Gary B. Huffnagle, Ph.D.
Professor,
Department of Internal Medicine (Pulmonary) and
Department of Microbiology and Immunology

ghuff@umich.edu


Research Description:

Our laboratory is interested in the microbial ecology of mucosal surfaces and the role of the microbiota in shaping the mucosal immunity. Epidemiologic and clinical data support the hypothesis that perturbations in the gastrointestinal microbiota due to antibiotic use and dietary differences in “industrialized” countries have disrupted the normal microbiota-mediated mechanisms of immunological tolerance in the mucosa, leading to an increase in the incidence of allergic airway disease. The data supporting this "Microflora Hypothesis" includes correlations between allergic airway disease and (1) antibiotic use early in life, (2) altered fecal microbiota and (3) dietary changes over the past two decades. Our laboratory has demonstrated that mice can develop allergic airway responses to allergens if their endogenous microbiota is altered at the time of first allergen exposure. These experimental and clinical observations are consistent with other studies demonstrating that the endogenous microbiota plays a significant role in shaping the development of the immune system. Data is beginning to accumulate that a "balanced" microbiota plays a positive role in maintaining mucosal immunologic tolerance long after post-natal development. Other studies have demonstrated that even small volumes delivered to the nasopharynx largely end up in the GI tract, suggesting that airway tolerance and oral tolerance may operate simultaneously. The mechanism of microbiota modulation of host immunity is not known; however, host and microbial oxylipins are one potential set of immunomodulatory molecules that may control mucosal tolerance. Probiotic and prebiotic immunotherapy may work through modulating the ecology of the GI microbiota.

Representative Publications:

Noverr MC, Falkowski NR, McDonald RA, McKenzie AN, Huffnagle GB. The development of allergic airway disease in mice following antibiotic therapy and fungal microbiota increase: role of genetics, antigen and IL-13. Infect Immun 2005; 73(1):30-8.

Hernandez YS, Arora S, McDonald RA, Toews GB, Huffnagle GB. Distinct roles for IL-4 and IL-10 in regulating T2 immunity during allergic bronchopulmonary mycosis. J Immunol 2005; 174(2):1027-36.

Lindell DM, Moore TA, McDonald RA, Toews GB, Huffnagle GB. Distinct compartmentalization of CD4+ T cell effector function versus proliferative capacity during pulmonary cryptococcosis. Am J Pathol 2006; 168(3):847-55.

Arora S, McDonald RA, Toews GB, Huffnagle GB. Effect of a CD4-depleting antibody on the development of C. neoformans-induced allergic bronchopulmonary mycosis in mice. Infect Immun 2006; 74(7):4339-48.

Rodriguez TE, Falkowski NR, Harkema JR, Huffnagle GB. Analysis of the role of neutrophils in preventing and resolving acute fungal sinusitis. Infect Immun 2007;75(12):5663-8.

Erb-Downward JR, Noggle RM, Williamson PR, Huffnagle GB. The role of laccase in prostaglandin production by Cryptococcus neoformans. Mol Microbiol 2008; 68(6):1428-37.

Lau HY, Huffnagle GB, Moore TA. Host and microbiota factors that control Klebsiella pneumoniae mucosal colonization in mice. Microbes Infect. 2008; 10(12-13):1283-90.

Shreiner A, Huffnagle GB, Noverr MC. The “Microflora Hypothesis” of Allergic Disease. Microbiota and Immunology, Landes Bioscience, M. Noverr & G. Huffnagle, eds. (2008).

Mason KL, Huffnagle GB. Control of mucosal polymicrobial populations by innate immunity. Cell Microbiol. 2009 Jun 25. [Epub ahead of print].

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