Gut microbiota alters the Th1/Th2 balance and aggravates food-allergic enteropathy in a mouse model

In non-IgE-mediated food allergy, food protein-induced enteropathy (FPE) can be evoked by the Th2 response. Some reports show that either Th2-biased immune responses or gut microbial dysbiosis can exacerbate food-allergic gastrointestinal inflammation. Nevertheless, it remains unclear whether gut microbiota directly affect Th2-biased immune responses involving FPE. To address this issue, we used OVA23-3 × BALB/cA mice, which is an FPE-like model. Feeding the mice an egg-white diet (EW) induced excessive Th2-type immune responses in CD4⁺ T cells in the mesenteric lymph nodes (MLNs), resulting in weight loss and enteropathy. Firstly, we compared specific pathogen-free (SPF) OVA23-3 × BALB/cA mice with germ-free (GF) OVA23-3 × BALB/cA mice when fed an EW diet. Symptoms shown in SPF mice were attenuated in GF mice, suggesting that gut microbiota may contribute to exacerbating symptoms. Additionally, we orally administered broad-spectrum antibiotics (Abx) to OVA23-3×BALB/cA mice and analyzed the gut microbiota. Compared with a no-Abx administration group, we found that Abx administration significantly altered the alpha and beta diversity of the gut microbiota in EW-fed mice. The presence of Alloprevotella, Bacteroides, and Muribaculaceae was reduced to approximately 10%. Both weight loss and enteropathy in EW-fed mice were ameliorated after Abx administration. Furthermore, administration of Abx to the EW-fed group improved the Th1/Th2 balance in MLN cells and decreased the mRNA expression of IL-33 and the aryl hydrocarbon receptor in the jejunum. These results suggest that some members of the gut microbiota disturb Th1/Th2 responses in the MLN, by affecting the small intestinal epithelium, thereby exacerbating Th2-biased responses and inducing food-allergic enteropathy.