<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Gut microbiota dysbiosis is linked to the development and responses of the immune system and can play an important role in the onset of allergic diseases including atopic dermatitis (AD). This study investigated the association between host genetics and the gut microbiota in AD.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>A global gene expression profiling of the gut epithelial colonocytes, genetic variations analysis, and the gut microbial composition analysis were performed.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>This study identified the upregulation of <jats:italic>PTGR2</jats:italic> (<jats:italic>p</jats:italic> = .028), a gene involved in prostaglandin catalysis and inflammatory responses, as a potential risk factor for AD. In subsequent fine mapping analysis using 17 single nucleotide polymorphisms (SNPs) of <jats:italic>PTGR2</jats:italic> in 864 Korean subjects (420 AD patients and 444 unaffected controls), several SNPs and haplotypes showed significant associations with AD and its SCORing AD (SCORAD) values (<jats:italic>p</jats:italic> = .002). To investigate host‐microbial interactions, further gut microbiota data and genotypes were obtained from an independent cohort of 176 subjects (91 AD patients and 85 controls). From correlation analysis, a significantly negative association between SNP and <jats:italic>Bifidobacterium</jats:italic> abundance was observed in AD patients (<jats:italic>p</jats:italic> = .005). In additional observations of <jats:italic>PTGR2</jats:italic>‐associated downstream molecules, NRF2 (<jats:italic>p</jats:italic> = .004) and several antioxidant genes (<jats:italic>GSTT1</jats:italic>, <jats:italic>GCLC</jats:italic>, <jats:italic>GPX1</jats:italic>; <jats:italic>p</jats:italic> < .05) showed significantly reduced expression in AD patients.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Our current findings suggest that the interaction between <jats:italic>PTGR2</jats:italic> dysregulated expression and a <jats:italic>Bifidobacterium</jats:italic> abundance affects a higher risk of AD and a more severe onset.</jats:p></jats:sec>