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IBD
Modulation of Gut Microbiota Composition by Serotonin Signaling Influences Intestinal Immune Response and Susceptibility to Colitis
Serotonin (5-hydroxytryptamine [5-HT]) is synthesized mainly within enterochromaffin (EC) cells in the gut, and tryptophan hydroxylase 1 (Tph1) is the rate-limiting enzyme for 5-HT synthesis in EC cells. Accumulating evidence suggests the importance of gut microbiota in intestinal inflammation. Considering the close proximity of EC cells and the microbes, we investigated the influence of gut-derived 5-HT on the microbiota and the susceptibility to colitis.Plant-based Enteral Nutrition Modifies the Gut Microbiota and Improves Outcomes in Murine Models of Colitis
Exclusive enteral nutrition (EEN), ie, restricting patients to commercially available liquid diets with avoidance of solid food, is an effective treatment for Crohn’s disease (CD).1 However, commercial formulas used for EEN generally have low fiber and high sugar content and contain emulsifiers that worsen colitis in animal models.2 Despite its efficacy, EEN appears to accentuate microbial changes observed in CD, specifically a loss of protective anaerobes and the growth of pathogens.3 Plant-based enteral nutrition (PBEN) represents a high-fiber alternative to conventional enteral nutrition (CEN) without added sugar or artificial ingredients.Mouse Model of Mutated in Colorectal Cancer Gene Deletion Reveals Novel Pathways in Inflammation and Cancer
The early events by which inflammation promotes cancer are still not fully defined. The MCC gene is silenced by promoter methylation in colitis-associated and sporadic colon tumors, but its functional significance in precancerous lesions or polyps is not known. Here, we aimed to determine the impact of Mcc deletion on the cellular pathways and carcinogenesis associated with inflammation in the mouse proximal colon.TTC7A: Steward of Intestinal Health
The increasing incidence of pediatric inflammatory bowel disease, coupled with the efficiency of whole-exome sequencing, has led to the identification of tetratricopeptide repeat domain 7A (TTC7A) as a steward of intestinal health. TTC7A deficiency is an autosomal-recessively inherited disease. In the 5 years since the original description, more than 50 patients with more than 20 distinct disease-causing TTC7A mutations have been identified. Patients show heterogenous intestinal and immunologic disease manifestations, including but not limited to multiple intestinal atresias, very early onset inflammatory bowel disease, loss of intestinal architecture, apoptotic enterocolitis, combined immunodeficiency, and various extraintestinal features related to the skin and/or hair.Loss of Forkhead Box O3 Facilitates Inflammatory Colon Cancer: Transcriptome Profiling of the Immune Landscape and Novel Targets
Diminished forkhead box O3 (FOXO3) function drives inflammation and cancer growth; however, mechanisms fostering these pathobiologies are unclear. Here, we aimed to identify in colon loss of FOXO3-dependent cellular and molecular changes that facilitate inflammation-mediated tumor growth.Toll-Like Receptor 7 Agonist–Induced Dermatitis Causes Severe Dextran Sulfate Sodium Colitis by Altering the Gut Microbiome and Immune Cells
Psoriasis and inflammatory bowel disease (IBD) are both chronic inflammatory diseases occurring in the skin and gut, respectively. It is well established that psoriasis and IBD have high concordance rates, and similar changes in immune cells and microbiome composition have been reported in both conditions. To study this connection, we used a combination murine model of psoriatic dermatitis and colitis in which mice were treated topically with the Toll-like receptor 7 agonist imiquimod (IMQ) and fed dextran sulfate sodium (DSS).Disruption of FOXP3–EZH2 Interaction Represents a Pathobiological Mechanism in Intestinal Inflammation
Forkhead box protein 3 (FOXP3)+ regulatory T cell (Treg) dysfunction is associated with autoimmune diseases; however, the mechanisms responsible for inflammatory bowel disease pathophysiology are poorly understood. Here, we tested the hypothesis that a physical interaction between transcription factor FOXP3 and the epigenetic enzyme enhancer of zeste homolog 2 (EZH2) is essential for gene co-repressive function.The Food Additive Maltodextrin Promotes Endoplasmic Reticulum Stress–Driven Mucus Depletion and Exacerbates Intestinal Inflammation
Food additives, such as emulsifiers, stabilizers, or bulking agents, are present in the Western diet and their consumption is increasing. However, little is known about their potential effects on intestinal homeostasis. In this study we examined the effect of some of these food additives on gut inflammation.NHE8 Deficiency Promotes Colitis-Associated Cancer in Mice via Expansion of Lgr5-Expressing Cells
Lgr5 overexpression has been detected in colorectal cancers (CRCs), including some cases of colitis-associated CRCs. In colitis-associated CRCs, chronic inflammation is a contributing factor in carcinogenesis. We recently reported that intestinal Na+/H+ exchanger isoform 8 (NHE8) plays an important role in intestinal mucosal protection and that loss of NHE8 expression results in an ulcerative colitis–like condition. Therefore, we hypothesized that NHE8 may be involved in the development of intestinal tumors.Mesenteric Adipose-derived Stromal Cells From Crohn’s Disease Patients Induce Protective Effects in Colonic Epithelial Cells and Mice With Colitis
Mesenteric adipose tissue hyperplasia is a hallmark of Crohn’s disease (CD). Recently, we showed that mesenteric adipose-derived stromal cells (ADSCs) from CD, ulcerative colitis, and control patients synthesize and release adipokines in a disease-dependent manner. Here we examined the expression profiles of CD and control patient-derived mesenteric ADSCs and studied the effects of their extracellular mediators on colonocyte signaling in vitro and experimental colitis in vivo. ADSCs were isolated from mesenteric fat of control and CD patients.Neonatal Colonic Inflammation Epigenetically Aggravates Epithelial Inflammatory Responses to Injury in Adult Life
Early life adversity is considered a risk factor for the development of gastrointestinal diseases, including inflammatory bowel disease. We hypothesized that early life colonic inflammation causes susceptibility to aggravated overexpression of interleukin (IL)1β.Nod-Like Receptor Pyrin-Containing Protein 6 (NLRP6) Is Up-regulated in Ileal Crohn’s Disease and Differentially Expressed in Goblet Cells
A contributing factor in the development of ulcerative colitis (UC) and Crohn’s disease (CD) is aberrant signaling of the innate immune complex known as the inflammasome. The inflammasome regulates the production of interleukin (IL)1β and drives downstream inflammatory pathways. In this study of human tissue (ethics approval: H11930), we provide evidence for the disease-specific up-regulation of NLRP6 transcript and protein in ileal CD and describe an NLRP6-expressing goblet cell (GC) located predominantly in the upper portion of the intestinal crypt.Epithelial Smad4 Deletion Up-Regulates Inflammation and Promotes Inflammation-Associated Cancer
Chronic inflammation is a predisposing condition for colorectal cancer. Many studies to date have focused on proinflammatory signaling pathways in the colon. Understanding the mechanisms that suppress inflammation, particularly in epithelial cells, is critical for developing therapeutic interventions. Here, we explored the roles of transforming growth factor β (TGFβ) family signaling through SMAD4 in colonic epithelial cells.Increased Pancreatic Protease Activity in Response to Antibiotics Impairs Gut Barrier and Triggers Colitis
Antibiotic (ABx) therapy is associated with increased risk for Crohn’s disease but underlying mechanisms are unknown. We observed high fecal serine protease activity (PA) to be a frequent side effect of ABx therapy. The aim of the present study was to unravel whether this rise in large intestinal PA may promote colitis development via detrimental effects on the large intestinal barrier.Bowel Location Rather Than Disease Subtype Dominates Transcriptomic Heterogeneity in Pediatric IBD
Genome-wide association studies have uncovered approximately 250 common loci with strong associations in inflammatory bowel disease (IBD).1 The current challenge is to understand the underlying molecular mechanisms whereby each locus predisposes to IBD.2 In this regard, transcriptomic profiling dissecting gene expression patterns in tissues where the chronic inflammation occurs, as well as studies on its genetic control (expression quantitative trail loci [eQTL]), are beginning to shed some light into IBD pathophysiology.Activation of Myofibroblast TRPA1 by Steroids and Pirfenidone Ameliorates Fibrosis in Experimental Crohn's Disease
The transient receptor potential ankyrin 1 (TRPA1) channel is highly expressed in the intestinal lamina propria, but its contribution to gut physiology/pathophysiology is unclear. Here, we evaluated the function of myofibroblast TRPA1 channels in intestinal remodeling.Thymic Stromal Lymphopoietin: To Cut a Long Story Short
Thymic stromal lymphopoietin (TSLP) was identified more than 20 years ago as a secreted factor of a mouse thymic stromal cell line; later, a human orthologue was also identified. The signaling pathway triggered by TSLP has been extensively studied, and upregulation of the cytokine itself is linked to the pathogenesis of numerous Th2-related diseases, including atopic dermatitis, asthma, allergic responses, as well as certain types of cancers. On the other hand, TSLP mediates several immune homeostatic functions in both the gut and the thymus.Pathophysiology of Intestinal Na+/H+ Exchange
Several members of the SLC9A family of Na+/H+ exchangers are expressed in the gut, with varying expression patterns and cellular localization. Not only do they participate in the regulation of basic epithelial cell functions, including control of transepithelial Na+ absorption, intracellular pH (pHi), cell volume, and nutrient absorption, but also in cellular proliferation, migration, and apoptosis. In addition, they modulate the extracellular milieu to facilitate other nutrient absorption and to regulate the intestinal microbial microenvironment.Disease-Associated Microbial Communities in Healthy Relatives: A Bacteria-Filled Crystal Ball?
The bacterial community within the gastrointestinal tract has been the subject of a great deal of investigation as well as a great deal of press. Numerous studies have shown that inflammatory bowel disease (IBD) is associated with an alteration in the ecological system within our gut,1 and findings from mouse models suggest that inflammation-associated microbiota transplanted from human IBD patients can contribute actively to colitis.2 Still, it is not clear whether dysbiosis is either necessary or sufficient as an initiating event—especially in human beings—or if in contrast only a microbiome that already has been shaped by the inflammatory state is able to contribute further to disease.Interferon-Alpha Promotes Th1 Response and Epithelial Apoptosis via Inflammasome Activation in Human Intestinal Mucosa
Several lines of investigation suggest that interferon (IFN) alpha can alter human intestinal mucosa homeostasis. These include the endogenous production of IFN alpha in celiac disease or inflammatory bowel diseases, as well as the occurrence of intestinal side effects of exogenous IFN alpha used as a therapeutic tool. Here, we present an ex vivo translational approach to investigate the effects of IFN alpha on the human normal intestinal mucosa, as well as its underlying mechanisms.Requirement of Gαq/Gα11 Signaling in the Preservation of Mouse Intestinal Epithelial Homeostasis
Proliferation, differentiation, and morphogenesis of the intestinal epithelium are tightly regulated by a number of molecular pathways. Coordinated action of intestine is achieved by gastrointestinal hormones, most of which exert these actions through G-protein–coupled receptors. We herein investigated the role of Gαq/11-mediated signaling in intestinal homeostasis.Zooming in on Inflammatory Bowel Disease: Microbial and Proteomic Features Associated With IBD in Colonic Microenvironments
Inflammatory bowel disease (IBD) is a multifactorial chronic intestinal inflammatory disorder characterized both by genetic and environmental factors.1 Among the latter, the microbiome recently emerged as one of the most promising avenues of research to understand the pathogenesis of IBD. Several studies have shown differences in microbiome composition and diversity in IBD patients compared with healthy controls.2,3 Larger cohorts have allowed for further characterization of the gut microbiota in IBD patients, including assays that determine function and activity of the microbiome and thus provide better mechanistic insights.A Disease-Associated Microbial and Metabolomics State in Relatives of Pediatric Inflammatory Bowel Disease Patients
Microbes may increase susceptibility to inflammatory bowel disease (IBD) by producing bioactive metabolites that affect immune activity and epithelial function. We undertook a family based study to identify microbial and metabolic features of IBD that may represent a predisease risk state when found in healthy first-degree relatives.Metagenomic Characterization of Microbial Communities In Situ Within the Deeper Layers of the Ileum in Crohn’s Disease
Microbial dysbiosis and aberrant host–microbe interactions in the gut are believed to contribute to the development and progression of Crohn’s disease (CD). Microbiome studies in CD typically have focused on microbiota in feces or superficial mucosal layers of the colon because accessing DNA from deeper layers of the bowel is challenging. In this study, we analyzed the deep tissue microbiome in patients who underwent surgical resection of the small intestine.Microgeographic Proteomic Networks of the Human Colonic Mucosa and Their Association With Inflammatory Bowel Disease
Interactions between mucosal cell types, environmental stressors, and intestinal microbiota contribute to pathogenesis in inflammatory bowel disease (IBD). Here, we applied metaproteomics of the mucosal–luminal interface to study the disease-related biology of the human colonic mucosa.
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