Fasano Laboratory: Alessio Fasano, MD

Overview

During research designed to develop a cholera vaccine in the late 1990s, I uncovered a toxin, zonula occludens, which causes diarrhea by loosening the tight junctions between enterocytes in the intestine, thus allowing intestinal permeability.

Subsequently, The Laboratory of Alessio Fasano, MD, at Massachusetts General Hospital identified the protein zonulin, which controls this process. We have since established the role of zonulin in the pathogenesis of celiac disease and type 1 diabetes.

We are currently investigating the composition and changes in the gastrointestinal microbiota to help determine why some individuals with an inherited predisposition to celiac disease develop clinical disease, while others do not.

We are also working to uncover a biomarker and to develop a diagnostic tool for non-celiac gluten sensitivity.

Our latest research includes a focus on how the gut microbiome is related to the development of autoimmune disorders.

Other current research projects include possible links between gluten-related disorders and conditions such as schizophrenia and autism spectrum disorder in certain subgroups of patients.

Research Projects

Combining the disciplines of microbiology, molecular and cell biology, and physiology, Dr. Fasano’s research focuses on the crosstalk between enteric pathogens and their hosts. Through his earlier work Dr. Fasano has elucidated various intracellular signaling pathways that govern eukaryotic cell functions.

Alternative to Gluten-free Diet

Through the discovery of a new enterotoxin named Zot (Zonula occludens toxin) in the late 1980s, Dr. Fasano and his colleagues began the study of the mechanism of action that involves the modulation of intercellular “tight junctions.” A series of seminal discoveries clarified that the paracellular space is not completely sealed, as previously believed, but is rather a sophisticated network of proteins forming tight junctions (TJ).

The discovery of Zot shed light on the modulation of TJ and led to the discovery of several other toxins that affect the paracellular pathway, opening new paradigms for bacterial pathogenesis.

Several years later, the Fasano team discovered zonulin, a Zot mammalian analogue involved in the regulation of TJ, and subsequently developed a zonulin inhibitor, Larazotide acetate. Safety and efficacy trials for the compound have been completed.

The only late-stage drug with a “Path Forward” agreement with the FDA for the primary endpoint, dose and phase 3 trial design, Larazotide is scheduled for Phase 3 trials late in 2016. With this trajectory, Larazotide could be the first drug approved for patients with celiac disease as early as 2018.

Role of Inflammation and Intestinal Permeability in Autoimmunity

The Fasano lab has a major research interest in the pathophysiology of the paracellular pathway and the structural changes of cell cytoskeleton and TJ induced by zonulin, its prokaryotic analogue Zot, and gluten peptides.

Research conducted and reviewed by the Fasano group has linked many autoimmune diseases, including type 1 diabetes, multiple sclerosis, rheumatoid arthritis, ankylosing sponditis, IgA nephropathy, and inflammatory bowel diseases to the common denominator of aberrant intestinal permeability.

Current research directed by Dr. Fasano encompasses both basic science focused on bacterial pathogenesis, the gut microbiome and intestinal mucosal biology, and translational science focused on interventional clinical trials in autoimmune and inflammatory diseases, including celiac disease and asthma.

Researchers are looking at how qualitative or quantitative defects in the regulation of the immune system and the role of dysbiosis can lead to the onset and progression of celiac disease and other autoimmune disorders.

Creating New Study Models

One objective of the Fasano lab is to understand the molecular mechanisms of the host’s functional and immune response to specific microorganisms.

This includes in-depth studies of bacteria-host interactions of three major gram negative bacterial human pathogens, including Helicobacter pylori, Salmonella enterica serovar Typhi, and Shigella dysenteriae-1, each primarily affecting a distinct major segment of the GI tract (i.e., the stomach, ileum and colon, respectively).

Using new methodologies to study, in vitro and ex vivo, it is hoped that this interplay between microorganisms and host will shed light on clinical conditions in which this interplay may lead to disease status.

To date, there are no ideal animal models to recapitulate celiac disease in humans. To support the ultimate goal of reversing or preventing celiac disease and other autoimmune disorders, Dr. Stefania Senger has developed an innovative technique using intestinal tissue from people who have undergone clinically indicated endoscopies.

She is engineering gut organoids to study the interaction between the gut tissue and the complex bacterial ecosystem in the intestine.

Investigating the Gut Microbiome and Other Factors in Disease Development

Through earlier work at the Center for Celiac Research at the University of Maryland School of Medicine, Dr. Fasano established that celiac disease affects approximately one percent of the U.S. population, a significantly higher number than previously believed.

In a large prospective study (www.cdgemm.org), the Fasano lab is currently investigating the composition of and changes in the gastrointestinal microbiota, along with environmental factors, to help determine why some individuals with an inherited predisposition to celiac disease develop clinical disease while others do not. International collaborators with the Fasano lab are also working to uncover a biomarker and to develop a diagnostic tool for non-celiac gluten sensitivity.

Dr. Fasano is also pursuing possible links between gluten-related disorders and conditions such as schizophrenia and autism spectrum disorder in certain subgroups of patients.

Lab Members

Principal Investigator

Alessio Fasano, MD
Director, Mucosal Immunology and Biology Research Center
Director, Center for Celiac Research
Associate Chief for Basic, Clinical and Translational Research
Division Chief, Department of Pediatric Gastroenterology and Nutrition, Mass General Hospital
Visiting Professor of Pediatrics, Harvard Medical School

Research Team

Karen Lammers, PhD 
Lecturer, Pediatrics, Harvard Medical School

Stefania Senger, PhD
Instructor, Pediatrics, Harvard Medical School

Maureen Leonard, MD 
Instructor in Pediatrics, Harvard Medical School
Clinical Director, Center for Celiac Research and Treatment
Associate Investigator, Nutrition Obesity Research Center, Harvard Medical School

Anna Sapone, MD, PhD
Research Fellow in Medicine (Ext), Beth Israel Deaconess Medical Center

Alba Miranda-Ribera, PhD, Research Fellow
Rachel H. Freire, PhD, Postdoctoral Researcher
Anil K. Verma, PhD, Postdoctoral Researcher
Gloria Serena, Graduate Research Assistant
Craig Sturgeon, Graduate Research Assistant
Jingang Lan, Research Laboratory Manager
Shu Yan, Research Technician
Laura Ingano, Research Technician
Stephanie Camhi, Clinical Research Coordinator
Rosiane Lima, Clinical Research Coordinator
Victoria Kenyon, Clinical Research Coordinator

Publications

View Dr. Fasano's full publications list