• cellular mechanisms
• inflammatory bowel disease
• intestinal fibrosis
• molecular mechanisms
• therapeutics
• traditional Chinese medicine

• Government of Jiangsu Province

• Crohn’s disease
• FAPI-PET/CT
• Fibrosis
• Ga-68-FAPI-46
• Strictures

• Crohn’s Disease
• Pharmacology
• Qingchang Tongluo Decoction
• intestinal fibrosis
• network pharmacology

• Molecular Docking Simulation
• Drugs, Chinese Herbal/pharmacology
• Drugs, Chinese Herbal/chemistry
• Animals
• Fibrosis/drug therapy
• Network Pharmacology
• Mice
• Mice, Inbred BALB C
• Crohn Disease/drug therapy
• Crohn Disease/pathology
• Crohn Disease/metabolism
• Rats
• Male
• Transforming Growth Factor beta1/metabolism
• Disease Models, Animal

• Crohn's disease
• diagnosis
• diagnostic biomarker
• postoperative recurrence
• protein-protein interaction (PPI) network
• remission

• Exosome
• adipose-derived stem cells
• creeping fat
• fibrosis
• miR-103a-3p

• Humans
• Crohn Disease/genetics
• MicroRNAs/metabolism
• Intestines
• Fibroblasts/metabolism
• Fibrosis
• Stem Cells
• Cell Proliferation/genetics

• 82170573 National Natural Science Foundation of China

• Humans
• Organoids
• Organogenesis
• Stem Cells
• Intestines
• Inflammatory Bowel Diseases/genetics

• DP2 HL127720 NHLBI NIH HHS
• UG3 DK122644 NIDDK NIH HHS
• R01 DK124369 NIDDK NIH HHS

• Elastography
• bowel ultrasound
• inflammation
• inflammatory bowel disease
• shear waves

• Crohn’s disease
• Inflammatory bowel disease
• Intestinal resection
• Liquid diet
• Stenosis
• Sub-occlusive episodes

• Dilatation
• Fibrosis
• Inflammatory bowel diseases
• Self-expandable metal stents
• Stricture

Insight in the pathogenesis of intestinal fibrosis is an unmet medical need in inflammatory bowel diseases. Studies in murine models and human organ fibrosis point to a potential role of innate lymphoid cells (ILC) in chronic intestinal inflammation and fibrosis.

Dextran sodium sulfate (DSS) in drinking water was used to induce chronic colitis and remodeling in C57Bl/6 wild type (WT), RAG‐deficient, RAG^−/− common γ chain deficient and anti‐CD90.2 monoclonal antibody treated RAG^−/− mice. Inflammation was scored by macroscopic and histological examination and fibrosis was evaluated by hydroxyproline quantification and histology.

In RAG^−/− mice (which have a normal ILC population but no adaptive immunity), chronic intestinal inflammation and fibrosis developed similarly as in WT mice, with a relative increase in ILC2 during repeated DSS exposure. Chronic colitis could also be induced in the absence of ILC (RAG^−/−γc^−/− or anti‐CD90.2 treated RAG^−/− mice) with no attenuation of fibrosis. Importantly, clinical recovery based on weight gain after stopping DSS exposure was impaired in ILC‐deficient or ILC‐depleted mice.

These data argue against a profibrotic effect of ILC in chronic colitis, but rather suggest that ILC have a protective and recovery‐enhancing effect after repeated intestinal injury.

• Crohn's disease
• innate immunity
• innate lymphoid cell
• intestinal fibrosis

• antifibrotic compounds
• intestinal fibrosis
• platelet-derived growth factor inhibitors
• precision-cut intestinal slices
• transforming growth factor-β1 inhibitors

The transient receptor potential (TRP) channels superfamily are a large group of proteins that play crucial roles in cellular processes. For example, these cation channels act as sensors in the detection and transduction of stimuli of temperature, small molecules, voltage, pH, and mechanical constrains. Over the past decades, different members of the TRP channels have been identified in the human gastrointestinal (GI) tract playing multiple modulatory roles. Noteworthy, TRPs support critical functions related to the taste perception, mechanosensation, and pain. They also participate in the modulation of motility and secretions of the human gut. Last but not least, altered expression or activity and mutations in the TRP genes are often related to a wide range of disorders of the gut epithelium, including inflammatory bowel disease, fibrosis, visceral hyperalgesia, irritable bowel syndrome, and colorectal cancer. TRP channels could therefore be promising drug targets for the treatment of GI malignancies. This review aims at providing a comprehensive picture of the most recent advances highlighting the expression and function of TRP channels in the GI tract, and secondly, the description of the potential roles of TRPs in relevant disorders is discussed reporting our standpoint on GI tract–TRP channels interactions.

• colorectal cancer
• gastrointestinal tract
• inflammatory bowel disease
• microbioma
• sensory transduction
• transient receptor potential ion channels
• visceral hypersensitivity

• Colorectal Neoplasms/metabolism
• Colorectal Neoplasms/pathology
• Gastrointestinal Diseases/metabolism
• Gastrointestinal Diseases/pathology
• Humans
• Hyperalgesia/metabolism
• Hyperalgesia/pathology
• Inflammatory Bowel Diseases/metabolism
• Inflammatory Bowel Diseases/pathology
• Transient Receptor Potential Channels/genetics
• Transient Receptor Potential Channels/metabolism

• Salmonella
• inflammation
• intestinal fibrosis
• proteases

Inflammatory bowel disease is known as the most chronic inflammatory disorder in colon, which subsequently progresses to intestinal obstruction and fistula formation. Many studies to date for the treatment of IBD have been focused on inflammation. However, most of the anti-inflammatory agents do not have anti-fibrotic effects and could not relieve intestinal stricture in IBD patients. Because preventing or reversing intestinal fibrosis in IBD is a major therapeutic target, we analyzed the papers focusing on TGF-β signaling in intestinal fibrosis. TGF-β is a good candidate to treat the intestinal fibrosis in IBD which involves TGF-β signaling pathway, EMT, EndMT, ECM, and other regulators. Understanding the mechanism involved in TGF-β signaling will contribute to the treatment and diagnosis of intestinal fibrosis occurring in IBD as well as the understanding of the molecular mechanisms underlying the pathogenesis.

• endothelial-to-mesenchymal transition
• epithelial-to-mesenchymal transition
• extracellular matrix
• inflammatory bowel disease
• intestinal fibrosis
• transforming growth factor-β

• Crohn's disease
• activity
• contrast enhanced ultrasound
• dynamic contrast enhanced MR enterography
• fibrosis
• pathology
• stricture

• Children
• Computed tomography enterography
• Crohn disease
• Inflammatory bowel disease
• Magnetic resonance enterography

Crohn's disease (CD) is a chronic relapsing and remitting inflammatory disease of the gastrointestinal tract. CD is rare in Taiwan and other Asian countries, but its prevalence and incidence have been steadily increasing. A steering committee was established by the Taiwan Society of Inflammatory Bowel Disease to formulate statements on the diagnosis and management of CD taking into account currently available evidence and the expert opinion of the committee. Thorough clinical, endoscopic, and histological assessments are required for accurate diagnosis of CD. Computed tomography and magnetic resonance imaging are complementary to endoscopic evaluation for disease staging and detecting complications. The goals of CD management are to induce and maintain remission, reduce the risk of complications, and improve quality of life. Corticosteroids are the mainstay for inducing re-mission. Immunomodulating and biologic therapies should be used to maintain remission. Patients should be evaluated for hepatitis B virus and tuberculosis infection prior to treatment and receive regular surveillance for cancer. These consensus statements are based on current local evidence with consideration of factors, and could be serve as concise and practical guidelines for supporting clinicians in the management of patients with CD in Taiwan.

• Consensus statements
• Crohn disease
• Disease management
• Inflammatory bowel diseases
• Taiwan

Intestinal fibrosis is a serious complication of inflammatory bowel disease, including Crohn’s disease and ulcerative colitis. There is no specific treatment for intestinal fibrosis. Studies have indicated that peroxisome proliferator-activated receptor- γ (PPAR-γ) agonists have anti-fibrogenic properties in organs besides the gut; however, their effects on human intestinal fibrosis are poorly understood. This study investigated the anti-fibrogenic properties and mechanisms of PPAR-γ agonists on human primary intestinal myofibroblasts (HIFs).

HIFs were isolated from normal colonic tissue of patients undergoing resection due to colorectal cancer. HIFs were treated with TGF-β1 and co-incubated with or without one of two synthetic PPAR-γ agonists, troglitazone or rosiglitazone. mRNA and protein expression of procollagen1A1, fibronectin, and α-smooth muscle actin were determined by semiquantitative reverse transcription-polymerase chain reaction and Western blot. LY294002 (Akt inhibitor) was used to examine whether Akt phosphorylation was a downstream mechanism of TGF-β1 induced expression of procollagen1A1, fibronectin, and α-smooth muscle actin in HIFs. The irreversible PPAR-γ antagonist GW9662 was used to investigate whether the effect of PPAR-γ agonists was PPAR-γ dependent.

Both PPAR-γ agonists reduced the TGF-β1-induced expression of α-smooth muscle actin which was integrated into stress fibers in HIFs, as determined by actin microfilaments fluorescent staining and α-smooth muscle actin-specific immunocytochemistry. PPAR-γ agonists also inhibited TGF-β1-induced mRNA and protein expressions of procollagen1A1, fibronectin, and α-smooth muscle actin. TGF-β1 stimulation increased phosphorylation of downstream signaling molecules Smad2, Akt, and ERK. TGF-β1 induced synthesis of procollagen1A1, fibronectin, and α-smooth muscle actin through a phosphatidylinositol 3-kinase/Akt-dependent mechanism. PPAR-γ agonists down regulated fibrogenesis, as shown by inhibition of Akt and Smad2 phosphorylation. This anti-fibrogenic effect was PPAR-γ independent.

Troglitazone and rosiglitazone suppress TGF-β1-induced synthesis of procollagen1A1, fibronectin, and α-smooth muscle actin in HIFs and may be useful in treating intestinal fibrosis.

The online version of this article (doi:10.1186/s12876-017-0627-4) contains supplementary material, which is available to authorized users.

• Extracellular matrix (ECM)
• Inflammatory bowel disease
• Intestinal fibrosis
• Myofibroblasts
• Rosiglitazone (RSG)
• Troglitazone (TRG)

The current in vitro or in vivo intestinal fibrosis models have many limitations. Recent advancements in the isolation and culturing of organoids has led to development of various three-dimensional (3D) intestinal disease models with in vivo physiology. In this study, we generated an organoid-based epithelial to mesenchymal transition (OEMT) model, which could be used as a novel intestinal fibrosis model. Intestinal epithelial organoids (IEOs) were isolated and cultured from the small intestines of normal mice. IEOs were treated with transforming growth factor- β1 (TGF-β1) or Tumor necrosis factor-α (TNF-α) to evaluate their phenotypic change. Raw 264.7 cells (macrophage) stimulated with lipopolysaccharide were co-cultured with IEOs in growth media with or without TGF-β1. TGF-β1 alone slightly induced epithelial to mesenchymal transition (EMT) in the IEOs but mainly disrupted them. Macrophage released cytokines synergistically induced mesenchymal phenotypic changes in TGF-β1 stimulated intestinal organoids. TNF-α and TGF-β1 synergistically induced proliferation of mesenchymal cells as well as EMT in the IEOs. We generated a novel OEMT model based on our finding that TNF-α and TGF-β synergistically induce type 2 EMT in IEOs. This 3D EMT model with in vivo physiology could be used to study EMT associated intestinal fibrosis.

• Crohn’s disease
• contrast media
• magnetic resonance imaging
• reproducibility of results
• ultrasonography

• Stricture
• consensus
• management

• Anti-Inflammatory Agents/therapeutic use
• Biomarkers/metabolism
• Crohn Disease/genetics
• Crohn Disease/pathology
• Crohn Disease/physiopathology
• Dilatation
• Endoscopy, Gastrointestinal
• Fibrosis/diagnosis
• Fibrosis/therapy
• Genetic Predisposition to Disease
• Humans
• Intestinal Mucosa/metabolism
• Intestinal Obstruction/diagnosis
• Intestinal Obstruction/etiology
• Intestinal Obstruction/pathology
• Intestinal Obstruction/therapy
• Intestines/pathology
• Intestines/surgery
• Laparoscopy
• Prognosis
• Risk Factors

• Crohn’s disease
• Fibrosis
• IBD
• cytokine
• inflammation

• COPD
• Crohn’s disease
• adenosine
• extracellular nucleotides
• fibrosis

• Adenosine/metabolism
• Animals
• Fibrosis/metabolism
• Humans
• Liver/metabolism
• Purinergic Agents/metabolism
• Signal Transduction/physiology
• Uridine Triphosphate/metabolism

• AR56672 NIAMS NIH HHS
• UL1TR000038 NCATS NIH HHS
• R01 AR056672 NIAMS NIH HHS
• AR568593 NIAMS NIH HHS
• R56 AR056672 NIAMS NIH HHS
• R01 DK103723 NIDDK NIH HHS
• UL1 TR000038 NCATS NIH HHS

Although radiotherapy is effective in managing abdominal and pelvic malignant tumors, radiation enteropathy is still unavoidable. This disease severely affects the quality of life of cancer patients due to some refractory lesions, such as intestinal ischemia, mucositis, ulcer, necrosis or even perforation. Current drugs or prevailing therapies are committed to alleviating the symptoms induced by above lesions. But the efficacies achieved by these interventions are still not satisfactory, because the milieus for tissue regeneration are not distinctly improved. In recent years, regenerative therapy for radiation enteropathy by using mesenchymal stem cells is of public interests. Relevant results of preclinical and clinical studies suggest that this regenerative therapy will become an attractive tool in managing radiation enteropathy, because mesenchymal stem cells exhibit their pro-regenerative potentials for healing the injuries in both epithelium and endothelium, minimizing inflammation and protecting irradiated intestine against fibrogenesis through activating intrinsic repair actions. In spite of these encouraging results, whether mesenchymal stem cells promote tumor growth is still an issue of debate. On this basis, we will discuss the advances in anticancer therapy by using mesenchymal stem cells in this review after analyzing the pathogenesis of radiation enteropathy, introducing the advances in managing radiation enteropathy using regenerative therapy and exploring the putative actions by which mesenchymal stem cells repair intestinal injuries. At last, insights gained from the potential risks of mesenchymal stem cell-based therapy for radiation enteropathy patients may provide clinicians with an improved awareness in carrying out their studies.

• Crohn’s disease
• extracellular matrix
• inflammatory bowel disease
• intestinal fibrosis
• matrix metalloproteinases
• tissue inhibitors of metalloproteinases
• ulcerative colitis

• Anti-microbial peptide
• collagen
• inflammatory bowel disease

• azathioprine
• crohn disease
• intestinal obstruction
• mesalamine

• Adult
• Azathioprine/therapeutic use
• Crohn Disease/drug therapy
• Crohn Disease/prevention & control
• Demography
• Female
• Humans
• Ileocecal Valve/pathology
• Ileocecal Valve/radiation effects
• Intestinal Obstruction/drug therapy
• Intestinal Obstruction/prevention & control
• Kaplan-Meier Estimate
• Male
• Mesalamine/therapeutic use
• Middle Aged
• Recurrence
• Smoking/adverse effects
• Treatment Outcome
• Young Adult

Crohn’s disease (CD) is a chronic remitting and relapsing disease. Fibrostenosing complications such as intestinal strictures, stenosis and ultimately obstruction are some of its most common long-term complications. Despite recent advances in the pathophysiological understanding of CD and a significant improvement of anti-inflammatory therapeutics, medical therapy for stricturing CD is still inadequate. No specific anti-fibrotic therapy exists and the incidence rate of strictures has essentially remained unchanged. Therefore, the current therapy of established fibrotic strictures comprises mainly endoscopic dilation as well as surgical approaches. However, these treatment options are associated with major complications as well as high recurrence rates. Thus, a specific anti-fibrotic therapy for CD is urgently needed. Importantly, there is now a growing body of evidence for prevention as well as effective medical treatment of fibrotic diseases of other organs such as the skin, lung, kidney and liver. In face of the similarity of molecular mechanisms of fibrogenesis across these organs, translation of therapeutic approaches from other fibrotic diseases to the intestine appears to be a promising treatment strategy. In particular transforming growth factor beta (TGF-β) neutralization, selective tyrosine kinase inhibitors, blockade of components of the renin-angiotensin system, IL-13 inhibitors and mammalian target of rapamycin (mTOR) inhibitors have emerged as potential drug candidates for anti-fibrotic therapy and may retard progression or even reverse established intestinal fibrosis. However, major challenges have to be overcome in the translation of novel anti-fibrotics into intestinal fibrosis therapy, such as the development of appropriate biomarkers that predict the development and accurately monitor therapeutic responses. Future clinical studies are a prerequisite to evaluate the optimal timing for anti-fibrotic treatment approaches, to elucidate the best routes of application, and to evaluate the potential of drug candidates to reach the ultimate goal: the prevention or reversal of established fibrosis and strictures in CD patients.

• Adolescent
• Adult
• Child
• Crohn Disease/pathology
• Female
• Fibrosis
• Humans
• Ilium/diagnostic imaging
• Ilium/pathology
• Image Processing, Computer-Assisted
• Inflammation
• Intestine, Small/diagnostic imaging
• Intestine, Small/pathology
• Magnetic Resonance Imaging/methods
• Male
• Prospective Studies
• Sensitivity and Specificity
• Tomography, X-Ray Computed/methods
• Young Adult

• UL1 RR025758 NCRR NIH HHS
• UL1 RR025758-02 NCRR NIH HHS

Inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), are chronic, progressive and disabling disorders. Over the last few decades, new therapeutic approaches have been introduced which have led not only to a reduction in the mortality rate but also offered the possibility of a favorable modification in the natural history of IBD. The identification of clinical, genetic and serological prognostic factors has permitted a better stratification of the disease, thus allowing the opportunity to indicate the most appropriate therapy. Early treatment with immunosuppressive drugs and biologics has offered the opportunity to change, at least in the short term, the course of the disease by reducing, in a subset of patients with IBD, hospitalization and the need for surgery. In this review, the crucial steps in the natural history of both UC and CD will be discussed, as well as the factors that may change their clinical course. The methodological requirements for high quality studies on the course and prognosis of IBD, the true impact of environmental and dietary factors on the clinical course of IBD, the clinical, serological and genetic predictors of the IBD course (in particular, which of these are relevant and appropriate for use in clinical practice), the impact of the various forms of medical treatment on the IBD complication rate, the role of surgery for IBD in the biologic era, the true magnitude of risk of colorectal cancer associated with IBD, as well as the mortality rate related to IBD will be stressed; all topics that are extensively discussed in separate reviews included in this issue of World Journal of Gastroenterology.

• Inflammatory bowel disease
• Ulcerative colitis
• Crohn’s disease
• Natural history
• Clinical course
• Complications
• Therapy
• Surgery
• Mortality

• Bone marrow
• Colon
• Colorectal cancer
• Fibrosis
• Mesencyhmal stem cells
• Myofibroblast
• Parathyroid hormone
• Transforming growth factor-β

• Cell Movement/physiology
• Cell Transformation, Neoplastic/pathology
• Colon/cytology
• Colon/pathology
• Colorectal Neoplasms/pathology
• Colorectal Neoplasms/physiopathology
• Disease Progression
• Epithelial Cells/cytology
• Epithelial Cells/pathology
• Epithelial Cells/physiology
• Humans
• Intestinal Mucosa/cytology
• Intestinal Mucosa/pathology
• Intestinal Mucosa/physiology
• Neoplasm Invasiveness
• Stem Cells/cytology
• Stem Cells/physiology
• Wound Healing