sirolimus and Inflammatory-Bowel-Diseases

Inflammatory bowel disease (IBD) is a general term for a group of chronic and progressive disorders. Several cellular and biomolecular pathways are implicated in the pathogenesis of IBD, yet the etiology is unclear. Activation of the mammalian target of rapamycin (mTOR) pathway in the intestinal epithelial cells was also shown to induce inflammation. This review focuses on the inhibition of the mTOR signaling pathway and its potential application in treating IBD. We also provide an overview of plant-derived compounds that are beneficial for the IBD management through modulation of the mTOR pathway. Data were extracted from clinical, in vitro and in vivo studies published in English between 1995 and May 2019, which were collected from PubMed, Google Scholar, Scopus and Cochrane library databases. Results of various studies implied that inhibition of the mTOR signaling pathway downregulates the inflammatory processes and cytokines involved in IBD. In this context, a number of natural products might reverse the pathological features of the disease. Furthermore, mTOR provides a novel drug target for IBD. Comprehensive clinical studies are required to confirm the efficacy of mTOR inhibitors in treating IBD.

Topics: Colitis; Humans; Inflammation; Inflammatory Bowel Diseases; Sirolimus; TOR Serine-Threonine Kinases

Inflammatory bowel disease (IBD) is an immune-mediated disease. Autotaxin (ATX) is associated with increased inflammatory molecules, however, its effect on IBD is not well understood. Autophagy plays an important role in IBD, whether ATX and autophagy act in concert in IBD remains unknown. This study is to explore the possible mechanisms of ATX affecting autophagy leading to the disruption of intestinal epithelial barrier, thereby exacerbating colitis. The expression of ATX was upregulated in UC patients and dextran sulfate sodium (DSS)-induced colitis mice. Here, we described that providing an ATX inhibitor during DSS colitis increased autophagy and ameliorated colonic inflammation. Conversely, intrarectal administration with recombinant (r)ATX increased colitis and decreased autophagy. This pro-colitic effect was attenuated in mice treated with rapamycin, resulting in increased autophagy activity and mild colitis. Moreover, the inhibitory effect of rATX on autophagy was confirmed in vitro and was reversed by the addition of rapamycin. The damaging effects of ATX on epithelial barrier function were reversed by ATX inhibitor or rapamycin treatment. In sum, our results show that ATX can inhibit autophagy through the mTOR pathway, resulting in exaggerated damage to the intestinal epithelial barrier during colitis. These findings suggest that ATX may be a key pro-colitic factor, and represent a potential therapeutic target for treating IBD in the future.

Topics: Animals; Autophagy; Colitis; Inflammation; Inflammatory Bowel Diseases; Mice; Sirolimus

Topics: Adaptor Protein Complex 2; Adaptor Proteins, Signal Transducing; Animals; Autophagy; Clathrin; Claudin-2; Claudins; Endocytosis; Humans; Inflammatory Bowel Diseases; Mice; Permeability; Sirolimus; Tight Junctions

Mitochondrial oxidative phosphorylation (OXPHOS) generates ATP, but OXPHOS also supports biosynthesis during proliferation. In contrast, the role of OXPHOS during quiescence, beyond ATP production, is not well understood. Using mouse models of inducible OXPHOS deficiency in all cell types or specifically in the vascular endothelium that negligibly relies on OXPHOS-derived ATP, we show that selectively during quiescence OXPHOS provides oxidative stress resistance by supporting macroautophagy/autophagy. Mechanistically, OXPHOS constitutively generates low levels of endogenous ROS that induce autophagy via attenuation of ATG4B activity, which provides protection from ROS insult. Physiologically, the OXPHOS-autophagy system (i) protects healthy tissue from toxicity of ROS-based anticancer therapy, and (ii) provides ROS resistance in the endothelium, ameliorating systemic LPS-induced inflammation as well as inflammatory bowel disease. Hence, cells acquired mitochondria during evolution to profit from oxidative metabolism, but also built in an autophagy-based ROS-induced protective mechanism to guard against oxidative stress associated with OXPHOS function during quiescence.

Topics: Adenosine Triphosphate; AMP-Activated Protein Kinases; Animals; Autophagy; Cysteine; Dextrans; DNA, Mitochondrial; Endothelial Cells; Fibroblasts; Formaldehyde; Humans; Inflammatory Bowel Diseases; Isothiocyanates; Lipopolysaccharides; Mechanistic Target of Rapamycin Complex 1; Mice; Microtubule-Associated Proteins; Mitochondria; Phosphatidylethanolamines; Reactive Oxygen Species; Respiration; Sirolimus

Inflammatory bowel disease (IBD) is a chronic condition driven by loss of homeostasis between the mucosal immune system, the commensal gut microbiota, and the intestinal epithelium. Our goal is to understand how these components of the intestinal ecosystem cooperate to control homeostasis. By combining quantitative measures of epithelial hyperplasia and immune infiltration with multivariate analysis of inter- and intracellular signaling, we identified epithelial mammalian target of rapamycin (mTOR) signaling as a potential driver of inflammation in a mouse model of colitis. A kinetic analysis of mTOR inhibition revealed that the pathway regulates epithelial differentiation, which in turn controls the cytokine milieu of the colon. Consistent with our in vivo analysis, we found that cytokine expression of organoids grown ex vivo, in the absence of bacteria and immune cells, was dependent on differentiation state. Our study suggests that proper differentiation of epithelial cells is an important feature of colonic homeostasis because of its effect on the secretion of inflammatory cytokines.

Topics: Animals; Autophagy; Cell Communication; Cell Differentiation; Colitis; Colon; Cytokines; Epithelium; Gastrointestinal Microbiome; Homeostasis; Inflammatory Bowel Diseases; Kinetics; Mice; Multivariate Analysis; Phosphorylation; Principal Component Analysis; Signal Transduction; Sirolimus; Systems Biology; TOR Serine-Threonine Kinases

Topics: Adaptor Proteins, Signal Transducing; Adolescent; Adult; Child; Chronic Disease; Diarrhea; Female; Genetic Predisposition to Disease; Humans; Immunologic Deficiency Syndromes; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Phenotype; Recurrence; Sirolimus; Treatment Outcome; Weight Gain; Young Adult

Management of refractory inflammatory bowel disease (IBD) in children is challenging and once response to conventional medical therapy deviates from the expected, options are often limited. Sirolimus is commonly used in post-transplantation management and is used sparsely as rescue therapy in refractory Crohn's disease. In the present study, we report the efficacy of sirolimus as an adjuvant immunosuppressive therapy in a retrospective case review of a selected group of IBD children who were refractory to the conventional treatments.. Medical records of children with refractory IBD unresponsive to conventional therapy and started on sirolimus between 2006 and 2012 were retrospectively reviewed. Clinical response, through Pediatric Ulcerative Colitis Activity Index (PUCAI) and Pediatric Crohn's Disease Activity Index (PCDAI), as well as intestinal inflammation, through specific histological scores, was evaluated.. The records of 14 patients were analyzed. Eleven of them had ulcerative colitis (UC) and 3 Crohn's disease (CD); mean age at diagnosis was 9.1 years (standard deviation 3.8). Of UC patients, 5 (45%) achieved clinical remission and 2 (18%) showed clinical response. All CD patients went into clinical remission. Mucosal healing was achieved by 5 children (45%) with UC and 2 (67%) with CD patients. One child with ulcerative colitis was weaned off adalimumab, while 2 children with CD were weaned off prednisolone and methotrexate successfully.. Our data provide evidence that sirolimus seems to be effective as rescue therapy in a subgroup of children with severe IBD refractory to conventional therapies by inducing both clinical remission and mucosal healing.

Topics: Child; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Intestinal Mucosa; Male; Recurrence; Remission Induction; Retrospective Studies; Sirolimus; Wound Healing

Post-renal transplant de-novo inflammatory bowel disease (IBD) may develop despite the presence of mycophenolate mofetil (MMF), a drug used for treatment of IBD, in the immunosuppressive regimen. A 39-year-old man received live unrelated renal transplant, and was started postoperatively on prednisolone, MMF, and tacrolimus, which was changed to sirolimus when he developed diabetes mellitus two months post-transplant. Nine months post-transplant, the patient developed recurrent attacks of bloody diarrhea and ischio-rectal abscesses complicated by anal fistulae not responding to routine surgical treatment. Colonoscopy diagnosed IBD, a Crohn's disease-like pattern. The patient was treated with steroids and 5-aminosalicylic acid (5-ASA) in addition to a two months course of ciprofloxacin and metronidazole. He became asymptomatic and rectal lesions healed within one month of treatment. The patient continued to be asymptomatic, and he maintained normal graft function on the same immunosuppressive treatment in addition to 5-ASA. We conclude that de-novo IBD disease can develop in renal transplant recipients in spite of immunosuppressive therapy including MMF.

Topics: Adult; Aminosalicylic Acids; Ciprofloxacin; Crohn Disease; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Kidney Transplantation; Male; Metronidazole; Mycophenolic Acid; Sirolimus; Treatment Outcome