Intestinal enteroids/organoids: A novel platform for drug discovery in inflammatory bowel diseases

The introduction of biologics such as anti-tumor necrosis factor(TNF)monoclonal antibodies followed by anti-integrins has dramatically changed the therapeutic paradigm of inflammatory bowel diseases(IBD).Furthermore,a newly developed anti-p40 subunit of interleukin(IL)-12 and IL-23(ustekinumab)has been recently approved in the United States for patients with moderate to severe Crohn’s disease who have failed treatment with anti-TNFs.However,these immunosuppressive therapeutics which focus on anti-inflammatory mechanisms or immune cells still fail to achieve long-term remission in a significant percentage of patients.This strongly underlines the need to identify novel treatment targets beyond immune suppression to treat IBD.Recent studies have revealed the critical role of intestinal epithelial cells(IECs)in the pathogenesis of IBD.Physical,biochemical and immunologic driven barrier dysfunctions of epithelial cells contribute to the development of IBD.In addition,the recent establishment of adult stem cell-derived intestinal enteroid/organoid culture technology has allowed an exciting opportunity to study human IECs comprising all normal epithelial cells.This long-term epithelial culture model can be generated from endoscopic biopsies or surgical resections and recapitulates the tissue of origin,representing a promising platform for novel drug discovery in IBD.This review describes the advantages of intestinal enteroids/organoids as a research tool for intestinal diseases,introduces studies with these models in IBD,and gives a description of the current status of therapeutic approaches in IBD.Finally,we provide an overview of the current endeavors to identify a novel drug target for IBD therapy based on studies with human enteroids/organoids and describe the challenges in using enteroids/organoids as an IBD model.

Development of innovative tools for investigation of nutrient-gut interaction

The gastrointestinal tract is the key interface between the ingesta and the human body.There is wide recognition that the gastrointestinal response to nutrients or bioactive compounds,particularly the secretion of numerous hormones,is critical to the regulation of appetite,body weight and blood glucose.This concept has led to an increasing focus on“gut-based”strategies for the management of metabolic disorders,including type 2 diabetes and obesity.Understanding the underlying mechanisms and downstream effects of nutrient-gut interactions is fundamental to effective translation of this knowledge to clinical practice.To this end,an array of research tools and platforms have been developed to better understand the mechanisms of gut hormone secretion from enteroendocrine cells.This review discusses the evolution of in vitro and in vivo models and the integration of innovative techniques that will ultimately enable the development of novel therapies for metabolic diseases.

Lgr5^+ intestinal stem cell sorting and organoid culture

Intestinal epithelial stem cells (IESCs) are one of the most rapidly self‐renewing and proliferating adult stem cells. The IESCs reside at the bottom of intestinal and colonic crypts, giving rise to all intestinal epithelial lineages and maintaining intestinal epithelial replenishment. The technique of three‐dimensional culture based upon intestinal stem cell biology has been recently developed to study gastrointestinal development and disease pathogenesis. Here, we summarize the techniques used to isolate Lgr5‐ positive IESCs to form the enteroids from intestine or colonoids from colon, and present the means to examine these organoid functions. This study will provide a simple and practical way for producing intestinal tissues in the laboratory.

Intestinal organoid as an in vitro model in studying host-microbial interactions

BACKGROUND： Organoid is an in vitro three-dimensional organ-bud that shows realistic microanatomy and physiological relevance. The progress in generating organoids that faithfully recapitulate human in vivo tissue composition has extended organoid applications from being just a basic research tool to a translational platform with a wide range of uses. Study of host- microbial interactions relies on model systems to mimic the in vivo infection. Researchers have developed various experimental models in vitro and in vivo to examine the dynamic host-microbial interactions. For some infectious pathogens, model systems are lacking whereas some of the used systems are far from optimal. OBJECTIVE： In the present work, we will review the brief history and recent findings using organoids for studying host- microbial interactions. METHODS： A systematic literature search was performed using the PubMed search engine. We also shared our data and research contribution to the field. RESULTS： we summarize the brief history of 3D organoids. We discuss the feasibility of using organoids in studying host- microbial interactions, focusing on the development of intestinal organoids and gastric organoids. We highlight the advantage and challenges of the new experimental models. Further, we discuss the future direction in using organoids in studying host- microbial interactions and its potential application in biomedical studies. CONCLUSION： In combination with genetic, transcriptome and proteomic profiling, both murine- and human-derived organoids have revealed crucial aspects of development, homeostasis and diseases. Specifically, human organoids from susceptible host will be used to test their responses to pathogens, probiotics, and drugs. Organoid system is an exciting tool for studying infectious disease, microbiome, and therapy.