• IBD
• autophagy
• gut microbiota
• rapamycin

• Mice
• Animals
• Gastrointestinal Microbiome
• Sirolimus/adverse effects
• Sirolimus/metabolism
• Hydroxychloroquine/adverse effects
• Hydroxychloroquine/metabolism
• Colitis/chemically induced
• Colitis/drug therapy
• Colitis/metabolism
• Inflammatory Bowel Diseases/pathology
• TOR Serine-Threonine Kinases/metabolism
• Autophagy-Related Proteins
• Dextran Sulfate
• Disease Models, Animal
• Mice, Inbred C57BL
• Colon/pathology

• 82270577 National Natural Science Foundation of China
• 2023A1515030214 Natural Science Foundation of Guangdong Province
• y2eyD2220570 The Fundamental Research Funds for the Central Universities
• y2eyD2220910 The Fundamental Research Funds for the Central Universities
• 202201020248 Guangzhou Planned Project of Science and Technology
• The Project of Key Medical Discipline in Guangzhou (2021-2023)
• 2019GX05 Innovative Clinical Technique of Guangzhou
• 2021A020530 Zhongshan Medical Science and Research Program
• Young Talent Support Project of Guangzhou Association for Science and Technology

• MDP
• NOD2
• autophagy
• colitis
• intestinal barrier

The intestinal mucosa exists in a state of “physiologic hypoxia,” where oxygen tensions are markedly lower than those in other tissues. Intestinal epithelial cells (IECs) have evolved to maintain homeostasis in this austere environment through oxygen-sensitive transcription factors, including hypoxia-inducible factors (HIFs). Using an unbiased chromatin immunoprecipitation (ChIP) screen for HIF-1 targets, we identify autophagy as a major pathway induced by hypoxia in IECs. One important function of autophagy is to defend against intracellular pathogens, termed “xenophagy.” Analysis reveals that HIF is a central regulator of autophagy and that in vitro infection of IECs with Salmonella Typhimurium results in induction of HIF transcriptional activity that tracks with the clearance of intracellular Salmonella. Work in vivo demonstrates that IEC-specific deletion of HIF compromises xenophagy and exacerbates bacterial dissemination. These results reveal that the interaction between hypoxia, HIF, and xenophagy is an essential innate immune component for the control of intracellular pathogens.

Dowdell et al. show that hypoxia, through stabilization of HIF-1α, activates autophagy in intestinal epithelial cells (IECs). Further, the model invasive bacterium Salmonella Typhimurium stabilizes HIF in IECs to trigger anti-bacterial autophagy (xenophagy). This mechanism demonstrates an essential mucosal innate immune response for control of invasive pathogens.

• CP: Immunology
• CP: Microbiology
• autophagy
• chromatin immunoprecipitation
• colitis
• colonoid
• hypoxia
• inflammation
• innate immunity
• mucosa
• neutrophil
• transcription

Recent genetic studies indicated that variants of autophagy genes were associated with the predisposition of Crohn's disease (CD). The autophagy deficiency may affect the innate and adaptive immunity, which is related to persistent and excessive inflammation of the bowel. However, it remains unclear how autophagy modulates the expression of immune response regulator NF-κB and proinflammatory cytokine TNF-α in CD.

We aimed to investigate the role of rapamycin on the expression of NF-κB p65 and TNF-α in 2, 4, 6-trinitrobenzene sulfonic acid (TNBS)-induced mouse colitis and lipopolysaccharide (LPS)-induced HT-29 cells.

TNBS-induced colitis mice were treated with saline or rapamycin, and the disease activity index (DAI) and histological scores of colonic mucosa were evaluated. The expressions of p65, ATG16L1 and LC3 were detected by western blot and immunohistochemistry staining. The monodansylcadaverine (MDC) staining and transmission electron microscopy were developed to study the autophagy in LPS-induced HT-29 cells. Expression of TNF-α from colon tissue and HT-29 cells were detected by ELISA. The expressions of p65, ATG16L1 and LC3 in active CD patients were also investigated.

Significantly more autophagosomes were observed in rapamycin-treated cells than in controls. Rapamycin remarkably upregulated the expression of ATG16L1 and LC3II, inhibited p65 nucleus translocation and secretion of TNF-α both in vivo and in vitro. The expression of both ATG16L1 and LC3II increased in mild to moderate CD specimens, while no significant difference was noted between severe CD and normal controls. The expression of p65 increased notably in severe CD compared to those in mild to moderate patients.

In LPS-treated HT-29 cells and TNBS-induced colitis, p65 is overexpressed, which results in exaggerated secretion of TNF-α and induce or worsen the inflammation in the bowel. Rapamycin protects against colitis through induction of autophagy, thus inhibiting the activation of NF-κB pathway and secretion of TNF-α.

• ageing
• autophagy
• cardiovascular disease
• endoplasmic reticulum stress
• mitophagy

Background: Ulcerative colitis (UC) is a chronic recurrent disease of unknown etiology. Recently, it has been reported that autophagy-related gene polymorphism is closely associated with increased risk of UC, and the therapeutic effect of some UC drugs is mediated by regulating autophagy pathways. This study aims to identify pivotal autophagy-related regulators in UC pathogenesis and provide novel molecular targets for the treatment of active UC.

Methods: Gene expression profiles and clinical information of active UC patients were obtained from GEO databases. CIBERSORT was adopted to evaluate the immune cell infiltration. We used weighted gene co-expression network analysis (WGCNA) and differential expression analysis to identify the pivotal modules and genes associated with active UC. Subsequently, we conducted validation in the validation set and explored its relationship with commonly used UC therapeutics.

Results: 36 healthy controls and 46 active UC patients have been obtained from the training set of GSE53306, GSE87466, and GSE134025. There were 423 differentially expressed genes (DEGs) found, which dramatically enriched in autophagy-related pathways. And more infiltration of mast cells, activated T cells, dendritic cells, and M1 macrophages were observed in the intestinal mucosa of active UC, while more infiltration of resting immune cells and M2 macrophages in healthy controls. WGCNA indicated that the turquoise and blue modules were the critical modules. CASP1, SERPINA1, and CCL2 have been identified as the hub autophagy-related genes of active UC, after combining DEGs and 232 autophagy-related genes from HADb with the genes of turquoise and blue modules, respectively. We further verified that CASP1, SERPINA1, and CCL2 were positively associated with active UC and served as an autophagy-related biomarker for active UC. Moreover, increased SERPINA1 in the involved intestinal mucosa was reduced in patients with active UC who responded to golimumab or glucocorticoid therapy. But, neither CASP1, SERPINA1, and CCL2 were changed by treatment of 5-aminosalicylic acid (5-ASA) and azathioprine.

Conclusion: CASP1, SERPINA1, and CCL2 are autophagy-related hub genes of active UC. And SERPINA1 may serve as a new pharmacological autophagy regulator of UC, which provides a new target for the use of small molecules targeting autophagy in the treatment of active UC.

• WGCNA
• autophagy
• biomarkers
• pharmacology
• ulcerative colitis

• Autophagy
• immune responses
• inflammatory bowel diseases
• intestinal homeostasis
• intestinal microbiota
• microbial infection

• Animals
• Apoptosis Regulatory Proteins/metabolism
• Autophagy/physiology
• Endoplasmic Reticulum Stress/physiology
• Gastrointestinal Microbiome/physiology
• Humans
• Inflammation/metabolism
• Intestines/pathology

• P30 MH062261 NIMH NIH HHS

• Azathioprine
• adherent-invasive E. coli
• autophagy
• mTORC1
• unfolded protein response

• Adolescent
• Autophagy
• Azathioprine/pharmacology
• Case-Control Studies
• Child
• Escherichia coli/drug effects
• Escherichia coli/growth & development
• Escherichia coli Infections/drug therapy
• Escherichia coli Infections/metabolism
• Escherichia coli Infections/microbiology
• Female
• Humans
• Immunosuppressive Agents/pharmacology
• Inflammatory Bowel Diseases/drug therapy
• Inflammatory Bowel Diseases/metabolism
• Inflammatory Bowel Diseases/pathology
• Leukocytes, Mononuclear/drug effects
• Leukocytes, Mononuclear/metabolism
• Leukocytes, Mononuclear/pathology
• Male
• Mechanistic Target of Rapamycin Complex 1/genetics
• Mechanistic Target of Rapamycin Complex 1/metabolism
• Unfolded Protein Response/drug effects
• eIF-2 Kinase/genetics
• eIF-2 Kinase/metabolism

• ETM/389 Chief Scientist Office
• G0800759 Medical Research Council
• ETM/137 Chief Scientist Office
• ETM/395 Chief Scientist Office
• G0800675 Medical Research Council

• ER stress
• IBD
• autophagy
• unfolded protein response

• Animals
• Autophagy
• Humans
• Inflammatory Bowel Diseases/physiopathology
• Signal Transduction
• Unfolded Protein Response

• Chief Scientist Office

• Autophagy
• Inflammation
• Oxidative stress
• mTOR

• Animals
• Autophagy
• Autophagy-Related Protein 5/metabolism
• Cell Line, Tumor
• Colitis/pathology
• Colitis, Ulcerative/metabolism
• Colitis, Ulcerative/pathology
• Female
• Gene Silencing
• Humans
• Inflammation/pathology
• Intestines/pathology
• Intestines/ultrastructure
• Lipopolysaccharides
• MAP Kinase Signaling System
• Mice, Inbred BALB C
• Myeloid Differentiation Factor 88/metabolism
• NF-kappa B/metabolism
• Oxidative Stress
• Phosphorylation
• TOR Serine-Threonine Kinases/metabolism
• Toll-Like Receptor 4/metabolism

Cronkhite-Canada syndrome is a rare syndrome consisting of extensive gastrointestinal polyposis and ectodermal changes including cutaneous hyperpigmentation, alopecia, and onychodystrophy. We report the case of a 45-year-old Caucasian male patient who failed multiple treatments over 2 years including steroids, azathioprine, adalimumab, and cyclosporine. He had recurrent and prolonged hospitalizations because of diarrhea, abdominal pain, weight loss, and malnutrition. Sirolimus was initiated with a significant clinical and endoscopic benefit apparent within, respectively, 2 and 8 weeks. An ongoing remission was achieved and maintained for over 6 months after prednisone tapering. We review the current evidence on treatment of Cronkhite-Canada syndrome and suggest the incorporation of sirolimus in that algorithm.

• Cronkhite-Canada syndrome
• sirolimus
• treatment

• ER stress
• IBD
• epithelial cell culture

• Adult
• Alleles
• Autophagy/genetics
• Autophagy-Related Protein-1 Homolog/genetics
• Autophagy-Related Proteins/genetics
• Biopsy
• Cells, Cultured
• Endoplasmic Reticulum Chaperone BiP
• Endoplasmic Reticulum Stress/drug effects
• Endoplasmic Reticulum Stress/genetics
• Enzyme Inhibitors/pharmacology
• Epithelial Cells/metabolism
• Epithelial Cells/physiology
• Female
• GTP-Binding Proteins/genetics
• Genotype
• Heat-Shock Proteins/genetics
• Humans
• Inflammatory Bowel Diseases/genetics
• Inflammatory Bowel Diseases/pathology
• Intestinal Mucosa/pathology
• Intracellular Signaling Peptides and Proteins/genetics
• Keratin-18/genetics
• Keratin-20/genetics
• Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics
• Male
• Membrane Proteins/genetics
• Middle Aged
• Patient Selection
• Precision Medicine
• Protein Tyrosine Phosphatases, Non-Receptor/genetics
• RNA, Messenger/metabolism
• Receptors, G-Protein-Coupled/genetics
• Thapsigargin/pharmacology
• X-Box Binding Protein 1/genetics

• 694679 European Research Council

Intestinal mucosal barrier, mainly composed of the intestinal mucus layer and the epithelium, plays a critical role in nutrient absorption as well as protection from pathogenic microorganisms. It is widely acknowledged that the damage of intestinal mucosal barrier or the disturbance of microorganism balance in the intestinal tract contributes greatly to the pathogenesis and progression of inflammatory bowel disease (IBD), which mainly includes Crohn’s disease and ulcerative colitis. Autophagy is an evolutionarily conserved catabolic process that involves degradation of protein aggregates and damaged organelles for recycling. The roles of autophagy in the pathogenesis and progression of IBD have been increasingly studied. This present review mainly describes the roles of autophagy of Paneth cells, macrophages, and goblet cells in IBD, and finally, several potential therapeutic strategies for IBD taking advantage of autophagy.

• Paneth cell
• autophagy
• goblet cell
• immune reaction
• inflammatory bowel disease
• macrophage

• basiliximab
• inflammatory bowel disease
• pediatric heart transplant

• Animal models
• Crohn׳s disease
• Experimental colitis
• Inflammatory bowel disease
• Translation
• Ulcerative colitis

• Animals
• Disease Models, Animal
• Humans
• Immunity, Innate
• Immunity, Mucosal
• Inflammatory Bowel Diseases/etiology
• Inflammatory Bowel Diseases/genetics
• Inflammatory Bowel Diseases/immunology
• Inflammatory Bowel Diseases/pathology
• Intestinal Mucosa/immunology
• Intestinal Mucosa/pathology
• Species Specificity
• Translational Research, Biomedical/methods

The intestinal mucosa undergoes a continual process of proliferation, differentiation and apoptosis, which is regulated by multiple signaling pathways. Notch signaling is critical for the control of intestinal stem cell maintenance and differentiation. However, the precise mechanisms involved in the regulation of differentiation are not fully understood. Previously, we have shown that tuberous sclerosis 2 (TSC2) positively regulates the expression of the goblet cell differentiation marker, MUC2, in intestinal cells. Using transgenic mice constitutively expressing a dominant negative TSC2 allele, we observed that TSC2 inactivation increased mTORC1 and Notch activities, and altered differentiation throughout the intestinal epithelium, with a marked decrease in the goblet and Paneth cell lineages. Conversely, treatment of mice with either Notch inhibitor dibenzazepine (DBZ) or mTORC1 inhibitor rapamycin significantly attenuated the reduction of goblet and Paneth cells. Accordingly, knockdown of TSC2 activated, whereas knockdown of mTOR or treatment with rapamycin decreased, the activity of Notch signaling in the intestinal cell line LS174T. Importantly, our findings demonstrate that TSC2/mTORC1 signaling contributes to the maintenance of intestinal epithelium homeostasis by regulating Notch activity.

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

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.

A simultaneous action of several pro-fibrotic mediators appears relevant in the development of fibrosis. There are evidences that transforming growth factor-β (TGF-β)/Smad3 pathway forms with αvβ6 integrin, mammalian target of Rapamycin (mTOR) and peroxisome proliferator-activated receptor-γ (PPARγ) a complex signalling network with extensive crosstalk and strong effects on fibrosis development. The present study evaluated the expression of TGFβ, Smad3, αvβ6 integrin, mTOR and PPARγ in 2, 4, 6-trinitrobenzenesulphonic acid (TNBS)-induced colorectal fibrosis in Smad3 wild-type (WT) and null mice. Smad3 WT mice treated with TNBS developed a marked colorectal fibrosis and showed a concomitant up-regulation of TGFβ, Smad3, αvβ6 and mTOR and a reduction of PPARγ expression. On the other hand, Smad3 Null mice similarly treated with TNBS did not develop fibrosis and showed a very low or even absent expression of TGFβ, Smad3, αvβ6 and mTOR and a marked over-expression of PPARγ. At the same time the expression of α-smooth muscle actin (a marker of activated myofibroblasts), collagen I-III and connective tissue growth factor (a downstream effector of TGFβ/Smad3-induced extracellular matrix proteins) were up-regulated in Smad3 WT mice treated with TNBS compared to Null TNBS-treated mice. These preliminary results suggest a possible interaction between these pro-fibrotic molecules in the development of intestinal fibrosis.

Fibrosis is a chronic and progressive process characterized by an excessive accumulation of extracellular matrix (ECM) leading to stiffening and/or scarring of the involved tissue. Intestinal fibrosis may develop in several different enteropathies, including inflammatory bowel disease. It develops through complex cell, extracellular matrix, cytokine and growth factor interactions. Distinct cell types are involved in intestinal fibrosis, such as resident mesenchymal cells (fibroblasts, myofibroblasts and smooth muscle cells) but also ECM-producing cells derived from epithelial and endothelial cells (through a process termed epithelial- and endothelial-mesenchymal transition), stellate cells, pericytes, local or bone marrow-derived stem cells. The most important soluble factors that regulate the activation of these cells include cytokines, chemokines, growth factors, components of the renin-angiotensin system, angiogenic factors, peroxisome proliferator-activated receptors, mammalian target of rapamycin, and products of oxidative stress. It soon becomes clear that although inflammation is responsible for triggering the onset of the fibrotic process, it only plays a minor role in the progression of this condition, as fibrosis may advance in a self-perpetuating fashion. Definition of the cellular and molecular mechanisms involved in intestinal fibrosis may provide the key to developing new therapeutic approaches.

• Inflammatory bowel disease
• Intestinal fibrosis
• Extracellular matrix
• Molecular mediators
• Myofibroblasts
• Inflammatory cells
• Epithelial cells
• Mesenchymal cells
• Endothelial cells

• autophagy
• inflammatory bowel disease
• crohn's disease
• anti-bacterial response
• mucosal immunology

• autophagy
• crohn's disease
• infection
• inflammation
• immunity
• cancer

• Animals
• Autophagy
• Bacterial Infections/complications
• Crohn Disease/complications
• Crohn Disease/immunology
• Crohn Disease/microbiology
• Crohn Disease/pathology
• Humans
• Immunity/immunology
• Inflammation/complications
• Neoplasms/complications

• R01 GM053396 NIGMS NIH HHS