Including Inflammatory Bowel Disease Research Articles

Expression of CD49f defines subsets of human regulatory Tcells with divergent transcriptional landscape and function that correlate with ulcerative colitis disease activity.

ObjectiveAdoptive regulatory T cell (Treg) therapy is being trialled for the treatment of different autoimmune disorders, including inflammatory bowel diseases (IBD). In‐depth understanding of the biological variability of Treg in the human blood may be required to improve IBD immune monitoring and treatment strategies.MethodsThrough a combination of quantitative proteomic, multiparametric flow cytometry, RNA‐sequencing data analysis and functional assays on Treg enriched from the blood of ulcerative colitis (UC) patients and healthy controls, we investigated the association between CD49f expression, Treg phenotype and function, and UC disease activity.ResultsHigh‐dimensional analysis and filtering defined two distinct subsets of human Treg based on the presence or absence of CD49f with divergent transcriptional landscape and functional activities. CD49f negative (CD49f−) Treg are enriched for functional Treg markers and present significantly increased suppressive capacity. In contrast, CD49fhigh Treg display a pro‐inflammatory Th17‐like phenotype and accumulate in the blood of patients with UC. Dysregulation on CD49f Treg subsets in patients with UC correlate with disease activity.ConclusionOverall, our findings uncover the importance of CD49f expression on Treg in physiological immunity and in pathological autoimmunity.

Research Advances in Protective Effects of Ursolic Acid and Oleanolic Acid Against Gastrointestinal Diseases.

The intestinal tract plays an essential role in protecting tissues from the invasion of external harmful substances due to impaired barrier function. Furthermore, it participates in immunomodulation by intestinal microorganisms, which is important in health. When the intestinal tract is destroyed, it can lose its protective function, resulting in multiple systemic complications. In severe cases, it may lead to systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS). Thus far, there are no curative therapies for intestinal mucosal barrier injury, other than a few drugs that can relieve symptoms. Thus, the development of novel curative agents for gastrointestinal diseases remains a challenge. Ursolic acid (UA) and its isomer, Oleanolic acid (OA), are pentacyclic triterpene acid compounds. Both their aglycone and glycoside forms have anti-oxidative, anti-inflammatory, anti-ulcer, antibacterial, antiviral, antihypertensive, anti-obesity, anticancer, antidiabetic, cardio protective, hepatoprotective, and anti-neurodegenerative properties in living organisms. In recent years, several studies have shown that UA and OA can reduce the risk of intestinal pathological injury, alleviate intestinal dysfunction, and restore intestinal barrier function. The present study evaluated the beneficial effects of UA and OA on intestinal damage and diseases, including inflammatory bowel disease (IBD) and colorectal cancer (CRC).

969. TNF-alpha inhibition in the setting of undiagnosed HIV infection: a call for enhanced screening guidelines

BackgroundDespite the risks of immunosuppression, recommendations regarding screening for HIV infection prior to initiation of biologic therapies targeting common autoimmune disorders, including inflammatory bowel disease (IBD) and inflammatory arthritides, are limited. Few cases of patients started on biologics while living with undiagnosed HIV have been reported.MethodsWe report 3 cases of patients initiated on biologics in the absence of recent or concurrent HIV screening who developed refractory disease or unanticipated complications and were later found to have undiagnosed chronic HIV infection.ResultsIn Case 1, a 53-year-old man who has sex with men (MSM) with negative HIV testing 10 years prior presented with presumed rheumatoid arthritis. He did not respond to methotrexate (MTX), so adalimumab (ADA) was started. HIV testing to evaluate persistent symptoms was positive 9 months later; CD4 was 800 cells/uL. Antiretroviral therapy (ART) resulted in resolution of symptoms, which were attributed to HIV-associated arthropathy.In Case 2, a 55-year-old woman with injection drug use in remission and no prior HIV testing presented with Hidradenitis Suppurativa (HS). She was initiated on infliximab (IFX) and MTX with good response. After she developed weight loss and lymphopenia, an HIV test was positive; CD4 was 334 cells/uL. Biologic HS therapy was discontinued, with subsequent poor HS control.In Case 3, a 32-year-old MSM with no prior HIV testing presented with presumed IBD; IFX and steroids were started. Symptoms progressed despite IBD-directed therapy, and he was diagnosed with extensive Kaposi Sarcoma (KS) with visceral and cutaneous involvement likely exacerbated by immunosuppression. HIV testing was positive; CD4 was 250 cells/uL. KS initially worsened due to ART-associated immune reconstitution inflammatory syndrome. He is now improving with systemic chemotherapy and ART. HIV-associated KS is presumed to be hte underlying diagnosis.ConclusionAll 3 patients had elevated risk for HIV infection, and 2 had final diagnoses attributed to chronic HIV infection, not warranting therapeutic immunosuppression. Screening for HIV infection prior to initiation of biologic therapy should be incorporated into clinical practice guidelines.Disclosures All Authors: No reported disclosures

Fecal microbiota transplantation as a new treatment for canine inflammatory bowel disease.

In human medicine, fecal microbiota transplantation (FMT) is an effective treatment for recurrent Clostridioides difficile infection. It has also been tested as a treatment for multiple gastrointestinal diseases, including inflammatory bowel disease (IBD). However, only a few studies have focused on the changes in the microbiome following FMT for canine IBD. Here, we performed FMT in nine dogs with IBD using the fecal matter of healthy dogs and investigated the subsequent changes in the fecal microbiome and clinical signs. In three dogs, the fecal microbiome was examined by 16S rRNA sequencing. Fusobacteria were observed at a low proportion in dogs with IBD. However, the post-FMT microbiome became diverse and showed a significant increase in Fusobacteria proportion. Fusobacterium was detected in the nine dogs by quantitative polymerase chain reaction. The proportion of Fusobacterium in the post-FMT fecal microbiome was significantly increased (p<0.05). The changes in clinical signs (e.g., vomiting, diarrhea, and weight loss) were evaluated according to the canine inflammatory bowel disease activity index. The score of this index significantly decreased in all dogs (p<0.05) with improvements in clinical signs. These improvements were related to the changes in the proportion of microbes, particularly the increase in Fusobacterium. The dogs with IBD showed a lower proportion of Fusobacterium than healthy dogs. This suggests that a low proportion of Fusobacterium is a characteristic feature of canine IBD and that Fusobacterium is involved in this disease. The results of this study may help elucidate the pathogenesis of this disease and its association with Fusobacterium.

Immune-mediated diseases and risk of Crohn's disease or ulcerative colitis: a prospective cohort study.

Although immune-mediated diseases (IMDs) including inflammatory bowel diseases (IBDs) are known to cluster, to what extent this is due to common environmental influences is unknown. To examine the incidence of IBD in individuals with another IMD. We used data from the prospective Nurses' Health Study II cohort (1995-2017) to examine the effect of diagnoses of several common IMDs on subsequent risk of Crohn's disease (CD) or ulcerative colitis (UC) using Cox proportional hazards models, adjusting for detailed diet and lifestyle confounders. We documented 132 cases of CD and 186 cases of UC over 2016163 person-years of follow-up (median age at IBD diagnosis 50years). Compared to participants with no history of IMD, the HRs of CD for those with 1 and≥2 IMDs were 2.57 (95% CI 1.77-3.74) and 2.74 (95% CI 1.36 to 5.49), respectively (Ptrend <0.0001). This association was only modestly attenuated by adjustment for environmental risk factors (HR 2.35 and 2.46, respectively). The risk of UC was not increased, with multivariable-adjusted HRs of 1.22 (95% CI 0.85-1.76) and 1.33 (95% CI 0.67-2.65) for those with 1 and≥2 IMDs, respectively, compared to those with none (Ptrend 0.16) (Pheterogeneity comparing CD and UC 0.037). Asthma, atopic dermatitis, psoriasis and rosacea were individually associated with higher risk of CD (HR ranging from 2.15 to 3.39) but not UC. Individuals with one or more IMDs are at an increased risk for CD but not UC.

Elucidation of Gut Microbiota-Associated Lipids Using LC-MS/MS and 16S rRNA Sequence Analyses.

SummaryHost-microbiota interactions create a unique metabolic milieu that modulates intestinal environments. Integration of 16S ribosomal RNA (rRNA) sequences and mass spectrometry (MS)-based lipidomics has a great potential to reveal the relationship between bacterial composition and the complex metabolic network in the gut. In this study, we conducted untargeted lipidomics followed by a feature-based molecular MS/MS spectral networking to characterize gut bacteria-dependent lipid subclasses in mice. An estimated 24.8% of lipid molecules in feces were microbiota-dependent, as judged by > 10-fold decrease in antibiotic-treated mice. Among these, there was a series of unique and microbiota-related lipid structures, including acyl alpha-hydroxyl fatty acid (AAHFA) that was newly identified in this study. Based on the integrated analysis of 985 lipid profiles and 16S rRNA sequence data providing 2,494 operational taxonomic units, we could successfully predict the bacterial species responsible for the biosynthesis of these unique lipids, including AAHFA.

Salivary Stress/Immunological Markers in Crohn's Disease and Ulcerative Colitis.

There is continuous and growing interest in research into new alternatives to standard biomarkers to detect and follow-up disease, reducing physical and psychological stress in patients needing regular and invasive medical examinations for the evaluation of pathologies, including inflammatory bowel diseases (IBD). Saliva is one of the most promising body fluids in the research of new biomarkers, thanks to the large number of molecules it contains. Many molecules present in saliva are often directly correlated to their concentration in the blood but may be affected by the condition of the oral cavity. This means that a careful selection of a specific biomarker is required for each pathology, especially pathologies such as IBD, which may induce inflammation in the oral cavity. Here, we analyze the currently used and the proposed new salivary biomarkers (i.e., calprotectin, cytokines, IgA, cortisol, and oxidative stress markers) for the detection and follow-up of the main subtypes of IBD, known as ulcerative colitis and Crohn’s disease.

Fatigue in inflammatory bowel disease and its impact on daily activities.

Fatigue is a common symptom of chronic inflammation, including inflammatory bowel disease (IBD), resulting in significant impairment in quality of life. To identify the prevalence of fatigue in a large IBD cohort compared to the general population, address risk factors, and evaluate its impact on daily life. We evaluated 1208 IBD patients from the Swiss Inflammatory Bowel Disease Cohort Study (SIBDCS) and 414 healthy controls. Significant fatigue was defined as a visual analogue scale (VAS-F, range 0-10) score≥4. Secondary endpoints were severity of fatigue and its impact on daily activities with the Fatigue Severity Scale (FSS), with a score≥4 indicative of fatigue. Demographic, IBD-related and psychiatric symptoms were assessed with a multivariate analysis of variance (MANOVA) model optimised for prediction of VAS-F (primary outcome) and FSS scores. Overall, 672 IBD patients (55.6%) reported significant fatigue compared to 145 (35%) controls (OR 2.71; 95% CI 2.08-3.54; P<0.001). In IBD, fatigue also significantly affected daily activities (FSS≥4; 405 (33.5%) IBD patients vs 81 (19.6%) controls, P<0.001). In the MANOVA model, fatigue levels were associated with female gender (coefficient 0.839; 0.556 - 1.123; P<0.001), younger age at diagnosis (-0.031 per year; -0.042- -0.019; P<0.001), shorter disease duration (-0.036 per year; -0.050- -0.022; P<0.001), nocturnal diarrhoea (0.718; 0.295-1.141; P=0.001), low educational level (P=0.034) and symptoms of depression and anxiety. Fatigue is both more frequent and more severe in patients with IBD than in the general population.

Reduction in Inflammatory Bowel Disease Healthcare During the Coronavirus Disease 2019 Pandemic: A Nationwide Retrospective Cohort Study

Coronavirus disease 2019 (COVID-19) caused a worldwide disruption of regular health care, with more than 37 million cases and over 1,000,000 deaths.1 After confirmation of the first COVID-19 patient in The Netherlands, a country with 17.4 million inhabitants and universal health care, on February 27, 2020, the pandemic rapidly spread across the country, reaching its first peak in April 2020.2 Regular health care, including inflammatory bowel disease (IBD) care, was strongly reduced to establish sufficient capacity for COVID-19 care and to prevent COVID-19 spread by patients and healthcare workers.

Biosimilars in inflammatory bowel disease.

The advent of biologics has changed outcomes in many chronic conditions, including inflammatory bowel disease (IBD). Biologics have been used for the induction and remission of ulcerative colitis and Crohn's disease for almost two decades and are effective in patients who used to fail conventional treatment with steroids, immunomodulators. The use of biologics in the treatment of IBD has increased over the last few years, partly due to the rise in its incidence and the use of biologics as a first-line treatment in severe disease as well as in complicated diseases like penetrating/fistulating Crohn's disease. However, their use is associated with a significant burden to the society with respect to healthcare costs, resulting in the premature discontinuation of therapy in some patients, leading to exacerbations and complications. The introduction of biosimilars a decade ago seems to be a promising approach to reducing the costs related to therapy. Since their introduction, numerous studies conducted in adults and some in children show the efficacy of biosimilars with a similar side-effect profile to biologics. This review discusses the history of biosimilars in the treatment of IBD, enumerates several such studies and discusses the possibility of using biosimilars in the future.

A STAT3 palmitoylation cycle promotes TH17 differentiation and colitis.

Cysteine palmitoylation (S-palmitoylation) is a reversible post-translational modification that is installed by the DHHC family of palmitoyltransferases and is reversed by several acyl protein thioesterases1,2. Although thousands of human proteins are known to undergo S-palmitoylation, how this modification is regulated to modulate specific biological functions is poorly understood. Here we report that the key T helper 17 (TH17) cell differentiation stimulator, STAT33,4, is subject to reversible S-palmitoylation on cysteine 108. DHHC7 palmitoylates STAT3 and promotes its membrane recruitment and phosphorylation. Acyl protein thioesterase 2 (APT2, also known as LYPLA2) depalmitoylates phosphorylated STAT3 (p-STAT3) and enables it to translocate to the nucleus. This palmitoylation-depalmitoylation cycle enhances STAT3 activation and promotes TH17 cell differentiation; perturbation of either palmitoylation or depalmitoylation negatively affects TH17 cell differentiation. Overactivation of TH17 cells is associated with several inflammatory diseases, including inflammatory bowel disease (IBD). In a mouse model, pharmacological inhibition of APT2 or knockout of Zdhhc7-which encodes DHHC7-relieves the symptoms of IBD. Our study reveals not only a potential therapeutic strategy for the treatment of IBD but also a model through which S-palmitoylation regulates cell signalling, which might be broadly applicable for understanding the signalling functions of numerous S-palmitoylation events.

Physical Activity Shapes the Intestinal Microbiome and Immunity of Healthy Mice but Has No Protective Effects against Colitis in MUC2-/- Mice.

The interactions among humans, their environment, and the trillions of microbes residing within the human intestinal tract form a tripartite relationship that is fundamental to the overall health of the host. Disruptions in the delicate balance between the intestinal microbiota and host immunity are implicated in various chronic diseases, including inflammatory bowel disease (IBD). There is no known cure for IBD; therefore, novel therapeutics targeting prevention and symptom management are of great interest. Recently, physical activity in healthy mice was shown to be protective against chemically induced colitis; however, the benefits of physical activity during or following disease onset are not known. In this study, we examine whether voluntary wheel running is protective against primary disease symptoms in a mucin 2-deficient (Muc2-/- ) lifelong model of murine colitis. We show that 6 weeks of wheel running in healthy C57BL/6 mice leads to distinct changes in fecal bacteriome, increased butyrate production, and modulation in colonic gene expression of various cytokines, suggesting an overall primed anti-inflammatory state. However, these physical activity-derived benefits are not present in Muc2-/- mice harboring a dysfunctional mucosal layer from birth, ultimately showing no improvements in clinical signs. We extrapolate from our findings that while physical activity in healthy individuals may be an important preventative measure against IBD, for those with a compromised intestinal mucosa, a commonality in IBD patients, these benefits are lost.IMPORTANCE Perturbation in the gut microbial ecosystem has been associated with various diseases, including inflammatory bowel disease. Habitual physical activity, through its ability to modulate the gut microbiome, has recently been shown to prophylactically protect against chemically induced models of murine colitis. Here, we (i) confirm previous reports that physical activity has limited but significant effects on the gut microbiome of mice and (ii) show that such changes are associated with anti-inflammatory states in the gut, such as increased production of beneficial short-chain fatty acids and lower levels of proinflammatory immune markers implicated in human colitis; however, we also show that (iii) these physical activity-derived benefits are completely lost in the absence of a healthy intestinal mucus layer, a hallmark phenotype of human colitis.

S0684 Experience of Hospital Admission and Surgery During the COVID-19 Pandemic: A Survey of IBD Patients

INTRODUCTION: The evolving COVID-19 has impacted patients globally, including inflammatory bowel disease (IBD) patients needing surgery At the same time, multiple publications and general surgical communities recommended postponing nonurgent elective surgery surgical experience during this pandemic from IBD patient's perspective has not been described in current literature Therefore, the aim of the current survey study was to evaluate changes in hospital admissions and surgeries during COVID-19 METHODS: A survey was distributed among IBD patients who underwent IBD-related surgeries between January 2020 to March 2020 in 4 major IBD centers in China The aims of this patient-targeted survey study were to evaluate changes in practice as well as the impact on patient experience RESULTS: A total of 126 patients received surgery during the pandemic, of whom 78 (61 9%) responded to the survey Sixty-four (82%) patients had Crohn's disease Patients undergoing surgery during the pandemic were mostly under the age of 40 (n = 52, 66 7%) COVID-19 testing was conducted in 60 (76 9%) patients and was all negative Twenty-six (33 3%) patients underwent surgery in January 2020 (the beginning of the pandemic) and 44 (56 4%) in March 2020 (the late phase of the pandemic), while only 8 (10 3%) patients received surgery during February 2020 (the peak of the pandemic) Elective surgery was conducted in 48 (61 5%) patients Postponed elective surgery was conducted in 18 (23 1%) patients, within whom 7 (38 9%) developed worsening of symptoms with 2 (11 1%) requiring emergent surgery The surgical indications were mainly bowel obstruction (n = 21, 26 9%) and perianal abscess (n = 18, 23 1%) Postoperative complications were noted in 5 1% of cases, but no re-operation was required Among these patients, 24 (70 5%) patients believed that the extensive testing process was the major contributing factor to the prolonged length of stay Regardless, 44 (56 4%) patients rated their overall experience as excellent Due to the ongoing COVID pandemic, 58 (74 4%) patients reported different levels of concerns for surgery CONCLUSION: Commonly performed IBD-related surgeries during the pandemic were for bowel obstruction or perianal abscess Surgery can be postponed during the COVID-19 pandemic under close monitor Overall hospital stay has been uneventful and satisfactory None of the respondents contracted COVID-19 Most patients do express a certain level of anxiety caused by the pandemic

TNF Receptor 1 Promotes Early-Life Immunity and Protects against Colitis in Mice

SUMMARYNeutralization of tumor necrosis factor (TNF) represents a widely used therapeutic strategy for autoimmune diseases including inflammatory bowel disease (IBD). However, the fact that many patients with IBD are non-responsive to anti-TNF therapies suggests the need for a better understanding of TNF signaling in IBD. Here, we show that co-deletion of TNF receptor 1 (TNFR1, Tnfrsf1a) in the Il10−/− spontaneous colitis model exacerbates disease, resulting in very-early-onset inflammation after weaning. The disease can be interrupted by treatment with antibiotics. The single deletion of TNFR1 induces subclinical colonic epithelial dysfunction and mucosal immune abnormalities, including accumulation of neutrophils and depletion of B cells. During the pre-disease period (before weaning), both Tnfr1−/− and Il10−/− Tnfr1−/− animals exhibit impaired expression of pro-inflammatory cytokines compared with wild-type and Il10−/− controls, respectively. Collectively, these results demonstrate the net anti-inflammatory functions of TNF/TNFR1 signaling through the regulation of colonic immune homeostasis in early life.

Review article: how the intestinal microbiota may reflect disease activity and influence therapeutic outcome in inflammatory bowel disease.

Intestinal bacteria produce metabolites and by-products necessary for homeostasis. Imbalance in this equilibrium is linked to multiple pathologies including inflammatory bowel disease (IBD). The role of the gut microbiota in determining treatment response is becoming apparent, and may act as biomarker for efficacy. To describe knowledge about the intestinal microbiota on disease severity and treatment outcomes in IBD METHODS: Descriptive review using PubMed to identify literature on the intestinal microbiota in IBD RESULTS: Severe IBD has a less diverse microbiota with fewer commensal microbiota communities and more opportunistic pathogenic bacteria originating from the oral cavity or respiratory tract. IBD treatments can alter gut microbiota composition, but in vitro/in vivo studies are needed to prove causation. A diversification of the microbiota is observed during remission. Patients with a more diverse baseline microbiome and higher microbial diversity show better response to anti-tumour necrosis factor-α, vedolizumab and ustekinumab therapy. Higher abundance of short chain fatty acid-producing bacteria, fewer mucus-colonising bacteria and lower abundance of pro-inflammatory bacteria have also been associated with a favourable outcome. Predictive models, based on a combination of microbiota, clinical data and serological markers, have good accuracy for treatment outcome and disease severity. The intestinal microbiota in IBD carries a set of promising biomarkers of disease activity and prediction of therapeutic outcome. Current insights may also help in designing microbiota modulation strategies to improve outcomes in IBD.

Dysbiosis of gut microbiota in inflammatory bowel disease: Current therapies and potential for microbiota-modulating therapeutic approaches.

There is a growing body of evidence reinforcing the unique connections between the host microbiome, health, and diseases. Due to the extreme importance of the symbiotic relationship between the intestinal microbiome and the host, it is not surprising that any alteration in the gut microbiota would result in various diseases, including inflammatory bowel disease (IBD), Crohn’s disease (CD) and ulcerative colitis (UC). IBD is a chronic, relapsing-remitting condition that is associated with significant morbidity, mortality, compromised quality of life, and costly medical care. Dysbiosis is believed to exacerbate the progression of IBD. One of the currently used treatments for IBD are anti-tumor necrosis factor (TNF) drugs, representing a biologic therapy that is reported to have an impact on the gut microbiota composition. The efficacy of anti-TNF agents is hindered by the possibility of non-response, which occurs in 10-20% of treated patients, and secondary loss of response, which occurs in up to 30% of treated patients. This underscores the need for novel therapies and studies that evaluate the role of the gut microbiota in these conditions. The success of any therapeutic strategy for IBD depends on our understanding of the interactions that occur between the gut microbiota and the host. In this review, the health and disease IBD-associated microbiota patterns will be discussed, in addition to the effect of currently used therapies for IBD on the gut microbiota composition, as well as new therapeutic approaches that can be used to overcome the current treatment constraints.

In Vitro Characterization of Gut Microbiota-Derived Commensal Strains: Selection of Parabacteroides distasonis Strains Alleviating TNBS-Induced Colitis in Mice.

Alterations in the gut microbiota composition and diversity seem to play a role in the development of chronic diseases, including inflammatory bowel disease (IBD), leading to gut barrier disruption and induction of proinflammatory immune responses. This opens the door for the use of novel health-promoting bacteria. We selected five Parabacteroides distasonis strains isolated from human adult and neonates gut microbiota. We evaluated in vitro their immunomodulation capacities and their ability to reinforce the gut barrier and characterized in vivo their protective effects in an acute murine model of colitis. The in vitro beneficial activities were highly strain dependent: two strains exhibited a potent anti-inflammatory potential and restored the gut barrier while a third strain reinstated the epithelial barrier. While their survival to in vitro gastric conditions was variable, the levels of P. distasonis DNA were higher in the stools of bacteria-treated animals. The strains that were positively scored in vitro displayed a strong ability to rescue mice from colitis. We further showed that two strains primed dendritic cells to induce regulatory T lymphocytes from naïve CD4+ T cells. This study provides better insights on the functionality of commensal bacteria and crucial clues to design live biotherapeutics able to target inflammatory chronic diseases such as IBD.

Mucins in Intestinal Mucosal Defense and Inflammation: Learning From Clinical and Experimental Studies

Throughout the gastrointestinal (GI) tract, a distinct mucus layer composed of highly glycosylated proteins called mucins plays an essential role in providing lubrication for the passage of food, participating in cell signaling pathways and protecting the host epithelium from commensal microorganisms and invading pathogens, as well as toxins and other environmental irritants. These mucins can be broadly classified into either secreted gel-forming mucins, those that provide the structural backbone for the mucus barrier, or transmembrane mucins, those that form the glycocalyx layer covering the underlying epithelial cells. Goblet cells dispersed among the intestinal epithelial cells are chiefly responsible for the synthesis and secretion of mucins within the gut and are heavily influenced by interactions with the immune system. Evidence from both clinical and animal studies have indicated that several GI conditions, including inflammatory bowel disease (IBD), colorectal cancer, and numerous enteric infections are accompanied by considerable changes in mucin quality and quantity. These changes include, but are not limited to, impaired goblet cell function, synthesis dysregulation, and altered post-translational modifications. The current review aims to highlight the structural and functional features as well as the production and immunological regulation of mucins and the impact these key elements have within the context of barrier function and host defense in intestinal inflammation.

Disease Risk–Associated Genetic Variants in STAT1 and STAT4 Function in a Complementary Manner to Increase Pattern-Recognition Receptor–Induced Outcomes in Human Macrophages

STAT proteins can regulate both pro- and anti-inflammatory cytokine signaling. Therefore, identifying consequences of modulating expression of a given STAT is ultimately critical for determining its potential as a therapeutic target and for defining the mechanisms through which immune-mediated disease variants in STAT genes contribute to disease pathogenesis. Genetic variants in the STAT1/STAT4 region are associated with multiple immune-mediated diseases, including inflammatory bowel disease (IBD). These diseases are characterized by dysregulated cytokine secretion in response to pattern-recognition receptor (PRR) stimulation. We found that the common IBD-associated rs1517352 C risk allele increased both STAT1 and STAT4 expression in human monocyte-derived macrophages (MDMs). We therefore hypothesized that the STAT1/STAT4 variant might regulate PRR-initiated responses in a complementary and cooperative manner because of the important role of autocrine/paracrine cytokines in modulating PRR-initiated signaling. STAT1 and STAT4 were required for PRR- and live bacterial-induced secretion of multiple cytokines. These outcomes were particularly dependent on PRR-initiated autocrine/paracrine IL-12-induced STAT4 activation to generate IFN-γ, with autocrine IFN-γ then signaling through STAT1. STAT1 and STAT4 also promoted bacterial-induced cytokines in intestinal myeloid cells and PRR-enhanced antimicrobial pathways in MDMs. Importantly, MDMs from rs1517352 C IBD risk allele carriers demonstrated increased TLR4-, IFN-γ- and IL-12-induced STAT1 and STAT4 phosphorylation and cytokine secretion and increased TLR4-enhanced antimicrobial pathways. Taken together, STAT1 and STAT4 expression is coregulated by a shared genetic region, and STAT1 /STAT4-immune disease-associated variants modulate IFN-γ- and IL-12-associated outcomes, and in turn, PRR-induced outcomes, highlighting that these genes cooperate to regulate pathways relevant to disease pathogenesis.

Impact of COVID-19 pandemic on the daily management of biotechnological therapy in inflammatory bowel disease patients: Reorganisational response in a high-volume Italian inflammatory bowel disease centre.

The coronavirus disease 2019 (COVID-19) pandemic is having a major clinical as well as organisational impact on the national health-care system in Italy, particularly in high-volume hospitals which are usually active for many essential clinical needs, including inflammatory bowel disease (IBD). Here, we report major clinical and organisational challenges at a high-volume Italian IBD centre one month after the start of the Italian government’s restrictions due to the COVID-19 pandemic. All routine follow-up IBD visits of patients in remission were cancelled or rescheduled for 8–12 weeks’ time. However, access to the hospital for therapy or for unstable/relapsing patients was not considered postponable. Everyone attending the centre (e.g. physicians, nurses, administrative personnel and patients) were advised to respect the general recommended rules for hand hygiene and social distancing, to disclose if they had a fever or cough or flu-like symptoms and to wear a surgical mask and gloves. At the entrance of the therapy area, a control station was set up in order to double-check all patients with a clinical interview and conduct thermal scanning. A total of 1451 IBD patients under biotechnological or experimental therapy actively followed in the CEMAD IBD centre were included in the study. About 65% of patients maintained their appointment schedules without major problems, while in 20% of cases planned infusions were delayed because of the patient’s decision or practical issues. About 10% of patients receiving subcutaneous therapy were allowed to collect their medicine without a follow-up visit. Finally, 10% of patients living outside the Lazio region requested access to their therapy at a local centre closer to their home. At present, five patients have been found to be positive for SARS-CoV-2 infection but with minimal symptoms, 22 are in ‘quarantine’ for contact considered to be ‘at risk’ for the infection. Up to now, none of them has experienced significant symptoms. This study represents the first observational detailed report about short-term impact of the COVID-19 pandemic on patient organisation and management in a high-volume IBD centre.