Featured
-
-
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
-
Article
| Open AccessEngineering tumor-colonizing E. coli Nissle 1917 for detection and treatment of colorectal neoplasia
There is an unmet medical need for the detection and treatment of early adenomas to prevent their progression to malignant disease. Here the authors show that orally administered E. coli Nissle 1917 can selectively colonize adenomas in mouse models and in patients as a detection tool, as well as deliver immunotherapeutics for colorectal neoplasia treatment.
- Candice R. Gurbatri
- , Georgette A. Radford
- & Tal Danino
-
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
-
Article
| Open AccessComprehensive proteogenomic characterization of early duodenal cancer reveals the carcinogenesis tracks of different subtypes
Duodenal cancer (DC) has complex subtypes and undergoes complicated morphological changes throughout progression, so understanding the molecular basis is crucial. Here, the authors perform a proteogenomics analysis of 156 DCs, revealing molecular subtypes as well as the roles of smoking, AARS1 and PARP1.
- Lingling Li
- , Dongxian Jiang
- & Chen Ding
-
Article
| Open AccessInterferon regulatory factor 1 (IRF-1) promotes intestinal group 3 innate lymphoid responses during Citrobacter rodentium infection
Innate lymphoid cells (ILC) are involved with different immune responses. Here the authors show that Interferon regulatory factor 1 (IRF1) is important for intestinal ILC3 accumulation during Citrobacter rodentium infection and promotes release of the protective cytokine IL-22 and response to IL-23.
- Angelika Schmalzl
- , Tamara Leupold
- & Stefan Wirtz
-
Article
| Open AccessInherited MUTYH mutations cause elevated somatic mutation rates and distinctive mutational signatures in normal human cells
Inherited mutations in MUTYH have been shown to predispose patients to colorectal cancers. Here, the authors show that MUTYH mutations lead to an increased somatic base substitution mutation rate in normal intestinal epithelial cells, which is the likely cause for the increased cancer risk.
- Philip S. Robinson
- , Laura E. Thomas
- & Michael R. Stratton
-
Article
| Open AccessTemporal changes in gastrointestinal fungi and the risk of autoimmunity during early childhood: the TEDDY study
Here, via metagenomics and ITS2 sequencing analysis of children's stool samples from three months to four years, the authors show that the fungal composition changes and relative abundance increases at weaning, but unlike bacteria, the overall levels of fungal diversity do not change substantially over time.
- Thomas A. Auchtung
- , Christopher J. Stewart
- & Joseph F. Petrosino
-
Article
| Open AccessAn efficient urine peptidomics workflow identifies chemically defined dietary gluten peptides from patients with celiac disease
Gluten peptides from wheat enter the bloodstream and are excreted in urine but are yet to be chemically characterised. Here, the authors show by mass spectrometry that quantitative and qualitative differences in urinary peptides can be detected between healthy people and patients with celiac disease.
- Brad A. Palanski
- , Nielson Weng
- & Joshua E. Elias
-
Article
| Open AccessTransglutaminase 3 crosslinks the secreted gel-forming mucus component Mucin-2 and stabilizes the colonic mucus layer
The colonic mucus layer is an organized system providing a physical barrier against pathogens and simultaneously harbouring the commensal flora. Here the authors report that transglutaminase 3 activity contributes to homeostasis of the colonic mucus layer and the lack of this enzymatic activity leads to increased susceptibility against DSS-induced colitis in mice.
- Jack D. A. Sharpen
- , Brendan Dolan
- & Christian V. Recktenwald
-
Article
| Open AccessReduced infant rhesus macaque growth rates due to environmental enteric dysfunction and association with histopathology in the large intestine
Environmental enteric dysfunction (EED), a subclinical disorder of intestinal function, is associated with malnutrition, infant growth stunting and pathologies in the small intestine. Here the authors report that infant rhesus macaques that are naturally exposed to enteric pathogens commonly linked to human growth stunting present with EED and growth faltering that associates with large intestine pathologies.
- Sara M. Hendrickson
- , Archana Thomas
- & Mark K. Slifka
-
Article
| Open AccessTrans-illumination intestine projection imaging of intestinal motility in mice
Current preclinical imaging of intestine in animal models cannot reveal intestinal dynamics in awake condition. Here the authors report a Transillumination Intestine Projection (TIP) imaging system for free-moving mice, and showed the intestine dynamics in conscious animal in natural physiological states.
- Depeng Wang
- , Huijuan Zhang
- & Jun Xia
-
Article
| Open AccessMaternal aryl hydrocarbon receptor activation protects newborns against necrotizing enterocolitis
Necrotizing enterocolitis (NEC) is a disease of prematurity requiring Toll-like receptor 4 (TLR4) activation on the gut epithelium. Here the authors show that the aryl hydrocarbon receptor (AHR) mediates NEC pathogenesis via effects on TLR4, and that supplementing the diet with AHR ligands during pregnancy or postnatally prevents NEC.
- Peng Lu
- , Yukihiro Yamaguchi
- & David J. Hackam
-
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 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 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 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 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 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 AccessInhibition of gelatinase B/MMP-9 does not attenuate colitis in murine models of inflammatory bowel disease
Metalloproteinase-9 has been suggested as therapeutic target to treat inflammatory bowel disease. Here de Bruynet al. show that genetic and pharmacological inhibition of metalloproteinase-9 does not ameliorate inflammation and fibrosis in mice challenged with acute and chronic colitis protocols.
- Magali de Bruyn
- , Christine Breynaert
- & Ghislain Opdenakker
-
Article
| Open AccessTRIM31 promotes Atg5/Atg7-independent autophagy in intestinal cells
While non-canonical, Atg5/Atg7-independent autophagy has been reported to occur, molecular details of alternative autophagy pathways remain unknown. Here, the authors report that the protein TRIM31 mediates alternative autophagy in intestinal cells, which protects against pathogenic bacteria.
- Eun A. Ra
- , Taeyun A. Lee
- & Boyoun Park
-
Article
| Open AccessFNDC4 acts as an anti-inflammatory factor on macrophages and improves colitis in mice
FDNC4 is a poorly characterized homologue of FNDC5/irisin, a myokine induced by exercise. Here the authors show that FDNC4 increases macrophage survival in growth factor deprivation, inhibits phagocytosis and transcriptional responses to M1 and M2 polarizing stimuli, and protects mice from DSS-induced colitis.
- Madeleen Bosma
- , Marco Gerling
- & Pontus Almer Boström
-
Article
| Open AccessThe REGγ-proteasome forms a regulatory circuit with IκBɛ and NFκB in experimental colitis
REGγ is a component of ubiquitin-independent 20S proteasome that targets many regulatory proteins for degradation. Here the authors show that REGγ is induced in DSS colitis and promotes degradation of IκBɛ, and that REGγ-deficient mice have less NFκB activation and are more resistant to the disease.
- Jinjin Xu
- , Lei Zhou
- & Xiaotao Li
-
Article
| Open AccessIntestinal microbiome analyses identify melanoma patients at risk for checkpoint-blockade-induced colitis
A subset of cancer patients treated with immune checkpoint blockade develops colitis. Here the authors show that lower abundance of Bacteroidetes and vitamin B biosynthetic modules in fecal samples of melanoma patients can predict their susceptibility to colitis following anti-CTLA-4 treatment.
- Krista Dubin
- , Margaret K. Callahan
- & Jedd D. Wolchok
-
Article
| Open AccessDual functions of Rap1 are crucial for T-cell homeostasis and prevention of spontaneous colitis
Rap1, a member of the Ras family of small guanine triphosphatases, mediates lymphocyte adhesion to high endothelial venules. Here the authors show that depending on its activation status Rap1 plays a dual role in T cell adhesion and by regulating T cell homeostasis is involved in the protection from colitis.
- Sayaka Ishihara
- , Akihiko Nishikimi
- & Koko Katagiri
-
Article
| Open AccessExperimental colitis in SIV-uninfected rhesus macaques recapitulates important features of pathogenic SIV infection
HIV-1 infection in humans and SIV infection in rhesus macaques are associated with mucosal damage to the gastrointestinal tract, microbial translocation and chronic immune activation. Here the authors develop a non-human primate DSS colitis model that recapitulates these aspects of the disease in uninfected rhesus macaques.
- Xing Pei Hao
- , Carissa M. Lucero
- & Jacob D. Estes
-
Article
| Open AccessIntestinal CD169+ macrophages initiate mucosal inflammation by secreting CCL8 that recruits inflammatory monocytes
Macrophages and dendritic cells residing in the lamina propria are involved in controlling mucosal immune balance. Here, the authors identify CD169+macrophages as contributors to the inflammation of DSS colitis through their role in mediating the recruitment of monocytes by secreting the cytokine CCL8.
- Kenichi Asano
- , Naomichi Takahashi
- & Masato Tanaka
-
Article
| Open AccessStereomicroscopic 3D-pattern profiling of murine and human intestinal inflammation reveals unique structural phenotypes
The gut epithelium is damaged in inflammatory bowel disease, but capturing such lesions by histology can be difficult. Here, the authors use stereomicroscopy to visualize different 3D inflammatory structures and associated microbes in humans and in 16 genetic mouse models relevant to intestinal inflammation.
- Alex Rodriguez-Palacios
- , Tomohiro Kodani
- & Fabio Cominelli
-
Article |
The non-muscle-myosin-II heavy chain Myh9 mediates colitis-induced epithelium injury by restricting Lgr5+ stem cells
Colitis is a common human disorder but the clinical interventions are limited as the pathological mechanisms are not very clear. Here the authors find an elevated expression of non-muscle-myosin-II heavy chain Myh9 in a colitis mouse model, and show that Myh9 expression reduction or activity inhibition ameliorates epithelial injuries.
- Bing Zhao
- , Zhen Qi
- & Ye-Guang Chen
-
Article |
IL-10 engages macrophages to shift Th17 cytokine dependency and pathogenicity during T-cell-mediated colitis
The pro-inflammatory cytokine IL-1ß promotes the accumulation of pathologic Th17 lymphocytes that contribute to colitis. Here the authors show that the critical role of IL-10 in colitis suppression can be explained by its inhibition of IL-1ß production in macrophages.
- Bofeng Li
- , Prajwal Gurung
- & Terrence L. Geiger
-
Article
| Open AccessGermline variants in the SEMA4A gene predispose to familial colorectal cancer type X
It is known that hereditary factors contribute to familial colorectal cancer type X. Here, the authors uncover the SEMA4A p.Val78Met germline mutation and show that the protein product is associated with changes in cell cycle progression in colorectal cancer cells.
- Eduard Schulz
- , Petra Klampfl
- & Heinz Sill
-
Article |
Autotransporters but not pAA are critical for rabbit colonization by Shiga toxin-producing Escherichia coli O104:H4
An outbreak of diarrhoea and haemolytic uraemic syndrome in Germany in 2011 was caused by a Shiga toxin-producing enteroaggregative E. coli, which carried the aggregative adherence plasmid pAA. Here, the authors show that autotransporters, but not pAA, are required for intestinal colonization in an infant rabbit model.
- Diana Munera
- , Jennifer M. Ritchie
- & Matthew K. Waldor
-
Article |
Persistent infection with Crohn’s disease-associated adherent-invasive Escherichia coli leads to chronic inflammation and intestinal fibrosis
Intestinal infection with adherent-invasive Escherichia coliis associated with Crohn’s disease in humans; however, its functional role remains unclear, in part due to a lack of animal models, which sustain chronic disease. Here the authors establish such a model in mice and show that it shares features with human Crohn’s disease.
- Cherrie-Lee N. Small
- , Sarah A. Reid-Yu
- & Brian K. Coombes
-
Article |
R-Spondin 2 signalling mediates susceptibility to fatal infectious diarrhoea
Citrobacter rodentiumis an intestinal pathogen of mice widely used to model enteropathogenicE. coli infection in humans. Using a forward genetic approach, Papapietro and colleagues identify R-Spondin 2 expression and resulting Wnt signalling activation as a major regulator of C. rodentium-induced colitis.
- Olivier Papapietro
- , Sarah Teatero
- & Samantha Gruenheid
-
Article |
MyD88 signalling in colonic mononuclear phagocytes drives colitis in IL-10-deficient mice
Mice lacking the anti-inflammatory cytokine IL-10 can develop colitis, which depends on inappropriate responses to commensal bacteria. Hoshiet al. now show that these responses are driven by colonic mononuclear phagocytes, providing insight to the initiating events, which may underlie inflammatory bowel disease.
- Namiko Hoshi
- , Dominik Schenten
- & Ruslan Medzhitov
-
Article
| Open AccessExtracellular ATP mediates mast cell-dependent intestinal inflammation through P2X7 purinoceptors
Mast cells are mediators of type I allergic disease and inflammation. Here, Kurashimaet al. show that mast cells are increased in the colons of mice with colitis, and that activation of the cells and subsequent inflammation can be blocked by inhibition of the purinoceptor, P2X7.
- Yosuke Kurashima
- , Takeaki Amiya
- & Hiroshi Kiyono
-
Article
| Open AccessProstaglandin E2 and SOCS1 have a role in intestinal immune tolerance
The gut is populated by a myriad of microorganisms and how the immune system tolerates their presence is of great interest. Here, by studying colon morphology in multiple knockout mice, the authors demonstrate a potential role for prostaglandin E2 and SOCS1 in mediating immune tolerance.
- Takatoshi Chinen
- , Kyoko Komai
- & Akihiko Yoshimura