Functional gastrointestinal disorders (FGIDs) have prominent sex differences in incidence, symptoms, and treatment response that are not well understood. Androgens are steroid hormones present at much higher levels in males than females and could be involved in these differences. In adults with irritable bowel syndrome (IBS), a FGID that affects 5% to 10% of the population worldwide, we found that free testosterone levels were lower than those in healthy controls and inversely correlated with symptom severity. To determine how this diminished androgen signaling could contribute to bowel dysfunction, we depleted gonadal androgens in adult mice and found that this caused a profound deficit in gastrointestinal transit. Restoring a single androgen hormone was sufficient to rescue this deficit, suggesting that circulating androgens are essential for normal bowel motility in vivo. To determine the site of action, we probed androgen receptor expression in the intestine and discovered, unexpectedly, that a large subset of enteric neurons became androgen-responsive upon puberty. Androgen signaling to these neurons was required for normal colonic motility in adult mice. Taken together, these observations establish a role for gonadal androgens in the neural regulation of bowel function and link altered androgen levels with a common digestive disorder.
ABSTRACT Objectives: Gender equality in the workplace has not been described in pediatric gastroenterology. Methods: An electronic survey that explored perceptions of career parity, work–life balance, and workplace harassment was sent to all members of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition. Reponses were anonymous. Results: Of the 303 respondents (21%), there was an even distribution across geographic region, age, and gender (54% men). Gender affected perception of salary and promotion; 46% of men but only 9% of women feel that “women earn the same as men” ( P < 0.001). Similarly, 48% of men but only 12% of women feel that “women rise at the same rate as men” ( P < 0.001). Both genders of academic practice respondents, compared with other practice models, perceived men were promoted more quickly than women ( P = 0.008). Women had higher dissatisfaction with mentoring than men (29% vs 13%, P = 0.03). Significantly more men than women reported spouses with “flexible jobs” (35% vs 14%, P < 0.001). Having a spouse with “flexible job” or having children (preschool or school age), however, did not affect satisfaction with work–life balance for either gender. Overall, women are more likely to be dissatisfied with work–life balance than men ( P = 0.046). Conclusions: Satisfaction with work–life balance is lower among women versus men pediatric gastroenterologists, but does not correlate with flexibility of spouse's job or caring for young children. Gender‐divergent perception of promotion, parity of compensation, and mentoring requires further investigation.
Abdominal pain represents a significant complaint in patients with irritable bowel syndrome (IBS). While the etiology of IBS is incompletely understood, prior exposure to gastrointestinal inflammation or psychologic stress is frequently associated with the development of symptoms. Inflammation or stress-induced expression of growth factors or cytokines may contribute to the pathophysiology of IBS. Here, we aimed to investigate the therapeutic potential of inhibiting the receptor of glial cell line-derived neurotrophic factor, rearranged during transfection (RET), in experimental models of inflammation and stress-induced visceral hypersensitivity resembling IBS sequelae. In RET-cyan fluorescent protein [(CFP) RetCFP/+] mice, thoracic and lumbosacral dorsal root ganglia were shown to express RET, which colocalized with calcitonin gene-related peptide. To understand the role of RET in visceral nociception, we employed GSK3179106 as a potent, selective, and gut-restricted RET kinase inhibitor. Colonic hyperalgesia, quantified as exaggerated visceromotor response to graded pressures (0–60 mm Hg) of isobaric colorectal distension (CRD), was produced in multiple rat models induced 1) by colonic irritation, 2) following acute colonic inflammation, 3) by adulthood stress, and 4) by early life stress. In all the rat models, RET inhibition with GSK3179106 attenuated the number of abdominal contractions induced by CRD. Our findings identify a role for RET in visceral nociception. Inhibition of RET kinase with a potent, selective, and gut-restricted small molecule may represent a novel therapeutic strategy for the treatment of IBS through the attenuation of post-inflammatory and stress-induced visceral hypersensitivity.
In the enteric nervous system (ENS), glia outnumber neurons by 4 to 6-fold and form an extensive network throughout the gastrointestinal tract. Enteric glia are essential for normal gastrointestinal function and play roles in regulating epithelial barrier integrity, epithelial cell proliferation and neuronal support. While glial subtypes can be clearly distinguished in the central and peripheral nervous systems (CNS and PNS), it remains unknown whether similar glial diversity exists in the ENS. Because of their morphology and expression of Glial Fibrillary Acidic Protein (GFAP), until recently, enteric glia were thought to resemble astrocytes. We tested the hypothesis that enteric glia instead constitute a unique and heterogeneous group of glial cells. To define the level of heterogeneity, we first analyzed expression of the markers S100β, Sox10, GFAP, and proteolipid protein 1 (PLP1) in the small and large intestine of adult mice. Sox10 and S100β are widely expressed by enteric glia throughout the intestine. GFAP expression, however, is more restricted. Marker expression in combination with cellular location reproducibly distinguished subpopulations of enteric glia, suggesting that functional subtypes are likely to exist. Unexpectedly, we found that PLP1 is widely expressed by enteric glia, although they do not myelinate axons. We then performed RNA sequencing analysis (RNA-Seq) on PLP1-expressing cells in the mouse intestine and compared their gene expression to that of other types of glia in the CNS and PNS. This showed that enteric glia are transcriptionally distinct from other glial classes, and share the greatest similarity to myelinating glia. The gene expression database generated by this study will facilitate future studies of glial function in gastrointestinal physiology.
Abstract Cerebral dopamine neurotrophic factor (CDNF) is expressed in the brain and is neuroprotective. We have previously shown that CDNF is also expressed in the bowel and that its absence leads to degeneration and autophagy in the enteric nervous system (ENS), particularly in the submucosal plexus. We now demonstrate that enteric CDNF immunoreactivity is restricted to neurons (submucosal > myenteric) and is not seen in glia, interstitial cells of Cajal, or smooth muscle. Expression of CDNF, moreover, is essential for the normal development and survival of enteric dopaminergic neurons; thus, expression of the dopaminergic neuronal markers, dopamine, tyrosine hydroxylase, and dopamine transporter are deficient in the ileum of Cdnf −/− mice. The normal age‐related decline in proportions of submucosal dopaminergic neurons is exacerbated in Cdnf −/− animals. The defect in Cdnf −/− animals is not dopamine‐restricted; proportions of other submucosal neurons (NOS‐, GABA‐, and CGRP‐expressing), are also deficient. The deficits in submucosal neurons are reflected functionally in delayed gastric emptying, slowed colonic motility, and prolonged total gastrointestinal transit. CDNF is expressed selectively in isolated enteric neural crest‐derived cells (ENCDC), which also express the dopamine‐related transcription factor Foxa2. Addition of CDNF to ENCDC promotes development of dopaminergic neurons; moreover, survival of these neurons becomes CDNF‐dependent after exposure to bone morphogenetic protein 4. The effects of neither glial cell‐derived neurotrophic factor (GDNF) nor serotonin are additive with CDNF. We suggest that CDNF plays a critical role in development and long‐term maintenance of dopaminergic and other sets of submucosal neurons.
Glial cells of the enteric nervous system (ENS) interact closely with the intestinal epithelium and secrete signals that influence epithelial cell proliferation and barrier formation in vitro. Whether these interactions are important in vivo, however, is unclear because previous studies reached conflicting conclusions [1]. To better define the roles of enteric glia in steady state regulation of the intestinal epithelium, we characterized the glia in closest proximity to epithelial cells and found that the majority express PLP1 in both mice and humans. To test their functions using an unbiased approach, we genetically depleted PLP1+ cells in mice and transcriptionally profiled the small and large intestines. Surprisingly, glial loss had minimal effects on transcriptional programs and the few identified changes varied along the gastrointestinal tract. In the ileum, where enteric glia had been considered most essential for epithelial integrity, glial depletion did not drastically alter epithelial gene expression but caused a modest enrichment in signatures of Paneth cells, a secretory cell type important for innate immunity. In the absence of PLP1+ glia, Paneth cell number was intact, but a subset appeared abnormal with irregular and heterogenous cytoplasmic granules, suggesting a secretory deficit. Consistent with this possibility, ileal explants from glial-depleted mice secreted less functional lysozyme than controls with corresponding effects on fecal microbial composition. Collectively, these data suggest that enteric glia do not exert broad effects on the intestinal epithelium but have an essential role in regulating Paneth cell function and gut microbial ecology.
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