal anti-flagellin antibodies protects against experimental colitis and ameliorates diet-induced obesity.
- Hao Q. Tran
- , Ruth E. Ley
- & Benoit Chassaing
-
Article
| Open AccessLeptin induces TNFα-dependent inflammation in acquired generalized lipodystrophy and combined Crohn’s disease
The adipokine leptin modulates intestinal inflammation in mice. Here the authors describe a patient with inflammatory bowel disease and lipodystrophy, providing evidence that leptin aggravates intestinal inflammation with proinflammatory effects on leukocytes that are reversible by TNFα blockade.
- Jörn F. Ziegler
- , Chotima Böttcher
- & Carl Weidinger
-
Article
| Open AccessEngineered E. coli Nissle 1917 for the delivery of matrix-tethered therapeutic domains to the gut
Anti-inflammatory treatments for gastrointestinal diseases can often have detrimental side effects. Here the authors engineer E. coli Nissle 1917 to create a fibrous matrix that has a protective effect in DSS-induced colitis mice.
- Pichet Praveschotinunt
- , Anna M. Duraj-Thatte
- & Neel S. Joshi
-
Article
| Open AccessIdentification of predictors of drug sensitivity using patient-derived models of esophageal squamous cell carcinoma
Predicting the drug response of patients with cancer is crucial for implementing targeted therapy. Here, Su et al. make patient-derived cell lines and perform targeted sequencing and RNA-seq to identify CDKN2A/2B loss as a predictor of response to CDK4/6 inhibitors in esophageal squamous cell carcinoma.
- Dan Su
- , Dadong Zhang
- & Weimin Mao
-
Article
| Open AccessEpithelial CD47 is critical for mucosal repair in the murine intestine in vivo
The role of the transmembrane glycoprotein CD47 in healing injured intestinal mucosa is unclear. Here, the authors show that selective loss of CD47 in the murine intestinal epithelium results in defective mucosal repair after colonic wounding, with suggested impaired cell migration in vitro.
- Michelle Reed
- , Anny-Claude Luissint
- & Charles A. Parkos
-
Article
| Open AccessEarly detection and staging of chronic liver diseases with a protein MRI contrast agent
Non-invasive early diagnosis of liver fibrosis is important to prevent disease progression and direct treatment strategies. Here the authors developed a collagen-targeting contrast agent for the detection of early stage fibrosis and non-alcoholic steatohepatitis by magnetic resonance and tested it in animal models.
- Mani Salarian
- , Ravi Chakra Turaga
- & Jenny J. Yang
-
Article
| Open AccessInterleukin 22 disrupts pancreatic function in newborn mice expressing IL-23
Necrotizing enterocolitis (NEC) is associated with severe neonatal morbidity. Here the authors show, mirroring the NEC phenotype, that IL-23 overexpression in neonates causes malabsorption and decreased expression of intestinal and pancreatic genes mediating food digestion and uptake through IL-22, which directly suppresses pancreatic cell differentiation.
- Lili Chen
- , Valentina Strohmeier
- & Glaucia C. Furtado
-
Article
| Open AccessGastroesophageal reflux GWAS identifies risk loci that also associate with subsequent severe esophageal diseases
Gastroesophageal reflux disease (GERD) is a major risk factor for Barret’s esophagus (BE) and esophageal adenocarcinoma (EA). Here, An et al. report 25 genetic loci for GERD, many of which associate with BE and EA or with other traits such as BMI.
- Jiyuan An
- , Puya Gharahkhani
- & Stuart MacGregor
-
Article
| Open AccessGenomic signatures reveal DNA damage response deficiency in colorectal cancer brain metastases
The development of brain metastases is a lethal yet poorly understood event in the evolution of many cancers. Here, the authors perform whole-genome and whole-exome sequencing on matched normal, primary and metastatic tissue samples to explore the genomic features of brain metastases in colorectal cancer.
- Jing Sun
- , Cheng Wang
- & Yanhong Gu
-
Article
| Open AccessConserved transcriptomic profile between mouse and human colitis allows unsupervised patient stratification
Clinical and molecular heterogeneity of ulcerative colitis presents unresolved challenges to identify predictive biomarkers of response to therapies. Here, the authors combine mouse colitis time course with patient biopsy transcriptomes, achieving unsupervised clustering of UC patients correlating with therapeutic outcomes in independent data sets.
- Paulo Czarnewski
- , Sara M. Parigi
- & Eduardo J. Villablanca
-
Article
| Open AccessMass cytometry reveals systemic and local immune signatures that distinguish inflammatory bowel diseases
Distinguishing clinical subtypes of IBD is critical for optimal treatments, outcome prediction, and better understanding of disease pathogenesis. Here the authors phenotype blood and intestinal immune cells by mass cytometry and identify signatures associated with distinct disease states.
- Samuel J. S. Rubin
- , Lawrence Bai
- & Aida Habtezion
-
Article
| Open AccessPhysical and functional interaction between A20 and ATG16L1-WD40 domain in the control of intestinal homeostasis
Maintaining the intestinal barrier function requires a balance of multiple signalling pathways. Here the authors show that A20, an anti-inflammatory and anti-apoptotic protein, and Atg1611, an autophagy regulator, cross-regulate their respective protein levels and function to serve compensatory and redundant roles in fine-tuning gut barrier homeostasis.
- Karolina Slowicka
- , Inmaculada Serramito-Gómez
- & Geert van Loo
-
Article
| Open AccessEarly life stress disrupts intestinal homeostasis via NGF-TrkA signaling
Early life stress has been associated with the occurrence of gastrointestinal diseases later in life, but underlying mechanisms remain poorly understood. Here, Wong et al. show that early life stress leads to expansion of intestinal stem cells and their differentiation into serotonin-producing enterochromaffin cells through crosstalk between NGF and Wnt signalling pathways.
- Hoi Leong Xavier Wong
- , Hong-yan Qin
- & Zhao-xiang Bian
-
Article
| Open AccessDuodenal bacterial proteolytic activity determines sensitivity to dietary antigen through protease-activated receptor-2
Gluten triggers celiac disease in genetically predisposed individuals, but additional unknown mechanisms are required. Here, the authors show that proteases from Pseudomonas aeruginosa can modulate inflammatory pathways that are relevant to the development of food sensitivities, independently of the trigger antigen.
- Alberto Caminero
- , Justin L. McCarville
- & Elena F. Verdu
-
Article
| Open AccessIntestinal epithelial N-acylphosphatidylethanolamine phospholipase D links dietary fat to metabolic adaptations in obesity and steatosis
Obesity is associated with altered N-acylethanolamine levels (NAE). Here the authors show that deletion of the gene encoding N-acylphosphatidylethanolamine phospholipase D, a key enzyme for NAE synthesis, in intestinal cells of mice leads to the development of obesity and hepatic steatosis via a mechanism involving the gut-brain axis.
- Amandine Everard
- , Hubert Plovier
- & Patrice D. Cani
-
Article
| Open AccessEnhancement of the gut barrier integrity by a microbial metabolite through the Nrf2 pathway
Urolithins are microbial metabolites derived from food polyphenols. Here, Singh et al. show that urolithin A and a synthetic analogue enhance gut barrier function via Nrf2-dependent pathways and mitigate inflammation and colitis in mice, highlighting a potential application for inflammatory bowel diseases.
- Rajbir Singh
- , Sandeep Chandrashekharappa
- & Venkatakrishna R. Jala
-
Article
| Open AccessUlcerative colitis mucosal transcriptomes reveal mitochondriopathy and personalized mechanisms underlying disease severity and treatment response
The severity of ulcerative colitis, and response to treatment, is highly variable. Here, the authors examine rectal gene expression signatures and faecal microbiomes of children and adults with the disease and provide new insights in to pathogenesis.
- Yael Haberman
- , Rebekah Karns
- & Lee A. Denson
-
Article
| Open AccessMolecular and functional heterogeneity of IL-10-producing CD4+ T cells
Tr1 cells are considered an immunosuppressive CD4 T cell population producing IL-10. Here the authors show that IL-10 is insufficient for Tr1 immunosuppression, define surface markers and transcriptional program of the immunosuppressive subset within Tr1, and reveal its deficiency in patients with IBD.
- Leonie Brockmann
- , Shiwa Soukou
- & Samuel Huber
-
Article
| Open AccessStructural assembly of the megadalton-sized receptor for intestinal vitamin B12 uptake and kidney protein reabsorption
Cubilin and the transmembrane protein amnionless (AMN) form the endocytic receptor cubam that is essential for intestinal vitamin B12 uptake. Here the authors present the 2.3 Å crystal structure of AMN in complex with the amino-terminal region of cubilin and discuss cubam architecture and disease causing mutations.
- Casper Larsen
- , Anders Etzerodt
- & Christian Brix Folsted Andersen
-
Article
| Open AccessTherapeutic faecal microbiota transplantation controls intestinal inflammation through IL10 secretion by immune cells
Faecal microbiota transplantation (FMT) is becoming a therapeutic option in several gastrointestinal disorders. Here, Burrello et al. study the immunological mechanisms by which FMT reduces colonic inflammation and initiates the restoration of intestinal homeostasis in a mouse model of colitis.
- Claudia Burrello
- , Federica Garavaglia
- & Federica Facciotti
-
Article
| Open AccessGenome-wide association meta-analysis yields 20 loci associated with gallstone disease
Genome-wide association studies have so far identified eight risk loci for gallstone disease. Here, the authors perform meta-analysis in cohorts from Iceland and the UK which reveals further 21 common and low-frequency risk variants that highlight the role of bile acid homeostasis in gallstone disease.
- Egil Ferkingstad
- , Asmundur Oddsson
- & Kari Stefansson
-
Article
| Open AccessA preclinical model of chronic pancreatitis driven by trypsinogen autoactivation
Inflammatory diseases of the pancreas are currently untreatable and lack a pre-clinical model that recapitulates the hallmarks of the human pathology. Here, the authors generate a knock-in mouse strain with increased tripsinogen autoactivation and show that it develops spontaneous pancreatic pathology with some key features of human pancreatitis.
- Andrea Geisz
- & Miklós Sahin-Tóth
Browse broader subjects
Browse narrower subjects
- Anal diseases
- Biliary tract disease
- Dysbiosis
- Enteric neuropathies
- Functional gastrointestinal disorders
- Gastroenteritis
- Gastrointestinal bleeding
- Gastrointestinal cancer
- Hepatitis
- Inflammatory bowel disease
- Intestinal diseases
- Liver diseases
- Motility disorders
- Nutrition disorders
- Oesophageal diseases
- Pancreatic disease
- Stomach diseases
- Ulcers