AbstractInflammatory bowel disease (IBD) arises by unknown environmental triggers in genetically susceptible individuals. Epigenetic regulation of gene expression may integrate internal and external influences and may thereby modulate disease susceptibility. Epigenetic modification may also affect the germ-line and in certain contexts can be inherited to offspring. This study investigates epigenetic alterations consequent to experimental murine colitis induced by dextran sodium sulphate (DSS), and their paternal transmission to offspring. Genome-wide methylome- and transcriptome-profiling of intestinal epithelial cells (IECs) and sperm cells of males of the F₀ generation, which received either DSS and consequently developed colitis (F₀^DSS), or non-supplemented tap water (F₀^Ctrl) and hence remained healthy, and of their F₁ offspring was performed using reduced representation bisulfite sequencing (RRBS) and RNA-sequencing (RNA-Seq), respectively. Offspring of F₀^DSS males exhibited aberrant methylation and expression patterns of multiple genes, including Igf1r and Nr4a2, which are involved in energy metabolism. Importantly, DSS colitis in F₀^DSS mice was associated with decreased body weight at baseline of their F₁ offspring, and these F₁ mice exhibited increased susceptibility to DSS-induced colitis compared to offspring from F₀^Ctrl males. This study hence demonstrates epigenetic transmissibility of metabolic and inflammatory traits resulting from experimental colitis.