Environmental enrichment prevents stress-induced epigenetic changes in the expression of glucocorticoid receptor and corticotrophin releasing hormone in the central nucleus of the amygdala to inhibit visceral hypersensitivity.

INTRODUCTION: Stress is a known trigger for the symptoms of irritable bowel syndrome (IBS), a gastrointestinal (GI) disorder that presents with abnormal bowel habits and abdominal pain due to visceral hypersensitivity. While behavioral therapies have been used to attenuate IBS symptoms, the underlying mechanisms by which these therapies interact with stress-induced pathology remains to be delineated. Here we use a rat model to test the hypothesis that exposure to environmental enrichment (EE) inhibits stress-induced changes within the brain-gut axis to prevent visceral and somatic hypersensitivity and colonic hyperpermeability. METHODS: Female rats (n = 8/group) were housed in EE one week before and one week during exposure to water avoidance stress (WAS) while controls were housed in standard cages (SH). One day after the final WAS exposure, colonic and somatic sensitivity were assessed by the visceromotor response (VMR) to colorectal distension (CRD) and withdrawal threshold elicited by an electronic von Frey on the hind paw of the rats respectively. All rats were returned to SH for 3 weeks before colonic and somatic sensitivity were reassessed on day 28. The rats were then immediately euthanized and the spinal cord was collected to assess changes in neuronal activation (assessed via ERK phosphorylation) in response to noxious CRD. A separate cohort of animals (n = 8/group) that did not undergo behavioral assessments was euthanized the day after the final WAS exposure and the central nucleus of the amygdala (CeA) was collected to investigate WAS and EE induced epigenetic changes at the glucocorticoid receptor (GR) and corticotrophin releasing hormone (CRH) promoter. The colon from these rats was also collected to assess colonic permeability via changes in transepithelial electrical resistance (TEER) in vitro. RESULTS: Exposure to stress persistently increased VMR to CRD (P < 0.01) and decreased the hind paw withdrawal threshold (P < 0.001) in female rats. WAS also decreased TEER in the colon tissue of female rats (p = 0.05). In the CeA, WAS induced a decrease in histone acetylation at the GR promoter but increased histone acetylation at the CRH promoter and reduced GR-CRH interactions in the CeA. Analysis of the spinal cord showed that WAS increased CRD-evoked ERK phosphorylation in the dorsal horn. Exposure to EE prevented WAS-induced changes in the CeA, dorsal horn and colon respectively to prevent visceral and somatic hypersensitivity. CONCLUSION: Our data reveals that behavioral therapies can produce long lasting molecular and epigenetic changes that can prevent stress-induced pathologies even after completion of the therapy. These results highlight the potential mechanisms by which behavioral therapies may ameliorate visceral pain associated stress-related pathologies such as the irritable bowel syndrome.

Rates of asymptomatic respiratory virus infection across age groups.

Respiratory viral infections are a leading cause of disease worldwide. A variety of respiratory viruses produce infections in humans with effects ranging from asymptomatic to life-treathening. Standard surveillance systems typically only target severe infections (ED outpatients, hospitalisations, deaths) and fail to track asymptomatic or mild infections. Here we performed a large-scale community study across multiple age groups to assess the pathogenicity of 18 respiratory viruses. We enrolled 214 individuals at multiple New York City locations and tested weekly for respiratory viral pathogens, irrespective of symptom status, from fall 2016 to spring 2018. We combined these test results with participant-provided daily records of cold and flu symptoms and used this information to characterise symptom severity by virus and age category. Asymptomatic infection rates exceeded 70% for most viruses, excepting influenza and human metapneumovirus, which produced significantly more severe outcomes. Symptoms were negatively associated with infection frequency, with children displaying the lowest score among age groups. Upper respiratory manifestations were most common for all viruses, whereas systemic effects were less typical. These findings indicate a high burden of asymptomatic respiratory virus infection exists in the general population.

Linaclotide inhibits colonic and urinary bladder hypersensitivity in adult female rats following unpredictable neonatal stress.

BACKGROUND: Irritable bowel syndrome (IBS) and bladder pain syndrome (BPS) are female-predominant, chronic functional pain disorders that are associated with early life stress (ELS) and therapeutic options for such patients remain limited. Linaclotide, a guanylate cyclase-C (GC-C) agonist, relieves abdominal pain and bowel symptoms in adult patients suffering from IBS with constipation. Here, we test the hypothesis that linaclotide will reverse colon and bladder hyperalgesia in a female-specific rodent model of adverse early life experience. METHODS: Neonatal rats were exposed to an odor-attachment learning paradigm of early life stress (ELS). In adulthood, the effect of linaclotide (3 µg kg-1  d-1 , p.o.) on colonic and bladder sensitivity was assessed via quantification of the visceromotor response to colorectal distension and the frequency of withdrawal responses to the application of von Frey hairs to the suprapubic region. In another cohort of rats, the effect of linaclotide on ELS-induced colonic and bladder permeability was investigated via measurements of transepithelial electrical resistance (TEER). KEY RESULTS: Rats exposed to unpredictable ELS exhibited colonic and bladder hypersensitivity that was significantly reduced by linaclotide compared to vehicle-treated controls. Colonic and bladder tissue isolated from adult rats exposed to unpredictable ELS exhibited a decrease in colonic and bladder TEER that was reversed by linaclotide. CONCLUSIONS AND INFERENCES: Our results demonstrate that neonatal rats exposed to unpredictable ELS develop increased sensitivity and permeability of the colon and bladder in adulthood through a mechanism involving activation of peripheral GC-C signaling.

Epigenetic modulation of chronic anxiety and pain by histone deacetylation.

Prolonged exposure of the central amygdala (CeA) to elevated corticosteroids (CORT) facilitates long-term anxiety and pain through activation of glucocorticoid receptors (GRs) and corticotropin-releasing factor (CRF). However, the mechanisms maintaining these responses are unknown. Since chronic phenotypes can be sustained by epigenetic mechanisms, including histone modifications such as deacetylation, we tested the hypothesis that histone deacetylation contributes to the maintenance of chronic anxiety and pain induced by prolonged exposure of the CeA to CORT. We found that bilateral infusions of a histone deacetylase inhibitor into the CeA attenuated anxiety-like behavior as well as somatic and visceral hypersensitivity resulting from elevated CORT exposure. Moreover, we delineated a novel pathway through which histone deacetylation could contribute to CORT regulation of GR and subsequent CRF expression in the CeA. Specifically, deacetylation of histone 3 at lysine 9 (H3K9), through the coordinated action of the NAD+-dependent protein deacetylase sirtuin-6 (SIRT6) and nuclear factor kappa B (NFκB), sequesters GR expression leading to disinhibition of CRF. Our results indicate that epigenetic programming in the amygdala, specifically histone modifications, is important in the maintenance of chronic anxiety and pain.

Disseminated histoplasmosis in AIDS patients in Maryland.

These patients demonstrate the difficulty in arriving at the diagnosis of disseminated histoplasmosis. The diagnosis in two of the three patients also served as the initial AIDS case-defining opportunistic infection. In each of these patients, the clinical presentations were atypical and in only one patient was a positive exposure history elicited. Recurrent bowel obstruction was the presenting complaint in the first patient and the diagnosis was made only on pathologic exam of the resected small bowel. The second patient's diagnosis was made on biopsy of the colon via colonoscopy. The third patient's diagnosis also eluded an extensive FUO workup; he was diagnosed by bone marrow culture and silver stain of a mediastinal lymph node biopsy, despite serial negative serologic tests for histoplasmosis. The first two patients had significant gastrointestinal disease which is a relatively unusual manifestation for disseminated histoplasmosis. The third patient illustrates the limited diagnostic usefulness of serologic testing in AIDS patients and the continued usefulness of bone marrow analysis in an FUO evaluation. In conclusion, these case presentations demonstrate that disseminated histoplasmosis in patients with HIV infection can present with unusual manifestations, outside of the typical endemic arca, without a positive exposure history or positive serologic test, and may be the initial AIDS case-defining opportunistic infection in these patients. Consequently, a disseminated histoplasmosis should be considered in all AIDS patients with perplexing clinical presentations.