Cathryn R. Nagler, PhD

Bunning Food Allergy Professor
Committee on Immunology

Department of Pathology
The University of Chicago
Donnelley Biological Sciences Learning Center (BSLC)
Jules F. Knapp Medical Research Center (JFK)
924 East 57th St., Room R-120
Chicago, IL 60637
Phone: 773.702.6317
Fax: 773.834.5251

Research Summary

Regulation of allergic responses to food by the commensal microbiota

Life-threatening anaphylactic responses to food are a public health problem that shows no sign of abating. The Centers for Disease Control and Prevention has documented an 18% increase in the prevalence of reported food allergy among children in the U.S. during the ten-year period from 1997-2007.  To understand what factors might be driving this increase, we have turned to the trillions of bacteria that populate our gastrointestinal tract, known collectively as the microbiome. Twenty-first century environmental interventions, including widespread antibiotic use, consumption of a high fat/low fiber Western diet, elimination of previously common enteropathogens (including helminthic parasites), reduced exposure to infectious disease, Caesarean birth and formula feeding have perturbed mutually beneficial interactions established with our commensal microbiome over millions of years of co-evolution. In genetically susceptible individuals, this dysbiosis can predispose to allergic disease.

Antibiotic use during infancy has often been cited as a factor in the rising prevalence of allergic disease. However, the mechanisms by which changes in the composition of the intestinal microbiota regulate allergic responses to food has been poorly understood. Murine models developed in our laboratory demonstrate that sensitization to a food allergen is enhanced in mice that have been treated by neonatal antibiotic administration (Abx) or are devoid of commensal microbes (germ free). By selectively colonizing germ free mice, we have shown that the allergy-protective capacity is contained within the Clostridia, a class of anaerobic spore-forming Firmicutes that reside in close proximity to the colonic epithelium. Moreover, reintroduction of a Clostridia-containing microbiota to Abx-treated mice blocks sensitization to a food allergen. Microarray analysis of intestinal epithelial cells isolated from gnotobiotic mice helped to identify a novel innate mechanism by which Clostridia protect against sensitization to dietary antigens. Defects in intestinal permeability have been implicated in aberrant allergic responses to food, but the mechanisms governing uptake of dietary antigen have not been clear. We find that Clostridia colonization induces the production of the barrier protective cytokine IL-22 by both innate lymphoid cells and T cells in the colonic lamina propria. IL-22 acts to reduce uptake of orally administered dietary antigen into the systemic circulation, thereby protecting against sensitization.

Our mouse model work is supported by translational studies comparing the fecal microbiota of healthy infants to that of infants with cow’s milk allergy (CMA). Working with a food allergy center at the University of Naples we found that, at diagnosis, the CMA infant microbiome has the diverse community structure typical of adults. Our collaborators have demonstrated that dietary management with an extensively hydrolyzed casein formula (EHCF) containing the probiotic Lactobacillus rhamnosus GG (LGG) results in a higher rate of tolerance acquisition in infants with CMA.  When we examined the influence of this dietary intervention on the composition of the gut microbiota we found that it did not result in an increased abundance of lactobacilli detectable in the feces of the treated infants.  Instead, treatment with EHCF plus LGG, but not a rice protein hydrolyzed formula (RHF), is associated with changes in microbial community structure that include the expansion of butyrate-producing Clostridia. CMA infants treated with EHCF plus LGG, but not RHF, had significantly higher levels of butyrate detectable in feces and an accelerated acquisition of tolerance to cow’s milk.

Ongoing work in our laboratory explores the cellular and molecular interactions by which commensal bacterial regulate sensitization to food allergens. Oral and subcutaneous allergen-specific desensitization protocols are already showing promise for treating food allergy. Our data suggest that pairing Clostridia enrichment of the gut microbiota with these tolerance inducing protocols may potentiate antigen specific tolerance to prevent or treat food allergy.  We are currently partnering with a biotech company to translate our mouse model findings to novel adjunctive probiotic therapies for patients with food allergy.

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Selected Papers

Nagler-Anderson, C., Bober, L.A., Robinson, M.E., Siskind, G.W. and Thorbecke, G.J. Suppression of type II collagen induced arthritis by intragastric administration of soluble type II collagen. Proc. Natl. Acad. Sci. 1986; 83: 7443-7446. PMID: 3463976

Shi, H.N., Ingui, C. J., Dodge, I. and C. Nagler-Anderson. A helminth induced mucosal Th2 response alters non-responsiveness to oral administration of soluble antigen. J. Immunol. 1998;160:2449-2455. PMID: 9498789

Fox, J.G., Beck, P., Dangler, C.A., Whary, M.T., Wang, T.C., Shi, H.N. and C. Nagler-Anderson. Concurrent enteric helminth infection modulates inflammation, gastric immune responses, and reduces Helicobacter-induced gastric atrophy. Nature Medicine 2000; 6: 536-542. PMID: 10802709

Shi, H.N., Liu, H.Y. and C. Nagler-Anderson. Enteric infection acts as an adjuvant for the response to a model food antigen, J. Immunol., 2000, 165: 6174-6182. PMID: 11086051

Bashir, M.E.H., Andersen, P., Fuss, I.J., Shi, H.N. and C. Nagler-Anderson. An enteric helminth infection protects against an allergic response to dietary antigen. J. Immunol. 2002, 169:3284-3292. PMID: 12218148

Bashir, M.E.H., Louie, S., Shi, H.N. and C. Nagler-Anderson. TLR-4 signaling by intestinal microbes influences susceptibility to food allergy. J.Immunol., 2004, 172, 6978-6987. PMID: 15153518

Iweala, O.I., Smith, D.S., Matharu, K.S., Sada-Ovalle, I..,DeKruyff, R.H., Umetsu, D.T., Behar, S.M and C. R. Nagler. Vaccine induced antibody isotypes are skewed by impaired CD4 T cell and invariant NKT cell effector responses in MyD88 deficient mice. J. Immunol., 2009, 183: 2252-2260. PMID: 19620295

Matharu, K.S, Mizoguchi, E., Alonso, C., Nguyen D., Mingle, B., Iweala, O.I., McBee, M. Stefka, AT, Prioult, G, Haigis, K.M., Bhan, A.K., Snapper, S.B., Murakami, H, Schauer D.B. Reinecker,H.C Mizoguchi, A. and C. R. Nagler. Toll-like receptor 4-mediated regulation of spontaneous Helicobacter-dependent colitis in IL-10 deficient mice. Gastroenterology 2009, 137:1380–1390. PMID: 19596011

McBee M.E., Zeng Y, Parry N, Nagler C.R., Tannenbaum S.R. and D.B. Schauer. Multivariate modeling identifies neutrophil- and Th17-related factors as differential serum biomarkers of chronic murine colitis. PLoS ONE 2010, 5: e13277.

Wang, Y., Devkota, S., Musch, M.W., Jabri, B., Nagler, C., Antonopoulos, D.A., Chervonsky, A and E.B. Chang. Regional mucosa- associated microbiota determine physiological expression of TLR2 and TLR4 in murine colon. PLoS ONE 2010, 5: e13607.

Wang, S. Villablanca, E.J., De Calisto, J., Gomes, D.C.O., Nguyen, D.D., Mizoguchi, E., Kagan, J.C., Reinecker, H.-C., Hacohen, N., Nagler, C., Xavier, R.J., Rossi-Bergmann, B., Chen, Y-B., Blomhoff, R., Snapper, S.B. and Mora, J.R. MyD88-dependent TLR1/2 signals educate dendritic cells with gut- specific imprinting properties. J. Immunol. 2011, 187: 141-150.

Upadhyay, V., Poroyko, V., Kim, T.J., Devkota, S., Fu, S., Liu, D., Tumanov, A.V., Koroleva, E.P, Deng, L., Nagler, C., Chang, E.B, Tang,H. and Fu, Y-F. Lymphotoxin regulates commensal responses to enable diet-induced obesity. Nat. Immunol. 2012, 13: 947-953.

Feehley, T., Stefka, A.T., Cao, S. and C.R. Nagler. Microbial regulation of allergic responses to food. Semin. Immunopathol. 2012, 34: 671-688.

Berni Canani, R., Stefka, A.T., Nocerino, R. Patton, T.J.,, Aitoro, R., Paparo, L., Calignano, A., Meli, R. Mattace Raso, G. Simeoli, R., Di Costanzo, M., Guandalini, S., Antonopoulos, D.A and C.R. Nagler. 2014. Extensively hydrolyzed casein formula containing Lactobacillus GG expands gut immunoregulatory bacteria in infants with cow’s milk allergy, in review

Stefka, A.T, Feehley, T., Tripathi, P., Qiu, J.,McCoy, K., Mazmanian, S., Seo, G-Y., Cao, S., Theriault, B, Antonopoulos, D., Zhou, L., Chang, E.B., Fu, Y-X., and C.R. Nagler. 2014. Commensal bacteria protect against food allergen sensitization. Proc. Natl. Acad. Sci. USA, in revision

Committee on Immunology (COI)

PubMed link to Cathryn Nagler publications.