Toll-Like Receptor 4 Signaling by Intestinal Microbes Influences Susceptibility to Food Allergy

Abstract

The mechanisms by which signaling by the innate immune system controls susceptibility to allergy are poorly understood. In this report, we show that intragastric administration of a food allergen with a mucosal adjuvant induces allergen-specific IgE, elevated plasma histamine levels, and anaphylactic symptoms in three different strains of mice lacking a functional receptor for bacterial LPS (Toll-like receptor 4 (TLR4)), but not in MHC-matched or congenic controls. Susceptibility to allergy correlates with a Th2-biased cytokine response in both the mucosal (mesenteric lymph node and Peyer’s patch) and systemic (spleen) tissues of TLR4-mutant or -deficient mice. TLR4-mutant mice are not inherently impaired in their ability to regulate Th1 cytokine production because they respond to stimulation via TLR9. Coadministration of CpG oligodeoxynucleotides during sensitization of TLR4-mutant mice with allergen plus CT abrogates anaphylactic symptoms and Ag-specific IgE, and results in a Th1-polarized cytokine response. When the composition of the bacterial flora is reduced and altered by antibiotic administration (beginning at 2 wk of age), TLR4 wild-type mice become as susceptible to the induction of allergy as their TLR4-mutant counterparts. Both allergen-specific IgE and Th2 cytokine responses are reduced in antibiotic-treated mice in which the flora has been allowed to repopulate. Taken together, our results suggest that TLR4-dependent signals provided by the intestinal commensal flora inhibit the development of allergic responses to food Ags.

Breast milk, microbiota, and intestinal immune homeostasis

“…Accordingly, early colonization is necessary for appropriate development of mucosal immune defense, which in turn is required for prevention of immune-mediated diseases later in life. In addition, clinical and animal studies have shown the loss of tolerance with extensive antibiotic treatment in adults (18,45,46). These observations may help to explain late onset expression of autoimmune disease or allergy, now commonly seen by physicians.…”

TLR Signaling in the Gut in Health and Disease

“…In an animal model of food allergy, TLR4 signaling and luminal bacteria were protective against the development of allergy (71). Stimuli such as CpG ODN that could shift the immune response toward Th1 development could rescue the allergic phenotype.…”

Commensal bacteria protect against food allergen sensitization

“…We evaluated the susceptibility of mice to food allergen sensitization by intragastric coadministration of peanut (PN) allergens and the mucosal adjuvant cholera toxin (CT), which induces PN-specific IgE, IgG1, and symptoms typical of systemic allergic hyperreactivity (12). Mice treated with Abx showed marked elevation in PN-specific IgE and…”