How antibiotics administered to newborns transform immunity into allergy

Numerous studies have revealed the impact of the microbiome on the initiation, exacerbation and resolution of a wide range of inflammatory diseases, including allergies. In most cases, the mechanisms underlying these responses remain obscure. However, researchers at the School of Biomedical Engineering at the University of British Columbia (UBC) have now identified a cascade of responses, triggered by antibiotic-induced gut dysbiosis, that lead to respiratory allergies, including asthma.“Our research finally shows how gut bacteria and antibiotics shape a newborn’s immune system to make them more prone to allergies,” said UBC department of medical genetics professor Kelly McNagny. “When you see something like this, it really changes the way you look at chronic disease. This is a well-defined pathway that may have lasting consequences for susceptibility to chronic disease in adulthood.”McNagny’s team had already shown that infants treated with antibacterial antibiotics, such as vancomycin (a glycopeptide antibiotic), had an intestinal microbiota less rich in bacteria-producing butyrate, a short-chain fatty acid, and that these babies were particularly susceptible to allergies. Researchers have also shown that this phenomenon could be mitigated or even reversed by supplementing newborns with butyrate. By studying the process in mice, they discovered how it is triggered.In an article published in the Journal of Allergy and Clinical Immunology, the scientists explain that they depleted the intestinal microbiota of test mice using low doses of vancomycin. In mice not supplemented with butyrate, they found that levels of ILC2 (innate lymphoid cell type 2) immune cells increased twice as fast in the lungs. These cells are among the first players in the immune response and are characterized by the rapid production of inflammatory cytokines. ILC2s have also been shown to play a critical role in the pathogenesis of asthma.“Intestinal dysbiosis leads to the expansion and priming of pulmonary ILC2s with enhanced effector functions. The result is exacerbated airway inflammation in response to alarmin signaling. This expansion and priming includes a doubling in the number of ILC2s in peripheral tissues, upregulation of ILC2 activation markers (KLRG1 and CD25), an enhanced capacity to produce effector cytokines (IL-2, -5, -13) and, most notably, IL-4 production in response to the pulmonary alarmin IL-33,” the research read. In contrast, in dysbiotic mice supplemented with butyrate, McNagny’s team observed that IL-4 cytokine levels were reduced in the lungs, preventing the multiplication of ILC2 cells. “Our results suggest that short-chain fatty acids may prevent pathological immune patterning induced by dysbiosis early in life. They also provide new insights into the role of microbial short-chain fatty acids in regulating ILC2 function,” concluded the researchers.A promising future for probioticsThanks to the identification of these cellular and molecular mechanisms, “We can now detect when a patient is on the verge of developing lifelong allergies, simply by the increase in ILC2,” said the study’s first author, Ahmed Kabil, in a statement. “And we can potentially target these cell types instead of relying on butyrate supplementation, which only works in early life,” added Kabil, a PhD student in UBC’s School of Biomedical Engineering.The researchers stress that infants should be treated with antibiotics if necessary, but they hope their findings will help determine which bacteria make them less susceptible to inflammatory diseases. Their work could also pave the way for the possibility of boosting useful bacteria through the use of probiotics. For McNagny, probiotics could thus “be the next big trend in childcare, because once we know which bacteria prevent disease, we can ensure that they are protected by those bacteria.”

How antibiotics administered to newborns transform immunity into allergy

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