OBJECTIVE: Regulatory T cells (Tregs) are key regulators in maintaining tissue homeostasis. Disrupted immune homeostasis is associated with Crohn\'s disease (CD) pathogenesis. Thus, Treg therapy represents a promising long-acting treatment to restore immune balance in the diseased intestine. CAR (Chimeric Antigen Receptor) T-cell therapy has revolutionized cancer treatment. This innovative approach also provides the opportunity to improve therapy for CD. By targeting a disease-relevant protein, Interleukin-23 receptor (IL23R), we engineered Tregs expressing IL23R-CAR for treating active CD.
METHODS: Intestinal IL23R expression from active CD was verified by immunohistochemical analysis. Phenotypic and functional characteristics of IL23R-CAR Tregs were assessed using in vitro assays and their migration capacity was monitored in a xenograft tumor model. Transcriptomic and proteomic analyses were performed to associate molecular profiles with IL23R-CAR Treg activation against colon biopsy-derived cells from active CD patients.
RESULTS: Our study showed that IL23R-CAR displayed negligible tonic signalling and strong signal-to-noise ratio. IL23R-CAR Tregs maintained regulatory phenotype during in vitro expansion, even when chronically exposed to proinflammatory cytokines and target antigen. IL23R engagement on IL23R-CAR Tregs triggered CAR-specific activation and significantly enhanced their suppressive activity. Also, IL23R-CAR Tregs migrated to IL23R-expressing tissue in humanized mice. Finally, IL23R-CAR Tregs elicited a specific activation against colon biopsy-derived cells from active CD, suggesting an efficient CAR engagement in active CD. Molecular profiling of CD patient biopsies also revealed transcriptomic and proteomic patterns associated with IL23R-CAR activation.
CONCLUSIONS: Overall, our results demonstrate that IL23R-CAR Tregs represent a promising therapy for active CD.

Live vaccines are contraindicated in patients on immunosuppressive therapy. We conducted a retrospective study evaluating the administration of a live vaccine in patients with IBD on immunosuppressive therapy. The primary outcome was to determine clinical or disseminated disease episodes within three months of vaccine administration in patients who inadvertently received a live vaccine. Thirty-five patients met the inclusion criteria. Twenty-two received the measles, mumps, and varicella (MMR) vaccine, nine received the live zoster vaccine, and one received the varicella vaccine (VAR). Three patients received both the MMR and VAR. The majority of our cohort (20, 57 %) were on anti-tumor necrosis factor, followed by azathioprine (12, 34 %) and vedolizumab (3, 9 %). Although live vaccines are contraindicated in patients on immunosuppressive therapy, none of the patients in this study reported any infections after inadvertent immunization. Further studies are required to address the safety and effectiveness of live vaccine administration in this population.

BACKGROUND: Inflammatory bowel disease (IBD) is a chronic and relapsing disease marked by chronic tissue inflammation that alters the integrity and function of the gut, seriously impacting patient health and quality of life. Aucklandiae Radix (AR), known as Mu Xiang in Chinese, is a traditional Chinese medicine documented in Chinese Pharmacopoeia with effects of strengthening the intestine and stopping diarrhea. However, the potential of AR in treating intestinal inflammation and its underlying mechanism have yet to be further elucidated.
OBJECTIVE: The objective of this study was to explore the protective effect and the potential mechanism attributable to AR for treating ulcerative colitis (UC).
METHODS: A murine model of UC was constructed using dextran sulfate sodium (DSS) to examine the therapeutic potential of AR in alleviating inflammation and modulating the immune response. Advanced techniques such as photocrosslinking target fishing technique, click chemistry, Western blot analysis, real-time quantitative PCR, flow cytometry, immunofluorescence, and immunohistochemistry were employed to unveil the therapeutic mechanism of AR for treating IBD.
RESULTS: AR decreased disease activity index (DAI) score to alleviate the course of IBD through ameliorating intestinal barrier function in DSS-induced mice. Furthermore, AR suppressed NF-κB and NLRP3 pathways to reduce the release of pro-inflammatory factors interleukin-6 and 1β (IL-6 and IL-1β) and tumor necrosis factor α (TNF-α), allowing to alleviate the inflammatory response. Flow cytometry revealed that AR could reduce the accumulation of intestinal macrophages and neutrophils, maintaining intestinal immune balance by regulating the ratio of Treg to Th17 cells. It was worth noting that pyruvate kinase isozyme type M2 (PKM2) served as a potential target of AR using the photocrosslinking target fishing technology, which was further supported by cellular thermal shift assay (CETSA), drug affinity target stability (DARTS), and PKM2 knockdown experiments.
CONCLUSIONS: AR targeted PKM2 to inhibit NF-κB and NLRP3 pathways, thereby modulating the inflammatory response and immunity to alleviate DSS-induced UC. These findings suggested the potential of AR in the treatment of UC and AR as a candidate for developing PKM2 regulators.

BACKGROUND: Inflammatory bowel disease (IBD) poses significant challenges for patients, requiring continuous monitoring and self-management to improve quality of life.
OBJECTIVE: This study aims to investigate the viewpoints of individuals living with IBD on the use of information and communication technology (ICT) for the self-management of their condition, with a particular focus on the concept of a \"smart\" toilet seat as an example of ICT for IBD self-management.
METHODS: We conducted an analysis of questionnaire responses obtained from 724 participants. They were encouraged to share their use cases and identify any perceived barriers associated with ICT adoption for managing their condition. To assess their responses, we used descriptive quantitative analysis, summative content analysis, and thematic qualitative analysis. We combined these results in an epistemic network analysis to look for meaningful patterns in the responses.
RESULTS: Of the 724 participants, more than half (n=405, 55.9%) were already using various forms of ICT for IBD self-management. The primary factor influencing their use of ICT was their affinity for interacting with technology. Distinct differences emerged between individuals who were using ICT and those who were not, particularly regarding their perceived use cases and concerns.
CONCLUSIONS: This study provides valuable insights into the perspectives of individuals with IBD on the use of ICT for self-management. To facilitate wider adoption, addressing privacy concerns, ensuring data security, and establishing reliable ICT integration will be critical.

Crohn\'s disease is a chronic inflammatory bowel condition causing symptoms, notably pain, due to ongoing intestinal inflammation or complications like abscesses, strictures, and fistulas, which are common in IBD patients. Abdominal pain affects up to 60 % of IBD patients, irrespective of disease severity, prompting medical attention. Various medications like NSAIDs, antidepressants, antispasmodics, anticonvulsants, and opioids are used to manage pain, but they have limited effectiveness and potential side effects, even during remission. In this case, a 20-year-old Caucasian female college student [height 5\'4″, weight 120lbs (54.4 kg)] with juvenile idiopathic arthritis and Crohn\'s disease experienced severe daily abdominal pain, negatively impacting her life. Despite a multimodal regimen, including gabapentin, nortriptyline, duloxetine, and acetaminophen, her pain persisted, significantly affecting her appetite, sleep, mood, activity level, and overall quality of life (QOL). To address this, dorsal root ganglion (DRG) stimulation was considered. The patient aimed for a 20 % pain reduction and improved QOL. Trial leads were placed along the T10 and T12 DRG, resulting in a 25 % pain reduction (8-6 out of 10) and substantial QOL improvement. She could eat, sleep without interruptions, walk longer distances, and be more active. The T12 lead was more effective than the T10, targeting upper abdomen stimulation. The patient and her mother were highly satisfied and opted for permanent implantation for the T11 and T12 DRG. While DRG stimulation was approved in 2016 for chronic pain, to our knowledge, this is the first reported case of its use in a patient with debilitating Crohn\'s disease.

Inflammatory Bowel Disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract characterized by disrupted immune function. Indeed, gut microbiota dysbiosis and metabolomic profile alterations, are hallmarks of IBD. In this scenario, metabolite-sensing G-protein coupled receptors (GPCRs), involved in several biological processes, have emerged as pivotal players in the pathophysiology of IBD. The aim of this study was to characterize the axis microbiota-metabolite-GPCR in intestinal surgical resections from IBD patients. Results showed that UC patients had a lower microbiota richness and bacterial load, with a higher proportion of the genus Cellulosimicrobium and a reduced proportion of Escherichia, whereas CD patients showed a decreased abundance of Enterococcus. Furthermore, metabolomic analysis revealed alterations in carboxylic acids, fatty acids, and amino acids in UC and CD samples. These patients also exhibited upregulated expression of most metabolite-sensing GPCRs analysed, which positively correlated with pro-inflammatory and pro-fibrotic markers. The role of GPR109A was studied in depth and increased expression of this receptor was detected in epithelial cells and cells from lamina propria, including CD68+ macrophages, in IBD patients. The treatment with β-hydroxybutyrate increased gene expression of GPR109A, CD86, IL1B and NOS2 in U937-derived macrophages. Besides, when GPR109A was transiently silenced, the mRNA expression and secretion of IL-1β, IL-6 and TNF-α were impaired in M1 macrophages. Finally, the secretome from siGPR109A M1 macrophages reduced the gene and protein expression of COL1A1 and COL3A1 in intestinal fibroblasts. A better understanding of metabolite-sensing GPCRs, such as GPR109A, could establish their potential as therapeutic targets for managing IBD.

The mechanism underlying intestinal fibrosis, the main complication of inflammatory bowel disease (IBD), is not yet fully understood, and there is no therapy to prevent or reverse fibrosis. We evaluated, in in vitro cellular models, the ability of different classes of drugs currently used in IBD to counteract two pivotal processes of intestinal fibrosis, the differentiation of intestinal fibroblasts to activated myofibroblasts using CCD-18Co cells, and the epithelial-to-mesenchymal transition (EMT) of intestinal epithelial cells using Caco-2 cells (IEC), both being processes induced by transforming growth factor-β1 (TGF-β1). The drugs tested included mesalamine, azathioprine, methotrexate, prednisone, methylprednisolone, budesonide, infliximab, and adalimumab. The expression of fibrosis and EMT markers (collagen-I, α-SMA, pSmad2/3, occludin) was assessed by Western blot analysis and by immunofluorescence. Of the drugs used, only prednisone, methylprednisolone, budesonide, and adalimumab were able to antagonize the pro-fibrotic effects induced by TGF-β1 on CCD-18Co cells, reducing the fibrosis marker expression. Methylprednisolone, budesonide, and adalimumab were also able to significantly counteract the TGF-β1-induced EMT process on Caco-2 IEC by increasing occludin and decreasing α-SMA expression. This is the first study that evaluates, using in vitro cellular models, the direct antifibrotic effects of drugs currently used in IBD, highlighting which drugs have potential antifibrotic effects.

OCTN1 and OCTN2 are membrane transport proteins encoded by the SLC22A4 and SLC22A5 genes, respectively. Even though several transcripts have been predicted by bioinformatics for both genes, only one functional protein isoform has been described for each of them. Both proteins are ubiquitous, and depending on the physiopathological state of the cell, their expression is regulated by well-known transcription factors, although some aspects have been neglected. A plethora of missense variants with uncertain clinical significance are reported both in the dbSNP and the Catalogue of Somatic Mutations in Cancer (COSMIC) databases for both genes. Due to their involvement in human pathologies, such as inflammatory-based diseases (OCTN1/2), systemic primary carnitine deficiency (OCTN2), and drug disposition, it would be interesting to predict the impact of variants on human health from the perspective of precision medicine. Although the lack of a 3D structure for these two transport proteins hampers any speculation on the consequences of the polymorphisms, the already available 3D structures for other members of the SLC22 family may provide powerful tools to perform structure/function studies on WT and mutant proteins.

BACKGROUND: Stress is a potentially significant risk factor for the occurrence and progression of inflammatory bowel disease (IBD).
METHODS: The study analyzed the level of stress, anxiety, and depression in patients with Crohn\'s disease (CD; n = 50) and ulcerative colitis (UC; n = 54) in comparison with non-IBD controls (n = 100), using Perceived Stress Scale (PSS), Patient Health Questionnaire (PHQ-9), and Hospital Anxiety and Depression Scale (HADS) questionnaires. Additionally, a correlation between psychological scores and expression of IL17A, IL17F, and IL23A genes in the intestinal mucosa of IBD patients was assessed.
RESULTS: Compared to controls, CD and UC patients had higher PSS (P = 4 × 10-14, P = 2.5 × 10-16), PHQ-9 (P = 2 × 10-16, P = 2 × 10-16), HADS depression (P = 2.6 × 10-10, P = 2.5 × 10-11), and HADS anxiety (P = 3.5 × 10-9, P = 1.2 × 10-11). We found a positive correlation between PSS and IL17F mRNA (rs = 0.43, P = .036) while HADS depression and HADS anxiety positively correlated with the IL23A mRNA in inflamed ileal mucosa of CD subjects (rs = 0.55, P = .0048; rs = 0.53, P = .0062).
CONCLUSIONS: A significantly higher psychological distress was identified in IBD patients. CD patients with increased ileal expression of IL17F and IL23A genes had higher PSS and HADS, suggesting a potential interplay between psychological distress and inflammation.
The study found elevated levels of perceived stress, depression, and anxiety in IBD. IL17F mRNA correlated with perceived stress while IL23A mRNA correlated with anxiety and depression (HADS) in the ileal mucosa of CD patients.

Nutritional epidemiological studies have evolved from a focus of single nutrients to diet patterns to capture the protective role of healthy diets on chronic disease development. Similarly, in inflammatory bowel disease (IBD), a healthy diet may be protective against its development in individuals with genetic susceptibility, but the definitions of the optimal diet pattern deserve further exploration. Hence, this review article presents evidence, mainly from prospective cohort studies, for the role of diet quality based on adherence to dietary guidelines, traditional and modern diet patterns in the prevention of IBD. Findings from a limited number of studies on diet quality suggest that high diet quality scores are associated with lower risk of developing Crohn\'s disease, but the data are inconsistent for ulcerative colitis (UC). There are signals that a Mediterranean diet pattern reduces the risk of Crohn\'s disease but, again, the data are inconsistent and further studies are much needed. Finally, the evidence is conflicting regarding the role of food additives, with difficulties in the assessment of their intake, namely non-nutritive sweeteners and emulsifiers, precluding accurate assessment of a relationship with IBD risk. In contrast, emerging evidence for a role of ultra-processed food in the development of Crohn\'s disease but not UC is identified. Given the potential influence of diet quality, a Mediterranean diet and ultra-processed food intake on the risk of Crohn\'s disease, assessment and implementation of dietary advice for these patients need to be tailored. The search for an optimal diet for UC remains elusive and further research for increasing the evidence in the area is greatly needed.