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| Open AccessHepatocytes differentiate into intestinal epithelial cells through a hybrid epithelial/mesenchymal cell state in culture
Hepatocytes dedifferentiate into progenitor-like cells in culture. Here, authors elucidate the dynamics and mechanisms of hepatocyte dedifferentiation and find an unexpected differentiation potential of hepatocytes into intestinal epithelial cells.
- Shizuka Miura
- , Kenichi Horisawa
- & Atsushi Suzuki
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| Open AccessMapping of mitogen and metabolic sensitivity in organoids defines requirements for human hepatocyte growth
Human hepatocytes remain hard to grow in vitro. Here, the authors temporally map the early stages of organoid growth initiated from fetal and adult hepatocytes, leveraging this knowledge to design maturation and improved expansion conditions.
- Delilah Hendriks
- , Benedetta Artegiani
- & Hans Clevers
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Article
| Open AccessBacterial peptidoglycan acts as a digestive signal mediating host adaptation to diverse food resources in C. elegans
Here, by using a food digestion model in C. elegans, the authors identify a mechanism by which bacterial peptidoglycan (PGN) interacts with Bacterial Colonization Factor-1 (BCF-1) triggering C. elegans to expand its ability to consume a wide range of foods in their natural environment.
- Fanrui Hao
- , Huimin Liu
- & Bin Qi
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Article
| Open AccessDysregulation of Wnt/β-catenin signaling contributes to intestinal inflammation through regulation of group 3 innate lymphoid cells
RORγt+ group 3 innate lymphoid cells are intimately involved in intestinal homeostasis, their dysregulation is linked to inflammatory gut diseases. Here the authors show that dysregulated Wnt/β-catenin signalling contributes to disturbed regulation of group 3 innate cells and intestinal inflammation.
- Jiacheng Hao
- , Chang Liu
- & Xiaohuan Guo
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Article
| Open AccessHeterozygous missense variant in GLI2 impairs human endocrine pancreas development
Mutations in the Hedgehog signaling have not been previously associated to diabetes. Here, authors identify a missense variant of GLI2 in a family with early-onset diabetes and report an essential role of this gene during human iPSC-based pancreatic differentiation.
- Laura M. Mueller
- , Abigail Isaacson
- & Francesca M. Spagnoli
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| Open AccessCellular reprogramming in vivo initiated by SOX4 pioneer factor activity
Upon physiological injury, hepatocytes transdifferentiate into biliary epithelial cells, a process involving molecular rewiring. Here, authors show that Sox4 organizes the early steps, acting as a pioneer factor to decommission hepatocyte enhancers and open chromatin around biliary genes.
- Takeshi Katsuda
- , Jonathan H. Sussman
- & Ben Z. Stanger
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| Open AccessThe gut ileal mucosal virome is disturbed in patients with Crohn’s disease and exacerbates intestinal inflammation in mice
Gut bacteriome dysbiosis has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Here, they authors characterize the small bowel (terminal ileum) virome and bacteriome of patients with Crohn´s Disease (CD), and show that ileal virions from CD patients causally exacerbate intestinal inflammation in IBD mouse models.
- Zhirui Cao
- , Dejun Fan
- & Tao Zuo
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Article
| Open AccessIntestinal IL-22RA1 signaling regulates intrinsic and systemic lipid and glucose metabolism to alleviate obesity-associated disorders
Interleukin (IL)-22 is critical in ameliorating obesity-induced metabolic disorders; however, it is unclear where IL-22 acts to mediate these outcomes. Here, the authors show in tissue-specific IL-22 receptor knockout mice a key role of intestinal epithelium-specific IL-22RA1 signaling in regulating intestinal metabolism and alleviating obesity-associated disorders.
- Stephen J. Gaudino
- , Ankita Singh
- & Pawan Kumar
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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 AccessIgG and IgM cooperate in coating of intestinal bacteria in IgA deficiency
IgA protects mucosal barriers by coating microorganisms, yet infection related complications are rare in human IgA deficiency. Authors here show that in humans lacking IgA, IgG assists IgM in coating of most bacterial families, thus contributing to gut mucosal defence.
- Carsten Eriksen
- , Janne Marie Moll
- & Susanne Brix
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Article
| Open AccessParabacteroides distasonis ameliorates insulin resistance via activation of intestinal GPR109a
Here, the authors show that the gut commensal Parabacteroides distasonis alleviates insulin resistance via nicotinic acid-intestinal GPR109a axis activation, a process promoted by Dendrobium officinale polysaccharide.
- Yonggan Sun
- , Qixing Nie
- & Shaoping Nie
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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 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 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 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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| 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 AccessTransparent tissue in solid state for solvent-free and antifade 3D imaging
Current liquid-based optical clearing protocols can suffer from solvent evaporation and photobleaching. Here, the authors develop a solid high-refractive-index polymer to embed mouse and human tissues for clearing and antifade high-resolution 3D imaging.
- Fu-Ting Hsiao
- , Hung-Jen Chien
- & Shiue-Cheng Tang
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| Open AccessAnatomical and functional maturation of the mid-gestation human enteric nervous system
Dershowitz and colleagues assess second trimester human fetal enteric nervous system development and function. They describe structural reorganization of the enteric nervous system that corresponds to gastrointestinal motility onset in ex vivo preparations.
- Lori B. Dershowitz
- , Li Li
- & Julia A. Kaltschmidt
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Article
| Open AccessIntegrative proteogenomic characterization of early esophageal cancer
The progression of oesophageal squamous cell carcinoma (ESCC) from early to advanced stages requires comprehensive molecular characterisation. Here, the authors perform a proteogenomics analysis of ESCC patient samples across nine histopathological stages and three phases, identifying key alterations and paths for progression.
- Lingling Li
- , Dongxian Jiang
- & Chen Ding
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Article
| Open AccessMicrobiota alters the metabolome in an age- and sex- dependent manner in mice
Commensal microbes contribute considerably to mammalian metabolism. Here the authors report the relative contributions of microbiome, age and sex to metabolism throughout the body and uncover age- and sex- specificity in how microbes affect metabolite levels in mice.
- Kirsty Brown
- , Carolyn A. Thomson
- & Kathy D. McCoy
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Article
| Open AccessIdentifying glycan consumers in human gut microbiota samples using metabolic labeling coupled with fluorescence-activated cell sorting
Dietary glycans are a major driver of the human gut microbiota composition. Here, the authors apply next-generation metabolic labeling coupled with fluorescence-activated cell sorting to identify and isolate gut bacteria consumers of dietary glycans in human stool samples, linking bacteria to the glycans they consume.
- Lharbi Dridi
- , Fernando Altamura
- & Bastien Castagner
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Article
| Open AccessIntestine-specific removal of DAF-2 nearly doubles lifespan in Caenorhabditis elegans with little fitness cost
The role of lifespan-regulating protein expression in specific tissues in C. elegans is murky. Here, the authors provide clarity by inducible degradation of longevity-related proteins, demonstrating that intestinal DAF-2 is a major determinant of lifespan in the worm.
- Yan-Ping Zhang
- , Wen-Hong Zhang
- & Meng-Qiu Dong
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Article
| Open AccessReduced alcohol preference and intake after fecal transplant in patients with alcohol use disorder is transmissible to germ-free mice
Gut microbiota composition is altered in patients with alcohol use disorder, and fecal microbiota transplant reduced alcohol craving in patients with alcohol use disorder and liver cirrhosis in a phase 1 clinical trial. Here the authors used stool samples collected in the trial to report that this phenotype is transmissible via microbial transfer to germ free mice, as assessed by reduced ethanol acceptance, intake and preference.
- Jennifer T. Wolstenholme
- , Justin M. Saunders
- & Jasmohan S. Bajaj
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Article
| Open AccessBiliary NIK promotes ductular reaction and liver injury and fibrosis in mice
Excessive expansion of cholangiocytes in the liver leads to ductular reaction and liver disease. Here, the authors show that genetic ablation, or pharmacological inhibition, of biliary NIK blocks ductular reaction, liver inflammation, and liver fibrosis in mice by modulating secretion of cholangiokines that mediate liver inflammation and fibrosis.
- Zhiguo Zhang
- , Xiao Zhong
- & Liangyou Rui
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Article
| Open AccessLoss of immunity-related GTPase GM4951 leads to nonalcoholic fatty liver disease without obesity
Obesity is a major risk factor for fatty liver disease. Here, using a forward genetic screen, the authors identify the gene GM4951 as a GTPase involved in lipid oxidation and development of NAFLD in mice.
- Zhao Zhang
- , Yu Xun
- & Bruce Beutler
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Article
| Open AccessMachine learning aided construction of the quorum sensing communication network for human gut microbiota
Microbes communicate with each other by Quorum sensing (QS) languages. Here the authors construct a QS database and the QS communication network to decipher intricate QSbased communications and form one of the key knowledge maps for human gut microbiota.
- Shengbo Wu
- , Jie Feng
- & Jianjun Qiao
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| Open AccessIntestinal fibroblastic reticular cell niches control innate lymphoid cell homeostasis and function
Fibroblastic reticular cells (FRCs) support localisation of immune cells in secondary lymphoid tissues but less is known about the lamina propria. Here the authors use scRNA-seq and intestinal infection to characterise FRCs in the intestinal lamina propria and show specialised niches that foster innate lymphoid cells during homeostasis and infection.
- Hung-Wei Cheng
- , Urs Mörbe
- & Burkhard Ludewig
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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
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Article
| Open AccessA propolis-derived small molecule ameliorates metabolic syndrome in obese mice by targeting the CREB/CRTC2 transcriptional complex
Disruption of CREB/CRTC2, a key gluconeogenic transcriptional complex, has been shown to ameliorate insulin resistance in mice. Here, the authors show that the inhibitor artipllin C and the synthetic compound A57, which presents with higher inhibitory activity, improve insulin sensitivity in obese mice by inhibiting CREB-CRTC2 interaction.
- Yaqiong Chen
- , Jiang Wang
- & Yi Liu
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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
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| Open AccessDietary excess regulates absorption and surface of gut epithelium through intestinal PPARα
Intestinal surface changes in size and function, but what propels these alterations is unknown. Here, the authors show that food excess increases the gut absorptive capacity, and that in presence of dietary lipids, intestinal PPARα is indispensable for the adaptive increase in villi length and function.
- Ozren Stojanović
- , Jordi Altirriba
- & Mirko Trajkovski
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Article
| Open AccessGWAS of serum ALT and AST reveals an association of SLC30A10 Thr95Ile with hypermanganesemia symptoms
Circulating liver enzymes, like alanine aminotransferase (ALT) and aspartate aminotransferase (AST), are highly heritable and predictive of disease. Here, the authors perform a genome-wide association study on ALT and AST, revealing a rare variant in SLC30A10 associated with elevated ALT and AST.
- Lucas D. Ward
- , Ho-Chou Tu
- & Paul Nioi
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Article
| Open AccessA stem cell population at the anorectal junction maintains homeostasis and participates in tissue regeneration
Transition zones connect distinct epithelia, contain cells expressing stem cell markers, and contribute to cancer development. Here, the authors examine the mouse anorectal junction, identifying a population of Krt17-positive basal cells that contribute to squamous and glandular epithelia during homeostasis and repair.
- Louciné Mitoyan
- , Véronique Chevrier
- & Géraldine Guasch
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Article
| Open AccessProteome-wide and matrisome-specific alterations during human pancreas development and maturation
The pancreatic extracellular matrix (ECM) is known to differ between species, age groups and physiological states, but its compositional changes throughout human life are not well understood. Here, the authors study how the proteome of pancreatic ECM changes during human development and maturation.
- Zihui Li
- , Daniel M. Tremmel
- & Lingjun Li
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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
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Article
| Open AccessThe ABCG2 Q141K hyperuricemia and gout associated variant illuminates the physiology of human urate excretion
The common ABCG2 variant Q141K contributes to hyperuricemia and gout risk. Here, using a human interventional study and a new orthologous mouse model, the authors report a tissue specific pathobiology of the Q141K variant, and support a significant role for ABCG2 in urate excretion in both the kidney and intestine.
- Kazi Mirajul Hoque
- , Eryn E. Dixon
- & Owen M. Woodward
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Article
| Open AccessA method for the generation of human stem cell-derived alpha cells
Deriving functional pancreatic cell types from human stem cells may have important clinical applications. Building on previous work, here the authors generate stem cell-derived alpha cells via a polyhormonal intermediate, which have a gene expression pattern similar to human islet alpha cells and behave as such when transplanted into mice.
- Quinn P. Peterson
- , Adrian Veres
- & Douglas A. Melton
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Article
| Open AccessNovel metabolic role for BDNF in pancreatic β-cell insulin secretion
Glucose metabolism is regulated by hypothalamic brain functions and factors produced by peripheral tissues. Here, the authors show that the regulator of food intake Brain-derived neurotrophic factor is also produced and secreted by muscle and stimulates pancreas insulin release.
- Gianluca Fulgenzi
- , Zhenyi Hong
- & Lino Tessarollo
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Article
| Open AccessGrasp55−/− mice display impaired fat absorption and resistance to high-fat diet-induced obesity
The physiological roles of the Golgi reassembly-stacking protein 55 (GRASP55/GORASP55) remain largely elusive. Here, the authors show that the Golgi-resident protein GRASP55 plays a crucial role in lipid homeostasis by regulating intestinal lipid uptake.
- Jiyoon Kim
- , Hyeyon Kim
- & Min Goo Lee
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Article
| Open AccessGut stem cell aging is driven by mTORC1 via a p38 MAPK-p53 pathway
Intestinal aging is associated with declines in structure and absorption of nutrients. Here, the authors show that aging related intestinal decline is mediated by activation of the mTORC1-p38MAPK-p53 pathway in intestinal stem cells and can be ameliorated by abrogating mTORC1 or p38MAPK activity.
- Dan He
- , Hongguang Wu
- & Baojie Li
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Article
| Open AccessDeletion of intestinal Hdac3 remodels the lipidome of enterocytes and protects mice from diet-induced obesity
Histone deacetylase 3 (HDAC3) is a regulator of lipid homeostasis in several tissues, however, its role in intestinal lipid metabolism was not yet known. Here the authors study intestine specific HDAC3 knock out mice and report that these animals have increased fatty acid oxidation and undergo remodeling of the intestinal epithelial cell lipidome.
- Mercedes Dávalos-Salas
- , Magdalene K. Montgomery
- & John M. Mariadason
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Article
| Open AccessTheabrownin from Pu-erh tea attenuates hypercholesterolemia via modulation of gut microbiota and bile acid metabolism
Pu-erh tea displays cholesterol-lowering properties. Here, Huang et al. show that this is mostly due to the action of a pigment in Pu-erh tea that induces changes in certain gut microbiota and bile acid levels, thus modulating the gut-liver metabolic axis.
- Fengjie Huang
- , Xiaojiao Zheng
- & Wei Jia
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Article
| Open AccessColonizing multidrug-resistant bacteria and the longitudinal evolution of the intestinal microbiome after liver transplantation
In a large prospective cohort of liver transplantation (LT) recipients, the authors identify associations between colonization by multidrug-resistant bacteria (MDRB) and microbiome dysbiosis pre- and post-LT, suggesting colonizing MDRB as an important target for microbiome-informed therapeutic approaches post-LT.
- Medini K. Annavajhala
- , Angela Gomez-Simmonds
- & Anne-Catrin Uhlemann
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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
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Article
| Open AccessActive thrombin produced by the intestinal epithelium controls mucosal biofilms
The roles played by thrombin in the human intestinal mucosa are unclear. Here, the authors show that the commensal microbiota modulates epithelial production of active thrombin, which controls biofilm growth and contributes to protection of the mucosa from bacterial invasion.
- Jean-Paul Motta
- , Alexandre Denadai-Souza
- & Nathalie Vergnolle
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Article
| Open AccessLiver-target nanotechnology facilitates berberine to ameliorate cardio-metabolic diseases
Berberine has lipid-lowering effects and other metabolic benefits, but it presents with poor bioavailability. Here the authors conjugate berberine to liver-targeting nanoparticles, and show increased accumulation of berberine in the liver, improved metabolic profiles and reduced atherosclerotic plaques in mice.
- Hui-Hui Guo
- , Chen-Lin Feng
- & Jian-Dong Jiang
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Article
| Open AccessThe H2A.Z histone variant integrates Wnt signaling in intestinal epithelial homeostasis
The histone variant, H2A.Z is known to regulate gene expression and cell proliferation. Here the authors show that H2A.Z has a central role in the control of intestinal epithelial homeostasis in mice, by preventing terminal differentiation of intestinal progenitors.
- Jérémie Rispal
- , Lucie Baron
- & Fabrice Escaffit