Human enteroids: Preclinical models of non-inflammatory diarrhea

Researchers need an available and easy-to-use model of the human intestine to better understand human intestinal physiology and pathophysiology of diseases, and to offer an enhanced platform for developing drug therapy. Our work employs human enteroids derived from each of the major intestinal sections to advance understanding of several diarrheal diseases, including those caused by cholera, rotavirus and enterohemorrhagic Escherichia coli. An enteroid bank is being established to facilitate comparison of segmental, developmental, and regulatory differences in transport proteins that can influence therapy efficacy. Basic characterization of major ion transport protein expression, localization and function in the human enteroid model sets the stage to study the effects of enteric infection at the transport level, as well as to monitor potential responses to pharmacological intervention

Infliximab-induced psoriasis and psoriasiform skin lesions in pediatric Crohn disease and a potential association with IL-23 receptor polymorphisms

Infliximab (IFX), an established therapy for pediatric Crohn disease (CD), is also efficacious in treating psoriasis, a skin disorder, in which tumor necrosis factor-α is implicated pathogenically. Paradoxically, there have been numerous reports of new-onset psoriasis following tumor necrosis factor-α antagonist therapy in adult patients with inflammatory bowel disease, but pediatric data are sparse. A retrospective review of all IFX-treated patients with CD, who subsequently developed psoriasis, at a single pediatric inflammatory bowel disease center, was performed. A subset of affected patients (10/18) and CD controls (147 of 172) treated with IFX but without the development of psoriasis were genotyped for polymorphisms in the interleukin-23 receptor (IL-23R) gene, which has been identified as conferring susceptibility to both CD and psoriasis. Eighteen (10.5%) of 172 IFX-treated patients with CD developed new-onset psoriasis (n = 17) or worsening of existing psoriasis (n = 1). The duration of IFX exposure was variable, ranging from 1 to 25 infusions. Three patients discontinued IFX because of this complication. Most patients responded well to topical steroid therapy. In comparison to disease-matched controls, patients with CD developing psoriasis following IFX therapy were more likely to be homozygous for specific polymorphisms in the IL-23R gene (rs10489628, rs10789229, and rs1343151). As in adults, the development of psoriasis or psoriasiform skin lesions occurs in pediatric patients with CD treated with IFX. Adequately powered studies are required to further explore the preliminary findings reported here to determine whether polymorphisms in the IL-23R gene have a role in the pathogenesis of this paradoxical process, which presently remains unexplaine

Effect of Exclusive Enteral Nutrition and Corticosteroid Induction Therapy on the Gut Microbiota of Pediatric Patients with Inflammatory Bowel Disease

Introduction: Exclusive enteral nutrition (EEN) and corticosteroids (CS) are effective induction therapies for pediatric Crohn’s Disease (CD). CS are also therapy for ulcerative colitis (UC). Host–microbe interactions may be able to explain the effectiveness of these treatments. This is the first prospective study to longitudinally characterize compositional changes in the bacterial community structure of pediatric UC and CD patients receiving EEN or CS induction therapy. Methods: Patients with diagnoses of CD or UC were recruited from McMaster Children’s Hospital (Hamilton, Canada). Fecal samples were collected from participants aged 5–18 years old undergoing 8 weeks of induction therapy with EEN or CS. Fecal samples were submitted for 16S rRNA sequencing. The Shannon diversity index and the relative abundance of specific bacterial taxa were compared using a linear mixed model. Results: The clustering of microbiota was the highest between patients who achieved remission compared to patients still showing active disease (p = 0.029); this effect was independent of the diagnosis or treatment type. All patients showed a significant increase in Shannon diversity over the 8 weeks of treatment. By week 2, a significant difference was seen in Shannon diversity between patients who would go on to achieve remission and those who would not. Conclusion: The gut microbiota of pediatric UC and CD patients was most influenced by patients’ success or failure to achieve remission and was largely independent of the choice of treatment or disease type. Significant differences in Shannon diversity indices occurred as early as week 2 between patients who went on to achieve remission and those who continued to have active disease

Nutritional therapies and their influence on the intestinal microbiome in pediatric inflammatory bowel disease

Inflammatory bowel disease (IBD) is a chronic, autoimmune disorder of the gastrointestinal tract with numerous genetic and environmental risk factors. Patients with Crohn’s disease (CD) or ulcerative colitis (UC) often demonstrate marked disruptions of their gut microbiome. The intestinal microbiota is strongly influenced by diet. The association between the increasing incidence of IBD worldwide and increased consumption of a westernized diet suggests host nutrition may influence the progression or treatment of IBD via the microbiome. Several nutritional therapies have been studied for the treatment of CD and UC. While their mechanisms of action are only partially understood, existing studies do suggest that diet-driven changes in microbial composition and function underlie the diverse mechanisms of nutritional therapy. Despite existing therapies for IBD fo-cusing heavily on immune suppression, nutrition is an important treatment option due to its supe-rior safety profile, potentially low cost, and benefits for growth and development. These benefits are increasingly important to patients. In this review, we will describe the clinical efficacy of the different nutritional therapies that have been described for the treatment of CD and UC. We will also describe the effects of each nutritional therapy on the gut microbiome and summarize the strength of the literature with recommendations for the practicing clinician

Chk1 is required for spindle checkpoint function

The spindle checkpoint delays anaphase onset in cells with mitotic spindle defects. Here, we show that Chk1, a component of the DNA damage and replication checkpoints, protects vertebrate cells against spontaneous chromosome missegregation and is required to sustain anaphase delay when spindle function is disrupted by taxol, but not when microtubules are completely depolymerized by nocodazole. Spindle checkpoint failure in Chk1-deficient cells correlates with decreased Aurora-B kinase activity and impaired phosphorylation and kinetochore localization of BubR1. Furthermore, Chk1 phosphorylates Aurora-B and enhances its catalytic activity in vitro. We propose that Chk1 augments spindle checkpoint signaling and is required for optimal regulation of Aurora-B and BubR1 when kinetochores produce a weakened signal. In addition, Chk1-deficient cells exhibit increased resistance to taxol. These results suggest a mechanism through which Chk1 could protect against tumorigenesis through its role in spindle checkpoint signaling