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Abstract

A tightly regulated immune response is essential to ensure protection from the plethora of microbial pathogens we encounter, while simultaneously averting spurious responses to innocuous environmental antigens, self-antigens, or commensal microflora. Advances in Western medicine and sanitation have dramatically reduced mortality and morbidity linked to infectious diseases, but at a cost: diminished microbial exposure has inadvertently altered normal immune cell development and heightened the risk of autoinflammatory and autoimmune disorders. Innate lymphoid cells (ILCs) are recently discovered innate counterparts of T lymphocytes but lack antigen specific T cell receptors. These cells colonize peripheral tissues in waves during pre and early postnatal development and subsequently become critical, long lived tissue resident regulators of immunity. Given their early developmental tissue colonization, longevity, and role as first responders in inflammation, ILCs are ideally positioned as regulators of long-term immune sculpting by the gut microbiome. I generated a novel transgenic mouse strain (Il17rb-CreERT2-eGFP) to selectively target ILC2s. Loss of gastrointestinal ILC2s led to increased ILC3/Th17 responses, and heightened susceptibility to Crohn’s disease–like fibrosis. Conversely, dampening ILC3/Th17 responses using isolithocholic acid (isoLCA), a microbial secondary bile acid and RORγt inverse agonist, reduced interleukin-17 (IL-17) production, protecting against fibrosis. Employing mouse models of allergic airway inflammation, I demonstrate that perinatal exposure to low doses of vancomycin amplified allergic responses in adulthood. ILC2s emerged as key regulators of peripheral type 2 immune sculpting, driving innate natural immunoglobulin E (IgE) production by B1 B cells and increased surface bound IgE on basophils and mast cells, exacerbating allergic inflammation. This enhanced lung ILC2/B1 cell/effector cell axis was completely suppressed with dietary short-chain fatty acid SCFA supplementation. Conversely, streptomycin treatment heightened susceptibility to hypersensitivity pneumonitis, marked by increased lung ILC3s and Th17 cells, and was significantly ameliorated by isoLCA or selective mammalian target of rapamycin complex 1 (mTORC1) inhibition. This highlights that antibiotic-induced dysbiosis, by skewing microbial communities, is remarkably selective in its effects on immune sculpting, with vancomycin exacerbating Th2-disease and streptomycin exacerbating Th1/Th17-linked diseases.