Comparison of Colonic Baseline Ion Secretion and Responses to Stress‐related Peptides between Male and Female Mice
Authors: Hua Howard , Karo Aaron , Agterberg Sita , Liu Sumei 
Published: June 2021

Background and AimsSex plays an important role in the symptoms of irritable bowel syndrome (IBS) and responses to treatment. Constipation‐predominant IBS (IBS‐C) is more prevalent in women, whereas diarrhea‐predominant IBS (IBS‐D) is more common in men. Stress has been shown to increase intestinal ion secretion and may exacerbate symptoms in IBS‐D. Most of the previous preclinical studies investigating the effects of stress on gut function were performed in male animals. The aim of the present study was to determine if there was a sex difference in baseline ion secretion in the mouse colon and/or its responses to stress‐related peptides, including corticotrophin releasing hormone (CRF), urocortin 1 (Ucn1), Ucn2, and Ucn3.MethodsAdult C57BL/6J mice (47 males and 20 females) were used in the present study. Mucosa/submucosa preparations from the proximal colon were mounted in Ussing flux chambers for measurement of short‐circuit current (Isc) as an indicator of mucosal ion secretion.ResultsMale mice were found to exhibit a significantly (p < 0.05) higher baseline Isc (70.90 ± 4.84 μA/cm2, n = 47) in the proximal colon than females (52.92 ± 4.40 μA/cm2, n = 20). In addition, male mice exhibited a greater increase in colonic Isc (ΔIsc) than did female mice in response to 1 μM of CRF (10.26 ± 1.31 μA/cm2 vs. 4.59 ± 1.21 μA/cm2, n = 5/group, p < 0.05), 1 μM of Ucn1 (16.65 ± 2.23 μA/cm2 vs. 6.80 ± 1.16 μA/cm2, n = 5/group, p < 0.01), 1 μM of Ucn2 (21.76 ± 4.58 μA/cm2 vs. 6.72 ± 0.57 μA/cm2, n = 5/group, p < 0.05), or 1 μM of Ucn3 (41.41 ± 8.91 μA/cm2 vs. 7.86 ± 1.47 μA/cm2, n = 5, p < 0.01). Colonic Isc response to the selective CRF1 receptor agonist, stressin I (1 μM) was similar in male and female mice (10.19 ± 2.19 μA/cm2 vs. 7.08 ± 5.16 μA/cm2, n = 4–5/group, p > 0.05). In male mice, Ucn3 caused a significantly higher ΔIsc than stressin I, CRF, Ucn1, or Ucn2. Contrastingly, female mice displayed a similar and weaker ΔIsc response to these peptides.ConclusionsMarked sex differences were observed in colonic baseline ion secretion and responses to stress‐related peptides. Male mice demonstrated a significantly higher baseline ion secretion in the proximal colon when compared with their female counter parts. In addition, CRF, Ucn1, Unc2, and Ucn3 evoked a greater increase in colonic ion secretion in male mice than female mice. Ucn3 is more efficacious than the other stress‐related peptides to evoke ion secretion in the male mouse colon, suggesting a predominant role of the CRF2 receptors in stimulation colonic ion secretion in males. Female mice, however, exhibited low level responses to these stress‐related peptides, and no significant differences were seen between these peptides‐evoked responses. The results suggest that the greater colonic baseline ion secretion and responses to stress‐related peptides in male mice may contribute to the high prevalence of IBS‐D in males.Support or Funding InformationNIH R15 DK097460‐01A1 (SL) and UWL graduate research service and educational leadership grant (AK). Howard Hua is a summer research fellow from Wheeler High School, Marietta, GA.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.