Enhancing Human Treg Cell Induction through Engineered Dendritic Cells and Zinc Supplementation.

Regulatory T (Treg) cells hold promise for the ultimate cure of immune-mediated diseases. However, how to effectively restore Treg function in patients remains unknown. Previous reports suggest that activated dendritic cells (DCs) de novo synthesize locally high concentrations of 1,25-dihydroxy vitamin D, i.e., the active vitamin D or 1,25(OH)2D by upregulating the expression of 25-hydroxy vitamin D 1α-hydroxylase. Although 1,25(OH)2D has been shown to induce Treg cells, DC-derived 1,25(OH)2D only serves as a checkpoint to ensure well-balanced immune responses. Our animal studies have shown that 1,25(OH)2D requires high concentrations to generate Treg cells, which can cause severe side effects. In addition, our animal studies have also demonstrated that dendritic cells (DCs) overexpressing the 1α-hydroxylase de novo synthesize the effective Treg-inducing 1,25(OH)2D concentrations without causing the primary side effect of hypercalcemia (i.e., high blood calcium levels). This study furthers our previous animal studies and explores the efficacy of the la-hydroxylase-overexpressing DCs in inducing human CD4+FOXP3+regulatory T (Treg) cells. We discovered that the effective Treg-inducing doses of 1,25(OH)2D were within a range. Additionally, our data corroborated that the 1α-hydroxylase-overexpressing DCs synthesized 1,25(OH)2D within this concentration range in vivo, thus facilitating effective Treg cell induction. Moreover, this study demonstrated that 1α-hydroxylase expression levels were pivotal for DCs to induce Treg cells because physiological 25(OH)D levels were sufficient for the engineered but not parental DCs to enhance Treg cell induction. Interestingly, adding non-toxic zinc concentrations significantly augmented the Treg-inducing capacity of the engineered DCs. Our new findings offer a novel therapeutic avenue for immune-mediated human diseases, such as inflammatory bowel disease, type 1 diabetes, and multiple sclerosis, by integrating zinc with the 1α-hydroxylase-overexpressing DCs.

Inflammation- and Gut-Homing Macrophages, Engineered to De Novo Overexpress Active Vitamin D, Promoted the Regenerative Function of Intestinal Stem Cells.

Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gut. Available drugs aim to suppress gut inflammation. These drugs have significantly delayed disease progression and improved patients' quality of life. However, the disease continues to progress, underscoring the need to develop novel therapies. Aside from chronic gut inflammation, IBD patients also experience a leaky gut problem due to damage to the intestinal epithelial layer. In this regard, epithelial regeneration and repair are mediated by intestinal stem cells. However, no therapies are available to directly enhance the intestinal stem cells' regenerative and repair function. Recently, it was shown that active vitamin D, i.e., 1,25-dihydroxyvitamin D or 1,25(OH)2D, was necessary to maintain Lgr5+ intestinal stem cells, actively cycling under physiological conditions. In this study, we used two strategies to investigate the role of 1,25(OH)2D in intestinal stem cells' regenerative function. First, to avoid the side effects of systemic high 1,25(OH)2D conditions, we used our recently developed novel strategy to deliver locally high 1,25(OH)2D concentrations specifically to inflamed intestines. Second, because of the Lgr5+ intestinal stem cells' active cycling status, we used a pulse-and-chase strategy via 5-bromo-2'-deoxyuridine (BrdU) labeling to trace the Lgr5+ stem cells through the whole epithelial regeneration process. Our data showed that locally high 1,25(OH)2D concentrations enhanced intestinal stem cell migration. Additionally, the migrated cells differentiated into mature epithelial cells. Our data, therefore, suggest that local delivery of high 1,25(OH)2D concentrations is a promising strategy to augment intestinal epithelial repair in IBD patients.

Progress in Corticosteroid Use in the Era of Biologics With Room for Improvement.

ABSTRACT: With the early success of their trials for the treatment of ulcerative colitis, corticosteroids gained popularity as a treatment for inflammatory bowel disease (IBD). However, when used chronically, corticosteroids are not effective in maintaining remission and associated with toxic effects. Steroid-free remission has become a major treatment goal. Prolonged corticosteroid use is currently a sign of suboptimal quality of care. Trends over the past 2 decades, spanning the emergence of biologic therapies for IBD, are explored here in the University of Manitoba IBD Epidemiologic Database.

Prevalence and Impact of Inflammatory Bowel Disease-Irritable Bowel Syndrome on Patient-reported Outcomes in CCFA Partners.

BACKGROUND: Inflammatory bowel disease (IBD) patients with persistent symptoms despite no or minimal inflammation are frequently described as having an overlap of IBD and irritable bowel syndrome (IBD-IBS). Limited data are available on how IBS impacts the individual patient with IBD. In this study, we aimed to evaluate the prevalence of IBD-IBS and investigate its impact on patient-reported outcomes. METHOD: We performed a cross-sectional analysis within the CCFA Partners Study. Bivariate analyses and logistic regression models were used to investigate associations between IBD-IBS and various demographic, disease factors, and patient-reported outcomes including anxiety, depression, sleep disturbances, pain interference, and social satisfaction. RESULTS: Of the 6309 participants included, a total of 1279 (20%) reported a coexisting IBS diagnosis. The prevalence of IBD-IBS in this cohort was similar within disease subtypes. A diagnosis of IBD-IBS was associated with higher narcotic use compared with those with no IBS diagnosis for both Crohn's disease, 17% versus 11% (P < 0.001) and ulcerative colitis/indeterminate colitis, 9% versus 5% (P < 0.001). Quality of life, as measured by Short Inflammatory Bowel Disease Questionnaire (SIBDQ) was lower in patients with IBD-IBS compared with those without. IBD-IBS diagnosis was associated with anxiety, depression, fatigue, sleep disturbances, pain interference, and decreased social satisfaction. CONCLUSIONS: In this sample of patients with IBD, high prevalence of concomitant IBS diagnosis was observed. IBD-IBS diagnosis was associated with increased narcotic use and adverse patient-reported outcome. Appropriate diagnosis, treatment, and counseling may help improve the functional status of IBD-IBS patients and decrease narcotic use.

The Impact of Ostomy on Quality of Life and Functional Status of Crohn's Disease Patients.

BACKGROUND: The potential need for an ostomy is a main concern for patients with inflammatory bowel disease. We performed this study to evaluate the impact of a long-term ostomy (≥6 mo duration) on the functional status and specific patient-reported outcomes in a population of patients with Crohn's disease (CD). METHODS: We performed a cross-sectional analysis within the Crohn's and Colitis Foundation of America Partners cohort. Bivariate analyses and logistic regression models were used to investigate associations between ostomy and various demographic, disease factors, and patient-reported outcomes for health-related quality of life. RESULTS: A total of 402 CD patients with ostomy for a minimum duration of 6 months were compared with 4331 CD patients with no ostomy. Patients with ostomy were more likely to be in clinical remission compared with those without ostomy, 48.5% versus 31.3%, respectively. Having an ostomy did not impact the overall health-related quality of life and was not associated with anxiety, depression, sleep disturbances, or reduced sexual interest and satisfaction. However, the presence of ostomy was associated with reduced social role satisfaction in both patients with controlled and active disease. Additionally, in the subset of patients who did not achieve clinical remission, those with ostomy experienced greater pain interference (odds ratio, 1.63; 95% confidence interval, 1.12-2.35) and fatigue (odds ratio, 1.66; 95% confidence interval, 1.15-2.39). CONCLUSIONS: Ostomy is well tolerated in CD patients, particularly when clinical remission is achieved.

Budesonide for the treatment of ulcerative colitis.

INTRODUCTION: Budesonide is a synthetic corticosteroid characterized by enhanced topical potency and limited systemic bioavailability. Its use in ulcerative colitis (UC) was limited to rectal preparations until recently when the new oral budesonide formulation incorporating the multi-matrix system technology was introduced. The purpose of this review is to evaluate the current role of oral and rectal budesonide in managing UC patients Areas covered: In this paper, we described the chemical structure and pharmacologic characteristics of the different oral and rectal budesonide preparations, provided a summary of the published trials that evaluated the efficacy and safety of budesonide in UC, and discussed the current status of its use in this population Expert opinion: Budesonide is effective in inducing remission in a subset of patients with mild-moderate UC. Nevertheless, the current evidence suggests inferiority of oral budesonide to 5-aminosalisylates (5-ASA) and systemic steroids, whereas rectal applications are comparable to other rectal steroid preparations, but still inferior to rectal 5-ASA. In clinical practice, several issues need clarification including, its exact position in the line of induction agents; the role of combining budesonide and 5-ASAs; the role of combining oral and rectal budesonide; and the role of budesonide in maintenance therapy.