Inflammatory Bowel Disease Therapeutics: A Focus on Probiotic Engineering.

Inflammatory bowel disease (IBD) is a chronic inflammatory condition of gastrointestinal (GI) tract with dysregulated mucosal immune functions and disturbed commensal ecosystem of the intestinal lumen. IBD is categorized into two major subsets: Crohn's disease (CD) and ulcerative colitis (UC). Though advent of biologics has shifted the treatment with relatively longer remission compared to small molecule pharmaceuticals, patients still suffer from long-term complications. Since gut-microbiome is now accepted as another human organ holding potential for long-lasting human health, probiotics, and its engineering hold great promises to treat several previously untreatable chronic inflammatory conditions including IBD. Several emerging biological engineering tools have unlimited potential to manipulate probiotic bacterial system. These can produce useful therapeutic biologics with a goal to either ameliorate and/or treat previously untreatable chronic inflammatory conditions. As gut-microbiome is diverse and vary in different ethnic, geographic, and cultural human population, it will be important to develop vision for personalized probiotic treatment and develop the technology thereof to make personalized probiotic options a reality. The aim of this review paper is to present an overview of the current knowledge on both pharmacological and nonpharmacological IBD treatment modalities with a special emphasis on probiotic strains that are developed through the probiotic engineering. These engineered probiotics contain the most anti-inflammatory cytokines found within the human immune response and are currently being used to treat the intestinal inflammation in IBD for the IBD treatment.

Mucosal Epithelial Jak Kinases in Health and Diseases.

Janus kinases (Jaks) are a family of nonreceptor tyrosine kinase that include four different members, viz., Jak1, Jak2, Jak3, and Tyk2. Jaks play critical roles in immune cells functions; however, recent studies suggest they also play essential roles in nonimmune cell physiology. This review highlights the significance of epithelial Jaks in understanding the molecular basis of some of the diseases through regulation of epithelial-mesenchymal transition, cell survival, cell growth, development, and differentiation. Growth factors and cytokines produced by the cells of hematopoietic origin use Jak kinases for signal transduction in both immune and nonimmune cells. Among Jaks, Jak3 is widely expressed in both immune cells and in intestinal epithelial cells (IECs) of both humans and mice. Mutations that abrogate Jak3 functions cause an autosomal severe combined immunodeficiency disease (SCID) while activating Jak3 mutations lead to the development of hematologic and epithelial cancers. A selective Jak3 inhibitor CP-690550 (Xeljanz) approved by the FDA for certain chronic inflammatory conditions demonstrates immunosuppressive activity in rheumatoid arthritis, psoriasis, and organ transplant rejection. Here, we also focus on the consequences of Jak3-directed drugs on adverse effects in light of recent discoveries in mucosal epithelial functions of Jak3 with some information on other Jaks. Lastly, we brief on structural implications of Jak3 domains beyond the immune cells. As information about the roles of Jak3 in gastrointestinal functions and associated diseases are only just emerging, in the review, we summarize its implications in gastrointestinal wound repair, inflammatory bowel disease, obesity-associated metabolic syndrome, and epithelial cancers. Lastly, we shed lights on identifying potential novel targets in developing therapeutic interventions of diseases associated with dysfunctional IEC.