MUCOSAL IMMUNOLOGY & BIOLOGY RESEARCH
Fasano Laboratory: Alessio Fasano, MD
Explore This Lab
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.
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.
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
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
- Hernandez L, Johnson TC, Naiyer AJ, Kryszak D, Ciaccio EJ, Min A, Bodenheimer HC Jr, Brown RS Jr, Fasano A, Green PH. Chronic hepatitis C virus and celiac disease, is there an association? Dig Dis Sci.2008; 53:256-261.
- Song KH, Fasano A, Eddington ND. Effect of the six-mer synthetic peptide (AT1002) fragment of zonula occludens toxin on the intestinal absorption of cyclosporin A. Int J Pharm.2008; 351(1-2):8-14.
- Song KH, Fasano A, Eddington ND. Enhanced nasal absorption of hydrophilic markers after dosing with AT1002, a tight junction modulator. Eur J Pharm Biopharm.2008; 69(1):231-237.
- Lammers KM, Lu R, Brownley J, Lu B, Gerard C, Thomas K, Rallabhandi P, Shea-Donohue T, Tamiz A, Alkan S, Netzel-Arnett S, Antalis T, Vogel SN, Fasano A.Gliadin induces an increase in intestinal permeability and zonulin release by binding to the chemokine receptor CXCR3. Gastroenterology. 2008; 135:194-204.
- Abu-Zekry M, Kryszak D, Diab M, Catassi C, Fasano A. Prevalence of celiac disease in Egyptian children disputes the east-west agriculture-dependent spread of the disease. J Pediatr Gastroenterol Nutr.2008; 47:136-40.
- Rallabhandi P, Nhu QM, Toshchakov VY, Piao W, Medvedev AE, Hollenberg MD, Fasano A, Vogel SN. Analysis of PAR2 and TLR4 signal transduction: A novel paradigm for receptor cooperativity. J Biol Chem. 2008; 283(36):24314-25.
- Harris KM, Fasano A, Mann DL. Cutting edge: IL-1 controls the IL-23 response induced by gliadin, the etiologic agent in celiac disease. J Immunol. 2008; 181:4457-60.
- Catassi C, Fasano A. Is this really celiac disease? Pitfalls in diagnosis. Curr Gastroenterol Rep. 2008 10:466-72.
- Lu R, Fasano S, Madayiputhiya N, Morin NP, Nataro J, Fasano A. Isolation, identification, and characterization of small bioactive peptides from Lactobacillus GG conditional media that exert both anti-gram-negative and gram-positive bactericidal activity. J Pediatr Gastroenterol Nutr. 2009; 49:23-30.
- Simpson M, Mojibian M, Barriga K, Scott FW, Fasano A, Rewers M, Norris JM. An exploration of Glo-3A antibody levels in children at increased risk for type 1 diabetes mellitus.Pediatr Diabetes. 2009; 10:563-72.
- Sapone A, Lammers KM, Mazzarella G, Mikhailenko I, Cartenì M, Casolaro V, Fasano A. differential mucosal IL-17 expression in two gliadin-induced disorders: gluten sensitivity and the autoimmune enteropathy celiac disease. Int Arch Allergy Immunol. 2009; 152:75-80.
- Tripathi A, Lammers KM, Goldblum S, Shea-Donohue T, Netzel-Arnett S, Buzza MS, Antalis TM, Vogel SN, Zhao A, Yang S, Arrietta MC, Meddings JB, Fasano A. Identification of human zonulin, a physiological modulator of tight junctions, as prehaptoglobin-2. Proc Natl Acad Sci U S A. 2009; 106:16799-804. PMID: 19805376.
- Nhu QM, Shirey K, Teijaro JR, Farber DL, Netzel-Arnett S, Antalis TM, Fasano A, Vogel SN. Novel signaling interactions between proteinase-activated receptor 2 and Toll-like receptors in vitro and in vivo. Mucosal Immunol. 2010; 3:29-39.
- Harris KM, Fasano A, Mann DL. Monocytes differentiated with IL-15 support Th17 and Th1 responses to wheat gliadin: implications for celiac disease.Clin Immunol. 2010; 135:430-9. PMID: 20153259.
- Buzza MS, Netzel-Arnett S, Shea-Donohue T, Zhao A, Lin CY, List K, Szabo R, Fasano A, Bugge TH, Antalis TM. Membrane-anchored serine protease matriptase regulates epithelial barrier formation and permeability in the intestine.Proc Natl Acad Sci U S A. 2010; 107:4200-5. PMID: 20142489.
- Visser JT, Lammers K, Hoogendijk A, Boer MW, Brugman S, Beijer-Liefers S, Zandvoort A, Harmsen H, Welling G, Stellaard F, Bos NA, Fasano A, Rozing J. Restoration of impaired intestinal barrier function by the hydrolysed casein diet contributes to the prevention of type 1 diabetes in the diabetes-prone BioBreeding rat. 2010; 53(12):2621-2628.
- Catassi C, Kryszak D, Bhatti B, Sturgeon C, Helzlsouer K, Clipp SL, Gelfond D, Puppa E, Sferruzza A, Fasano A. Natural history of celiac disease autoimmunity in a USA cohort followed since 1974. Ann Med. 2010; 42:530-8. PMID: 20868314.
- Cascella NG, Kryszak D, Bhatti B, Gregory P, Kelly DL, Mc Evoy JP, Fasano A, Eaton WW. Prevalence of celiac disease and gluten sensitivity in the United States clinical antipsychotic trials of intervention effectiveness study population.Schizophr Bull. 2011; 37:94-100.
- Goldblum SE, Rai U, Tripathi A, Thakar M, De Leo L, Di Toro N, Not T, Ramachandran R, Puche AC, Hollenberg MD, Fasano A. The active Zot domain (aa 288-293) increases ZO-1 and myosin 1C serine/threonine phosphorylation, alters interaction between ZO-1 and its binding partners, and induces tight junction disassembly through proteinase activated receptor 2 activation. FASEB J. 2011; 25:144-158.
- Lammers KM, Khandelwal S, Chaudhry F, Kryszak D, Puppa EL, Casolaro V, Fasano A. Identification of a novel immunomodulatory gliadin peptide that causes interleukin-8 release in a chemokine receptor CXCR3-dependent manner only in patients with coeliac disease. 2011; 132:432-40. PMID: 21091908.
- Sapone A, Lammers KM, Casolaro V, Cammarota M, Giuliano MT, De Rosa M, Stefanile R, Mazzarella G, Tolone C, Russo MI, Esposito P, Ferraraccio F, Cartenì M, Riegler G, de Magistris L, Fasano A. Divergence of gut permeability and mucosal immune gene expression in two gluten-associated conditions: celiac disease and gluten sensitivity. BMC Med. 2011; 9:23. PMID: 21392369.
- Salerno-Goncalves R, Fasano A, Sztein MB. Engineering of a multicellular organotypic model of the human intestinal mucosa. Gastroenterology. 2011; 141:e18-20. PMID: 21723866.
- Nair P, Kamra A, Kessie G, Kalavapudi S, Chen J-H, Shores R, Madairos L, Fasano A, Nair P. Markers of inflammation and lineage on exfoliated colonic cells in exfoliated colonic cells in pediatric inflammatory bowel disease. J Gastrointest Dig Syst, 2011; 8:1-6. PMID: 23519721
- Siniscalco D, Sapone A, Giordano C, Cirillo A, de Novellis V, de Magistris L, Rossi F, Fasano A, Maione S, Antonucci N. The expression of caspases is enhanced in peripheral blood mononuclear cells of autism spectrum disorder patients. J Autism Dev Disord.; 2012; 42:1403-1410. PMID: 21969075.
- Netzel-Arnett S, Buzza MS, Shea-Donohue T, Desilets A, Leduc R, Fasano A, Bugge TH, Antalis TM. Matriptase protects against experimental colitis and promotes intestinal barrier recovery. Inflamm Bowel Dis.; 2012; 18:1303-1316 PMID: 22081509.
- Silva MA, Jury J, Sanz Y, Wiepjes M, Huang X, Murray JA, David CS, Fasano A, Verdu EF. Increased bacterial translocation in gluten-sensitive mice is independent of small intestinal paracellular permeability defect. Dig Dis Sci. 2012; 38-47. PMID: 21822909.
- Sellitto M, Bai G, Serena G, Fricke WF, Sturgeon C, Gajer P, White JR, Koenig SS, Sakamoto J, Boothe D, Gicquelais R, Kryszak D, Puppa E, Catassi C, Ravel J, Fasano A. Proof of concept of microbiome-metabolome analysis and delayed gluten exposure on celiac disease autoimmunity in genetically at-risk infants. PLoS ONE. 2012; 7:e33387.
- Rossi F, Bellini G, Tolone C, Luongo L, Mancusi S, Papparella A, Sturgeon C, Fasano A, Nobili B, Perrone L, Maione S, del Giudice EM. The cannabinoid receptor type 2 Q63R variant increases the risk of celiac disease: implication for a novel molecular biomarker and future therapeutic intervention.Pharmacol Res. 2012; 66:88-94. PMID: 22465144.
- Ahn R, Ding YC, Murray J, Fasano A, Green PH, Neuhausen SL, Garner C. Association analysis of the extended MHC region in celiac disease implicates multiple independent susceptibility loci.PLoS ONE. 2012; 7:e36926. PMID: 22615847.
- Lionetti E, Castellaneta S, Pulvirenti A, Tonutti E, Francavilla R, Fasano A, Catassi C; Italian Working Group of Weaning and Celiac Disease Risk. Prevalence and natural history of potential celiac disease in at-family-risk infants prospectively investigated from birth.J Pediatr. 2012; 161:: 22704250.
- Jackson J, Eaton W, Cascella N, Fasano A, Warfel D, Feldman S, Richardson C, Vyas G, Linthicum J, Santora D, Warren KR, Carpenter WT Jr, Kelly DL. A gluten-free diet in people with schizophrenia and anti-tissue transglutaminase or anti-gliadin antibodies. Schizophr Res. 2012; 140:262-3. PMID: 22771303.
- Faherty C, Harper JM, Shea-Donohue T, Barry EM, Kaper JB, Fasano A, Nataro JP. Gastrointestinal conditions in children with autism spectrum disorder: developing a research agenda. PLoS ONE. 2012; 7:e49980. PMID: 23166804.
- Faherty C, Harper JM, Shea-Donohue T, Barry EM, Kaper, JB, Fasano, A, Nataro, J. Chromosomal and plasmid-encoded factors of shigella flexneri induce secretogenic activity ex vivo. PLoS ONE. 2012; 7:e49980.
- Gibert A, Kruizinga AG, Neuhold S, Houben GF, Canela MA, Fasano A, Catassi C. Might gluten traces in wheat substitutes pose a risk in patients with celiac disease? A population-based probabilistic approach to risk estimation. Am J Clin Nutr. 2013; 97:109-116. PMID: 23193005.
- Vajro P, Paolella G, Fasano A. Microbiota and gut-liver axis: a mini-review on their influences on obesity and obesity related liver disease. J Pediatr Gastroenterol Nutr. 2013; 56:461-8 PMID: 23287807.
- Fiorentino M, Ding H, Blanchard TG, Czinn SJ, Sztein MB, Fasano A. Helicobacter pylori-induced disruption of monolayer permeability and pro-inflammatory cytokine secretion in polarized human gastric epithelial cells. Infect Immun. 2013; 81: 876-83 PMID: 23297384.
- Hollon JR, Cureton PA, Martin ML, Puppa E, Fasano A. Trace gluten contamination may play a role in mucosal and clinical recovery in a subgroup of diet-adherent non-responsive celiac disease patients. BMC Gastroenterol. 2013; 13(40). doi:10.1186/1471-230X-13-40.
- Fiorentino M, Lammers KM, Levine MM, Sztein MB, Fasano A. In vitro intestinal mucosal epithelial responses to wild-type Salmonella typhi and attenuated typhoid vaccines. Frontiers in Immunology. 2013; 4:1-15.
- Cascella NG, Santora D, Gregory P, Kelly DL, Fasano A, Eaton WW. Increased prevalence of transglutaminase 6 antibodies in sera from schizophrenia patients.Schizophr Bull. 2012; Apr 19. [Epub ahead of print]. PMID: 22516148.
- Rittirsch D, Flierl MA, Nadeau BA, Day DE, Huber-Lang MS, Grailer JJ, Zetoune FS, Andjelkovic AV, Fasano A, Ward PA. Zonulin as prehaptoglobin2 regulates lung permeability and activates the complement system.Am J Physiol Lung Cell Mol Physiol. 2013 Apr 5. [Epub ahead of print]
- Siniscalco D, Sapone A, Giordano C, Cirillo A, de Magistris L, Rossi F, Fasano A, Bradstreet JJ, Maione S, Antonucci N. Cannabinoid Receptor Type 2, but not Type 1, is Up-Regulated in Peripheral Blood Mononuclear Cells of Children Affected by Autistic Disorders.J Autism Dev Disord. 2013 Apr 13. [Epub ahead of print]
- Alaish SM, Smith AD, Timmons J, Greenspon J, Eyvazzadeh D, Murphy E, Shea-Donahue T, Cirimotich S, Mongodin E, Zhao A, Fasano A, Nataro JP, Cross A. Gut microbiota, tight junction protein expression, intestinal resistance, bacterial translocation and mortality following cholestasis depend on the genetic background of the host. Gut Microbes. 2013 Apr 15; 4(4). [Epub ahead of print].
- Fasano A, Araya M, Bhatnagar S, Cameron D, Catassi C, Dirks M, Mearin ML, Ortigosa L, Phillips A. Celiac Disease Working Group. Federation of International Societies of Pediatric Gastroenterology, Hepatology, and Nutrition Consensus report on celiac disease. J Pediatr Gastroenterol Nutr. 2008; 47:214-9.
- Fasano A.Physiological, pathological, and therapeutic implications of zonulin-mediated intestinal barrier modulation: living life on the edge of the wall. Am J Pathol. 2008; 173:1243-52.
- Catassi C, Fasano A. Celiac disease. Curr Opin Gastroenterol. 2008; 24:687-91.
- Visser J, Rozing J, Sapone A, Lammers K, Fasano A. Tight junctions, intestinal permeability, and autoimmunity: celiac disease and type 1 diabetes paradigms. Ann N Y Acad Sci. 2009; 1165:195-205.
- Fasano A. Surprises from celiac disease. Sci Am. 2009; 301:54-61.
- Zawahir S, Safta A, Fasano A. Pediatric celiac disease. Curr Opin Pediatr. 2009; 1165:655-660.
- Fasano A.Should we screen for celiac disease? BMJ 2009; 339:b3592.
- Fasano A, Counts D. Commentary on anti-pituitary antibodies in children with newly diagnosed celiac disease: a novel finding contributing to linear growth.Am J Gastroenterol. 2010; 105(3):697-8.PMID: 20203647.