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| Open AccessIdentification and validation of a blood- based diagnostic lipidomic signature of pediatric inflammatory bowel disease
Diagnostic blood-based biomarkers of pediatric IBD are limited. Here, the authors demonstrate a diagnostic lipidomic signature, comprising only of two molecular lipids. Translation of this signature into a scalable test has the potential to support clinical decision making.
- Samira Salihovic
- , Niklas Nyström
- & Jonas Halfvarson
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Article
| Open AccessTargeted delivery of the probiotic Saccharomyces boulardii to the extracellular matrix enhances gut residence time and recovery in murine colitis
In this study, the authors engineered a targeted Saccharomyces boulardii probiotic yeast platform, showing it exhibits high adherence to extracellular matrix proteins, resulting in longer gut residence, higher colon concentrations, and enhanced recovery in murine colitis.
- Mairead K. Heavey
- , Anthony Hazelton
- & Juliane Nguyen
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| Open AccessDiet-omics in the
S tudy ofU rban andR uralC rohn diseaseE volution (SOURCE) cohortExposures rather than genetics likely contribute to the worldwide increased prevalence of Crohn Disease (CD). Here, the authors constructed the Study Of Urban and Rural Crohn disease Evolution (SOURCE), a multicenter and multi-omics cross-sectional study, to identify that time spent by rural residents in urban environments is linked with changes in gut microbial composition and metabolomics, which mirrored those seen in CD. Reviewer recognition:
- Tzipi Braun
- , Rui Feng
- & Yael Haberman
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Article
| Open AccessThe gut commensal Blautia maintains colonic mucus function under low-fiber consumption through secretion of short-chain fatty acids
Here, the authors show that elevating fiber intake in humans alters their gut microbiota, which, upon transplantation into mice, enhances intestinal mucus function, and identify a crucial role played by the commensal bacterium Blautia and its fermentation products.
- Sandra M. Holmberg
- , Rachel H. Feeney
- & Bjoern O. Schroeder
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Article
| Open AccessDHX9 maintains epithelial homeostasis by restraining R-loop-mediated genomic instability in intestinal stem cells
Inflammatory bowel disease (IBD) is featured with epithelial barrier dysfunction, however, the underlying mechanism is less clear. Here, the authors show that DHX9 deficiency in intestinal stem cells (ISCs) induces accumulation of abnormal R-loops and subsequent genomic instability, leading to impairment of ISCs and development of IBD.
- Xingxing Ren
- , Qiuyuan Liu
- & Shu Zhu
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Article
| Open AccessDiindoles produced from commensal microbiota metabolites function as endogenous CAR/Nr1i3 ligands
Here, combining metabolomic, proteomic and biophysical analyses, the authors identify and characterize a series of diindole molecules produced from commensal bacteria metabolites that act as specific agonists for the orphan constitutive androstane receptor (CAR), having potential to modulate gut and liver inflammation, metabolic diseases and cancer.
- Jiabao Liu
- , Ainaz Malekoltojari
- & Henry M. Krause
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| Open AccessTargeting P2Y14R protects against necroptosis of intestinal epithelial cells through PKA/CREB/RIPK1 axis in ulcerative colitis
P2Y14R regulates necroptosis of intestinal epithelial cells though PKA/CREB/RIPK1 axis in the pathogenesis of ulcerative colitis (UC). Targeting P2Y14R with a small molecule inhibitor improves dextran sulfate sodium-induced UC in mice, suggesting P2Y14R as a promising target for treatment of UC.
- Chunxiao Liu
- , Hui Wang
- & Qinghua Hu
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Article
| Open AccessTargeted delivery of Fc-fused PD-L1 for effective management of acute and chronic colitis
Triggering the PD-1/PD-L1 immune checkpoint is an attractive therapeutic approach in inflammatory bowel disease, and PD-L1, conjugated to the Fc part of an immunoglobulin (PD-L1-Fc) has been shown to be effective in mouse models. Here authors show that fusing to reactive oxygen species (ROS)-responsive nanoparticles improves effect of PD-L1-Fc due to targeting to inflammation sites, while systemic toxicity is reduced.
- Xudong Tang
- , Yangyang Shang
- & Lei Chen
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Article
| Open AccessMucosal host-microbe interactions associate with clinical phenotypes in inflammatory bowel disease
Here, through parallel profiling of the mucosal transcriptome and microbiome of intestinal biopsies derived from patients with IBD and from non-IBD controls, the authors characterize interactions between gene expression and microbiota composition associated with traits of patients with inflammatory bowel diseases. Peer Review Information: Nature Communications thanks Robert Häsler, and the other, anonymous, reviewers for their contribution to the peer review of this work. A peer review file is available.
- Shixian Hu
- , Arno R. Bourgonje
- & Rinse K. Weersma
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Article
| Open AccessDubosiella newyorkensis modulates immune tolerance in colitis via the L-lysine-activated AhR-IDO1-Kyn pathway
Here, Zhang et al. identify a metabolic axis by which Lys-producing commensal bacterium Dubosiella newyorkensis mediates a Treg-mediated immunosuppressive microenvironment by activating AhR-IDO1-Kyn metabolic circuitry in dendritic cells.
- Yanan Zhang
- , Shuyu Tu
- & Shu Jeffrey Zhu
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Article
| Open AccessEtrolizumab-s fails to control E-Cadherin-dependent co-stimulation of highly activated cytotoxic T cells
The clinical success of anti- αEβ7 antibody Etrolizumab for Crohn’s disease is less than what is expected based on proof-of-concept studies. Here authors show, by characterization of T cells from Etrolizumab-treated patients, in vitro functional assays and reanalysis of public single cell datasets on Etrolizumab-treated patients, that at high level of T cell activation, which characterises T cells in Crohn’s disease, E-Cadherin-αEβ7 interactions become resistant to Etrolizumab inhibition.
- Maximilian Wiendl
- , Mark Dedden
- & Sebastian Zundler
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Article
| Open AccessAltered DNA methylation within DNMT3A, AHRR, LTA/TNF loci mediates the effect of smoking on inflammatory bowel disease
Cigarette smoking is an established risk factor for inflammatory bowel disease. The authors suggest that smoking may affect the risk of Crohn’s disease and ulcerative colitis by modulating the DNA methylation status of the DNMT3A, LTA/TNF, and AHRR region, respectively.
- Han Zhang
- , Rahul Kalla
- & Xue Li
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Article
| Open AccessDietary L-Tryptophan consumption determines the number of colonic regulatory T cells and susceptibility to colitis via GPR15
Environmental factors such as diet have been shown to be involved with the development of colitis. Here the authors show that L-tryptophan promotes the development of GPR15+ Treg cells via the host IDO1/2 pathway and that tryptophan consumption in mice reduces severity of colitis in a C. rodentium mouse model.
- Nguyen T. Van
- , Karen Zhang
- & Sangwon V. Kim
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| 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 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 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 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 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 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 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 AccessTemperature-triggered in situ forming lipid mesophase gel for local treatment of ulcerative colitis
Treatment of the chronic disease ulcerative colitis is impeded by systemic side effects of orally administered drugs. Here the authors develop a gel that uses the rectal temperature as a mechanism to trigger solidification for localized delivery of colitis therapeutics.
- Marianna Carone
- , Marianne R. Spalinger
- & Simone Aleandri
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| 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 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 AccessIdentifying high-impact variants and genes in exomes of Ashkenazi Jewish inflammatory bowel disease patients
Inflammatory bowel disease (IBD) is highly prevalent among the Ashkenazi Jewish population. Here, the authors identify novel IBD-associated variants and genes, validated by transcriptomic and phenome-wide associations.
- Yiming Wu
- , Kyle Gettler
- & Yuval Itan
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Article
| Open AccessChronic exposure to synthetic food colorant Allura Red AC promotes susceptibility to experimental colitis via intestinal serotonin in mice
Allura Red AC is a dye used in food products. Here the authors report that chronic, long-term exposure to Allura Red AC increases susceptibility to experimental colitis in mice dependent on the serotonin biosynthetic enzyme TPH1, while intermittent exposure more typical for the human setting did not increase susceptibility to experimental colitis.
- Yun Han Kwon
- , Suhrid Banskota
- & Waliul I. Khan
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Article
| Open AccessDNA methyltransferase 3A controls intestinal epithelial barrier function and regeneration in the colon
DNA methyltransferase 3 A (DNMT3A) is involved in DNA methylation, and genetic variants in the DNMT3 locus have been associated with inflammatory bowel disease. Here the authors report that DNMT3A controls intestinal epithelial barrier function and restoration of the gut barrier function after intestinal epithelial perturbation.
- Antonella Fazio
- , Dora Bordoni
- & Philip Rosenstiel
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Article
| Open AccessInterleukin-22 regulates neutrophil recruitment in ulcerative colitis and is associated with resistance to ustekinumab therapy
Mechanisms of non-response to ustekinumab, a biologic targeting IL-23, are currently unclear. Here, the authors show that the transcriptional program regulated by IL-22, an IL-23 responsive cytokine, is enriched in patients with ulcerative colitis unresponsive to ustekinumab and associated with higher colon neutrophil recruitment and activation of upstream IL-22 regulators.
- Polychronis Pavlidis
- , Anastasia Tsakmaki
- & Nick Powell
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Article
| Open AccessIn vivo self-assembled siRNA as a modality for combination therapy of ulcerative colitis
Management of ulcerative colitis can require a combination of treatments targeting different pathways. Here the authors design a therapy for ulcerative colitis based on a multitargeted genetic circuit to simultaneously target TNF-α, B7-1 and integrin α4, and show the therapy is effective in male mice with induced or spontaneous genetic colitis.
- Xinyan Zhou
- , Mengchao Yu
- & Xi Chen
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Article
| Open AccessMannose ameliorates experimental colitis by protecting intestinal barrier integrity
New potential therapies for inflammatory bowel disease are needed as not all patients respond to or maintain a response to conventional therapies. Here the authors report that mannose supplementation ameliorates experimental colitis in male mice, potentially via effects on intestinal epithelium lysosomal integrity.
- Lijun Dong
- , Jingwen Xie
- & Daming Zuo
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Article
| Open AccessCholesterol sulfate alleviates ulcerative colitis by promoting cholesterol biosynthesis in colonic epithelial cells
New treatment strategies are required for ulcerative colitis. Here the authors show in mouse models that cholesterol sulfate, an endogenous active cholesterol derivative, contributes to the healing of the mucosal barrier by promoting cholesterol biosynthesis in colonic epithelial cells and exhibits therapeutic efficacy against ulcerative colitis.
- Dongke Xu
- , Ruijun Ma
- & Xiaobo Li
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Article
| Open AccessHigh-dimensional profiling reveals Tc17 cell enrichment in active Crohn’s disease and identifies a potentially targetable signature
The T cell compartment in patients with Crohn's disease is dysregulated. Here the authors use cytometric profiling to reveal an enrichment of distinct Tc17 cells during active Crohn's disease and may suggest CD6 as a potential target for therapeutic studies.
- A.-M. Globig
- , A. V. Hipp
- & B. Bengsch
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Article
| Open AccessA systems genomics approach to uncover patient-specific pathogenic pathways and proteins in ulcerative colitis
Single Nucleotide Polymorphisms (SNPs) affect cellular regulatory networks, and SNP co-occurrences contribute to disease pathogenesis in ulcerative colitis (UC). Here the authors introduce iSNP, a precision medicine pipeline that combines genomics and network biology approaches to uncover patient specific pathways affected in complex diseases.
- Johanne Brooks-Warburton
- , Dezso Modos
- & Tamas Korcsmaros
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Article
| Open AccessAntibody decay, T cell immunity and breakthrough infections following two SARS-CoV-2 vaccine doses in inflammatory bowel disease patients treated with infliximab and vedolizumab
Vaccination is effective in protecting from COVID-19. Here the authors report immune responses and breakthrough infections in twice-vaccinated patients receiving anti-TNF treatments for inflammatory bowel disease, and find dampened vaccine responses that implicate the need of adapted vaccination schedules for these patients.
- Simeng Lin
- , Nicholas A. Kennedy
- & Jeannie Bishop
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Article
| Open AccessThe spatial transcriptomic landscape of the healing mouse intestine following damage
The colon is comprised of specialized cells that interact with each other to function, however, the molecular regionalization of the colon is incompletely understood. Here, the authors use spatial transcriptomics to generate a publicly available resource defining the transcriptomic regionalization of the colon during steady state and mucosal healing.
- Sara M. Parigi
- , Ludvig Larsson
- & Eduardo J. Villablanca
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Article
| Open AccessMicrobial enzymes induce colitis by reactivating triclosan in the mouse gastrointestinal tract
Triclosan (TCS), an antimicrobial agent commonly found in consumer products, has been reported to exacerbates colitis in animal models. Here, using in vitro and in vivo approaches, the authors show that gut bacterial enzymes can drive the metabolic activation and gut toxicity of TCS, highlighting an important role of intestinal microbial factors in the complex etiology of colitis.
- Jianan Zhang
- , Morgan E. Walker
- & Guodong Zhang
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Article
| Open AccessNanoparticle-assembled bioadhesive coacervate coating with prolonged gastrointestinal retention for inflammatory bowel disease therapy
The development of a drug delivery system capable of prolonged retention in the gastrointestinal tract remains a clinical challenge. Here the authors present a bio-adhesive liquid coacervate coating on the intestinal tract that acts as a flowable drug carrier, mediates the sustained release of diverse drugs, and potentially enhances therapeutic efficacy against gastrointestinal diseases.
- Pengchao Zhao
- , Xianfeng Xia
- & Liming Bian
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Article
| Open AccessInvestigating the shared genetic architecture between multiple sclerosis and inflammatory bowel diseases
An epidemiological association between multiple sclerosis (MS) and inflammatory bowel disease (IBD) is well-established, but a genetic link is unclear. Here, the authors investigate the shared genetic architecture between MS and IBD to shed light on the biological basis of comorbidity.
- Yuanhao Yang
- , Hannah Musco
- & Yuan Zhou
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Article
| Open AccessMitochondrial transcription factor A in RORγt+ lymphocytes regulate small intestine homeostasis and metabolism
RORγt is known to play critical roles in the regulation of a number of immune cell subsets. Here the authors implicate mitochondrial transcription factor A in the regulation of intestinal RORγt + lymphocyte homeostasis and metabolic control in a murine in vivo model.
- Zheng Fu
- , Joseph W. Dean
- & Liang Zhou
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Article
| Open AccessArtificial intelligence guided discovery of a barrier-protective therapy in inflammatory bowel disease
Traditional drug discovery process use differential, Bayesian and other network based approaches. We developed a Boolean approach for building disease maps and prioritizing pre-clinical models to discover a first-in-class therapy to restore and protect the leaky gut barrier in inflammatory bowel disease.
- Debashis Sahoo
- , Lee Swanson
- & Pradipta Ghosh
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Article
| Open AccessCritical role of interferons in gastrointestinal injury repair
Despite being prevalent yet well studied, ulcerative colitis still has poorly characterized pathophysiology. Here the authors use mouse colitis models to find that type I and III interferon (IFN) both contribute to ameliorating the disease, with IFN signaling in either the epithelial or hematopoietic compartment sufficient for this protective effect.
- Constance McElrath
- , Vanessa Espinosa
- & Sergei V. Kotenko
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Article
| Open AccessSingle-cell analyses of Crohn’s disease tissues reveal intestinal intraepithelial T cells heterogeneity and altered subset distributions
Crohn’s disease results from transmural inflammation in the gut, but analyses of local immune populations are still lacking. Here, the authors show, by combining multiple single-cell approaches, that intraepithelial and lamina propria T cells are heterogenous, show unique phenotypes, and exhibit altered subsets upon inflammation.
- Natalia Jaeger
- , Ramya Gamini
- & Marco Colonna
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Article
| Open AccessInflammation status modulates the effect of host genetic variation on intestinal gene expression in inflammatory bowel disease
Inflammatory bowel diseases are heterogeneous, and little is known about how underlying genetic variation can affect their development. Here, the authors report that intestinal inflammation modulates the effect of host genetics on the gut mucosal expression of 190 genes in the context of inflammatory bowel diseases.
- Shixian Hu
- , Werna T. Uniken Venema
- & Rinse K. Weersma
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Article
| Open AccessPancreatic glycoprotein 2 is a first line of defense for mucosal protection in intestinal inflammation
Glycoprotein-2 (GP-2) can protect the intestinal epithelial barrier from bacteria and is associated with protection against Crohn’s disease. Here, the authors show pancreatic GP-2 is the source of the intestine’s luminal GP-2 that binds bacteria and prevents them from attaching to the epithelium, also limiting pathology in a DSS colitis mouse model.
- Yosuke Kurashima
- , Takaaki Kigoshi
- & Hiroshi Kiyono
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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
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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
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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
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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
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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