Polymeric Films for the Encapsulation, Storage, and Tunable Release of Therapeutic Microbes.
- 作者列表："Qiu K","Young I","Woodburn BM","Huang Y","Anselmo AC
:Microbe-based therapeutics (MBTs) are an emerging therapeutic modality for treating gastrointestinal infections and inflammatory bowel diseases. Current formulations for oral delivery of MBTs use capsules to achieve safe gastric transit, but oral formulations that control the spatiotemporal concentration of MBTs are yet to be developed, despite well-established connections between all therapeutics and their location, concentration, and distribution at sites of action. The development of a multi-functional polymer-based encapsulation system to formulate MBTs for enhanced storage and delivery through formulation of a model MBT, Lactobacillus casei ATCC393, is reported here. This approach enables the additive inclusion of excipients and polymers to grant specific functions, toward the development of a modular MBT platform. Through addition of established excipients, the formulation provides long-term storage of the encapsulated MBT. By adding higher molecular weight polymers, the release kinetics of the encapsulated MBTs can be modified. The inclusion of a mucoadhesive polymer significantly increases the adhesion force between the formulation and the intestinal tissue. Together, mucoadhesive and sustained release properties can be used to modulate the spatiotemporal concentration of MBTs. The formulation is compatible with standard oral capsules, thus maintaining existing clinical advantages of oral capsules while providing new functions from film encapsulation.
: 基于微生物的治疗药物 (MBTs) 是治疗胃肠道感染和炎症性肠病的新兴治疗方式。目前用于口服递送 MBTs 的制剂使用胶囊来实现安全的胃转运，但是控制 MBTs 时空浓度的口服制剂尚未开发, 尽管所有治疗方法与其在作用部位的位置、浓度和分布之间建立了良好的联系。本文报道了一种基于多功能聚合物的包封系统的开发，通过配制模型 MBT -- 干酪乳杆菌 ATCC393 来配制用于增强储存和递送的 MBTs。这种方法使得赋形剂和聚合物的添加剂包含能够赋予特定的功能，朝着模块化 MBT 平台的发展。通过添加已建立的赋形剂，该制剂提供了封装的 MBT 的长期储存。通过添加较高分子量的聚合物，可以改变封装的 MBTs 的释放动力学。包含粘膜粘附聚合物显著增加了制剂和肠组织之间的粘附力。同时，粘膜粘附和缓释特性可用于调节 MBTs 的时空浓度。该配方与标准口服胶囊相容，从而保持了口服胶囊现有的临床优势，同时提供了来自薄膜封装的新功能。
METHODS::Chronic diseases, including inflammatory bowel disease (IBD) urgently need new biomarkers as a significant proportion of patients, do not respond to current medications. Inflammation is a common factor in these diseases and microbial sensing in the intestinal tract is critical to initiate the inflammation. We have identified ELMO1 (Engulfment and Cell Motility Protein-1) as a microbial sensor in epithelial and phagocytic cells that turns on inflammatory signals. Using a stem-cell-based "gut-in-a-dish" coculture model, we studied the interactions between microbes, epithelium and monocytes in the context of IBD. To mimic the in-vivo cell physiology, enteroid-derived monolayers (EDMs) were generated from the organoids isolated from WT and ELMO1-/- mice and colonic biopsies of IBD patients. The EDMs were infected with the IBD-associated microbes to monitor the inflammatory responses. ELMO1-depleted EDMs displayed a significant reduction in bacterial internalization, a decrease in pro-inflammatory cytokine productions and monocyte recruitment. The expression of ELMO1 is elevated in the colonic epithelium and in the inflammatory infiltrates within the lamina propria of IBD patients where the higher expression is positively correlated with the elevated expression of pro-inflammatory cytokines, MCP-1 and TNF-α. MCP-1 is released from the epithelium and recruits monocytes to the site of inflammation. Once recruited, monocytes require ELMO1 to engulf the bacteria and propagate a robust TNF-α storm. These findings highlight that the dysregulated epithelial ELMO1→MCP-1 axis can serve as an early biomarker in the diagnostics of IBD and other inflammatory disorders.
METHODS:BACKGROUND:Peripheral blood eosinophilia (PBE) is a biomarker of an aggressive multiyear natural history in adults with inflammatory bowel diseases (IBDs). Additionally, PBE at diagnosis is associated with higher disease activity in pediatric-onset IBD. We sought to determine if PBE can function as a biomarker of long-term disease severity in pediatric-onset IBD patients who are followed into adulthood. METHODS:We analyzed a consented, prospective, natural history IBD registry at an adult tertiary center from 2009 to 2018. Prevalence of PBE was evaluated in both pediatric- and adult-onset IBD patients. Demographics, clinical characteristics, and health care utilization data were compared in patients with and without PBE. RESULTS:Among 2800 adult IBD patients, 23.4% had pediatric-onset disease. PBE was found in 34% of the pediatric-onset patients compared with 26.8% of the adult-onset IBD patients (P < 0.001). In the pediatric-onset IBD cohort, PBE was associated with higher rates of allergies (P < 0.0001), but not of asthma, allergic rhinitis, or primary sclerosing cholangitis. In the adult IBD patients with pediatric-onset disease, PBE was associated with higher rates of C-reactive protein elevation (P < 0.0001), erythrocyte sedimentation rate elevation (P < 0.0001), higher health care utilization, and higher average health care charges per year (P < 0.00001). CONCLUSIONS:Peripheral blood eosinophilia was more prevalent in adult IBD patients with pediatric-onset compared with adult-onset disease. Among all IBD patients with long-term follow-up, PBE defined a subgroup with more severe illness. These data suggest that PBE may be a biomarker for a high-risk subgroup with high cost trajectory and long-term severity in pediatric-onset IBD that persists into adulthood.
METHODS::Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders with a complex pathogenesis, affecting people of all ages. They are characterized by alternating phases of clinical relapse and remission, depending on the fine balance between immune cells and the gut microbiota. The cross talk between cells of the immune system and the gut microbiota can result in either tolerance or inflammation, according to multifactorial triggers, ranging from environmental factors to genetic susceptibility. Glucocorticoid (GC) administration remains the first-line treatment for IBDs, although long-term use is limited by development of serious adverse effects. Recently, new alternative pharmacological therapies have been developed, although these are not always effective in IBD patients. There is a constant demand for effective new drug targets to guarantee total remission and improve the quality of life for IBD patients. The glucocorticoid-induced leucine zipper (GILZ) has been implicated as a promising candidate for this purpose, in view of its powerful anti-inflammatory effects that mimic those of GCs while avoiding their unwanted adverse reactions. Here we present and discuss the latest findings about the involvement of GILZ in IBDs.