Interdependence between Chromogranin-A, Alternatively Activated Macrophages, Tight Junction Proteins and the Epithelial Functions. A Human and In-Vivo/In-Vitro Descriptive Study.

Background: Ulcerative colitis (UC) is characterized by altered chromogranin-A (CHGA), alternatively activated macrophages (M2) and intestinal epithelial cells (IECs). We previously demonstrated that CHGA is implicated in colitis progression by regulating the macrophages. Here, we investigated the interplay between CHGA, M2, tight junctions (TJ) and IECs in an inflammatory environment. Methods: Correlations between CHGA mRNA expression of and TJ proteins mRNA expressions of (Occludin [OCLN], zonula occludens-1 [ZO1], Claudin-1 [CLDN1]), epithelial associated cytokines (interleukin [IL]-8, IL-18), and collagen (COL1A2) were determined in human colonic mucosal biopsies isolated from active UC and healthy patients. Acute UC-like colitis (5% dextran sulphate sodium [DSS], five days) was induced in Chga-C57BL/6-deficient (Chga-/-) and wild type (Chga+/+) mice. Col1a2 TJ proteins, Il-18 mRNA expression and collagen deposition were determined in whole colonic sections. Naïve Chga-/- and Chga+/+ peritoneal macrophages were isolated and exposed six hours to IL-4/IL-13 (20 ng/mL) to promote M2 and generate M2-conditioned supernatant. Caco-2 epithelial cells were cultured in the presence of Chga-/- and Chga+/+ non- or M2-conditioned supernatant for 24 h then exposed to 5% DSS for 24 h, and their functional properties were assessed. Results: In humans, CHGA mRNA correlated positively with COL1A2, IL-8 and IL-18, and negatively with TJ proteins mRNA markers. In the experimental model, the deletion of Chga reduced IL-18 mRNA and its release, COL1A2 mRNA and colonic collagen deposition, and maintained colonic TJ proteins. Chga-/- M2-conditioned supernatant protected caco-2 cells from DSS and oxidative stress injuries by improving caco-2 cells functions (proliferation, viability, wound healing) and by decreasing the release of IL-8 and IL-18 and by maintaining the levels of TJ proteins, and when compared with Chga+/+ M2-conditioned supernatant. Conclusions: CHGA contributes to the development of intestinal inflammation through the regulation of M2 and epithelial cells. Targeting CHGA may lead to novel biomarkers and therapeutic strategies in UC.

Cesarean Section Delivery Is Not a Risk Factor for Development of Inflammatory Bowel Disease: A Population-based Analysis.

BACKGROUND & AIMS: Mode of birth affects development of the intestinal microbiota, and microbial dysbiosis has been associated with inflammatory bowel disease (IBD). We performed a population-based analysis to determine whether mode of delivery (cesarean section vs. vaginal delivery) affects risk of IBD. METHODS: We collected data from the University of Manitoba IBD Epidemiology Database, which contains records on all Manitobans diagnosed with IBD from 1984 through 2010. Starting in 1970, 6-digit family health registration numbers were used in Manitoba to link mothers with their offspring. Maternal health records, including dates and modes of delivery and siblings of individuals with IBD, were identified. RESULTS: We obtained data on 1671 individuals with IBD and 10,488 controls (individuals without IBD, matched by age, sex, and area of residence at IBD diagnosis) linked to mothers' obstetrical records. Higher proportions of urban than rural residents were delivered by cesarean section for IBD cases (12.8% vs. 9.7%, P = .05) and controls (13.3% vs. 9.4%, P < .0001). A higher percentage of men with Crohn's disease than women with Crohn's disease were born via cesarean section (13.5% vs. 8.4%, P = .01). Overall, there was no difference in the percentage of IBD cases born by cesarean section (11.6%) vs. controls (11.7%, P = .93). In multivariate analysis, birth by cesarean section was not associated with an increased risk of subsequent IBD, controlling for age, sex, urban residence, and income (odds ratio, 1.04; 95% confidence interval, 0.89-1.23). Persons with IBD were no more likely to have been born by cesarean section than their siblings without IBD (1740 siblings from 1615 families) (11.6% vs. 11.3%; odds ratio, 1.14; 95% confidence interval, 0.72-1.80; P = .79). CONCLUSIONS: People with IBD were not more likely to have been born via cesarean section than controls or siblings without IBD. These findings indicate that events of the immediate postpartum period that shape the developing intestinal microbiome do not affect risk for IBD.

Acute dextran sulfate sodium (DSS)-induced colitis promotes gut microbial dysbiosis in mice.

UNLABELLED: The most widely used and characterized experimental model of ulcerative colitis (UC) is the epithelial erosion, dextran sulfate sodium (DSS)-induced colitis, which is developed by administration of DSS in drinking water. We investigated fecal and colonic mucosa microbial composition and functional changes in mice treated with DSS. C57Bl/6 mice received 5% DSS in drinking water for 5 days. Inflammation was evaluated clinically and by analysis of colonic tissue cytokine levels and C-reactive protein (CRP) in the serum. Colonic mucosa and fecal samples were used for DNA extraction and the V4 region of bacterial 16S rRNA gene was subjected to MiSeq Illumina sequencing. Alpha- and beta-diversities, and compositional differences at phylum and genus levels were determined, and bacterial functional pathways were predicted. DSS increased disease severity, serum CRP and cytokines IL-1ß and IL-6, but decreased bacterial species richness, and shifted bacterial community composition. Bacteroides, Turicibacter, Escherichia, Clostridium, Enterobacteriaceae, Clostridiaceae, Bacteroidaceae, Bacteroidales, among other taxa were associated with DSS treatment in fecal and colonic samples. Also, DSS altered microbial functional pathways in both colonic mucosa and fecal samples. CONCLUSIONS: The development of colitis in DSS model was accompanied with reduced microbial diversity and dysbiosis of gut microbiota at lower taxonomical levels.

Targeted inhibition of serotonin type 7 (5-HT7) receptor function modulates immune responses and reduces the severity of intestinal inflammation.

Mucosal inflammation in conditions ranging from infective acute enteritis or colitis to inflammatory bowel disease is accompanied by alteration in serotonin (5-hydroxytryptamine [5-HT]) content in the gut. Recently, we have identified an important role of 5-HT in the pathogenesis of experimental colitis. 5-HT type 7 (5-HT7) receptor is one of the most recently identified members of the 5-HT receptor family, and dendritic cells express this receptor. In this study, we investigated the effect of blocking 5-HT7 receptor signaling in experimental colitis with a view to develop an improved therapeutic strategy in intestinal inflammatory disorders. Colitis was induced with dextran sulfate sodium (DSS) or dinitrobenzene sulfonic acid (DNBS) in mice treated with selective 5-HT7 receptor antagonist SB-269970, as well as in mice lacking 5-HT7 receptor (5-HT7(-/-)) and irradiated wild-type mice reconstituted with bone marrow cells harvested from 5-HT7(-/-) mice. Inhibition of 5-HT7 receptor signaling with SB-269970 ameliorated both acute and chronic colitis induced by DSS. Treatment with SB-269970 resulted in lower clinical disease, histological damage, and proinflammatory cytokine levels compared with vehicle-treated mice post-DSS. Colitis severity was significantly lower in 5-HT7(-/-) mice and in mice reconstituted with bone marrow cells from 5-HT7(-/-) mice compared with control mice after DSS colitis. 5-HT7(-/-) mice also had significantly reduced DNBS-induced colitis. These observations provide us with novel information on the critical role of the 5-HT7 receptor in immune response and inflammation in the gut, and highlight the potential benefit of targeting this receptor to alleviate the severity of intestinal inflammatory disorders such as inflammatory bowel disease.

The role of different serotonin receptor subtypes in seizure susceptibility.

5-Hydroxytryptamine (5-HT) has the most diverse set of receptors in comparison with any other neurotransmitter or hormone in the body. To date, seven families of 5-HT receptors have been characterized. A great number of studies have been published regarding the role of 5-HT and its receptors in seizures. However, with a few exceptions, the net effect of activating or inhibiting each 5-HT receptor subtype on the development or severity of seizures remains controversial. Additionally, the results of studies, which have used knockout animals to investigate the role of 5-HT receptors in seizures, have sometimes been contradictory to those which have used pharmacological tools. The present study aims to review the available data regarding the influence of each receptor subtype on seizure development and, when possible, reconcile between the apparently different results obtained in these studies.

Brain-Gut Axis: Invasive and Noninvasive Vagus Nerve Stimulation, Limitations, and Potential Therapeutic Approaches.

Inflammatory bowel disease (IBD) is a chronic relapsing condition with no known etiology and is characterized by disrupted gut homeostasis, chronic inflammation, and ulcerative lesions. Although current treatments can reduce disease activity, IBD frequently recurs once treatments are discontinued, indicating that treatments are ineffective in providing long-term remission. The lack of responsiveness and reluctance of some affected persons to take medications because of potential adverse effects has enhanced the need for novel therapeutic approaches. The vagus nerve (VN) is likely important in the pathogenesis of IBD, considering the decreased activity of the parasympathetic nervous system, especially the VN, and the impaired interaction between the enteric nervous system and central nervous system in patients with IBD. Vagus nerve stimulation (VNS) has demonstrated anti-inflammatory effects in various inflammatory disorders, including IBD, by inhibiting the production of inflammatory cytokines by immune cells. It has been suggested that stimulating the vagus nerve to induce its anti-inflammatory effects may be a potential therapeutic approach for IBD. Noninvasive techniques for VNS have been developed. Considering the importance of VN function in the brain-gut axis, VNS is a promising treatment option for IBD. This review discusses the potential therapeutic advantages and drawbacks of VNS, particularly the use of noninvasive transcutaneous auricular vagus nerve stimulation.

As some patients do not respond well to current treatments, novel therapeutic approaches are needed for inflammatory bowel disease (IBD). With diminished parasympathetic anti-inflammatory activity in IBD patients, especially in the vagus nerve, stimulation of the vagus nerve may be a potential therapeutic approach.

Tropisetron attenuates amyloid-beta-induced inflammatory and apoptotic responses in rats.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder featured by deposition of beta-amyloid (Aß) plaques in the hippocampus and associated cortices and progressive cognitive decline. Tropisetron, a selective 5-HT3 receptor antagonist, is conventionally used to counteract chemotherapy-induced emesis. Recent investigations describe antiphlogistic properties for tropisetron. It has been shown that tropisetron protects against rat embolic stroke. We investigated protective properties of tropisetron in a beta-amyloid (Aß) rat model of AD and possible involvement of 5-HT3 receptors. MATERIAL AND METHODS: Aß (1-42) was injected into the hippocampus of male rats. Animals were treated intracerebroventricularly with tropisetron, mCPBG (selective 5-HT3 receptor agonist) or mCPBG plus tropisetron on days 1, 3, 5 and 7. Seven days following Aß administration, inflammatory markers (TNF-α, COX-2, iNOS and NF-κB), apoptotic markers (caspase 3 cytochrome c release) and calcineurin phosphatase activity were assessed in hippocampus. RESULTS: Seven days following Aß inoculation, control animals displayed dramatic increase in TNF-α, COX-2, iNOS, NF-κB, active caspase 3, cytochrome c release and calcineurin phosphatase activity in the hippocampus. Tropisetron significantly diminished the elevated levels of these markers and reversed the cognitive deficit. Interestingly, tropisetron was also found to be a potent inhibitor of calcineurin phosphatase activity. The selective 5-HT3 receptor agonist mCPBG, when co-administered with tropisetron, completely reversed the procognitive and anti-apoptotic properties of tropisetron while it could only partially counteract the anti-inflammatory effects. mCPBG alone significantly aggravated Aß-induced injury. CONCLUSION: Our findings indicate that tropisetron protects against Aß-induced neurotoxicity in vivo through both 5-HT3 receptor-dependent and independent pathways.

The Editorial Position on 'Recent Advances in Multifunctional Antimicrobial Peptides as Preclinical Therapeutic Studies and Clinical Future Applications'.

Antibiotic resistance has recently been recognized as an alarming issue and one of the leading causes of death worldwide [...].

Serotonin activates dendritic cell function in the context of gut inflammation.

Mucosal inflammation in the gut is characterized by infiltration of innate and adaptive immune cells and by an alteration in serotonin-producing enterochromaffin cells. We investigated the role of serotonin in the function of dendritic cells (DCs) and sequential T-cell activation in relation to generation of gut inflammation. DCs isolated from tryptophan hydroxylase-1-deficient (TPH1(-/-)) mice, which have reduced serotonin in the gut, and wild-type (TPH1(+/+)) mice with or without dextran sulfate sodium (DSS)-induced colitis were stimulated with lipopolysaccharide to assess interleukin-12 (IL-12) production. Isolated DCs from TPH1(+/+) and TPH1(-/-) mice were also cocultured with CD4(+) T cells of naive TPH1(+/+) mice to assess the role of serotonin in priming T cells. In addition, serotonin-pulsed DCs were transferred to TPH1(-/-) mice to assess the effect on DSS-induced colitis. Consistent with a reduced severity of colitis, DCs from DSS-induced TPH1(-/-) mice produced less IL-12 compared with the TPH1(+/+) mice. In vitro serotonin stimulation restored the cytokine production from TPH1(-/-) DCs and adoptive transfer of serotonin-pulsed DCs into TPH1(-/-) up-regulated colitis. Furthermore, CD4(+) T cells primed by TPH1(-/-) DCs produce reduced the levels of IL-17 and interferon-γ. This study provides novel information on serotonin-mediated immune signaling and promotion of interactions between innate and adaptive immune responses in the context of gut inflammation, which may ultimately lead to improved strategies to combat gut inflammatory disorders.

Recent Advances in Multifunctional Antimicrobial Peptides as Immunomodulatory and Anticancer Therapy: Chromogranin A-Derived Peptides and Dermaseptins as Endogenous versus Exogenous Actors.

Antimicrobial peptides (AMPs) are produced by all living organisms exhibiting antimicrobial activities and representing the first line of innate defense against pathogens. In this context, AMPs are suggested as an alternative to classical antibiotics. However, several researchers reported their involvement in different processes defining them as Multifunctional AMPs (MF-AMPs). Interestingly, these agents act as the endogenous responses of the human organism against several dangerous stimuli. Still, they are identified in other organisms and evaluated for their anticancer therapy. Chromogranin A (CgA) is a glyco-phosphoprotein discovered for the first time in the adrenal medulla but also produced in several cells. CgA can generate different derived AMPs influencing numerous physiological processes. Dermaseptins (DRSs) are a family of α-helical-shaped polycationic peptides isolated from the skin secretions of several leaf frogs from the Phyllomedusidae family. Several DRSs were identified as AMPs and, until now, more than 65 DRSs have been classified. Recently, these exogenous molecules were characterized for their anticancer activity. In this review, we summarize the role of these two classes of MF-AMPs as an example of endogenous molecules for CgA-derived peptides, able to modulate inflammation but also as exogenous molecules for DRSs, exerting anticancer activities.

Impaired parasympathetic function increases susceptibility to inflammatory bowel disease in a mouse model of depression.

Clinical and experimental evidence indicates that intestinal inflammatory conditions can be exacerbated by behavioral conditions such as depression. The recent demonstration of a tonic counterinflammatory influence mediated by the vagus nerve in experimental colitis provides a potential link between behavior and gut inflammation. Here we show that experimental conditions that induced depressive-like behaviors in mice increased susceptibility to intestinal inflammation by interfering with the tonic vagal inhibition of proinflammatory macrophages and that tricyclic antidepressants restored vagal function and reduced intestinal inflammation. These results show that reserpine-induced monoamine depletion and maternal separation, 2 models for depression, produced a vulnerability to colitis by a mechanism involving parasympathetic transmission and the presence of gut macrophages. The tricyclic antidepressant desmethylimipramine protected against this vulnerability by a vagal-dependent mechanism. Together these results illustrate the critical role of the vagus in both the vulnerability to inflammation induced by depressive-like conditions and the protection afforded by tricyclic antidepressants and rationalize a clinical evaluation of both parasympathomimetics and tricyclic antidepressants in treatment of inflammatory bowel disease.

Mucin gene deficiency in mice impairs host resistance to an enteric parasitic infection.

BACKGROUND & AIMS: Hyperplasia of mucin-secreting intestinal goblet cells accompanies a number of enteric infections, including infections by nematode parasites. Nevertheless, the precise role of mucins in host defense in nematode infection is not known. We investigated the role of the mucin (Muc2) in worm expulsion and host immunity in a model of nematode infection. METHODS: Resistant (BALB/c, C57BL/6), susceptible (AKR), and Muc2-deficient mouse strains were infected with the nematode, Trichuris muris, and worm expulsion, energy status of the whipworms, changes in mucus/mucins, and inflammatory and immune responses were investigated after infection. RESULTS: The increase in Muc2 production, observed exclusively in resistant mice, correlated with worm expulsion. Moreover, expulsion of the worms from the intestine was significantly delayed in the Muc2-deficient mice. Although a marked impairment in the development of periodic acid Schiff (PAS)-stained intestinal goblet cells was observed in Muc2-deficient mice, as infection progressed a significant increase in the number of PAS-positive goblet cells was observed in these mice. Surprisingly, an increase in Muc5ac, a mucin normally expressed in the airways and stomach, was observed after infection of only the resistant animals. Overall, the mucus barrier in the resistant mice was less permeable than that of susceptible mice. Furthermore, the worms isolated from the resistant mice had a lower energy status. CONCLUSIONS: Mucins are an important component of innate defense in enteric infection; this is the first demonstration of the important functional contribution of mucins to host protection from nematode infection.

Pancreastatin Reduces Alternatively Activated Macrophages, Disrupts the Epithelial Homeostasis and Aggravates Colonic Inflammation. A Descriptive Analysis.

Ulcerative colitis (UC) is characterized by modifying alternatively activated macrophages (AAM) and epithelial homeostasis. Chromogranin-A (CHGA), released by enterochromaffin cells, is elevated in UC and is implicated in inflammation progression. CHGA can be cleaved into several derived peptides, including pancreastatin (PST), which is involved in proinflammatory mechanisms. Previously, we showed that the deletion of Chga decreased the onset and severity of colitis correlated with an increase in AAM and epithelial cells' functions. Here, we investigated PST activity in colonic biopsies of participants with active UC and investigated PST treatment in dextran sulfate sodium (DSS)-induced colitis using Chga-/- mice, macrophages, and a human colonic epithelial cells line. We found that the colonic protein expression of PST correlated negatively with mRNA expression of AAM markers and tight junction (TJ) proteins and positively with mRNA expression of interleukin (IL)-8, IL18, and collagen in human. In a preclinical setting, intra-rectal administration of PST aggravated DSS-induced colitis by decreasing AAM's functions, enhancing colonic collagen deposition and disrupting epithelial homeostasis in Chga+/+ and Chga-/- mice. This effect was associated with a significant reduction in AAM markers, increased colonic IL-18 release, and decreased TJ proteins' gene expression. In vitro, PST reduced Chga+/+ and Chga-/- AAM polarization and decreased anti-inflammatory mediators' production. Conditioned medium harvested from PST-treated Chga+/+ and Chga-/- AAM reduced Caco-2 cell migration, viability, proliferation, and mRNA levels of TJ proteins and increased oxidative stress-induced apoptosis and proinflammatory cytokines release. In conclusion, PST is a CHGA proinflammatory peptide that enhances the severity of colitis and the inflammatory process via decreasing AAM functions and disrupting epithelial homeostasis.

Impact of intrarectal chromofungin treatment on dendritic cells-related markers in different immune compartments in colonic inflammatory conditions.

BACKGROUND: Chromofungin (CHR: chromogranin-A 47-66) is a chromogranin-A derived peptide with anti-inflammatory and anti-microbial properties. Ulcerative colitis (UC) is characterized by a colonic decrease of CHR and a dysregulation of dendritic CD11c+ cells. AIM: To investigate the association between CHR treatment and dendritic cells (DCs)-related markers in different immune compartments in colitis. METHODS: A model of acute UC-like colitis using dextran sulphate sodium (DSS) was used in addition to biopsies collected from UC patients. RESULTS: Intrarectal CHR treatment reduced the severity of DSS-induced colitis and was associated with a significant decrease in the expression of CD11c, CD40, CD80, CD86 and interleukin (IL)-12p40 in the inflamed colonic mucosa and CD11c, CD80, CD86 IL-6 and IL-12p40 within the mesenteric lymph nodes and the spleen. Furthermore, CHR treatment decreased CD80 and CD86 expression markers of splenic CD11c+ cells and decreased NF-κB expression in the colon and of splenic CD11c+ cells. In vitro, CHR decreased CD40, CD80, CD86 IL-6 and IL-12p40 expression in naïve bone marrow-derived CD11c+ DCs stimulated with lipopolysaccharide. Pharmacological studies demonstrated an impact of CHR on the NF-κB pathway. In patients with active UC, CHR level was reduced and showed a negative linear relationship with CD11c and CD86. CONCLUSION: CHR has protective properties against intestinal inflammation via the regulation of DC-related markers and CD11c+ cells. CHR could be a potential therapy of UC.

Crohn's and Colitis Canada's 2021 Impact of COVID-19 and Inflammatory Bowel Disease in Canada: COVID-19 Vaccines-Biology, Current Evidence and Recommendations.

The COVID-19 pandemic has ushered a globally focused vaccine development program that produced multiple successful vaccines within a year. Four SARS-CoV-2 vaccines have been approved for use in Canada, using two different technologies, all of which have shown excellent efficacy in reducing the rate of symptomatic COVID-19 infection and 100% efficacy in preventing death from COVID-19. People with inflammatory bowel disease (IBD), like many others with immune-mediated chronic diseases, were excluded from the pivotal trials of these vaccines, leading to early hesitancy by regulatory bodies to endorse administering the vaccines to these groups. However, recent data has shown that the adverse event rate to SARS-CoV-2 vaccine among people with IBD is similar to the general population. Early data has further shown that people with IBD are capable of mounting a robust immune response to SARS-CoV-2 vaccines, particularly following a second dose, whereas the response to the first dose is blunted in those receiving anti-TNF therapy or conventional immunosuppressants (azathioprine, 6-mercaptopurine, methotrexate). Based on these data and evidence from previous vaccine programs among people with IBD, multiple national and international expert panels have recommended that individuals with IBD receive complete vaccination against SARS-CoV-2 as soon as possible.

Crohn's and Colitis Canada's 2021 Impact of COVID-19 and Inflammatory Bowel Disease in Canada: Executive Summary.

Persons with inflammatory bowel disease (IBD) make up more than 0.75% of the Canadian population in 2021. Early in the COVID-19 pandemic, individuals with IBD, particularly those on immunosuppressive therapies, were concerned that their health status may place them at higher risk of contracting COVID-19 or experiencing more severe disease course if infected with SARS-CoV-2. In response, Crohn's and Colitis Canada developed the COVID-19 and IBD Taskforce in March 2020 to rapidly synthesize the evolving knowledge of COVID-19 as relevant to Canadians with IBD. The Taskforce communicated expert information directly to the Canadian IBD community through online tools and a webinar series. In order to understand the full impact of COVID-19 on the IBD community, Crohn's and Colitis Canada commissioned a policy report that was informed through a systematic literature review and synthesized across working groups along the following domains: Epidemiology, Children and Expectant Mothers with IBD, Seniors with IBD, Mental Health, Risk Factors and Medications, Vaccines, and Healthcare Delivery during the Pandemic and the Future Model of IBD Care. This report from Canadian physicians, researchers, and IBD community representatives highlights the physical, mental, and health systems impact of COVID-19 on the entire spectrum of the IBD community, including children, adolescents, adults, seniors, and pregnant people with IBD. This executive summary provides an overview of the crucial information from each of the chapters of the policy report, supplemented with additional information made available through Crohn's and Colitis Canada's webinar-based knowledge translation platform.

Crohn's and Colitis Canada's 2021 Impact of COVID-19 & Inflammatory Bowel Disease in Canada: A Knowledge Translation Strategy.

The prevalence of inflammatory bowel diseases (IBD), Crohn's disease and ulcerative colitis, in Canada, is over 0.75% in 2021. Many individuals with IBD are immunocompromised. Consequently, the World Health Organization's declaration of a global pandemic uniquely impacted those with IBD. Crohn's and Colitis Canada (CCC) formed the COVID-19 and IBD Taskforce to provide evidence-based guidance during the pandemic to individuals with IBD and their families. The Taskforce met regularly through the course of the pandemic, synthesizing available information on the impact of COVID-19 on IBD. At first, the information was extrapolated from expert consensus guidelines, but eventually, recommendations were adapted for an international registry of worldwide cases of COVID-19 in people with IBD. The task force launched a knowledge translation initiative consisting of a webinar series and online resources to communicate information directly to the IBD community. Taskforce recommendations were posted to CCC's website and included guidance such as risk stratification, management of immunosuppressant medications, physical distancing, and mental health. A weekly webinar series communicated critical information directly to the IBD community. During the pandemic, traffic to CCC's website increased with 484,755 unique views of the COVID-19 webpages and 126,187 views of the 23 webinars, including their video clips. CCC's COVID-19 and IBD Taskforce provided critical guidance to the IBD community as the pandemic emerged, the nation underwent a lockdown, the economy reopened, and the second wave ensued. By integrating public health guidance through the unique prism of a vulnerable population, CCC's knowledge translation platform informed and protected the IBD community.

Reactivation of inflammatory bowel disease in a mouse model of depression.

BACKGROUND & AIMS: Patients with inflammatory bowel disease (IBD) frequently also have depression, yet little is known of its role in IBD pathogenesis. We investigated whether the development of depression after the establishment of chronic inflammation reactivates an acute relapse of IBD and underlying pharmacologic mechanisms in mouse models. METHODS: Colitis was induced by administration of dextran sulfate sodium (DSS) or dinitrobenzenesulfonic acid to C57BL/6 mice. Depression was induced by olfactory bulbectomy or chronic intracerebroventricular injection of reserpine. Colitis was reactivated by subsequent exposure to DSS or dinitrobenzenesulfonic acid. Some mice were given the antidepressant desmethylimipramine. Acute DSS-colitis was induced in mice lacking the alpha 7 subunit of the nicotinic acetylcholine receptor (alpha 7nAchR), and vagotomy was performed. Disease severity and colon tissue histology and inflammation were evaluated. Levels of C-reactive protein and proinflammatory cytokines were determined by enzyme-linked immunosorbent assay analysis of colon samples and macrophage culture. RESULTS: Induction of depression reactivated inflammation in mice in which colitis had been established and become quiescent. The induction was associated with impaired cholinergic inhibition of proinflammatory cytokine secretion by macrophages and mediated by alpha 7nAchR on these cells; macrophages isolated from depressed mice showed increased proinflammatory cytokine secretion. Depression-induced reactivation of colitis was prevented by desmethylimipramine and accompanied by a normalization of proinflammatory cytokine secretion. CONCLUSIONS: Depression reactivates dormant chronic colitis via the alpha 7nAchR. These findings encourage closer monitoring of behavior for signs of depression in IBD patients because treatment might prevent inflammatory conditions. Furthermore, alpha 7nAchR agonists might achieve this effect without the need for psychotropic medication.

Serotonin has a key role in pathogenesis of experimental colitis.

BACKGROUND & AIMS: Mucosal changes in inflammatory bowel disease are characterized by ulcerative lesions accompanied by a prominent infiltrate of immune cells as well as alteration in serotonin (5-hydroxytryptamine [5-HT])-producing enterochromaffin cells. We investigated the role of 5-HT in colonic inflammation in mice. METHODS: Colitis was induced with dextran sulfate sodium or dinitrobenzene sulfonic acid in tryptophan hydroxylase 1-deficient (TPH1(-/-)) mice, which have markedly reduced 5-HT in the gastrointestinal tract, and in mice given the 5-HT synthesis inhibitor parachlorophenylalanine. RESULTS: Delayed onset, decreased severity of clinical disease, and significantly lower macroscopic and histologic damage scores were observed in TPH1(-/-) mice, compared with wild-type mice, and in mice given parachlorophenylalanine after induction of colitis by dextran sulfate sodium. This was associated with down-regulation of macrophage infiltration and production of proinflammatory cytokines. 5-HT stimulated production of proinflammatory cytokines from macrophages collected from the peritoneal cavity of wild-type mice; this process was inhibited by a nuclear factor kappaB inhibitor, indicating a critical role for nuclear factor kappaB signaling in 5-HT-mediated activation of immune cells. Restoration of 5-HT levels in TPH1(-/-) mice by the 5-HT precursor 5-hydroxytryptophan increased the severity of DSS-induced colitis. We also observed significant reduction in severity of colitis in TPH1(-/-) mice after induction of dinitrobenzene sulfonic acid-induced colitis. CONCLUSIONS: 5-HT is involved in the pathogenesis of inflammation in experimental colitis. These findings provide insight into the mechanisms of gastrointestinal inflammation and could lead to new therapeutic strategies for inflammatory disorders.

A Gene Expression Analysis of M1 and M2 Polarized Macrophages.

Macrophages are professional innate immune cells that are broadly disseminated throughout the body, shape various innate and adaptive immune responses, and play crucial roles in inflammation, homeostasis, wound healing, and tissue remodelling. According to their surrounding microenvironments, macrophages can differentiate themselves in different phenotypes. Over the last two decades, gene expression profiling has been used to decipher new transcripts associated with macrophage phenotypes. This chapter outlines protocols used to isolate and culture murine macrophages and how they can be "polarized" to obtain a specific phenotype. Furthermore, we describe a protocol for gene expression profiling using a quantitative real-time polymerase chain reaction (qPCR), a high-standard technology in the field of gene expression.