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The human gut, where intricate interactions among the gut microbiota, intestinal epithelium, and the immune system occur, is particularly susceptible to inflammatory triggers from the environment. The gut microbiota, consisting of over a hundred trillion diverse microorganisms, plays a crucial role in maintaining homeostasis by finely tuning the differentiation and activation of immune cells. However, genetic deficiencies that disrupt the balance of gut microbiota and immune tolerance can result in exaggerated immune responses and subsequent acute and chronic inflammation. Especially, chronic inflammation, exemplified by inflammatory bowel disease (IBD), can be a predisposing factor to increase the risk of colorectal cancer and immune-related disorders in other organs.
Although recent research has illuminated the alterations in gut microbiota and immune cell activity triggered by acute and chronic inflammation, the precise molecular mechanisms underlying these changes and their impact on gut homeostasis remain limited. For better gut health, the Jang Lab is dedicated to unraveling the molecular basis of these interactions to identify microbial, epithelial, and immune factors for regulating interactions of the microbe-epithelia-immune system through multidiscipline approaches including microbiology, cell biology, developmental biology, immunology, and genetics. Our oervaching goal is to attain a comprehensive understanding of the onset of various inflammatory diseases and cancer, ultimately paving the way for the development of personalized therapeutic interventions.
Jang et al., 2023. Cell Host & Microbe
How dose single bacterial species and its factors affect interactions with intestinal epithelium and immune system?
How dose single bacterial species and its factors affect interactions with intestinal epithelium and immune system?
We demonstrated that a member of gut microbiota, Enterococcus faecium, and its secreted endopeptidase SagA prevents chronic inflammation via the NOD2-IL-1β-IL-22 axis. In this sense, we are currently extending our understanding of SagA-producing bacteria in the gut microbiota for regulating the development of colitis-associated cancer.
We further aim to discover the mechanism in which an underrepresented member of gut microbiota and its factor(s) altered in patients with acute and chronic inflammation regulates interactions of the microbe-epithelia-immune system.
Jang et al., 2023. Cell Host & Microbe
Jang et al., 2022. PLoS Biology
What happens during the infection of pathogens to host carrying mutation(s) of human genes that are associated with host-microbe interaction?
What happens during the infection of pathogens to host carrying mutation(s) of human genes that are associated with host-microbe interaction?
Variants of the intracellular microbial sensor nucleotide-binding oligomerization domain-containing protein 2 (NOD2) are among the strongest genetic risk factors for IBD. Especially, the three major NOD2 variants linked to IBD [Arg702Trp, Gly908Arg, and a frameshift deletion mutation at L1007 (L1007fs)] result in the loss of muropeptide recognition and nuclear factor kappa B (NF-κB) signaling in vitro. We generated mice harboring the equivalent of the human Arg702Trp variant (Gln675Trp) and are investigating how human NOD2 mutation(s) influences an acute inflammation triggered by enteric pathogens.
We further endeavor to discover unknown variants of gene(s) that regulates human-restricted pathogens such as Salmonella Typhi and Vibrio cholerae using human intestinal organoids.
Jang et al., 2024. Gastroenterology
What and how are intestinal stem cells changed after acute or chronic inflammation and how do these changes affect drug responsivenss?
What and how are intestinal stem cells changed after acute or chronic inflammation and how do these changes affect drug responsivenss?
Patient-derived intestinal organoids (PDIOs) represent a 3D culture system from stem cells that recreates the architecture and cell composition of an individual’s in vivo intestinal epithelium. We have made progress that stem cells isolated from inflamed tissue-derived PDIOs retain the altered epigenetic traits and subsequent transcriptional changes that determine the phenotypic variances. Accordingly, we believe that this heterogeneity can also influence drug responsiveness. Indeed, our recent study provided mechanistic evidence in which patients with ulcerative colitis are primarily unresponsive to tofacitinb, a pan Janus kinase inhibitor, using patient-derived intestinal organoids.
We are currently expanding our insights to other drugs targeting immune cells by developing a co-culture system of PDIOs and syngeneic T cells.
Schematic diagram of our long-term goal
How does the intake of non-nutritional products affect interactions of microbe-epithelia-immune system?
How does the intake of non-nutritional products affect interactions of microbe-epithelia-immune system?
The consumption of nutrients and non-nutritive products significantly impacts the interactions of the microbe-epithelia-immune system. We particularly focus on non-nutritive products. Artificial sweeteners, possessing sweetness up to 20,000 times that of sucrose with a zero glycemic index, are extensively used in various foods. Particulate matter, a primary component of air pollution, comprises particles with a diameter of 2.5 μm originating from fossil fuel combustion and industrial waste.
Recent dietary imbalances exacerbated by increased consumption of non-nutritive products are linked to inflammatory diseases in the gut and other organs. However, the mechanisms governing the regulation of microbe-epithelia-immune system interactions under inflammatory conditions remain unclear. Therefore, we are currently developing a mouse model to explore the molecular mechanisms in which the non-nutritive products render organs susceptible to inflammatory disease.
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