Oxytocin regulates gastrointestinal motility, inflammation, macromolecular permeability, and mucosal maintenance in mice

Abstract

Enteric neurons express oxytocin (OT); moreover, enteric neurons and enterocytes express developmentally regulated OT receptors (OTRs). Although OT (with secretin) opposes intestinal inflammation, physiological roles played by enteric OT/OTR signaling have not previously been determined. We tested hypotheses that OT/OTR signaling contributes to enteric nervous system (ENS)-related gastrointestinal (GI) physiology. GI functions and OT effects were compared in OTR-knockout (OTRKO) and wild-type (WT) mice. Stool mass and water content were greater in OTRKO mice than in WT. GI transit time in OTRKO animals was faster than in WT; OT inhibited in vitro generation of ENS-dependent colonic migrating motor complexes in WT but not in OTRKO mice. Myenteric neurons were hyperplastic in OTRKO animals, and mucosal exposure to cholera toxin (CTX) in vitro activated Fos in more myenteric neurons in OTRKO than WT than in WT mice; OT inhibited the CTX response in WT but not in OTRKO mice. Villi and crypts were shorter in OTRKO than in WT mice, and transit-amplifying cell proliferation in OTRKO crypts was deficient. Macromolecular intestinal permeability in OTRKO was greater than WT mice, and experimental colitis was more severe in OTRKO mice; moreover, OT protected WT animals from colitis. Observations suggest that OT/OTR signaling acts as a brake on intestinal motility, decreases mucosal activation of enteric neurons, and promotes enteric neuronal development and/or survival. It also regulates proliferation of crypt cells and mucosal permeability; moreover OT/OTR signaling is protective against inflammation. Oxytocinergic signaling thus appears to play an important role in multiple GI functions that are subject to neuronal regulation.

Serotonin transporter variant drives preventable gastrointestinal abnormalities in development and function

“…Internal pressure was raised to initiate CMMCs, and spatiotemporal maps of colon diameter as a function of time were constructed. CMMC frequency, velocity, and length of conduction were measured (74,75). See Supplemental Methods for further details.…”

Translational and therapeutic potential of oxytocin as an anti-obesity strategy: Insights from rodents, nonhuman primates and humans

“…Based on the finding that circulating OT may act through central [106] or peripheral OTRs to reduce food intake [105,106] and the observation that peripheral administration can stimulate the release of CNS OT [32], further studies are needed to address the relevance of peripheral OTR signaling in the setting of diet-induced obesity [60,105,106,153,154,160] and whether activation of CNS OT circuits is, in fact, necessary in order to maximize its therapeutic potential when given systemically. While rodent and the small number of nonhuman primate and human studies are promising thus far, OTRs may alter the function of other G protein-coupled receptors, including the beta-2 adrenergic receptor [238].…”

“…These data are mixed, however, as peripheral treatment with OT has been reported to have no effect on gastric emptying rate in humans [157] and rats [158] or a stimulatory effect on gastric motility in rabbits, possibly due to species differences [159]. However, systemic OT reduces gastric emptying in both mice [160] and rats [153,154]. Furthermore, these effects are also attenuated by pretreatment with an OTR antagonist, Atosiban [153,154], suggesting that these effects are mediated by OTRs.…”

“…Interestingly, chronic systemic OT also reduces IL-6 secretion from epididymal fat in hyperlipidemic apolipoprotein E (ApoE) deficient mice [187] and C-reactive protein in Watanabe Heritable Hyperlipidemic rabbits [188]. OTR deficient mice also display increased levels of IL1-β, IL-6 and tumor necrosis factor alpha (TNF-α) mRNA expression in the colons following experimental colitis, findings that suggest a possible protective anti-inflammatory effect [160]. These findings support an anti-inflammatory role of OT in peripheral tissues in genetically obese and hyperlipidemic animals.…”

Calming Cycle Theory and the Co-Regulation of Oxytocin

“…Importantly, it was shown that OTR expression is developmentally regulated during the milk-suckling period in the enteric nervous system and in the epithelial lining, and that toward the end of this period the epithelial OTR translocates to the cryptvillus junctions and to the crypts. In addition, the receptor was found to be expressed at high levels during the suckling period (Welch, Margolis, Li, & Gershon, 2014). It is now established that oxytocin is antiinflammatory in animal models of colitis (Cetinel et al, 2010;Welch et al, 2010) and that gastrointestinal structure, motility, macromolecular permeability, mucosal maintenance, and inflammatory responses are altered in OTR deficient mice (Welch, Margolis et al, 2014).…”