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Nicholas Constantine Zachos, Ph.D.

Headshot of Nicholas Constantine Zachos
  • Director, Integrated Physiology Core, Hopkins Digestive Disease Research Core Center
  • Associate Professor of Medicine

Research Interests

Intestinal Stem Cells; Organoids; Mucosal Immunology; Host-Pathogen Interactions; Protein Trafficking ...read more

Background

Dr. Nicholas Zachos is an Associate Professor of Medicine in the Gastroenterology and Hepatology division. His research program investigates intestinal stem cell and innate immune responses to enteric pathogen infections in the gut.

Dr. Zachos holds a Ph.D. from Eastern Virginia Medical School and completed a postdoctoral fellowship in the Division of Gastroenterology and Hepatology at the Johns Hopkins University School of Medicine before joining the Johns Hopkins faculty.

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Titles

  • Director, Integrated Physiology Core, Hopkins Digestive Disease Research Core Center
  • Associate Professor of Medicine

Departments / Divisions

Centers & Institutes

Education

Degrees

  • Ph.D.; Eastern Virginia Medical School of The Medical College of Hampton Roads - Norfolk (Virginia) (2002)

Additional Training

  • Johns Hopkins University School of Medicine, Division of Gastroenterology and Hepatology, Baltimore, MD, Postdoctoral Fellow

Research & Publications

Research Summary

The regulation of luminal surveillance and antigen sampling across mucosal surfaces remains an important and fundamental area of investigation. This is particularly true for the intestinal epithelium, which is constantly challenged to maintain homoeostasis with the complex microbiome while protecting the mucosa from pathogenic organisms. Microfold (M) cells of the Peyer’s patch (PP) play a crucial role in immune surveillance of the gut environment by transporting luminal antigens to underlying immune cells. This process is necessary to instruct appropriate immune responses; however, emerging evidence suggests a correlation between dysregulated microbiota and the development of GI diseases. Thus, there remains a need to understand the mechanisms responsible for mucosal responses to gut antigens in human disease. In addition, there is a need to investigate these mechanisms in primary models of the human intestinal mucosa. 

Human intestinal stem cell-derived epithelial cultures, or enteroids, provide a precision medicine-based approach to dissect the heterogeneity in GI diseases. Human intestinal enteroids (HIEs) are derived from LGR5+ actively dividing stem cells located at the base on the intestinal crypt. These stem cells give rise to all epithelial lineages including absorptive enterocytes, secretory cells (goblet, enteroendocrine, Paneth), as well as specialized epithelial cells including tuft and M cells. Advances in stem cell culture technology allow for the indefinite propagation of HIEs without changes in karyotype, genotype, or phenotype. Intestinal stem cells have defined epigenetic profiles that allows HIEs to mimic not only the intestinal segment from which they are derived, but also recapitulate patient-specific disease phenotypes of the donor at the time of specimen collection. 

Since the intestinal mucosa is a complex collection of multiple cell types in addition to the epithelium, our goal is to create co-culture models that include all human innate immune cells (e.g. antigen-presenting cells and innate lymphocytes) that normally reside in the intestinal mucosa. 

The proposed research program will define how gut antigens affect the integrity and surveillance functions of the intestinal epithelium and stimulate immune responses in novel co-culture models of the human intestinal mucosa, including PPs. These studies will be performed using HIEs from healthy donors and from patients with documented GI diseases since disease phenotypes are preserved in HIEs. Our research program will lead to the identification of the molecular mechanisms responsible for GI diseases in human models and the development of novel therapeutic strategies to treat them.

Selected Publications

View all on PubMed

Zachos NC, Kovbasnjuk O, Foulke-Abel J, In J, Blutt SE, de Jonge HR, Estes MK, Donowitz M. Human enteroids/colonoids functionally recapitulate normal intestinal physiology and pathophysiology. Journal of Biological Chemistry. 2016; 291: 3759-3766

Noel GN, Baetz NW, Staab JF, Donowitz M, Kovbasnjuk O, Pasetti M, Zachos NC.  A primary human macrophage-enteroid co-culture model to investigate mucosal gut physiology and host-pathogen interactions.  Nature Scientific Reports. 2017; 7: 45270

Noel G, Doucet M, Nataro JP, Kaper JB, Zachos NC, Pasetti MF.  Enterotoxigenic Escherichia coli is phagocytosed by macrophages underlying villus-like intestinal epithelial cells: modeling ex vivo innate immune defenses of the human gut.  Gut Microbes. 2017; Oct. 31.

Hasan NM, Johnson KF, Yin J, Baetz NW, Sherman V, Blutt SE, Estes MK, Kumbhari V, Zachos NC, Kovbasnjuk O. Intestinal stem cell derived enteroids from morbidly obese patients preserve obesity-related phenotypes: elevated glucose absorption and gluconeogenesis. Molecular Metabolism. 2020; 44: 101129

Donowitz M, Turner JR, Verkman AS, Zachos NC. Current and potential future applications of human stem cell models in drug development. Journal of Clinical Investigation. 2020; 130: 3342-3344

Contact for Research Inquiries

Zachos Laboratory
720 Rutland Avenue
943 Ross Research Building
Baltimore, MD 21205 map

Phone: 410-614-0128

Activities & Honors

Honors

  • 2012 W. Leigh Thompson Excellence in Research Award

Memberships

  • American Gastroenterological Association
  • American Physiological Society

Videos & Media

Recent News Articles and Media Coverage

3D Tissue Models Offer Window Into How Gut Cells Fight Infection, Inside Tract (Fall 2019)

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