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In this study we aimed to identify clinically relevant patterns of cytomegalovirus (CMV) infection in inflammatory bowel disease. Twenty-two patients with severe ulcerative colitis (UC), 12 with moderate UC, and 16 with Crohn's disease were studied retrospectively. We confirmed CMV infection immunohistochemically. The patients were classified into three groups according to the density of CMV-infected cells. Clinicopathologic features were compared between the groups. Dense CMV infection was found only in five patients with severe UC. Scattered CMV infection was found in nine patients with severe UC, three with moderate UC, and one patient with Crohn's disease, and in three controls (normal mucosa from early colorectal cancer specimens). For patients with severe UC, severity of CMV infection tended to correlate with older age and more rapid deterioration, including toxic megacolon and panperitonitis. The dense CMV group took significantly higher final daily doses of steroids before the operation, and showed steroid resistance. The frequency of emergency surgery was higher and postoperative hospital stay was significantly longer in the dense CMV group. No significant differences were observed in sex, disease duration, steroid administration (total amount or duration), or frequencies of other therapies among the three groups. Immunohistochemically, CMV positivity in endothelial cells around the ulcer base was a significant feature in dense CMV infection, compared with scattered CMV infection. Older patients with severe steroid-resistant UC may be at particular risk for CMV infection. Dense CMV infection, especially when it occurs predominantly in endothelial cells, may be a useful marker for clinically relevant CMV infection.

Abstract Background The effect of immunosuppressive treatment for immune-mediated diseases on risk of the novel coronavirus disease 2019 (COVID-19) has not been established. We aimed to define the effect of targeted biologic and immunomodulator therapy on risk of COVID-19 in a multi-institutional cohort of patients with inflammatory bowel disease (IBD). Methods We identified patients 18 years and older who received care for IBD at Partners Healthcare between January 2019 and April 2020. The primary outcome was development of COVID-19 defined as a positive polymerase chain reaction test for severe acute respiratory syndrome coronavirus 2. Multivariable regression models were used to examine the effect of immunosuppression on risk of COVID-19 and its outcomes. Results In a cohort of 5302 IBD patients, 39 (0.7%) developed COVID-19. There was no difference in age, sex, or race between IBD patients with and without COVID-19. The rate of COVID-19 was similar between patients treated with immunosuppression (0.8%) compared with those who were not (0.64%; P = 0.55). After adjusting for age, sex, race, and comorbidities, use of immunosuppressive therapy was not associated with an increased risk of COVID-19 (odds ratio, 1.73; 95% confidence interval, 0.82–3.63). The presence of obesity was associated with a higher risk of COVID-19 (odds ratio, 8.29; 95% confidence interval, 3.72–18.47). There were 7 hospitalizations, 3 intensive care unit stays, and 1 death. Older age and obesity but not immunosuppressive treatment were associated with severe COVID-19 infection. Conclusions The use of systemic immunosuppression was not associated with an increased risk of COVID-19 in a multi-institutional cohort of patients with IBD.

The role of bacteriophage in Crohn's disease (CD) is unknown. This study investigated the abundance of phages in ileal and colonic samples from pediatric CD patients and controls. Ileal and colonic biopsies from 6 CD patients, gut wash samples from 3 CD patients, and ileal biopsies from 6 noninflammatory bowel disease patients (controls) were analyzed for the presence of bacteriophage using 454 high-throughput pyrosequencing. A sequence-independent single-primer amplification method was used to amplify viral sequences. A total of 186,143 high quality reads were obtained from the 4 sample populations. Contigs and sequence clusters (generated from unassembled singletons) were aligned with sequences from the National Center for Biotechnology Information viral reference database and analyzed by MEGAN. The largest number of viral hits was obtained from the CD gut wash samples (n = 691), followed by CD ileal samples (n = 52), control ileum samples (n = 20), and CD colonic samples (n = 1). The most abundant virus sequences identified belonged to the Caudovirales phage. Our study characterized a diverse phage community in the gut of CD patients. In this study, we have identified differences in phage composition between CD patients and control individuals. The large abundance of phages in CD ileum tissue and CD gut wash sample suggests a role of phage in CD development. The role of phage dysbiosis in CD is currently unknown but opens up a new area of research.

Inflammatory bowel disease (IBD) includes patients affected by Crohn’s disease or ulcerative colitis. IBD is thought to be a chronic immune-mediated disease, but its origin remains elusive, and this limits new therapeutic approaches. Human endogenous retroviruses (HERVs) originate from ancestral infections and represent 8% of the human genome. HERVs are no longer infectious, but some retroviral sequences can be activated, and their aberrant expressions have been implicated in inflammatory and autoimmune disorders. HERV transcription is regulated by TRIM28 and SETDB1, which are also directly involved in epigenetic processes and modulation of the immune response. Using a PCR real-time Taqman amplification assay, we assessed, for the first time, the transcription levels of pol genes of HERV-H, -K, and -W families of env genes of syncytin 1 (SYN1), SYN2, and HERV-W, as well as of TRIM28 and SETDB1 in the whole blood of 48 patients with Crohn’s disease (CD), 20 with ulcerative colitis (UC), and in healthy controls (HC) of comparable age. The transcriptional levels of HERV-H-pol (p = 0.0003) and HERV-K-pol (p = 0.001) were significantly higher in IBD patients compared with HC, with no differences between patients with CD and UC. No significant differences were found for the remaining HERVs between IBD patients and HC. The transcript levels of TRIM28 were significantly downregulated in IBD patients (p < 0.001), without differences between CD and UC, while the SETDB1 levels were preserved. The enhanced transcription of HERV-H-pol and HERV-K-pol, as well as the impaired activation of TRIM28, were not influenced by clinical disease activity and type of treatment. The overexpression of HERVs and impaired transcription of TRIM28 in patients affected by CD or UC suggest that they might be the main actors in the pathophysiology of IBD, opening the way to innovative targeted interventions.

The SARS-CoV-2 coronavirus infects cells through the cellular receptor angiotensin-converting enzyme 2 (ACE2), and the protease TMPRSS2 for the priming of viral spike protein. Thus, changes in these key proteins due to chronic conditions can increase risk for SARS-CoV2 infection; but significance of changes may differ is these changes correspond to full-length species or proteolytic fragments. Here, we determined that full-length ACE2 decreased in the plasma of uninfected Crohn’s disease (CD) patients before treatment onset compared to controls. TMPRSS2 is mostly presented in plasma as full-length species and as an active peptidase fragment, but also as a prodomain fragment, which is the unique species remarkably decreased in plasma from CD patients. Patients treated with the anti-TNFα adalimumab showed recovery in ACE2 levels, while those treated with infliximab, or with the anti-IL-12/23 ustekinumab, still displayed a decrease in full-length species, as well as in cleaved fragments. Patients treated with azathioprine displayed similar ACE2 levels to that of controls, except a decrease in one of the ACE2 fragments. Uniquely, patients treated with azathioprine or with ustekinumab showed partial recovery in the reduction of the TMPRSS2-prodomain fragment characterized in treatment-naïve patients. Our data suggest that CD and common therapies are not related to increased susceptibility for SARS-CoV-2.

Epstein–Barr virus (EBV) exacerbates inflammatory bowel disease (IBD) and is challenging to monitor with invasive or costly tests. We investigated whether explainable machine learning can predict EBV infection from routine clinical data in ulcerative colitis (UC) and Crohn’s disease (CD). In this retrospective study (June 2018–December 2022), EBV status was defined by EBV-DNA > 400 copies/mL. After cleaning, the training cohort (2018–2019) included 174 patients (CD = 122, UC = 52) and the test cohort (2020–2022) included 100 patients. Twenty-one demographic, clinical, and laboratory variables were modeled with ten classifiers; the four best were stacked. Five-fold cross-validation and resampling addressed overfitting and class imbalance. Shapley Additive Explanations (SHAP) provided model interpretability. The ensemble model exhibited high predictive accuracy, achieving area under the ROC curve (AUC) values of 0.93 (overall), 0.97 (CD), and 0.88 (UC) in the training set. In the validation set, AUC values were 0.95 (overall), 0.89 (CD), and 0.97 (UC). SHAP analysis identified age, hemoglobin (HB), total bile acids (TBA), and platelet count (PLT) as significant predictors. Age increased predicted risk in the overall and CD cohorts but decreased risk in UC. TBA emerged as a critical predictor in UC, reflecting its role in bile acid metabolism, while PLT influenced risk across the total patient population, indicating its involvement in coagulation and immune responses. An explainable stacking model using routine biomarkers accurately predicts EBV infection in IBD and reveals subtype-specific determinants. Prospective, multi-center and time-aware validation, and integration into decision-support tools are warranted for clinical deployment.

Background The gut virome has been implicated in inflammatory bowel disease (IBD), yet a full understanding of the gut virome in IBD patients, especially across diverse geographic populations, is lacking. Results In this study, we conducted a comprehensive gut virome-wide association study in a Chinese cohort of 71 IBD patients (15 with Crohn’s disease and 56 with ulcerative colitis) and 77 healthy controls via viral-like particle (VLP) and bulk virome sequencing of their feces. By utilizing an integrated gut virus catalog tailored to the IBD virome, we revealed fundamental alterations in the gut virome in IBD patients. These characterized 139 differentially abundant viral signatures, including elevated phages predicted to infect Escherichia , Klebsiella , Enterococcus_B , Streptococcus , and Veillonella species , as well as IBD-depleted phages targeting Prevotella , Ruminococcus_E , Bifidobacterium , and Blautia species . Remarkably, these viral signatures demonstrated high consistency across diverse populations such as those in Europe and the USA, emphasizing their significance and broad relevance in the disease context. Furthermore, fecal virome transplantation experiments verified that the colonization of these IBD-characterized viruses can modulate experimental colitis in mouse models. Conclusions Building upon these insights into the IBD gut virome, we identified potential biomarkers for prognosis and therapy in IBD patients, laying the foundation for further exploration of viromes in related conditions. -rW5fkHC-UvmYPog5oPfKK Video Abstract

The aim of this study was to survey the bacterial and viral communities in different types of samples from patients with Crohn's disease (CD) at different stages of the disease to relate their distribution with the origin and progression of this disorder.MethodsA total of 42 fecal samples and 15 biopsies from 20 patients with CD and 20 healthy control individuals were collected for bacterial 16S rRNA gene profiling and DNA/RNA virome metagenomic analysis through 454 pyrosequencing. Their composition, abundance, and diversity were analyzed, and comparisons of disease status, patient status, and sample origin were used to determine statistical differences between the groups.ResultsBacterial composition and relative abundance in new-onset patients with CD differed markedly from control individuals. Individual variability and sample origin had a stronger impact on viral communities than the disease, contrary to what was observed for bacterial populations although increased numbers of overrepresented viruses were observed in feces from patients with CD. Correlation-based networks were constructed to show potential relations between bacteria and between those and viruses.ConclusionsThe bacterial community reflects the disease status of individuals more accurately than their viral counterparts. However, numerous viral biomarkers specifically associated with CD disease were identified. Because viruses can modulate bacterial communities, the correlation networks between both communities constitute a step forward in unraveling their interactions under normal and CD disease conditions.

The potential negative impact of cytomegalovirus (CMV) in ulcerative colitis (UC) and Crohn's disease (CD) warrants efforts to improve the yield of diagnostic techniques.MethodsWe retrospectively determined the optimal biopsy location and number from sixty-eight patients with inflammatory bowel disease (66% UC, 31% CD, and 3% inflammatory bowel disease-unclassified) with CMV disease between 2005 and 2011. Biopsies with endoscopic and histologic inflammation were analyzed by immunohistochemistry and/or in situ hybridization. The proportion of positive biopsies was determined, and using data from the 25th percentile, we assessed the number of biopsies required to achieve an 80% probability of a single positive biopsy.ResultsOf the patients with a diagnosis by immunohistochemistry and/or in situ hybridization, 27 of 61 (44%; 95% confidence interval, 32–57) were positive by hematoxylin and eosin, and 11 of 36 (31%; 95% confidence interval, 16–46) had systemic CMV by polymerase chain reaction. Of the patients with biopsies proximal and distal to the splenic flexure, 1 of 11 with UC and 4 of 8 with CD had a diagnosis limited to the right colon. Twenty percent of biopsies were positive by immunohistochemistry or in situ hybridization (20% in UC and 17% in CD). Eleven biopsies in UC and 16 in CD were required to achieve an 80% probability of a positive biopsy.ConclusionsBiopsy location and number are important considerations when assessing for CMV. We recommend a flexible sigmoidoscopy with 11 biopsies in UC and a colonoscopy with 16 biopsies in CD.

Key Points Genetic and genomic technologies, such as nucleic acid-based pathogen detection and genome-wide association studies, have expanded our view of the viruses that can infect our mucosal surfaces, and of human genetic variations that affect host–virus interactions. These new technologies have revealed a high prevalence of viruses in healthy hosts, indicating that in many cases the presence of a virus is not sufficient to cause disease. Furthermore, these new technologies have shown that the 'one pathogen–one disease' model may not be applicable for many diseases. In these diseases, the genetics of the host and environmental conditions combine with the presence of a pathogen to determine the outcome of the infection. Mounting evidence indicates that type I diabetes, Crohn's disease and asthma may follow this model. Mutations in host genes involved in antiviral defence can predispose the host to type 1 diabetes. Changes in a large regulatory network that lead to a heightened immune response have been implicated, by genome-wide association studies, as factors that predispose people to this disease, although no virus has been tied directly to the disease. Crohn's disease is probably the result of a combination of environmental, genetic and viral factors. Mutations in genes that encode parts of the host innate immune system or autophagy pathway have been shown to sensitize model hosts to particular viruses, leading to Crohn's disease. In the case of asthma, studies have indicated that viral infections, particularly with human rhinoviruses, are the most common cause of disease exacerbations. Furthermore, a severe response to rhinovirus infection in childhood correlates with subsequent disease development. However, as the majority of the population is repeatedly exposed to rhinoviruses, additional host factors must be required as well. Many diseases may be caused by the combination of a specific host genetic background and a viral infection. Here, Foxman and Iwasaki describe how viral infections may be involved in type 1 diabetes, asthma and inflammatory bowel disease. New technologies have widened our view of 'complex diseases': those with both genetic and environmental risk factors. In this Review, we explore recent genetic and virological evidence implicating host–virus interactions in three diseases: type 1 diabetes, inflammatory bowel disease and asthma. The viruses implicated in these diseases cause mucosal infections that affect most of the population but are asymptomatic or mild in many hosts. These findings place a new emphasis on common viral infections as important environmental factors in the pathogenesis of complex diseases, and they compel the field to pursue a better understanding of host interactions with the human virome.