The prevalence of food allergy is rising at an alarming rate in the United States and in other parts of the developed world. Environmental stimuli that alter populations of beneficial commensal bacteria have been implicated in this increase. Earlier work from our laboratory showed that mice unable to signal via TLR4 exhibit enhanced allergic responses to food. We hypothesized that commensal bacteria were the source of the TLR4 ligand and demonstrated that neonatal administration of a cocktail of broad-spectrum antibiotics (Abx) induced an allergic response in TLR4 sufficient mice equivalent to that seen in TLR4 mutant mice. In the preliminary data presented in this revised application we have established a novel gnotobiotic model of food allergy and show that a defined bacterial consortium, derived directly from the intestinal microbiota of healthy mice, protects against systemic hyperreactivity to a food allergen. We demonstrate that bacteria in the Clostridia class selectively induce a barrier protective response that includes activation of the IL-23/IL-22 axis, induction of the expression of the anti-microbial peptides Reg3b and Reg3g and the expansion of intestinal Tregs and IgA secreting B cells;part of this response is TLR4-dependent. We hypothesize that a Clostridia-containing microbiota is sufficient to elicit a barrier protective response that protects against allergic responses to food. In the experiments proposed we will examine how allergy-protective bacterial populations deliver signals to their hosts at both the cellular and molecular level. Seven new figures of preliminary data are provided in support of the two Aims outlined in this revised application.
Aim 1 will determine which cellular interactions with commensal bacteria are necessary and sufficient to induce a barrier protective response. We have used Cre- Lox technology to generate mice with targeted mutations in MyD88 signaling in CD11c+ dendritic cells (DC) and in intestinal epithelial cells (IEC). We will also examine whether TLR4 signaling is required by the Tregs themselves. Microarray analysis of intestinal epithelial cells highlighted two novel genes/pathways selectively upregulated in the epithelium of Clostridia colonized mice;the anti-microbial peptide Reg3b and a target gene for the aryl hydrocarbon receptor (Ahr). Both pathways have been intimately linked to the regulation of intestinal immunity.
Aim 2 a will examine how Ahr-mediated signals and IL22 contribute to a Clostridia induced barrier protective response that prevents against an allergic response to food. Finally, Aim 2b will examine how Clostridia mediated activation of the innate and adaptive immune system impacts epithelial tight junction protein expression and function. The successful completion of the Aims proposed holds promise for the development of novel approaches to prevent or treat food allergy based on modulation of the composition of intestinal microbiota.
The prevalence of food allergy is rising at an alarming rate in the United States and in other parts of the developed world. No treatment other than strict avoidance is currently available, making allergic reactions to food particularly problematic in school and childcare settings. The experiments proposed examine how intestinal bacterial populations regulate allergic responses to food. The information obtained from these studies may lead to the development of novel approaches to prevent or treat food allergy by modulating the composition of the intestinal microbiota.
|Kim, Yun-Gi; Sakamoto, Kei; Seo, Sang-Uk et al. (2017) Neonatal acquisition of Clostridia species protects against colonization by bacterial pathogens. Science 356:315-319|
|Plunkett, Catherine H; Nagler, Cathryn R (2017) The Influence of the Microbiome on Allergic Sensitization to Food. J Immunol 198:581-589|
|Seo, Goo-Young; Lee, Jeong-Min; Jang, Young-Saeng et al. (2017) Mechanism underlying the suppressor activity of retinoic acid on IL4-induced IgE synthesis and its physiological implication. Cell Immunol 322:49-55|
|Lei, Yuk Man; Chen, Luqiu; Wang, Ying et al. (2016) The composition of the microbiota modulates allograft rejection. J Clin Invest 126:2736-44|
|Wesemann, Duane R; Nagler, Cathryn R (2016) The Microbiome, Timing, and Barrier Function in the Context of Allergic Disease. Immunity 44:728-38|
|Nutsch, Katherine; Chai, Jiani N; Ai, Teresa L et al. (2016) Rapid and Efficient Generation of Regulatory T Cells to Commensal Antigens in the Periphery. Cell Rep 17:206-220|
|Berni Canani, Roberto; Sangwan, Naseer; Stefka, Andrew T et al. (2016) Lactobacillus rhamnosus GG-supplemented formula expands butyrate-producing bacterial strains in food allergic infants. ISME J 10:742-50|
|Berni Canani, Roberto; Gilbert, Jack A; Nagler, Cathryn R (2015) The role of the commensal microbiota in the regulation of tolerance to dietary allergens. Curr Opin Allergy Clin Immunol 15:243-9|
|Yano, Jessica M; Yu, Kristie; Donaldson, Gregory P et al. (2015) Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell 161:264-76|
|Lax, Simon; Nagler, Cathryn R; Gilbert, Jack A (2015) Our interface with the built environment: immunity and the indoor microbiota. Trends Immunol 36:121-3|
Showing the most recent 10 out of 14 publications