Estrogen Reduction Drives Greater Susceptibility to Short-Term Diet-Induced Gastrointestinal Dysmotility in Female Mice

Objectives: Long-term high-fat high-sucrose diet (HFHSD) predisposes male and female mice to gastrointestinal (GI) dysmotility.Clinically, dysmotility is more prevalent in females, suggesting that sex hormones may differentially regulate GI function.In this study, we investigated whether short-term HFHSD is sufficient to induce sex-and hormone-dependent alterations in GI motility.Methods: Ovariectomized (OVX) female and orchiectomized (ORX) male mice were fed either a normal diet (ND) or HFHSD for 1.5 months.GI motility was evaluated before surgery, after gonadectomy, and following estrogen treatment using total transit time, colonic transit time, and fecal output.Findings: Short-term HFHSD-fed female mice exhibited delayed GI motility, whereas males remained largely unaffected.Among ND-fed females, reduced estrogen levels during diestrus were associated with slowed colonic transit.In HFHSD-fed females, estrogen levels were reduced even during proestrus and were similarly linked to delayed motility.ND-fed OVX females developed dysmotility comparable to that of short-term HFHSD-fed intact females, and HFHSD did not further worsen motility in OVX mice.Exogenous estrogen restored GI motility in short-term HFHSD-fed OVX females.In males, GI motility was delayed in both ND-fed ORX and short-term HFHSDfed ORX mice, underscoring hormone dependence in both sexes.Conclusions: While both estrogen and testosterone deficiencies impair Gl motility, females exhibit greater vulnerability to short-term HFHSD-induced dysmotility due to estrogen reduction.