Elements of the lean gut environment protect against severe atopic dermatitis in high fat diet-fed mice

Diet controls core physiological processes, yet how it regulates immune responses in the context of inflammatory disease is not well understood. Previous work from our lab demonstrated that high fat diet (HFD)-fed mice exhibit a non-canonical T helper type 17 (TH17) dominated response to atopic dermatitis (AD), which classically elicits a TH2 response in control lean fat diet (LFD)-fed mice, rendering HFD-fed mice incapable of benefitting from targeted anti-TH2 therapies for AD (Bapat et al., Nature 2022). Diet robustly remodels the gut microbiome, which in turn has been shown to have long-range effects on tissue physiology and inflammation. We hypothesized that diet-induced alterations in the microbiome were important drivers of the TH2 to TH17 inflammatory switch in HFD-fed mice. To test this hypothesis, we conducted bed-swapping experiments, in which we exposed HFD-fed mice to bedding and fecal pellets from LFD-fed mice and vice-versa. Interestingly, we found that HFD-fed mice exposed to LFD-fed bedding presented with a TH2 dominant response to AD challenge and less severe disease score relative to the HFD-fed control. Additionally, we conducted untargeted serum metabolics and 16S metagenomic sequencing of these mice, data which we will describe here. Surprisingly, depletion of the bacterial microbiome via antibiotic administration had no effect on AD severity of LFD-fed vs HFD-fed mice relative to water only controls. TH17 cells are important for anti-fungal immunity, and so further work will be aimed at understanding the potential role of the fungal microbiome on T cell response and disease severity.