TLR4 regulates proinflammatory intestinal immune responses mediated by an atopic gut microbiota

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The increasing prevalence of food allergies has been causally associated with the depletion of allergy protective intestinal bacteria. However, few studies have investigated the role of the gut microbiota in promoting allergic responses. In a cohort of infants affected by cow’s milk allergy (CMA), we have identified a patient with a proinflammatory and atopic microbiota. In comparison to a healthy microbiota, this CMA-associated gut microbiota has increased abundance of Bacteroidetes, a Gram-negative phylum of bacteria that has been associated with increased incidence of allergy. Using this microbiota, we investigated the host-microbe interactions that mediate these intestinal inflammatory responses. To examine these interactions, we used mice with global and conditional abrogation in TLR4 signaling, since Gram- negative bacteria signal through this receptor via membrane-derived lipopolysaccharide (LPS). We show that this donor’s microbiota induces expression of serum amyloid A1 ( Saa1 ) and other Th17-, B cell-, and Th2-associated genes in the ileal epithelium. Accordingly, this microbiota also induces Th17 cells, as well as regulatory T cell populations and fecal IgA. Importantly, we used both antibiotic treated SPF and rederived germ-free mice with a conditional mutation of TLR4 in the CD11c + compartment to demonstrate that the induction of proinflammatory genes, fecal IgA, and Th17 cells is dependent on TLR4 signaling. Furthermore, metagenomic sequencing revealed that the CMA-associated gut microbiota also has increased abundance of LPS biosynthesis genes. Lastly, upon sensitization with β-lactoglobulin, this CMA microbiota induces a TLR4-dependent mixed type 2/type 3 response in innate lymphoid cells (ILCs) during the early phases of allergic sensitization. Taken together, our results show that a Bacteroidetes-enriched microbiota with increased abundance of LPS genes promotes proinflammatory gene expression and a mixed type 2/type 3 response in a subset of infants with cow’s milk allergy.

Paper Highlights

  • A cow’s milk allergy (CMA)-associated gut microbiota has an enrichment of Bacteroidetes, which is associated with atopy

  • The CMA-associated gut microbiota promotes intestinal inflammation, which includes inflammatory gene expression, induction of Th17 cells, and production of IgA

  • Proinflammatory responses induced by the CMA-associated gut microbiota are dependent on TLR4 signaling in various cellular compartments

  • Upon sensitization, the CMA-associated gut microbiota induces an innate mixed type 2/type 3 inflammatory response

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