Psychological stress-induced colonic barrier dysfunction: Role of immune-mediated mechanisms.

BACKGROUND: Evidence suggests that patients with irritable bowel syndrome (IBS) exhibit increases in gut permeability and alterations in tight junction (TJ) protein expression. Although psychological stress worsens IBS symptoms, the mechanisms by which stress enhances gut permeability and affects TJ protein expression remain to be determined. Here, we test the hypothesis that chronic intermittent psychological stress activates the release of proinflammatory cytokines to alter TJ proteins and promotes increased gut permeability. METHODS: Male Fischer-344 rats were subjected to 1 hour of water avoidance stress (WAS) or SHAM stress per day for 7 days. Following the stress protocol, colonic permeability was measured via transepithelial electrical resistance (TEER) and macromolecular flux of horseradish peroxidase (HRP). In tissue isolated from rats exposed to the WAS or SHAM stress, TJ proteins claudin-2, junctional adhesion molecule-A (JAM-A) and zonula occluden-1 (ZO-1) were measured via Western blotting, histological appearance of the colonic segments was assessed via hematoxylin and eosin staining, and an inflammatory cytokine panel was quantified via quantitative reverse transcription-polymerase chain reaction. KEY RESULTS: Repetitive daily exposure to WAS decreased the TEER, increased the macromolecular flux of HRP, and altered the expression of claudin-2, JAM-A and ZO-1 proteins within colonic tissue compared to SHAM controls. In the absence of a histologically defined inflammation, the cytokine profiles of WAS-treated animals revealed an increase in interleukin-1ß and tumor necrosis factor (TNF)-α. Subsequent analysis revealed a significant positive correlation between TNF-α and expression of TJ protein claudin-2. CONCLUSIONS & INFERENCES: Our findings suggest that chronic stress increases colonic permeability via sub-inflammatory cytokine-mediated remodeling of TJ protein expression.

Sex differences in stress-induced visceral hypersensitivity following early life adversity: a two hit model.

BACKGROUND: Early life adversity (ELA) has been indicated as a risk factor for the development of stress axis dysfunction in adulthood, specifically in females. We previously showed that unpredictable ELA induces visceral hyperalgesia in adult female rats. It remains to be determined whether ELA alters visceral nociceptive responses to stress in adulthood. The current study tested the hypothesis that following ELA, exposure to an adulthood stressor, or second hit, serves as a risk factor for exaggerated stress-induced visceral hypersensitivity that is sex-specific. METHODS: Following ELA, adult stress was induced via a single exposure (acute) or repetitive daily exposure, 1 h/day for 7 days (chronic), to water avoidance stress (WAS). KEY RESULTS: Acute WAS increased pain behaviors in all adult female rats, however, females that experienced unpredictable ELA exhibited significantly more pain behaviors compared to those exposed to predictable ELA or controls. Following chronic WAS, all adult females exhibited increased pain responses, however, an exaggerated response was observed in rats exposed to unpredictable or predictable ELA compared to controls. Similarly, in adult male rats exposure to acute or chronic WAS increased pain behaviors, however, there were no differences in pain behaviors between ELA groups. CONCLUSIONS & INFERENCES: This study highlights a novel consequence of ELA on stress-induced visceral nociception in adulthood that is sex-specific. More importantly, our study suggests that ELA not only serves as a risk factor for development of chronic pain in adulthood, but also serves as a predisposition for worsening of visceral pain following adult stress in female rats.

Neurobiology of early life stress and visceral pain: translational relevance from animal models to patient care.

BACKGROUND: Epidemiological studies show that females are twice as likely to receive a diagnosis of irritable bowel syndrome (IBS) than their male counterparts. Despite evidence pointing to a role for sex hormones in the onset or exacerbation of IBS symptoms, the mechanism by which ovarian hormones may predispose women to develop IBS remains largely undefined. On the other hand, there is a growing body of research showing a correlation between reports of early life stress (ELS) and the diagnosis of IBS. Current treatments available for IBS patients target symptom relief including abdominal pain and alterations in bowel habits, but are not directed to the etiology of the disease. PURPOSE: To better understand the mechanisms by which sex hormones and ELS contribute to IBS, animal models have been developed to mirror complex human experiences allowing for longitudinal studies that investigate the lifelong consequences of ELS. These preclinical models have been successful in recapitulating ELS-induced visceral pain. Moreover, in female rats the influence of cycling hormones on visceral hypersensitivity resembles that seen in women with IBS. Such studies suggest that rodent models of ELS may serve as pivotal tools in determining (i) the etiology of IBS, (ii) novel future treatments for IBS, and (iii) improving individualized patient care. The current review aims to shed light on the progress and the challenges observed by clinicians within the field of gastroenterology and the preclinical science aimed at addressing those challenges in an effort to understand and more efficiently treat functional gastrointestinal disorders (FGIDs) in both children and adults.

Gender specific effects of neonatal limited nesting on viscerosomatic sensitivity and anxiety-like behavior in adult rats.

BACKGROUND: Evidence exists to suggest that early life stress (ELS), such as neglect or abuse has profound effects on the developing brain. The current study tests the hypothesis that ELS in the form of neonatal limited nesting (LN) may serve as a predisposing factor for the development of altered nociceptive processing and comorbid increases in anxiety-like behavior in adulthood. METHODS: Both male and female neonatal Sprague-Dawley rats were subjected to LN from postnatal day (PND) 2-9, while a control group was exposed to standard cage bedding. In adulthood, visceral sensitivity was assessed by quantifying a visceromotor behavioral response to graded isobaric pressures of colorectal distension. Hindpaw withdrawal thresholds in response to von Frey filaments were used to measure somatic sensitivity. Anxiety-like behavior was assessed in adult life using both the elevated plus maze and open field assay. KEY RESULTS: Early life stress in the form of neonatal LN induced visceral and somatic hypersensitivity in adult male rats and augmented anxiety-like behavior. However, in adult cycling females, neonatal LN did not alter nociceptive processing or lead to changes in the levels of anxiety-like behavior. CONCLUSIONS & INFERENCES: Our findings suggest that in male rats the LN model is a novel tool to investigate the long-term consequences of adverse early life experience on adult health.