Crohn’s disease (CD) pathogenicity involves interplay of genetic and environmental factors (G+E). CD subjects and mice harboring ATG16L1 T300A, a key CD susceptibility allele, showed Paneth cell (PC) defects upon exposure to cigarette smoking, a known CD environmental risk factor. Thus, PC phenotype can integrate G+E effects. RNA-seq of full thickness ileum showed reduced PPAR-γ signaling in T300A-smoked mice. Treatment with the PPAR-γ agonist rosiglitazone rescued PC defects in T300A-smoked mice.