Background/AimsWistar rat dams exposed to limited nesting stress (LNS) from post-natal days (PND) 2 to 10 display erratic maternal behavior, and their pups show delayed maturation of the hypothalamic-pituitary-adrenal axis and impaired epithelial barrier at PND10 and a visceral hypersensitivity at adulthood. Little is known about the impact of early life stress on the offspring before adulthood and the influence of sex. We investigated whether male and female rats previously exposed to LNS displays at weaning altered corticosterone, intestinal permeability, and microbiota. MethodsWistar rat dams and litters were maintained from PND2 to 10 with limited nesting/bedding materials and thereafter reverted to normal housing up to weaning (PND21). Control litters had normal housing. At weaning, we monitored body weight, corticosterone plasma levels (enzyme immunoassay), in vivo intestinal to colon permeability (fluorescein isothiocyanate-dextran 4 kDa) and fecal microbiota (DNA extraction and amplification of the V4 region of the 16S ribosomal RNA gene). ResultsAt weaning, LNS pups had hypercorticosteronemia and enhanced intestinal permeability with females > males while body weights were similar. LNS decreased fecal microbial diversity and induced a distinct composition characterized by increased abundance of Gram positive cocci and reduction of fiber-degrading, butyrate-producing, and mucus-resident microbes. ConclusionsThese data indicate that chronic exposure to LNS during the first week post-natally has sustained effects monitored at weaning including hypercorticosteronemia, a leaky gut, and dysbiosis. These alterations may impact on the susceptibility to develop visceral hypersensitivity in adult rats and have relevance to the development of irritable bowel syndrome in childhood.
There is growing evidence supporting a role of extracellular alpha-synuclein in the spreading of Parkinson's disease (PD) pathology. Recent pathological studies have raised the possibility that the enteric nervous system (ENS) is one of the initial sites of alpha-synuclein pathology in PD. We therefore undertook this survey to determine whether alphasynuclein can be secreted by enteric neurons. Alphasynuclein secretion was assessed by immunoblot analysis of the culture medium from primary culture of ENS. We show that alpha-synuclein is physiologically secreted by enteric neurons via a conventional, endoplasmic reticulum/Golgidependent exocytosis, in a neuronal activity-regulated manner. Our study is the first to evidence that enteric neurons are capable of secreting alpha-synuclein, thereby providing new insights into the role of the ENS in the pathophysiology of PD.
Colon cancer stem cells (CSCs) are regulated by their cellular microenvironment that delivers paracrine signals crucial to CSC maintenance and tumor growth. Among CSC neighboring cells are enteric glial cells (EGCs) that are potent regulators of intestinal epithelium functions, but whose impact on CSCs has never been studied. We hypothesized that EGCs modulate CSC functions and associated tumorigenesis. In vitro. CSCs were FACS‐isolated from HT29 colon cancer epithelial cells (CD44High/CD133High) and 3D cultured in Matrigel in presence of EGCs seeded on Transwell filters. Impact of EGCs was assessed on numbers and size of tumorspheres grown from CSCs and compared to known EGC‐derived soluble factors. In vivo. CSCs were injected alone vs. concomitantly with EGCs subcutaneously in immunodeficient mice. In vitro EGCs increased numbers and size of tumorspheres grown from CSCs. In vivo concomitant injection of CSCs and EGCs increased tumor load vs. CSCs alone. In vitro EGC‐conditioned medium (CM) did not impact CSCs, but CM of EGCs that had been pre‐incubated with HT29 cells increased tumorsphere numbers, indicating that tumor cells activate EGCs to acquire pro‐tumorigenic abilities. Among all known glial factors tested, only prostaglandin E2 (PGE2) reproduced EGC effects on CSCs. HT29 cells increased expression of mPGES‐1 (enzyme generating PGE2) and PGE2 release in EGCs. CAY10526 (mPGES‐1 inhibitor) abolished pro‐tumorigenic properties induced by HT29 cells in EGCs. These results suggest that tumor cells activate EGCs to acquire pro‐tumorigenic abilities, and that tumor‐activated EGCs stimulate CSC tumorigenicity via PGE2‐dependent pathways.
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