Inflammatory Bowel Research Articles

MR2938 relieves DSS-induced colitis in mice through inhibiting NF-κB signaling and improving epithelial barrier

Abstract Damage to the epithelial barrier is among key processes contributing to initiation and chronic inflammation in inflammatory bowel diseases (IBD). Only management therapy exists for IBD (e.g., anti-inflammatory and immunomodulatory agents, JAK/STAT inhibitors), and while novel therapeutic approaches have shown great potential, issues remain including route of administration, development of resistance to therapy and toxicity. Thus, novel small molecule inhibitors which can alleviate colonic inflammation and restore intestinal barrier functions are needed. Our previous study identified a new quinazolinone derivative MR2938, inspired by marine natural product penipanoid C, displaying impressive anti-inflammatory effects. In vivo efficacy study indicated that MR2938 had a dose-dependent effect on improving colitis symptoms, gut-barrier disruption, and colonic inflammation in an acute dextran sulfate sodium (DSS)-induced murine colitis as a model of epithelial injury relevant to IBD. Evaluation of potential mechanism involved in MR2938 efficacy demonstrated that MR2938 inhibited NF-κB-mediated inflammatory responses, and attenuated intestinal epithelial tight junction damage by restoring the expression of Occludin and ZO-1. Taken together, these data suggest that MR2938 is a promising lead compound for the treatment of IBD.

Association between vitamin C, D, and K intake and inflammatory bowel disease risk: findings from 2009 to 2010 NHANES

Association between vitamin C, D, and K intake and inflammatory bowel disease risk: findings from 2009 to 2010 NHANES

Symptom Resolution and Meaningful Improvement in Quality of Life With Risankizumab in Patients With Ulcerative Colitis: Post Hoc Analysis of the Randomized INSPIRE and COMMAND Studies

Introduction: Patients with ulcerative colitis (UC) experience disruptive symptoms that can impair quality of life (QoL). This study examined the effect of risankizumab (RZB) induction and maintenance treatment on symptom resolution and health-related QoL (HRQoL) outcomes. Methods: For the 12-week induction, patients were randomized to intravenous (IV) RZB 1200 mg (RZB1200) or placebo (PBO). For the 52-week maintenance, clinical responders to induction were re-randomized to subcutaneous (SC) RZB 180 mg (RZB180), RZB 360 mg (RZB360), or PBO (RZB withdrawal). This post hoc analysis assessed individual and comprehensive resolution of UC-related symptoms and clinically meaningful within-person changes (MWPCs) for HRQoL outcomes. Results: RZB improved symptomatic outcomes compared with PBO at week 4 (nominal P ≤ .001; abdominal pain, bowel urgency, fecal incontinence [nominal P ≤ .01]) through the 12-week induction (P ≤ .001; abdominal pain [P ≤ .01]; fecal incontinence, sleep interruption [nominal P ≤ .001]). Greater improvements were achieved with RZB compared with PBO (RZB withdrawal) for symptomatic outcomes through the 52-week maintenance. More patients treated with RZB achieved comprehensive symptom resolution (complete resolution of all six UC-related symptoms) compared with PBO at week 12 of induction (RZB1200, 21.8%; PBO, 9.5% [nominal P ≤ .001]) and week 52 of maintenance (RZB180, 23.5%; RZB360, 19.4%; PBO [RZB withdrawal], 14.2%; nominal P ≤ .05 and P = .1358, respectively). RZB compared with PBO improved MWPCs across HRQoL outcomes at week 12 of induction (nominal P ≤ .001; work time missed [nominal P = .0033]). At week 52 of maintenance, RZB180 compared with PBO (RZB withdrawal) improved MWPCs across HRQoL outcomes (nominal P ≤ .001; overall work impairment [nominal P ≤ .01], work time missed [nominal P = .3324], impairment while working [nominal P ≤ .05]) and more patients treated with RZB360 achieved MWPCs for the Ulcerative Colitis Symptom Questionnaire (UCSQ), Inflammatory Bowel Disease Questionnaire (IBDQ), and the 36-Item Short-Form Survey physical component summary (SF-36 PCS; all nominal P ≤ .05). Conclusion: RZB treatment improved UC-related symptoms and HRQoL outcomes compared with PBO in patients with UC. Clinical trials: NCT03398148; NCT03398135

Racial Disparities In Utilization Of Medications And Disease Outcomes In Inflammatory Bowel Disease Patients

Abstract Background Although traditionally associated with White European ancestry, inflammatory bowel disease (IBD) has increased among different races and ethnicities. Large studies conducted in the United States (US) and Canada have identified more complex disease phenotypes among Black patients. Our study aimed to investigate disparities in IBD treatments and outcomes between Black and White patients in the US. Methods Using TriNetX database, adult IBD patients were divided into two groups based on race: Black and White patients with IBD, Crohn’s disease (CD) or ulcerative colitis (UC). Medical therapy and disease outcomes were evaluated in both groups with 1:1 propensity-score matching. Methodologic limitations include the potential for missing data, lack of information on socioeconomic strata, and patient-level medication coverage plans. Results In comparison to White patients, Black patients with CD were less likely to receive advanced therapies; Adalimumab (adjusted odds ratio- aOR 0.89), Certolizumab (0.81), Vedolizumab (0.66), Ustekinumab (0.82), or Tofacitinib (0.58). Black patients with UC were less likely to receive advanced therapies; Adalimumab (0.83), Golimumab (0.62), Vedolizumab (0.69), Ustekinumab (0.73) or Tofacitinib (0.55). Black patients with IBD were at higher odds of utilizing corticosteroids (CD 1.18 and UC 1.20) and opioids (CD 1.26 and UC 1.09). Black patients with CD had higher rates of hospitalization (1.35) and perianal abscess (1.56), perianal fistula (1.28) and intestinal fistula (1.38). Black patients with UC had higher rates of hospitalization (1.29), Clostridioides difficile infection (1.11), and toxic megacolon (1.34). Conclusions There were racial disparities in IBD medical therapy and disease outcomes. Black IBD patients had lower treatment with advanced therapies, higher opioid and corticosteroid use, and higher IBD-related complications.

Non-invasive monitoring of inflammatory bowel disease using intestinal ultrasound

Non-invasive monitoring of inflammatory bowel disease using intestinal ultrasound

The characteristics of pediatric-onset inflammatory bowel disease based on our 20-year-long study

The characteristics of pediatric-onset inflammatory bowel disease based on our 20-year-long study

T cell branched glycosylation as a mediator of colitis-associated colorectal cancer progression: a potential new risk biomarker in Inflammatory Bowel Disease.

Inflammatory Bowel Disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract, established as a risk factor for Colorectal Cancer (CRC) development. Long-standing inflammation appears to play a central role in Colitis-associated Colorectal Cancer (CAC). However, the molecular mechanism underlying CAC progression is still elusive. Previous evidence showed that levels of branched glycosylation regulate T cell-mediated immune response associated with IBD severity. Here, we revealed that colonic T cells from IBD patients are dynamically regulated by branched N-glycosylation and associated with the risk of CAC development. The combined analysis of human IBD and CAC clinical samples, together with glycoengineered mouse model susceptible to CAC, revealed a gradual and dynamic increase of branched N-glycans in T cells from colitis to dysplasia and cancer. This glycosylation switch was shown to impose inhibitory properties in T cells, precluding an effective anti-tumor immune response. Mechanistically, we demonstrated that the deletion of branched N-glycans in Mgat5 KO mice led to CAC suppression due to increased infiltration of CD8+ and γδ T cells, contributing to an effective anti-tumor immune response. From the clinical standpoint, we demonstrated that branched N-glycosylation levels detected in inflamed lesions from IBD patients predicted CAC progression with a sensitivity of 83.3% and specificity of 67.9%, when assessed together with age at diagnosis. Overall, we here disclosed a new mechanism underlying CAC development, identifying a potential clinical biomarker plausible to improve the efficacy of cancer surveillance programs through the early identification of high risk IBD patients, for preventive clinical and therapeutic strategies.

The efficacy, safety, and persistence of vedolizumab versus adalimumab in patients with inflammatory bowel disease: a systematic review and meta-analysis.

This systematic review and meta-analysis compared the efficacy, safety, and treatment persistence of vedolizumab and adalimumab in patients with inflammatory bowel disease (IBD). Through a comprehensive search of three databases up to September 2024, we calculated pooled effect estimates for binary outcomes using risk ratios (RR) with 95% confidence intervals (CIs). Heterogeneity was evaluated using Cochran's I2 and Q statistics, with a random-effects model applied when I2 exceeded 50%, and a fixed-effects model used otherwise. For randomized trials, the Cochrane Risk of Bias Tool was applied; the Newcastle-Ottawa Scale assessed nonrandomized trials. We analyzed 12 studies involving 4095 patients. The findings showed that vedolizumab had higher clinical remission and response rates compared to adalimumab (RR: 1.24, 95% CI 1.14-1.34, P < 0.01; RR: 1.11, 95% CI 1.01-1.22, P = 0.03). However, no significant differences were observed in endoscopic remission between the two treatments (RR: 0.74, 95% CI 0.47-1.18, P = 0.21). Safety outcomes, based on adverse and serious adverse event rates, have no significant differences (RR: 0.67, 95% CI 0.41-1.12, P = 0.13; RR: 0.78, 95% CI 0.36-1.68, P = 0.53). Treatment persistence also showed no significant difference between vedolizumab and adalimumab (RR: 0.78, 95% CI 0.55-1.12, P = 0.19). Our study suggests that vedolizumab may be more effective than adalimumab in alleviating symptoms and achieving clinical response. Importantly, this effectiveness is achieved without an increase in adverse events. No significant difference was found in treatment persistence. However, high heterogeneity may weaken the evidence, requiring further randomized trials for confirmation.

Biosilicification-mimicking chiral nanostructures for targeted treatment of inflammatory bowel disease

The cascade reaction of lipopolysaccharides (LPS), cell-free DNA (cfDNA), and reactive oxygen species (ROS), drives the development of inflammatory bowel disease (IBD). Herein, we construct polyethylenimide (PEI)-L/D-tartaric acid (L/D-TA) complexes templated mesoporous organosilica nanoparticles (MON) (PEI-L/D-TA@MON) by mimicking biosilicification under ambient conditions within seconds. The chiral nanomedicines include four functional moieties, wherein PEI electrostatically attracts cfDNA, tetrathulfide bonds reductively react with ROS, silanol groups adsorb LPS, and L/D-TA enables chiral recognition and inflammatory localization. Following oral administration, PEI-L-TA@MON exhibiting preferential conformation stereoscopically matches with mucosa and anchors onto inflammatory intestine for lesion targeting. PEI-L-TA@MON eliminates LPS, ROS, and cfDNA, alleviating oxidative stress, inhibiting inflammatory cascade, and maintaining immune homeostasis to achieve IBD therapy. In addition, the rapid synthesis, low cost, energy-free preparation, negligible toxicity, satisfactory therapeutic effect, and facile conversion on therapeutic modes of PEI-L-TA@MON will bring changes for IBD treatment, providing research values and translational clinical prospects.

Incorporating Best-Worst Scaling (BWS) Questions into Focus Groups to Improve Understanding of Patient Preferences and Refine BWS Attributes.

Best-worst scaling (BWS) is a stated preference elicitation method used for prioritizing attributes of healthcare interventions. Best-worst scaling attribute development is commonly based on literature review, qualitative work, and methodological/clinical expert input. There is limited research incorporating BWS in focus groups as part of the attribute development process. We sought to explore how incorporating BWS questions using the list of potential attributes in focus groups could be used to improve understanding of patient preferences and refine the list of potential BWS attributes as part of the attribute development process. We administered BWS questions on healthcare priorities for inflammatory bowel disease in five focus groups with Canadian patients with inflammatory bowel disease to (1) understand the "what," "how," and "why" of participant choices and (2) note how participants understand the attributes and the language they use to refine the list of potential BWS attributes. A list of 20 potential attributes was used to generate the BWS questions. We coded most/least important choices ("what") and used a thematic analysis to derive subthemes indicating "how" and "why" participants made their choices. We coded how participants understood the attributes/BWS questions and language used when discussing the attributes. Across the 36 participants, the most frequently chosen most/least important attributes were summarized. Three subthemes explaining the "how" and "why" of participant choices were identified: perceived gain; influence of individual experiences; current health state and personal circumstances. Participants identified challenges understanding specific attributes and BWS questions, and provided suggestions for modifications to attribute language/descriptions. Administering BWS questions in focus groups provided: (1) insight into the assumptions participants made when completing the BWS questions; (2) clarity in language and attribute descriptions, and challenges participants had when completing the BWS questions that can be used to refine the list of potential attributes as part of the attribute development process; and (3) understanding of which attributes were most/least important and why to identify potential attributes to remove during the next steps of the attribute development process. Best-worst scaling questions conducted within focus groups can stimulate discussions around relative importance and prioritization of attributes. Through open dialogue, this method can unveil unforeseen responses or identify areas that are unclear and enable a transparent approach to refine the list of potential attributes as part of the attribute development process.

CKMT1 deficiency contributes to mitochondrial dysfunction and promotes intestinal epithelial cell apoptosis via reverse electron transfer-derived ROS in colitis

Mitochondrial dysfunction contributes to the pathogenesis of ulcerative colitis (UC). As a mitochondrial isozyme of creatine kinases, which control energy metabolism, CKMT1 is thought to be a critical molecule in biological processes. However, the specific role of CKMT1 in intestinal inflammation remains largely unknown. Here, we observed markedly decreased CKMT1 expression in the colon tissues of UC patients and dextran sodium sulfate (DSS)-induced colitis mice. We generated intestinal epithelial-specific CKMT1 knockout mice and demonstrated the key role of CKMT1 in mitochondrial homeostasis, intestinal epithelial barrier function, oxidative stress, and apoptosis. In the in vitro experiments, CKMT1 expression limited the activation of the intrinsic and extrinsic apoptotic pathways in IECs. Mechanistically, the loss of CKMT1 expression in IECs increased TNF-α-induced mitochondrial reactive oxygen species (ROS) generation via reverse electron transfer (RET). RET-ROS promoted mitochondrial permeability transition pore (mPTP) opening, ultimately resulting in cell apoptosis during intestinal inflammation. In conclusion, our data demonstrated that CKMT1 is important in maintaining intestinal homeostasis and mitochondrial function. This study provides a promising basis for future research and a potential therapeutic target for inflammatory bowel disease (IBD).

Epidemiology, Natural History and Treatment of IBD in Africa: A Scoping Review.

Epidemiology, Natural History and Treatment of IBD in Africa: A Scoping Review.

Gut Microbial Targets in Inflammatory Bowel Disease: Current Position and Future Developments

Gut Microbial Targets in Inflammatory Bowel Disease: Current Position and Future Developments

The interrelationship between intestinal immune cells and enteric α-synuclein in the progression of Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder primarily characterized by motor impairment, resulting from the accumulation of α-synuclein and neuronal cell death in the substantia nigra of the midbrain. Emerging evidence suggests that α-synuclein aggregation may originate in the enteric nervous system (ENS) and subsequently propagate to the brain via the vagus nerve. Clinical observations, such as prodromal gastrointestinal dysfunction in PD patients and the increased incidence of PD among individuals with inflammatory bowel disease, support the hypothesis that abnormal intestinal inflammation may contribute to the onset of motor dysfunction and neuropathology in PD. This review examines recent findings on the interplay between intestinal immune cells and α-synuclein aggregation within the framework of gut-originated PD pathogenesis. It begins by discussing evidence linking dysbiosis and intestinal inflammation to α-synuclein aggregation in the ENS. Additionally, it explores the potential role of intestinal immune cells in influencing enteric neurons and α-synuclein aggregation, furthering the understanding of PD development.

Risk Factors for Contraceptive Failure and Unintended Pregnancy Among Women With Inflammatory Bowel Disease.

Risk Factors for Contraceptive Failure and Unintended Pregnancy Among Women With Inflammatory Bowel Disease.

Common Regulatory Mechanisms Mediated by Cuproptosis Genes in Inflammatory Bowel Disease and Major Depressive Disorder

Common Regulatory Mechanisms Mediated by Cuproptosis Genes in Inflammatory Bowel Disease and Major Depressive Disorder

Escin Ia Ameliorates DSS-Induced Chronic Colitis in Mice by Inhibiting Inflammation and Oxidative Stress via the LOXL2/MMP-9 Pathway.

Escin Ia Ameliorates DSS-Induced Chronic Colitis in Mice by Inhibiting Inflammation and Oxidative Stress via the LOXL2/MMP-9 Pathway.

TXM-CB13 Improves the Intestinal Mucosal Barrier and Alleviates Colitis by Inhibiting the ROS/TXNIP/TRX/NLRP3 and TLR4/MyD88/NF-κB/NLRP3 Pathways.

The activation of inflammasomes (NLRP3 and NLRP1) is central to the pathogenesis of inflammatory bowel disease (IBD). Here we examined the protective effects of a thioredoxin-mimetic peptide CB13 (TXM-CB13), known for its antioxidative stress and anti-inflammatory properties. We examined the effects of TXM-CB13 on dextran sulfate sodium (DSS)-induced colitis and lipopolysaccharide (LPS)-induced NLRP3 inflammasome activation in RAW264.7 macrophages. TXM-CB13 appeared to alleviate symptoms of DSS-induced colitis and to significantly suppress the protein and mRNA levels of NLRP3, Mlck, and IL-1β in colonic tissues. Additionally, TXM-CB13 treatment increased the levels of the intestinal barrier proteins Occludin, ZO-1, and NLRP1, as shown through immunohistochemistry and Western blot analysis. In vitro, TXM-CB13 inhibited LPS-induced TLR4 signaling, reducing MyD88 levels and consequently attenuating the activation of the NF-κB pathways, including p-IκB-α/IκB-α and p-NF-κB-p65/NF-κB-p65. This inhibition further reduced the activation of the NLRP3 inflammasome components, NLRP3, ASC, Caspase-1, GSDMD, and IL-1β. In addition, TXM-CB13 prevented the ROS-mediated dissociation of TXNIP from TRX, inhibiting NLRP3 activation. These findings suggest that TXM-CB13 is a potential therapeutic candidate for IBD through its modulation of the TLR4/MyD88/NF-κB/NLRP3 and ROS/TXNIP/TRX/NLRP3 pathways.

Exploring Biomarkers of Systemic Oxidative Stress and Placental Insufficiency in Pregnant Women with Inflammatory Bowel Diseases.

Exploring Biomarkers of Systemic Oxidative Stress and Placental Insufficiency in Pregnant Women with Inflammatory Bowel Diseases.

SOD mimics delivered to the gut using lactic acid bacteria mitigate the colitis symptoms in a mouse model of Inflammatory Bowel Diseases

Inflammatory bowel diseases (IBD), which include Crohn’s disease and ulcerative colitis represent a global health issue as a prevalence of 1% is expected in the western world by the end of this decade. These idiseases are associated with a high oxidative stress that induces inflammatory pathways and severely damages the gut tissues. IBD patients suffer from antioxidant defenses weakening, through, for instance, an impaired activity of superoxide dismutases (SOD) — that catalyze the dismutation of superoxide — or other endogenous antioxidant enzymes including catalase and glutathione peroxidase. Manganese complexes mimicking SOD activity have shown beneficial effects on cells and murine models of IBD. However, efficient SOD mimics are often manganese complexes that can suffer from decoordination and thus inactivation in acidic stomachal pH. In order to improve their delivery in the gut after oral administration, two SOD mimics Mn1 and Mn1C were loaded into lactic acid bacteria that serve as delivery vectors. When orally administrated to mice suffering from a colitis, these chemically modified bacteria (CMB) showed protective effects on the global health status of mice. In addition, they have shown beneficial effects on lipocalin-2 content and intestinal permeability. Interestingly, mRNA SOD2 content in colon homogenates was significantly decreased upon mice feeding with CMB loaded with Mn1C, suggesting that the beneficial effects observed may be due to the release of the SOD mimic in the gut that complement for this enzyme. These CMB represent new efficient chemically modified antioxidant probiotics for IBD treatment.