ABSTRACT
Inflammatory bowel disease (IBD) is a chronic disorder of the gastrointestinal tract that has limited treatment options. To gain insight into the pathogenesis of chronic colonic inflammation (colitis), we performed a multiomics analysis that integrated RNA microarray, total protein mass spectrometry (MS), and phosphoprotein MS measurements from a mouse model of the disease. Because we collected all three types of data from individual samples, we tracked information flow from RNA to protein to phosphoprotein and identified signaling molecules that were coordinately or discordantly regulated and pathways that had complex regulation in vivo. For example, the genes encoding acute-phase proteins were expressed in the liver, but the proteins were detected by MS in the colon during inflammation. We also ascertained the types of data that best described particular facets of chronic inflammation. Using gene set enrichment analysis and trans-omics coexpression network analysis, we found that each data set provided a distinct viewpoint on the molecular pathogenesis of colitis. Combining human transcriptomic data with the mouse multiomics data implicated increased p21-activated kinase (Pak) signaling as a driver of colitis. Chemical inhibition of Pak1 and Pak2 with FRAX597 suppressed active colitis in mice. These studies provide translational insights into the mechanisms contributing to colitis and identify Pak as a potential therapeutic target in IBD.
Subject(s)
Colitis/genetics , Gene Expression Profiling/methods , Proteomics/methods , Signal Transduction/genetics , p21-Activated Kinases/genetics , Animals , Cells, Cultured , Colitis/metabolism , Disease Models, Animal , Gene Regulatory Networks/genetics , Humans , Mice, Inbred C57BL , Pyridones/pharmacology , Pyrimidines/pharmacology , Signal Transduction/drug effects , p21-Activated Kinases/metabolismABSTRACT
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.
Subject(s)
Colitis/metabolism , Colon/immunology , Cytokines/metabolism , Animals , Autophagy , Cell Communication , Cell Differentiation , Colon/metabolism , Colon/pathology , Epithelium/immunology , Epithelium/metabolism , Gastrointestinal Microbiome , Homeostasis , Inflammatory Bowel Diseases/immunology , Inflammatory Bowel Diseases/metabolism , Inflammatory Bowel Diseases/pathology , Kinetics , Mice , Multivariate Analysis , Phosphorylation , Principal Component Analysis , Signal Transduction , Sirolimus/pharmacology , Systems Biology , TOR Serine-Threonine Kinases/antagonists & inhibitors , TOR Serine-Threonine Kinases/metabolismABSTRACT
Inflammatory bowel diseases (IBD) are chronic autoimmune conditions of the gut affecting both pediatric and adult patients. Medical therapy is often successful at inducing and maintaining remission and preventing disease complications. The mainstays of treatment are medications and other therapies that reduce inflammation and suppress the overactive immune system. Here we review current medical therapies for pediatric IBD, discuss future therapeutics, and present current treatment goals and approaches.
Subject(s)
Anti-Inflammatory Agents/therapeutic use , Colitis, Ulcerative/drug therapy , Crohn Disease/therapy , Diet Therapy , Enteral Nutrition , Immunosuppressive Agents/therapeutic use , Child , Combined Modality Therapy , HumansABSTRACT
BACKGROUND: The Anti-Inflammatory Diet (IBD-AID) is a nutritional regimen for inflammatory bowel disease (IBD) that restricts the intake of certain carbohydrates, includes the ingestion of pre- and probiotic foods, and modifies dietary fatty acids to demonstrate the potential of an adjunct dietary therapy for the treatment of IBD. METHODS: Forty patients with IBD were consecutively offered the IBD-AID to help treat their disease, and were retrospectively reviewed. Medical records of 11 of those patients underwent further review to determine changes in the Harvey Bradshaw Index (HBI) or Modified Truelove and Witts Severity Index (MTLWSI), before and after the diet. RESULTS: Of the 40 patients with IBD, 13 patients chose not to attempt the diet (33%). Twenty-four patients had either a good or very good response after reaching compliance (60%), and 3 patients' results were mixed (7%). Of those 11 adult patients who underwent further medical record review, 8 with CD, and 3 with UC, the age range was 19-70 years, and they followed the diet for 4 or more weeks. After following the IBD-AID, all (100%) patients were able to discontinue at least one of their prior IBD medications, and all patients had symptom reduction including bowel frequency. The mean baseline HBI was 11 (range 1-20), and the mean follow-up score was 1.5 (range 0-3). The mean baseline MTLWSI was 7 (range 6-8), and the mean follow-up score was 0. The average decrease in the HBI was 9.5 and the average decrease in the MTLWSI was 7. CONCLUSION: This case series indicates potential for the IBD-AID as an adjunct dietary therapy for the treatment of IBD. A randomized clinical trial is warranted.
