Prenatal stress induces changes in PAR2- and M3-dependent regulation of colon primitive cells

Abstract

Prenatal stress is associated with a high risk of developing adult intestinal pathologies, such as irritable bowel syndrome, chronic inflammation and cancer. Although epithelial stem cells and progenitors have been implicated in intestinal pathophysiology, how prenatal stress could impact their functions is still unknown. We have investigated the proliferative and differentiation capacities of primitive cells using epithelial crypts isolated from colons of adult male and female mice whose mothers have been stressed during late gestation. Our results show that stem cell/progenitor proliferation and differentiation in vitro are negatively impacted by prenatal stress in male progeny. This is promoted by a reinforcement of the negative proliferative/differentiation control by the protease activated receptor 2 (PAR2) and the muscarinic receptor 3 (M3), two G protein coupled receptors present in the crypt. Conversely, prenatal stress does not change in vitro proliferation of colon primitive cells in female progeny. Importantly, this maintenance is associated with a functional switch in the M3 negative control of colonoid growth, becoming proliferative following prenatal stress. Additionally, the proliferative role of PAR2 specific to females is maintained under prenatal stress, even though PAR2-targeted stress signals Dusp6 and activated GSK3β are increased, reaching the levels of males. An epithelial serine protease could play a critical role in the activation of the survival kinase GSK3β in colonoids from prenatally stressed female progeny. Altogether, our results show that following prenatal stress, colon primitive cells cope with stress through sexually dimorphic mechanisms that could pave the way to dysregulated crypt regeneration and intestinal pathologies.

Intestinal organoids to model Salmonella infection and its impact on progenitors

“…The ileum, caecum, and colon were removed and placed in phosphate-buffered saline without Ca 2+ and Mg 2+ (PBS; Thermo Fisher Scienti c). The crypts were isolated as described by Berger et al 30 . The number of crypts was estimated using a bright eld optical microscopy (Nikon).…”

Intestinal organoids to model Salmonella infection and its impact on progenitors

“…The crypts were isolated as described by Berger et al . 33 . The number of crypts was estimated using a bright field optical microscopy (Nikon).…”

The impact of acute and chronic stress on gastrointestinal physiology and function: a microbiota–gut–brain axis perspective

“…Importantly, increasing evidence from preclinical and human studies indicates that stressors encountered during pregnancy have enduring consequences on offspring health, with alterations in immune function (Chen, Bischoff et al., 2022; Couret et al., 2009), gut microbiota composition (Galley et al., 2021; Golubeva et al., 2015; Gur et al., 2019; Jašarević et al., 2017; Zijlmans et al., 2015), HPA axis function (Golubeva et al., 2015; Kapoor et al., 2006) and behaviour (Chen, Bischoff et al., 2022; Gur et al., 2019). In the rodent gut, prenatal stress impairs intestinal epithelial cell proliferation and differentiation (Berger et al., 2022; Sun, Xie et al., 2021), alters host gene expression related to tryptophan metabolism (Galley et al., 2021), and reduces innervation in the distal colon (Golubeva et al., 2015). Emerging data implicate the gut microbiota in both the neuropsychiatric and GI consequences of prenatal stress.…”