ORMDL3 regulates NLRP3 inflammasome activation by maintaining ER-mitochondria contacts in human macrophages and dictates ulcerative colitis patient outcome.

Genome-wide association studies in inflammatory bowel disease have identified risk loci in the orosomucoid-like protein 3/ORMDL sphingolipid biosynthesis regulator 3 (ORMDL3) gene to confer susceptibility to ulcerative colitis (UC), but the underlying functional relevance remains unexplored. Here, we found that a subpopulation of the UC patients who had higher disease activity shows enhanced expression of ORMDL3 compared to the patients with lower disease activity and the non-UC controls. We also found that the patients showing high ORMDL3 mRNA expression have elevated interleukin-1ß cytokine levels indicating positive correlation. Further, knockdown of ORMDL3 in the human monocyte-derived macrophages resulted in significantly reduced interleukin-1ß release. Mechanistically, we report for the first time that ORMDL3 contributes to a mounting inflammatory response via modulating mitochondrial morphology and activation of the NLRP3 inflammasome. Specifically, we observed an increased fragmentation of mitochondria and enhanced contacts with the endoplasmic reticulum (ER) during ORMDL3 over-expression, enabling efficient NLRP3 inflammasome activation. We show that ORMDL3 that was previously known to be localized in the ER also becomes localized to mitochondria-associated membranes and mitochondria during inflammatory conditions. Additionally, ORMDL3 interacts with mitochondrial dynamic regulating protein Fis-1 present in the mitochondria-associated membrane. Accordingly, knockdown of ORMDL3 in a dextran sodium sulfate -induced colitis mouse model showed reduced colitis severity. Taken together, we have uncovered a functional role for ORMDL3 in mounting inflammation during UC pathogenesis by modulating ER-mitochondrial contact and dynamics.

Post-infection irritable bowel syndrome following Coronavirus disease-19: A systematic review and meta-analysis.

BACKGROUND AND OBJECTIVES: Persistent gastrointestinal (GI) symptoms and functional gastrointestinal disorders (FGIDs) are increasingly being recognized after Coronavirus disease-19 (COVID-19). Though quite a few studies addressed irritable bowel syndrome (IBS) following COVID-19, the disorders' prevalence varies greatly. We evaluated, (i) overall frequency of post-COVID-19 IBS, (ii) relative risk of development of IBS among COVID-19 patients compared to healthy controls using systematic review and meta-analysis techniques. METHODS: Literature search was performed for studies on GI symptoms and FGIDs after COVID-19 using electronic databases (Medline, Scopus, Cochrane Central Register of Controlled Trials, Google Scholar and Web of Science) till April 28, 2023. We included studies reporting IBS after COVID-19 with any duration of follow-up and any number of subjects. Studies on pediatric population and those not providing relevant information were excluded. Relative risk of development of IBS using Rome criteria among COVID-19 patients compared to healthy controls was calculated. Analysis was done using MedCalc (Applied Math, Mariakerke, Belgium, version 7.2) and Comprehensive Meta-Analysis version 3.3.070 (Biostat Inc. Englewood, NJ 07631, USA). RESULTS: Of the available studies, 13 (four case-control) reporting on IBS after COVID-19 met inclusion criteria. Among 3950 COVID-19 patients and 991 controls, 7.2% of COVID-19 patients and 4.9% of healthy controls developed IBS. Of the four case-control studies reporting post-COVID-19 IBS, patients with COVID-19 were 2.65 (95% confidence interval [CI] 0.538 to 13.039) times more likely to have post-COVID-19 IBS as compared to healthy controls. CONCLUSIONS: Patients with COVID-19 are more likely to develop post-COVID-19 IBS than healthy controls. The heterogeneity of studies, different criteria used by various studies to diagnose post-COVID-19 IBS and some studies not meeting the six-month follow-up duration of the Rome criteria for diagnosing IBS are limitations of this systematic review.

CLUH functions as a negative regulator of inflammation in human macrophages and determines ulcerative colitis pathogenesis.

Altered mitochondrial function without a well-defined cause has been documented in patients with ulcerative colitis (UC). In our efforts to understand UC pathogenesis, we observed reduced expression of clustered mitochondrial homolog (CLUH) only in the active UC tissues compared with the unaffected areas from the same patient and healthy controls. Stimulation with bacterial Toll-like receptor (TLR) ligands similarly reduced CLUH expression in human primary macrophages. Further, CLUH negatively regulated secretion of proinflammatory cytokines IL-6 and TNF-α and rendered a proinflammatory niche in TLR ligand-stimulated macrophages. CLUH was further found to bind to mitochondrial fission protein dynamin related protein 1 (DRP1) and regulated DRP1 transcription in human macrophages. In the TLR ligand-stimulated macrophages, absence of CLUH led to enhanced DRP1 availability for mitochondrial fission, and a smaller dysfunctional mitochondrial pool was observed. Mechanistically, this fissioned mitochondrial pool in turn enhanced mitochondrial ROS production and reduced mitophagy and lysosomal function in CLUH-knockout macrophages. Remarkably, our studies in the mouse model of colitis with CLUH knockdown displayed exacerbated disease pathology. Taken together, this is the first report to our knowledge explaining the role of CLUH in UC pathogenesis, by means of regulating inflammation via maintaining mitochondrial-lysosomal functions in the human macrophages and intestinal mucosa.

Serological response to vaccination against coronavirus disease-19 in patients with inflammatory bowel disease.

Vaccination against coronavirus disease-19 (COVID-19) is effective in preventing the occurrence or reduction in the severity of the infection. Patients with inflammatory bowel disease (IBD) are on immunomodulators, which may alter serological response to vaccination against COVID-19. Accordingly, we studied (i) the serological response to vaccination against COVID-19 in IBD patients and (ii) a comparison of serological response in IBD patients with that in healthy controls. A prospective study was undertaken during a 6-month period (July 2021 to January 2022). Seroconversion was assessed among vaccinated, unvaccinated IBD patients and vaccinated healthy controls using anti-severe acute respiratory syndrome coronavirus 2 immunoglobulin G (anti-SARS-CoV-2 IgG) antibody detection enzyme-linked immunosorbent assay (ELISA) kit, and optical density (OD) was measured at 450 nm. OD is directly proportional to the antibody concentration. One hundred and thirty-two blood samples were collected from 97 IBD patients (85 [87.6%] ulcerative colitis and 12 [12.4%] Crohn's disease). Forty-one of the seventy-one (57.7%) unvaccinated and 60/61 (98.4%) vaccinated IBD patients tested positive (OD > 0.3) for SARS-CoV-2 IgG antibodies. Fourteen of the sixteen (87.5%) healthy controls tested positive for SARS-CoV-2 IgG antibodies. Vaccinated IBD patients had higher ODs than unvaccinated IBD patients (1.31 [1.09-1.70] vs. 0.53 [0.19-1.32], p < 0.001) and 16 vaccinated healthy controls (1.31 [1.09-1.70] vs. 0.64 [0.43-0.78], p < 0.001). Three of the seventy-one (4.2%) unvaccinated IBD patients reported having recovered from COVID-19. Most IBD patients seroconvert after vaccination against SARS-CoV-2, similar to a healthy population. A large proportion of IBD patients had anti-SARS-CoV-2 antibodies even before vaccination, suggesting the occurrence of herd immunity.

Care of inflammatory bowel disease patients during coronavirus disease-19 pandemic using digital health-care technology.

Background and Aim: Although telemedicine is an option for the care of inflammatory bowel disease (IBD) patients during the Coronavirus Disease (COVID)-19 pandemic, its feasibility and acceptability data are scant. Data on the frequency of COVID-19 among patients with IBD, quality of life (QOL), access to health care, psychological stress, and anxiety during the COVID-19 pandemic are scant. Methods: Video/audio consultation for IBD patients was undertaken after a web-based appointment, and data on acceptability, IBD control, Hospital Anxiety Depression Scale (HADS), and World Health Organization Quality of Life questionnaire (WHOQOL-Bref) were obtained electronically. IBD patients were assessed for COVID-19 symptoms or contact history and tested using reverse transcriptase polymerase chain reaction (RT-PCR) on naso- oro-pharyngeal swabs, and data were compared with 16,317 non-IBD controls. Results: Teleconsultation was feasible and acceptable. IBD patients had COVID-19 as frequently as non-IBD controls despite immunosuppressive therapy, possibly due to their awareness and preventive practices. Although the physical, psychological, and social QOL scores during the COVID-19 pandemic were comparable to the prepandemic period, the environmental scores were worse. Psychological tension and interference with work due to pain were lower during the pandemic, which might be influenced by the control of the disease. Conclusions: Teleconsultation is a feasible and acceptable alternative for IBD patients. They had COVID-19 as frequently as non-IBD controls despite a high frequency of immunosuppressive treatment, possibly due to their awareness of the disease and preventive practices. The QOL scores (except the environmental domains) and psychological issues were quite comparable or even better during the COVID-19 pandemic than earlier.