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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 AccessGut microbiome composition and metabolic activity in women with diverticulitis
Here, the authors present a multi-omics examination of stool samples obtained from individuals with diverticulitis and controls, uncovering disruptions in the balance of microbial composition and metabolites, as well as co-occurring microbe-metabolite associations relevant to the disease.
- Wenjie Ma
- , Yiqing Wang
- & Andrew T. Chan
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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 AccessDiet changes due to urbanization in South Africa are linked to microbiome and metabolome signatures of Westernization and colorectal cancer
Here, the authors present a comparative analysis of the diet, microbiome and metabolome of rural and urban Xhosa people in South Africa, associating urban diets with higher abundances of pro-neoplastic microbial metabolites.
- M. C. Ramaboli
- , S. Ocvirk
- & S. J. D. O’Keefe
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Article
| Open AccessMalnutrition enteropathy in Zambian and Zimbabwean children with severe acute malnutrition: A multi-arm randomized phase II trial
Childhood malnutrition in Africa is a glaring example of global inequality, and mortality remains high. Here, the authors report the results of the TAME randomized phase II clinical trial, in which intestinal healing was the target of four potential interventions in malnourished children in Zambia and Zimbabwe.
- Kanta Chandwe
- , Mutsa Bwakura-Dangarembizi
- & Paul Kelly
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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 AccessClinically used broad-spectrum antibiotics compromise inflammatory monocyte-dependent antibacterial defense in the lung
Authors utilise a murine model of infection to provide mechanistic insight into how antimicrobial therapy may be a predisposing risk factor for hospital-acquired pneumonia. They show that antibiotic-induced microbiota perturbations compromise inflammatory monocytes and thereby impair antibacterial defence.
- Patrick J. Dörner
- , Harithaa Anandakumar
- & Bastian Opitz
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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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Article
| Open AccessAutologous cell transplantation for treatment of colorectal aganglionosis in mice
Neurointestinal diseases cause significant morbidity and effective treatments are lacking. Here, authors perform autologous cell transplantation of enteric neural stem cells in a mouse model of colonic aganglionosis and report restoration of colonic contractile activity.
- Weikang Pan
- , Ahmed A. Rahman
- & Ryo Hotta
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Article
| Open AccessInhibition of urease-mediated ammonia production by 2-octynohydroxamic acid in hepatic encephalopathy
Hepatic encephalopathy is a severe complication of liver disease with a growing prevalence. Here, the authors present a hydroxamate-based urease inhibitor to target the production of intestinal ammonia, one of the contributors to the pathogenesis of hepatic encephalopathy.
- Diana Evstafeva
- , Filip Ilievski
- & Jean-Christophe Leroux
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Article
| Open AccessInhibition of 7-dehydrocholesterol reductase prevents hepatic ferroptosis under an active state of sterol synthesis
Ferroptosis has been connected to liver disease through unclear mechanisms. Here, the authors identify the terminal enzyme of cholesterol synthesis, 7-dehydrocholesterol reductase, as a regulator of ferroptosis in hepatocytes that suppresses ferroptosis through 7-dehydrocholesterol accumulation.
- Naoya Yamada
- , Tadayoshi Karasawa
- & Masafumi Takahashi
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Article
| Open AccessEnabling large-scale screening of Barrett’s esophagus using weakly supervised deep learning in histopathology
Diagnosis of Barrett’s esophagus depends on pathologist assessment of stained slides. Here, the authors utilise a deep learning approach to prioritize potential cases using diagnostic labels in two datasets, with the aim to improve Barrett’s screening capacity.
- Kenza Bouzid
- , Harshita Sharma
- & Javier Alvarez-Valle
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Article
| 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 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 AccessWASH interventions and child diarrhea at the interface of climate and socioeconomic position in Bangladesh
Household water, sanitation, and handwashing (WASH) interventions can reduce diarrhoea-related morbidity in young children. Here, the authors report findings from a pre-specified secondary analysis of a cluster-randomised trial assessing how WASH impacts vary by socioeconomic position and season.
- Pearl Anne Ante-Testard
- , Francois Rerolle
- & Benjamin F. Arnold
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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 AccessEFHD2 suppresses intestinal inflammation by blocking intestinal epithelial cell TNFR1 internalization and cell death
Physiologically, the host suppresses intestinal epithelial cell death to prevent intestinal inflammation. Here, the authors show that EF-hand domain-containing protein D2 (EFHD2) endogenously suppresses intestinal epithelial cell death by blocking TNFR1 internalization and protects the intestine from excessive inflammation.
- Jiacheng Wu
- , Xiaoqing Xu
- & Xuetao Cao
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Article
| Open AccessA multicenter clinical AI system study for detection and diagnosis of focal liver lesions
Early detection and accurate diagnosis of focal liver lesions are crucial for effective treatment and prognosis. Here, the authors present a fully automated diagnostic system that leverages multi-phase CT scans and clinical features, for diagnosing liver lesions.
- Hanning Ying
- , Xiaoqing Liu
- & Xiujun Cai
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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 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
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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 AccessEfficacy of Bifidobacterium animalis subsp. lactis BL-99 in the treatment of functional dyspepsia: a randomized placebo-controlled clinical trial
Functional dyspepsia (FD) is a common chronic gastrointestinal disorder. Here, in a randomized, parallel-group, positive-drug, and placebo-controlled clinical trial, the authors show that supplementation with the probiotic Bifidobacterium animalis subsp. lactis BL-99 (BL-99) improves FD clinical response rate and promotes accumulation of SCFA-producing microbiota.
- Qi Zhang
- , Guang Li
- & Fazheng Ren
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Article
| Open AccessCharacterizations of a neutralizing antibody broadly reactive to multiple gluten peptide:HLA-DQ2.5 complexes in the context of celiac disease
Targeting gluten antigens presents a plausible therapy option for celiac disease. Here the authors generate and characterize a broadly neutralizing antibody recognizing more than 25 gluten peptide:HLA-DQ2.5 complexes, with structural analyses implicating its mode of interaction, and with mouse in vivo studies supporting its therapeutic feasibility.
- Yuu Okura
- , Yuri Ikawa-Teranishi
- & Tomoyuki Igawa
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Article
| Open AccessCdo1-Camkk2-AMPK axis confers the protective effects of exercise against NAFLD in mice
The role of Cdo1 in exercise-mediated metabolic health and NAFLD is not clear. Here, the authors show that hepatic Cdo1 tethers Camkk2 to AMPK by interacting with both of them, thereby activating AMPK signaling to blunt hepatosteatosis and to promote exercise-mediated alleviation of NAFLD in mice.
- Min Chen
- , Jie-Ying Zhu
- & Liang Guo
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Article
| Open AccessMapping and modeling human colorectal carcinoma interactions with the tumor microenvironment
Tumour-microenvironment interactions, pivotal in cancer progression, are challenging to replicate in vitro. Here, the authors use single-cell RNA-seq to analyse these interactions in colorectal cancer within organoid models, and aim to emulate and understand these crucial interactions by introducing specific microenvironmental components.
- Ning Li
- , Qin Zhu
- & Christopher J. Lengner
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Article
| Open AccessMulti-omics analysis of hospital-acquired diarrhoeal patients reveals biomarkers of enterococcal proliferation and Clostridioides difficile infection
Antibiotics can cause hospital-acquired diarrhoea, resulting in gut microbiota and metabolome changes. Here, the authors study the faecal microbiota and metabolome of 169 patients, offering insights into these changes, and identified biomarkers for diagnostics.
- Marijana Bosnjak
- , Avinash V. Karpe
- & Dena Lyras
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Article
| Open AccessIntestinal Atp8b1 dysfunction causes hepatic choline deficiency and steatohepatitis
Choline is an essential nutrient derived primarily from dietary phosphatidylcholine, and its deficiency causes steatohepatitis. Here, the authors show that intestinal Atp8b1 contributes to choline metabolism through lysoPC absorption and that its dysfunction causes choline deficiency and steatohepatitis.
- Ryutaro Tamura
- , Yusuke Sabu
- & Hisamitsu Hayashi
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Article
| Open AccessIndocyanine green fluorescence imaging-guided versus conventional laparoscopic lymphadenectomy for gastric cancer: long-term outcomes of a phase 3 randomised clinical trial
Due to high rate of metastasis, lymphadenectomy is a cornerstone of the surgical treatment of gastric cancer however the accurate dissection of lymph nodes (LN) can be challenging. Here, the authors present the long-term outcomes of a randomised control trial investigating indocyanine green fluorescence image-guided LN retrieval in gastric cancer patients undergoing laparoscopic gastrectomy.
- Qi-Yue Chen
- , Qing Zhong
- & Chang-Ming Huang
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Article
| Open 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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Article
| Open AccessMicrobiome and metabolome features in inflammatory bowel disease via multi-omics integration analyses across cohorts
Gut microbiota play pivotal roles in IBD. Here, Ning et al. use a multi-omics approach to characterize gut microbiota and metabolites alterations, and potential pathogenic bacteria associated with IBD, with the aim to help develop more precise biomarkers for IBD diagnosis and drug targets
- Lijun Ning
- , Yi-Lu Zhou
- & Jie Hong
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Article
| Open 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 AccessPreservation versus resection of Denonvilliers’ fascia in total mesorectal excision for male rectal cancer: follow-up analysis of the randomized PUF-01 trial
Total mesorectal excision (TME) for rectal cancer can require partial resection of Denonvilliers’ fascia (DVF). Here the authors report the secondary outcomes of a randomized trial to evaluate the safety and effect of DVF preservation during laparoscopic TME on postoperative urogenital function and oncological safety in male patients with mid-low rectal cancer.
- Jiafeng Fang
- , Bo Wei
- & Hongbo Wei
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Article
| Open AccessLactylation of METTL16 promotes cuproptosis via m6A-modification on FDX1 mRNA in gastric cancer
Cuproptosis regulation in tumors is unclear. Here the authors find that copper promotes METTL16 lactylation, inducing cuproptosis via stabilizing FDX1 in gastric cancer. Targeting lactyl-METTL16 and cuproptosis offers a potential feasible strategy for cancer therapy.
- Lianhui Sun
- , Yuan Zhang
- & Chen Huang
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Article
| Open 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 AccessZSP1601, a novel pan-phosphodiesterase inhibitor for the treatment of NAFLD, A randomized, placebo-controlled phase Ib/IIa trial
Non-alcoholic fatty liver disease is a growing health burden with limited treatment options worldwide. Herein the authors report a randomized, double-blind, placebo-controlled, multiple-dose trial of a first-in-class pan-phosphodiesterase inhibitor ZSP1601 in NAFLD patients.
- Yue Hu
- , Haijun Li
- & Yanhua Ding
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Article
| Open AccessTripartite motif containing 26 prevents steatohepatitis progression by suppressing C/EBPδ signalling activation
Nonalcoholic steatohepatitis (NASH) is a heterogeneous disease with complicated pathogenesis. Here the authors identify that the E3 ligase TRIM26 confers protection against NASH development via suppression of CCAAT/enhancer binding protein delta (C/EBPδ).
- Minxuan Xu
- , Jun Tan
- & Lianyi Han
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Article
| Open AccessCSTF2 mediated mRNA N6-methyladenosine modification drives pancreatic ductal adenocarcinoma m6A subtypes
N6-methyladenosine (m6A) modification has important implications in different cancer subtypes. Here, the authors perform transcriptomic m6A profiling to identify two subtypes of pancreatic ductal adenocarcinoma with differential m6A modifications and different clinical outcomes, which is driven by m6A regulator CSTF2.
- Yanfen Zheng
- , Xingyang Li
- & Zhixiang Zuo
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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 AccessGenome-wide enhancer-gene regulatory maps link causal variants to target genes underlying human cancer risk
Here, the authors apply the Activity-by-Contact (ABC) model to infer enhancer-gene regulation and the effect of associated variants across multiple cancer types, integrating genetic and multi-omics data. Then, they explore the mechanisms associated with ABC regulatory variants in colorectal cancer.
- Pingting Ying
- , Can Chen
- & Xiaoping Miao
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Article
| Open AccessTHBS1-producing tumor-infiltrating monocyte-like cells contribute to immunosuppression and metastasis in colorectal cancer
Thrombospondin-1 (THBS1) is a matricellular protein highly expressed in inflammatory processes, including cancer. Here the authors show that bone-marrow derived monocyte-like cells are the primary source of THBS1 in colorectal cancer, associated with mesenchymal characteristics, immunosuppression and a poor prognosis.
- Mayuki Omatsu
- , Yuki Nakanishi
- & Hiroshi Seno
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Article
| Open AccessPhage-microbe dynamics after sterile faecal filtrate transplantation in individuals with metabolic syndrome: a double-blind, randomised, placebo-controlled clinical trial assessing efficacy and safety
Bacteriophages (phages) can modify the gut microbiome to benefit human health. Here, the authors report the results of a double blind, randomized, placebo-controlled trial, showing that faecal filtrate transplantation (FFT), containing phages from lean healthy donors, is safe and improves glycemic variability in patients with metabolic syndrome, while shifting the gut phage composition.
- Koen Wortelboer
- , Patrick A. de Jonge
- & Hilde Herrema
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Article
| Open AccessHyodeoxycholic acid ameliorates nonalcoholic fatty liver disease by inhibiting RAN-mediated PPARα nucleus-cytoplasm shuttling
Nonalcoholic fatty liver disease (NAFLD) is often linked to disrupted bile acid homeostasis. Here, the authors show hyodeoxycholic acid (HDCA) ameliorates nonalcoholic fatty liver disease by inhibiting the formation of RAN/CRM1/PPARα nuclear export heterotrimer, resulting in increased nuclear localization of PPARα and activated fatty acid oxidation.
- Jing Zhong
- , Xiaofang He
- & Houkai Li
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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 AccessDesmoplastic stroma restricts T cell extravasation and mediates immune exclusion and immunosuppression in solid tumors
Tumor stroma is a key component of the immunosuppressive tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC). Here, in preclinical PDAC models, the authors show that depletion of FAP-expressing cancer associated fibroblasts with FAP-targeted CAR T cells results in a loss of the integrity of the desmoplastic matrix, rendering tumors more susceptible to sequential treatment with mesothelin-targeted CAR-T cells.
- Zebin Xiao
- , Leslie Todd
- & Ellen Puré
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Article
| Open AccessA ferroptosis-targeting ceria anchored halloysite as orally drug delivery system for radiation colitis therapy
Radiation colitis is a major side effect for pelvic radiotherapy patients, but there are limited available treatments. Here, the authors use a halloysite clay based material for the alleviation of radiation colitis in mice by inhibiting ferroptosis.
- Yue Feng
- , Xiang Luo
- & Mingxian Liu
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Article
| Open AccessRORγt-Raftlin1 complex regulates the pathogenicity of Th17 cells and colonic inflammation
IL-17 secreting Th17 cells have established roles in numerous immune-pathologies but paradoxically are required homeostatically in the maintenance of the intestinal barrier. Here the authors establish Raftlin-1 in the recruitment of phospholipids that are linked to the emergence of pathogenic Th17 cells in animal models of bowel inflammation.
- Amir Kumar Singh
- , Ritesh Kumar
- & K. Venuprasad
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