Exacerbation Of Colitis Research Articles

SAFETY AND EFFECTIVENESS OF THE BNT162B2 MRNA COVID-19 VACCINE IN A NATIONWIDE COHORT OF PATIENTS WITH INFLAMMATORY BOWEL DISEASE

BACKGROUND & AIMSThe effectiveness of currently available SARS-CoV-2 vaccines in patients with inflammatory bowel disease (IBD) remains unknown. We aimed to determine the effectiveness of the Pfizer-BNT162b2 mRNA vaccine in a nationwide cohort of patients with IBD in Qatar.METHODSUsing a cohort design, we compared 476 IBD patients vaccinated identified between January 1, 2021, and March 31, 2021, with 476 matched unvaccinated controls (matched on age and date of SARS-CoV-2 testing). Study outcomes included documented SARS-CoV-2 infection, symptomatic COVID-19, and COVID-19 related hospitalization. We also studied the side effects of the vaccination, including the effect on IBD exacerbation and hospitalizations related to adverse events.RESULTSTotal follow-up was 23,289 person-days for the vaccinated and 23,653 person-days for the unvaccinated group. Vaccine effectiveness >14 days [AAB1] after the second dose was 85.1% (95% CI: 65.2, 93.6) for confirmed infection, and 87.1% (95% CI: 63.6, 95.4)[AAB2] for symptomatic infection. No patient required hospitalization >14 days after the second vaccine dose. Estimated vaccine effectiveness between 22 to 35 days after the first dose was 14.8% (95% CI: -151.5, 71.2) [AAB3] for any documented infection, and 59.8% (95% CI: -106.1, 92.2) for symptomatic COVID-19 disease. For patients taking biologics with or without immunomodulators, vaccine effectiveness >14 days after the second dose was 94% (95% CI: 53.1, 99.2), and 92.7% (95% CI: 45.1, 99.0) for any documented infection and symptomatic COVID-19 respectively. Vaccine effectiveness was 87.4% (95% CI: 46.0, 97.1) for any documented infection and 91.7% (95% CI: 37.2, 98.9) for symptomatic COVID-19 during the same period for patients taking immunomodulators alone. None of the vaccinated patients required intensive care unit admission or died. No patient had IBD exacerbation or required hospitalization for vaccination-related adverse events.CONCLUSIONIn a nationwide cohort of IBD patients, the BNT162b2 mRNA vaccine was safe and highly effective.

NOVEL CONTRIBUTIONS OF CLAUDIN-4 TO EPITHELIAL BARRIER REGULATION AND COLITIS

Abstract Intestinal barrier dysfunction is linked to human IBD and contributes to progression of experimental, immune-mediated colitis. Claudin family tight junction proteins are critical determinants of epithelial paracellular permeability and barrier function. Expression of one of these, claudin-2, a pore-forming claudin, is specifically upregulated in IBD. We have shown that claudin-2 overexpression or, conversely, channel inhibition, augment or attenuate, respectively, immune-mediated colitis severity. We sought to understand claudin contributions to barrier function using in vitro and in vivo models. Claudin-4 overexpression has been shown to reduce cation permeability in vitro, leading to the conclusion that this protein is a barrier-forming claudin. We found, however, that, in the absence of claudin-2 expression, neither knockout nor overexpression of claudin-4 affected barrier function. Instead, claudin-4 specifically suppressed claudin-2 pore function by destabilizing claudin-2 polymers and disrupting claudin-2 anchoring at the tight junction. Thus, claudin-4 is not barrier-forming but is the first pore-regulating claudin. Together with observations that claudin-2 exacerbates colitis in vivo and that claudin-4 antagonizes claudin-2 function in vitro led us to hypothesize that intestinal epithelial claudin-4 knockout would exacerbate colitis. Knockout mice were, however, protected from both immune-mediated and DSS-induced chemical colitis. Conversely, transgenic claudin-4 overexpression exacerbated colitis. Preliminary in vitro studies suggest that claudin-4 may limit collective migration and epithelial wound repair. As a whole, our studies require a reconsideration of claudin functional classifications and reveal unanticipated contributions of claudin-4 to barrier regulation and epithelial wound repair. The relationship between these functions and claudin-4 downregulation in human IBD remains to be explored.

SAFETY AND EFFECTIVENESS OF THE BNT162B2 MRNA COVID-19 VACCINE IN A NATIONWIDE COHORT OF PATIENTS WITH INFLAMMATORY BOWEL DISEASE

The effectiveness of currently available SARS-CoV-2 vaccines in patients with inflammatory bowel disease (IBD) remains unknown. We aimed to determine the effectiveness of the Pfizer-BNT162b2 mRNA vaccine in a nationwide cohort of patients with IBD in Qatar. Using a cohort design, we compared 476 IBD patients vaccinated identified between January 1, 2021, and March 31, 2021, with 476 matched unvaccinated controls (matched on age and date of SARS-CoV-2 testing). Study outcomes included documented SARS-CoV-2 infection, symptomatic COVID-19, and COVID-19 related hospitalization. We also studied the side effects of the vaccination, including the effect on IBD exacerbation and hospitalizations related to adverse events. Total follow-up was 23,289 person-days for the vaccinated and 23,653 person-days for the unvaccinated group. Vaccine effectiveness >14 days [AAB1] after the second dose was 85.1% (95% CI: 65.2, 93.6) for confirmed infection, and 87.1% (95% CI: 63.6, 95.4)[AAB2] for symptomatic infection. No patient required hospitalization >14 days after the second vaccine dose. Estimated vaccine effectiveness between 22 to 35 days after the first dose was 14.8% (95% CI: -151.5, 71.2) [AAB3] for any documented infection, and 59.8% (95% CI: -106.1, 92.2) for symptomatic COVID-19 disease. For patients taking biologics with or without immunomodulators, vaccine effectiveness >14 days after the second dose was 94% (95% CI: 53.1, 99.2), and 92.7% (95% CI: 45.1, 99.0) for any documented infection and symptomatic COVID-19 respectively. Vaccine effectiveness was 87.4% (95% CI: 46.0, 97.1) for any documented infection and 91.7% (95% CI: 37.2, 98.9) for symptomatic COVID-19 during the same period for patients taking immunomodulators alone. None of the vaccinated patients required intensive care unit admission or died. No patient had IBD exacerbation or required hospitalization for vaccination-related adverse events. In a nationwide cohort of IBD patients, the BNT162b2 mRNA vaccine was safe and highly effective.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

The Periodontopathic Pathogen, Porphyromonas gingivalis, Involves a Gut Inflammatory Response and Exacerbates Inflammatory Bowel Disease.

Periodontal disease (PD) is one of the most prevalent disorders globally and is strongly associated with many other diseases. Inflammatory bowel disease (IBD), an inflammatory condition of the colon and the small intestine, is reported to be associated with PD through undetermined mechanisms. We analyzed taxonomic assignment files from the Crohn’s Disease Viral and Microbial Metagenome Project (PRJEB3206). The abundance of Porphyromonadaceae in fecal samples was significantly different between patients with Crohn’s disease and control volunteers. Dextran sulfate sodium was used to induce colitis in mice to reveal the effect of this periodontopathic pathogen in vivo. After intrarectal implantation of Porphyromonas gingivalis (Pg)—the primary pathogen causing PD—the disease activity index score, colonic epithelial loss, and inflammatory cell infiltration were intensified. In addition, tumor necrosis factor-α and interleukin-6 showed the highest levels in Pg-infected colons. This revealed the importance of Pg in the exacerbation of IBD. Thus, simultaneous treatment of PD should be considered for people with IBD. Moreover, implantation of Pg in the rectum worsened the clinical symptoms of colitis in mice. Because Pg participates in the pathogenesis of IBD, reducing the chances of it entering the intestine might prevent the worsening of this disorder.

Facilitation of colonic T cell immune responses is associated with an exacerbation of dextran sodium sulfate\u2013induced colitis in mice lacking microsomal prostaglandin E synthase-1

BackgroundMicrosomal prostaglandin E synthase-1 (mPGES-1) is a key enzyme that acts downstream of cyclooxygenase and plays a major role in inflammation by converting prostaglandin (PG) H2 to PGE2. The present study investigated the effect of genetic deletion of mPGES-1 on the development of immunologic responses to experimental colitis induced by dextran sodium sulfate (DSS), a well-established model of inflammatory bowel disease (IBD).MethodsColitis was induced in mice lacking mPGES-1 (mPGES-1−/− mice) and wild-type (WT) mice by administering DSS for 7 days. Colitis was assessed by body weight loss, diarrhea, fecal bleeding, and histological features. The colonic expression of mPGES-1 was determined by real-time PCR, western blotting, and immunohistochemistry. The impact of mPGES-1 deficiency on T cell immunity was determined by flow cytometry and T cell depletion in vivo.ResultsAfter administration of DSS, mPGES-1−/− mice exhibited more severe weight loss, diarrhea, and fecal bleeding than WT mice. Histological analysis further showed significant exacerbation of colonic inflammation in mPGES-1−/− mice. In WT mice, the colonic expression of mPGES-1 was highly induced on both mRNA and protein levels and colonic PGE2 increased significantly after DSS administration. Additionally, mPGES-1 protein was localized in the colonic mucosal epithelium and infiltrated inflammatory cells in underlying connective tissues and the lamina propria. The abnormalities consistent with colitis in mPGES-1−/− mice were associated with higher expression of colonic T-helper (Th)17 and Th1 cytokines, including interleukin 17A and interferon-γ. Furthermore, lack of mPGES-1 increased the numbers of Th17 and Th1 cells in the lamina propria mononuclear cells within the colon, even though the number of suppressive regulatory T cells also increased. CD4+ T cell depletion effectively reduced symptoms of colitis as well as colonic expression of Th17 and Th1 cytokines in mPGES-1−/− mice, suggesting the requirement of CD4+ T cells in the exacerbation of DSS-induced colitis under mPGES-1 deficiency.ConclusionsThese results demonstrate that mPGES-1 is the main enzyme responsible for colonic PGE2 production and deficiency of mPGES-1 facilitates the development of colitis by affecting the development of colonic T cell–mediated immunity. mPGES-1 might therefore impact both the intestinal inflammation and T cell–mediated immunity associated with IBD.

Effects of Temperature, Seasons, Atmosphere, and Climate on the Exacerbation of Inflammatory Bowel Diseases: A Systematic Review and Meta-Analysis

Effects of Temperature, Seasons, Atmosphere, and Climate on the Exacerbation of Inflammatory Bowel Diseases: A Systematic Review and Meta-Analysis

Tuberous Sclerosis Complex 1 Deficiency in Macrophages Promotes Unclassical Inflammatory Response to Lipopolysaccharide In Vitro and Dextran Sodium Sulfate-Induced Colitis in Mice.

Human tuberous sclerosis (TSC) is mainly caused by genetic mutations of tuberous TSC1or TSC2. Recent studies found that TSC1 deficiency promoted classical M1 macrophage polarization. However, whether TSC1 regulates other inflammatory cytokine expression in lipopolysaccharidem (LPS)-stimulated macrophages is unknown. Herein, we studied the cytokine expression profile of wild-type (WT) and TSC1-deleted macrophages after LPS stimulation in vitro and the pathogenesis of dextran sodium sulfate (DSS)-induced colitis in mice with myeloid-specific TSC1 deletion (TSC1cKO mice). We found that TSC1-deficient macrophages exhibited the enhanced secretion of interleukin-17A (IL-17A), IL-17F, and interferon-gamma (IFN-γ) in response to LPS stimulation in vitro. This is in contrast to LPS-stimulated WT macrophages, which usually do not. Importantly, TSC1cKO mice exhibited exacerbated DSS-induced acute colitis with severer symptoms. MTOR deletion or rapamycin treatment significantly reversed the enhanced expressions of IL-17A, IL-17F, and IFN-γ in LPS-stimulated TSC1-deficient macrophages in vitro and rescued the enhanced DSS-induced colitis in TSC1cKO mice, indicating that TSC1 deficiency increased these cytokine productions in an mTOR-dependent manner. RNA-sequencing and molecular studies indicated that TSC1 deficiency enhanced the aerobic glycolysis process and the activities of mTOR-STAT3-RORγT pathway in LPS-stimulated macrophages. Inhibition of aerobic glycolysis, STAT3, or RORγT reversed IL-17 and IFN-γ expression in LPS-treated TSC1-deficient macrophages. Thus, TSC1 is essential for macrophages to shut down IL-17A, IL-17F, and IFN-γ expression during LPS stimulation by suppressing the aerobic glycolysis process and mTOR-STAT3, RORγT, and T-bet pathways. The present study uncovered the key role of TSC1 in shutting down IL-17A, IL-17F, and IFN-γ expressions in LPS-treated macrophages.

P2RY13 Exacerbates Intestinal Inflammation by Damaging the Intestinal Mucosal Barrier via Activating IL-6/STAT3 Pathway.

The pathogenesis of ulcerative colitis (UC) is unclear, while genetic factors have been confirmed to play an important role in its development. P2RY13 is a G protein-coupled receptor (GPCRs), which are involved in the pathogenesis of inflammation and immune disorders. According to GEO database analysis, we first observed that the expression of P2Y13 was increased in UC patients. Therefore, we sought to determine the role of P2Y13 in the development of colitis. Our data showed that P2RY13 was highly expressed in the inflamed intestinal tissues of UC patients. In mice, pharmacological antagonism of P2Y13 can significantly attenuate the intestinal mucosal barrier disruption. In LPS-induced NCM460 cell, knockdown or pharmacological inhibition of P2RY13 increased the expression of intestinal tight junction protein and reduced apoptosis. In addition, we found that the effect of P2Y13 on colitis is related to the activation of the IL-6/STAT3 pathway. Activation of P2Y13 increases IL-6 expression and promotes STAT3 phosphorylation and nuclear transport. Deletion of the STAT3 gene in the intestinal epithelial cells of mice significantly mitigated the exacerbation of colitis due to P2Y13 activation. Thus, P2Y13 can aggravate intestinal mucosal barrier destruction by activating the IL-6/STAT3 pathway. P2Y13 might be a potential drug target for UC.

Differential effects of various dietary proteins on dextran sulfate sodium-induced colitis in mice.

Chronic colitis is a risk factor for colorectal cancer (CRC) development in both animals and humans. Previously, we reported that a diet rich in protein (with casein as the protein source) significantly increased the risk of mouse CRC development in a dose-dependent manner. In this study, we investigated the effects of different protein sources on the risk of colitis development. Balb/c mice were divided into 7 experimental groups: 20% casein (20C), 20C-dextran sulfate sodium (DSS), 40% casein-DSS (40CD), 40% whey protein-DSS (40WD), 40% soy protein-DSS (40SD), 40% white meat-DSS (40WMD), and 40% red meat-DSS (40RMD). Mice were fed an experimental diet for 4 wk and received 3% DSS in their drinking water for 6 days during the 4th wk of the experimental period. Compared to other groups, the 40CD group showed the most aggravated colitis with increased disease activity and inflammatory markers. In the 40RMD group, interleukin (IL)-6 levels were the highest among all the groups. The 40SD group showed conflicting effects, for example, elevated mortality and disease activity but decreased nitric oxide (NO) levels. The 40WD group showed attenuated colitis with increased IL-10 levels and decreased NO levels. The 40WMD group showed conflicting effects, including decreased NO levels and elevated fecal lipocalin-2 and IL-6 levels. These results suggest that, at levels of 40% in the diet, casein and red meat exacerbate colitis, whereas whey protein mitigates it the most effectively.

Protein Kinase CK2 Acts as a Molecular Brake to Control NADPH Oxidase 1 Activation and Colon Inflammation.

Background & AimsNADPH oxidase 1 (NOX1) has emerged as a prime regulator of intestinal mucosa immunity and homeostasis. Dysregulation of NOX1 may cause inflammatory bowel disease (IBD). It is not clear how NOX1 is regulated in vivo under inflammatory conditions. We studied the role of CK2 in this process.MethodsThe NOX1 organizer subunit, NADPH oxidase organizer 1 (NOXO1), was immunoprecipitated from cytokine-treated colon epithelial cells, and bound proteins were identified by mass spectrometry analysis. Sites on NOXO1 phosphorylated by CK2 were identified by nanoscale liquid chromatography coupled to tandem mass spectrometry. NOX1 activity was determined in colon epithelial cells and colonoids in the presence or absence of CX-4945, a CK2 specific inhibitor. Acute colitis was induced by administration of trinitrobenzenesulfonic acid in mice treated or not with CX-4945. Colon tissues were analyzed by histologic examination, quantitative polymerase chain reaction, and Western blots. CK2 activity, markers of inflammation, and oxidative stress were assessed.ResultsWe identified CK2 as a major partner of NOXO1 in colon epithelial cells under inflammatory conditions. CK2 directly binds NOXO1 at the C-terminus containing the Phox homology domain and phosphorylates NOXO1 on several sites. CX-4945 increased ROS generation by NOX1 in human colon epithelial cells and organoids. Strikingly, CK2 activity was reduced in trinitrobenzenesulfonic acid–induced acute colitis, and CX-4945 exacerbated colitis inflammation as shown by increased levels of CXCL1, ROS generation, lipid peroxidation, and colon damage.ConclusionsThe ubiquitous protein kinase CK2 limits NOX1 activity via NOXO1 binding and phosphorylation in colonic epithelial cells and lessens experimental colitis. Loss of CK2 activity during acute colitis results in excessive ROS production, contributing to the pathogenesis. Strategies to activate CK2 could be an effective novel therapeutic approach in IBD.

Rice hull insoluble dietary fiber alleviated experimental colitis induced by low dose of dextran sulfate sodium in cadmium-exposed mice.

Cadmium (Cd), an important toxic environmental pollutant, can invade the gastrointestinal tract and induce the occurrence of gastrointestinal diseases. This study aimed to investigate the protective effect of rice hull insoluble dietary fiber (RHF) on Cd-promoted colitis induced by low dose of dextran sulfate sodium. Administration of RHF attenuated inflammation by limiting Cd accumulation and regulating intestinal immune homeostasis in colitis mice with Cd exposure. RHF could maintain the structure of the gut barrier by increasing mucin secretion and intestinal tight connectivity in mice. Subsequently, RHF repressed the colonic inflammation mediated by the TLR4/MyD88/NF-κB pathway, and inhibited the transcription regulation of inflammatory cytokines. Furthermore, RHF showed an enhancement of a variety of probiotics, such as Eubacterium and Faecalibaculum. RHF also inhibited the growth of pathogenic bacteria, including Erysipelatoclostridium, Helicobacter and Bacteroides. The growth of beneficial bacteria was also accompanied by reversing the decline in short-chain fatty acids, supporting the initial potentiality of RHF as a prebiotic in cases of damage by Cd exposure in colitis mice. Importantly, RHF also remained resistant to Cd toxicity in colitis mice when the gut microbiota was depleted by antibiotics. We suggest that RHF could be used as a novel dietary supplement strategy against Cd-exacerbated colitis.

Low-Salt Diet Attenuates B-Cell- and Myeloid-Cell-Driven Experimental Arthritides by Affecting Innate as Well as Adaptive Immune Mechanisms.

A link between high sodium chloride (salt) intake and the development of autoimmune diseases was previously reported. These earlier studies demonstrated exacerbation of experimental autoimmune encephalomyelitis and colitis by excess salt intake associated with Th17- and macrophage-mediated mechanisms. Little is known about the impact of dietary salt intake on experimental arthritides. Here, we investigated if salt restriction can exert beneficial effects on collagen-induced arthritis (CIA) and K/BxN serum transfer-induced arthritis (STIA). CIA depends on both adaptive and innate immunity, while STIA predominantly mimics the innate immune cell-driven effector phase of arthritis. In both models, low salt (LS) diet significantly decreased arthritis severity compared to regular salt (RS) and high salt (HS) diet. We did not observe an aggravation of arthritis with HS diet compared to RS diet. Remarkably, in STIA, LS diet was as effective as IL-1 receptor blocking treatment. Complement-fixing anti-CII IgG2a antibodies are associated with inflammatory cell infiltration and cartilage destruction. LS diet reduced anti-CII IgG2a levels in CIA and decreased the anti-CII IgG2a/IgG1 ratios pointing toward a more Th2-like response. Significantly less inflammatory joint infiltrates and cartilage breakdown associated with reduced protein concentrations of IL-1 beta (CIA and STIA), IL-17 (CIA), and the monocyte chemoattractant protein-1 (MCP-1) (CIA) were detected in mice receiving LS diet compared to HS diet. However, we did not find a reduced IL-17A expression in CD4+ T cells upon salt restriction in CIA. Analysis of mRNA transcripts and immunoblots revealed a link between LS diet and inhibition of the p38 MAPK (mitogen-activated protein kinase)/NFAT5 (nuclear factor of activated T-cells 5) signaling axis in STIA. Further experiments indicated a decreased leukodiapedesis under LS conditions. In conclusion, dietary salt restriction ameliorates CIA and STIA, indicating a beneficial role of LS diet during both the immunization and effector phase of immune-mediated arthritides by predominantly modulating the humoral immunity and the activation status of myeloid lineage cells. Hence, salt restriction might represent a supportive dietary intervention not only to reduce cardiovascular risk, but also to improve human inflammatory joint diseases like rheumatoid arthritis.

Periodontitis Salivary Microbiota Worsens Colitis

Evidence suggests that periodontitis contributes to the pathogenesis of inflammatory bowel disease, including Crohn’s disease and ulcerative colitis. However, few studies have examined the role of swallowing and saliva in the pathogenesis of gastrointestinal diseases. Saliva contains an enormous number of oral bacteria and is swallowed directly into the intestine. Here, we explored the influence of periodontitis salivary microbiota on colonic inflammation and possible mechanisms in dextran sulfate sodium (DSS)–induced colitis. The salivary microbiota was collected from healthy individuals and those with periodontitis and gavaged to C57BL/6 mice. Periodontitis colitis was induced by DSS for 5 d and ligature for 1 wk. The degree of colon inflammation was evaluated through hematoxylin and eosin staining, ELISA, and quantitative real-time polymerase chain reaction. Immune parameters were measured with quantitative real-time polymerase chain reaction, flow cytometry, and immunofluorescence. The gut microbiota and metabolome analyses were performed via 16S rRNA gene sequencing and liquid chromatography–mass spectrometry. Although no significant colitis-associated phenotypic changes were found under physiologic conditions, periodontitis salivary microbiota exacerbated colitis in a periodontitis colitis model after DSS induction. The immune response more closely resembled the pathology of ulcerative colitis, including aggravated macrophage M2 polarization and Th2 cell induction (T helper 2). Inflammatory bowel disease–associated microbiota, such as Blautia, Helicobacter, and Ruminococcus, were changed in DSS-induced colitis after periodontitis salivary microbiota gavage. Periodontitis salivary microbiota decreased unsaturated fatty acid levels and increased arachidonic acid metabolism in DSS-induced colitis, which was positively correlated with Aerococcus and Ruminococcus, suggesting the key role of these metabolic events and microbes in the exacerbating effect of periodontitis salivary microbiota on experimental colitis. Our study demonstrated that periodontitis contributes to the pathogenesis of colitis through the swallowing of salivary microbiota, confirming the role of periodontitis in systemic disease and providing new insights into the etiology of gastrointestinal inflammatory diseases.

Protective Role of Spermidine in Colitis and Colon Carcinogenesis

Because inflammatory bowel disease is increasing worldwide and can lead to colitis-associated carcinoma (CAC), new interventions are needed. We have shown that spermine oxidase (SMOX), which generates spermidine (Spd), regulates colitis. Here we determined whether Spd treatment reduces colitis and carcinogenesis. SMOX was quantified in human colitis and associated dysplasia using quantitative reverse-transcription polymerase chain reaction and immunohistochemistry. We used wild-type (WT) and Smox-/- C57BL/6 mice treated with dextran sulfate sodium (DSS) or azoxymethane (AOM)-DSS as models of colitis and CAC, respectively. Mice with epithelial-specific deletion of Apc were used as a model of sporadic colon cancer. Animals were supplemented or not with Spd in the drinking water. Colonic polyamines, inflammation, tumorigenesis, transcriptomes, and microbiomes were assessed. SMOX messenger RNA levels were decreased in human ulcerative colitis tissues and inversely correlated with disease activity, and SMOX protein was reduced in colitis-associated dysplasia. DSS colitis and AOM-DSS-induced dysplasia and tumorigenesis were worsened in Smox-/- vs WT mice and improved in both genotypes with Spd. Tumor development caused by Apc deletion was also reduced by Spd. Smox deletion and AOM-DSS treatment were both strongly associated with increased expression of α-defensins, which was reduced by Spd. A shift in the microbiome, with reduced abundance of Prevotella and increased Proteobacteria and Deferribacteres, occurred in Smox-/- mice and was reversed with Spd. Loss of SMOX is associated with exacerbated colitis and CAC, increased α-defensin expression, and dysbiosis of the microbiome. Spd supplementation reverses these phenotypes, indicating that it has potential as an adjunctive treatment for colitis and chemopreventive for colon carcinogenesis.

Prenatal Maternal Stress Exacerbates Experimental Colitis of Offspring in Adulthood.

The prevalence of inflammatory bowel disease (IBD) is increasing worldwide and correlates with dysregulated immune response because of gut microbiota dysbiosis. Some adverse early life events influence the establishment of the gut microbiota and act as risk factors for IBD. Prenatal maternal stress (PNMS) induces gut dysbiosis and perturbs the neuroimmune network of offspring. In this study, we aimed to investigate whether PNMS increases the susceptibility of offspring to colitis in adulthood. The related index was assessed during the weaning period and adulthood. We found that PNMS impaired the intestinal epithelial cell proliferation, goblet cell and Paneth cell differentiation, and mucosal barrier function in 3-week-old offspring. PNMS induced low-grade intestinal inflammation, but no signs of microscopic inflammatory changes were observed. Although there was no pronounced difference between the PNMS and control offspring in terms of their overall measures of alpha diversity for the gut microbiota, distinct microbial community changes characterized by increases in Desulfovibrio, Streptococcus, and Enterococcus and decreases in Bifidobacterium and Blautia were induced in the 3-week-old PNMS offspring. Notably, the overgrowth of Desulfovibrio persisted from the weaning period to adulthood, consistent with the results observed using fluorescence in situ hybridization in the colon mucosa. Mechanistically, the fecal microbiota transplantation experiment showed that the gut microbiota from the PNMS group impaired the intestinal barrier function and induced low-grade inflammation. The fecal bacterial solution from the PNMS group was more potent than that from the control group in inducing inflammation and gut barrier disruption in CaCo-2 cells. After treatment with a TNF-α inhibitor (adalimumab), no statistical difference in the indicators of inflammation and intestinal barrier function was observed between the two groups. Finally, exposure to PNMS remarkably increased the values of the histopathological parameters and the inflammatory cytokine production in a mouse model of experimental colitis in adulthood. These findings suggest that PNMS can inhibit intestinal development, impair the barrier function, and cause gut dysbiosis characterized by the persistent overgrowth of Desulfovibrio in the offspring, resulting in exacerbated experimental colitis in adulthood.

Electrical and viscoelastic parameters of erythrocytes as predictors of exacerbation in inflammatory bowel diseases

The aim of this work is to study the electrical and viscoelastic parameters of erythrocytes for patients with inflammatory bowel diseases (IBD), examined in dynamics, as possible predictors of exacerbation of the disease. Material and methods. In dynamics, 23 patients with IBD (37.9 ± 4.3 years) were examined. The first examination was carried out in the stage of exacerbation, the second – after 6–12 months – in the stage of remission of IBD. Additionally, 36 patients with IBD in remission were examined to assess the predictive capabilities of erythrocyte parameters with subsequent monitoring of their condition for 6–12 months. The electrical and viscoelastic parameters of erythrocytes were investigated by dielectrophoresis. Statistical processing was carried out using a system of machine learning methods – Random Forest, MATLAB (R2019a, MathWorks). Results and discussion. The parameters of erythrocytes, which are predictors of exacerbation of IBD, were revealed: an increase in the proportion of deformed cells (p = 0.0001); altered nature of the erythrocyte surface (p = 0.011); increased electrical conductivity of membranes (p = 0.0019); reduced dipole moment (p = 0.0015), the rate of directional movement of erythrocytes to the electrodes (p = 0.005) (paired and unpaired Volcano plot methods), reduced deformation amplitude at a frequency of 5×105 Hz (p = 0.009), capacity of erythrocyte membranes (p = 0.029 ) (unpaired Volcano plot method). Indicators associated with changes in the charge of cells, the structure of erythrocyte membranes and the level of energy metabolism of the cell turned out to be significant. A high diagnostic accuracy of these indicators was established as predictors: the proportion of deformed cells (AUC 0.939), a summarized viscosity index (AUC 0.932). Cluster analysis of the values of erythrocyte parameters – predictors of exacerbation made it possible to stratify the risk of exacerbation: at the most altered levels of parameters – the development of exacerbation after 2.5–4.5 months, intermediate levels – after 4–6 months, minimally changed – after 8–12 months (predictive accuracy – 92 %). Conclusions. The revealed electrical and viscoelastic parameters of erythrocytes should be considered as promising predictors of exacerbation in patients with IBD.

Dietary Exposure to the Food Contaminant Deoxynivalenol Triggers Colonic Breakdown by Activating the Mitochondrial and the Death Receptor Pathways.

The food contamination by mycotoxins is of increasing public health concerns. Deoxynivalenol (DON), a mycotoxin contaminating cereals, has been associated with the exacerbation of inflammatory bowel diseases (IBD), thereby raising the question of its role in the development of IBD. Moreover, the effect of DON on the colon is poorly described. Wistar rats exposed (1-4 weeks) to low doses of DON (2 or 9mg kg-1 feed) show microscopic alterations of colonic tissue (dilated lymphatic vessels, luminal debris, and cubic and flattened enterocytes). Ingestion of DON also alters colonic functions by increasing paracellular permeability while reducing the expression of the tight junction proteins and increased apoptosis in colonic tissue. Pro-apoptotic factors Bax/Bak, cytochrome C, and caspase 9 are upregulated, whereas expression of anti-apoptotic protein Bcl2 tends to decrease for the mitochondrial pathway. An increased expression of FasR and caspase-8 is observed for the extrinsic pathway. An increase in the pro-inflammatory markers TNFα, IL-17, and myeloperoxidase is also observed. These results indicate that the dietary exposure to low levels of DON in food targets the colon inducing a health-threatening breakdown of the colonic barrier, highlighting oral exposure to DON as a potential risk factor in triggering IBD.

Serum Levels of Chemerin in Patients with Inflammatory Bowel Disease as an Indicator of Anti-TNF Treatment Efficacy.

Chemerin belongs to the adipokines—proteins secreted by white adipose tissue. It plays an important role in angiogenesis and metabolism and its levels correlate with inflammation severity in many clinical states. Circulating chemerin levels in IBD are only rarely evaluated, with inconsistent results. The possible impact of anti-TNF therapy treatment in IBD on chemerin levels has not been addressed. The study aim was to evaluate the serum levels of chemerin in patients with inflammatory bowel disease (IBD), depending on disease severity as well as anti-TNF treatment. Serum chemerin was measured with ELISA in 77 patients with IBD as well as in 42 healthy controls (HCs). Twenty-six participants who underwent anti-TNF therapy were re-examined after 14 weeks. Overall, IBD patients had significantly higher serum chemerin levels than HCs. In patients with IBD exacerbation, chemerin levels were significantly higher compared to the remission group. Serum chemerin levels were significantly higher in UC patients compared to CD. Chemerin correlated with the severity of CD, but not with UC. Serum levels of chemerin decreased significantly after 14 weeks of anti-TNF treatment. Chemerin correlated with the clinical severity of IBD, and its levels decreased after anti-TNF treatment, which suggests its relationship with disease activity. It may be assumed that chemerin levels may possibly be useful for anti-TNF clinical course and treatment monitoring.

Porphyromonas gingivalis exacerbates ulcerative colitis via Porphyromonas gingivalis peptidylarginine deiminase

Ulcerative Colitis (UC) has been reported to be related to Porphyromonas gingivalis (P. gingivalis). Porphyromonas gingivalis peptidylarginine deiminase (PPAD), a virulence factor released by P. gingivalis, is known to induce inflammatory responses. To explore the pathological relationships between PPAD and UC, we used homologous recombination technology to construct a P. gingivalis strain in which the PPAD gene was deleted (Δppad) and a Δppad strain in which the PPAD gene was restored (comΔppad). C57BL/6 mice were orally gavaged with saline, P. gingivalis, Δppad, or comΔppad twice a week for the entire 40 days (days 0−40), and then, UC was induced by dextran sodium sulfate (DSS) solution for 10 days (days 31−40). P. gingivalis and comΔppad exacerbated DDS-induced colitis, which was determined by assessing the parameters of colon length, disease activity index, and histological activity index, but Δppad failed to exacerbate DDS-induced colitis. Flow cytometry and ELISA revealed that compared with Δppad, P. gingivalis, and comΔppad increased T helper 17 (Th17) cell numbers and interleukin (IL)-17 production but decreased regulatory T cells (Tregs) numbers and IL-10 production in the spleens of mice with UC. We also cocultured P. gingivalis, Δppad, or comΔppad with T lymphocytes in vitro and found that P. gingivalis and comΔppad significantly increased Th17 cell numbers and decreased Treg cell numbers. Immunofluorescence staining of colon tissue paraffin sections also confirmed these results. The results suggested that P. gingivalis exacerbated the severity of UC in part via PPAD.

Multidetector computed tomography: a corner stone imaging modality in evaluation of acute small bowel diseases

BackgroundThe diagnosis of acute small bowel diseases is one of the challenging issues that confronted by the radiologists so accurate diagnosis is essential to determine the appropriate way of management. CT has become the preferred imaging tool to evaluate acute small bowel diseases. Our study aimed to assess the role of MDCT in evaluation of acute abdomen secondary to small bowel origin by identification and differentiation between different acute small bowel pathologies.ResultsThirty-eight patients presented with acute abdomen of small bowel origin from June 2019 to September 2019. The mean age of incidence was 48 ± 19 years ranged from 4 to 88 years. Males represented by 23 patients (60.5%). Acute exacerbation of inflammatory bowel diseases (Crohn’s disease) represented by (34.2%), small bowel obstruction (31.6%), ischemic bowel diseases (21.1%), small bowel perforation (10.5%) and infectious (TB enteritis) small bowel disease (2.6%). MDCT had an overall high sensitivity (97.3%) in assessment of acute small bowel diseases in correlation with post-operative data and follow-up response to management.ConclusionsMDCT is a reliable diagnostic imaging tool for assessment of patients with acute abdomen secondary to small bowel origin with high-efficiency in differentiation between different pathological entities that causing acute abdomen.