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A specific component of the intestinal microbiota exacerbates the severity of allergic asthma

Burgess, Stacey L
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1368026710

Abstract Details

, PhD, University of Cincinnati, Medicine: Immunology.
Asthma is a complex inflammatory respiratory disorder that is driven by inappropriate Th cell-mediated immune responses to inhaled allergens. While mild forms of the disease are driven by Th2-mediated immune responses, recent evidence suggests that more severe forms of the disease are driven by the combination of Th2 and Th17-mediated immune responses. The incidence of asthma in developed nations has increased significantly in the past few decades and this increase in incidence has occurred at the same time as changes in lifestyle that have altered the milieu of commensal and pathogenic organisms that humans encounter and are colonized by. Specifically, changes in the composition of the bacterial intestinal microbiota in early life, including shifts in Clostridia species, have been associated with an increased risk of the development of asthma and allergic diseases in humans. Furthermore, several specific bacteria have been shown to be protective in murine models of asthma, largely via induction of regulatory immune responses. However bacterial species that might drive more severe disease remain less defined. Segmented filamentous bacteria (SFB), or Candidatus savagella, are Clostridia related bacteria and a component of both the mouse and the human intestinal microbiota at a young age. They also are known to drive potent IL-17A induction in the intestine and to influence extra intestinal autoimmune diseases. Thus, we explored the hypothesis that SFB in early life contributes to severe asthma in a murine model. Through a series of approaches, we specifically show that intestinal colonization with SFB drives more severe asthma in a mouse model of allergic asthma. Furthermore we demonstrate that the ability of this gut tropic bacterium to drive severe asthma is dependent upon its ability to induce Th17 cytokine production. SFB-driven IL-17A alone is insufficient to enhance asthma severity, but when in the presence of IL-13, it is able to drive the severe phenotype. In exploring the mechanisms by which SFB may drive Th17-dependent severe asthma, we adoptively transferred bone marrow derived dendritic cells from SFB-colonized and SFB-free mice. Strikingly, we show that BMDDCs from SFB-colonized mice drive both Th17 cytokine production in the lung and more severe AHR. The ability of DCs from SFB-colonized mice to drive heightened airway responses is further associated with enhanced production and responsiveness to the Th17-promoting serum factor, serum amyloid A. This work thus suggests that transient colonization with SFB is sufficient to drive lasting changes to the ability of dendritic cell precursors to drive T cell responses that alter the severity of allergic asthma. This observation might also help to explain human data suggesting that early childhood colonization with certain bacteria can drive lasting changes in susceptibility to asthma. Our studies also highlighted the potential use of translation blocking oligonucleotides to target specific bacteria in vivo. In conclusion, our studies show for the first time that colonization with a specific gut microbe early in life can predispose towards Th17-skewed immune responses to subsequent encounters with aeroallergens resulting in the development of severe asthma.
Marsha Wills-Karp, Ph.D. (Committee Chair)
George Deepe, M.D. (Committee Member)
Simon Hogan, Ph.D. (Committee Member)
Edith Janssen, Ph.D. (Committee Member)
Malak Kotb, Ph.D. (Committee Member)
162 p.
Immunology
Asthma; microbiota; microbiome; segmented filamentous bacteria; Th17; allergy;

Recommended Citations

Citations

  • Burgess, S. L. (n.d.). A specific component of the intestinal microbiota exacerbates the severity of allergic asthma [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1368026710

    APA Style (7th edition)

  • Burgess, Stacey. A specific component of the intestinal microbiota exacerbates the severity of allergic asthma. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1368026710.

    MLA Style (8th edition)

  • Burgess, Stacey. "A specific component of the intestinal microbiota exacerbates the severity of allergic asthma." Doctoral dissertation, University of Cincinnati. Accessed APRIL 05, 2025. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1368026710

    Chicago Manual of Style (17th edition)

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This open access ETD is published by University of Cincinnati and OhioLINK.