Inflammatory Bowel Disease Drugs Research Articles

What Happens to Patients with Inflammatory Bowel Disease Who Are Intolerant to Thiopurines?

Introduction: The clinical consequences for patients with inflammatory bowel disease (IBD) who stop treatment owing to side effects have not been fully investigated. Methods: This retrospective observational study aimed to compare patients who discontinued thiopurine treatment due to side effects with those who tolerated thiopurine treatment in the use of other IBD drugs, surgery, and fecal calprotectin values in the first 5 years after the start of thiopurine treatment. Results: The proportion of patients with IBD who initiated thiopurine treatment at our clinic was 44% (32% ulcerative colitis and 64% Crohn's disease) and 31% (n = 94) of those patients had to stop thiopurine treatment within 5 years due to side effects. Patients who discontinued thiopurine treatment due to intolerance were significantly older (median age 33 vs. 27 years, p = 0.003), significantly more often used prednisolone (89 vs. 76%, p = 0.009), and used to a lesser extent TNF inhibitors at the start of thiopurine treatment (3% vs. 9%, p = 0.062). Budesonide treatment and non-TNF inhibitor second-line therapy were significantly more commonly used in patients who discontinued thiopurine treatment owing to side effects, but there were no statistically significant differences in the use of other treatments. The proportion of patients with a median FC >200 μg/g was significantly higher during follow-up in patients with UC who discontinued thiopurine treatment owing to side effects. Conclusions: Patients who discontinued thiopurines owing to side effects were prescribed more budesonide and non-TNF inhibitor second-line therapy, but there were no differences in the use of TNF inhibitors, prednisolone, or surgery.

Targeting the Interleukin 23 Pathway in Inflammatory Bowel Disease.

Interleukin (IL) 23, a member of the IL12 family of cytokines, maintains intestinal homeostasis, but is also implicated in the pathogenesis of inflammatory bowel diseases (IBDs). The IL23 receptor is a heterodimer composed of disulfide-linked p19 and p23 subunits. Humanized monoclonal antibodies selectively targeting the p19 subunit of IL23 are poised to become prominent drugs in IBDs. In this review, we discuss the pharmacodynamic and pharmacokinetic properties of the currently available IL23p19 inhibitors and discuss the mechanistic underpinnings of their therapeutic effects, including the mechanism of action, epitope affinity, potency, and downstream signaling. Furthermore, we address available data on the efficacy, safety, and tolerability of IL23-specific p19 inhibitors in the treatment of IBDs and discuss important studies performed in other immune-mediated inflammatory diseases. Finally, we evaluate the potential for combining classes of biological therapies and provide future directions on the development of precision medicine-guided positioning of IL23p19 inhibitors in IBD.

MiR-146a alleviates inflammatory bowel disease in mice through systematic regulation of multiple genetic networks.

Inflammatory bowel disease (IBD) is a chronic disease involving multiple genes, and the current available targeted drugs for IBD only deliver moderate efficacy. Whether there is a single gene that systematically regulates IBD is not yet known. MiR-146a plays a pivotal role in repression of innate immunity, but its function in the intestinal inflammation is sort of controversy, and the genetic regulatory networks regulated by miR-146a in IBD has not been revealed. RT-qPCR was employed to detect the expression of miR-146a in IBD patients and in a mouse IBD model induced by dextran sulfate sodium (DSS), and then we generated a miR-146a knock-out mouse line with C57/Bl6N background. The disease activity index was scored in DSS-treated miR-146a deficiency mice and their wild type (WT) littermates. Bulk RNA-sequencing, RT-qPCR and immunostaining were done to illustrate the downstream genetic regulatory networks of miR-146a in flamed colon. Finally, the modified miR-146a mimics were used to treat DSS-induced IBD in miR-146a knock-out and WT IBD mice. We showed that the expression of miR-146a in the colon was elevated in dextran sulfate sodium (DSS)-induced IBD mice and patients with IBD. DSS induced dramatic body weight loss and more significant rectal bleeding, shorter colon length, and colitis in miR-146a knock-out mice than WT mice. The miR-146a mimics alleviated DSS-induced symptoms in both miR-146a-/- and WT mice. Further RNA sequencing illustrated that the deficiency of miR-146a de-repressed majority of DSS-induced IBD-related genes that cover multiple genetic regulatory networks in IBD, and supplementation with miR-146a mimics inhibited the expression of many IBD-related genes. Quantitative RT-PCR or immunostaining confirmed that Ccl3, Saa3, Csf3, Lcn2, Serpine1, Serpine2, MMP3, MMP8, MMP10, IL1A, IL1B, IL6, CXCL2, CXCL3, S100A8, S100A9, TRAF6, P65, p-P65, and IRAK1 were regulated by miR-146a in DSS induced IBD. Among them, MMP3, MMP10, IL6, IL1B, S100A8, S100A9, SERPINE1, CSF3, and IL1A were involved in the active stage of IBD in humans. Our date demonstrated that miR-146a acts as a top regulator in C57/BL6N mice to systematically repress multiple genetic regulatory networks involved in immune response of intestine to environment factors, and combinatory treatment with miR-146a-5p and miR-146a-3p mimics attenuates DSS-induced IBD in mice through down-regulating multiple genetic regulatory networks which were increased in colon tissue from IBD patients. Our findings suggests that miR-146a is a top inhibitor of IBD, and that miR-146a-5p and miR-146a-3p mimics might be potential drug for IBD.

Bazedoxifene attenuates dextran sodium sulfate-induced colitis in mice through gut microbiota modulation and inhibition of STAT3 and NF-κB pathways

Inflammatory bowel disease (IBD) is a chronic and relapsing inflammatory disorder of the gastrointestinal tract for which treatment options remain limited. In this study, we used a dual-luciferase-based screening of an FDA-approved drug library, identifying Bazedoxifene (BZA) as an inhibitor of the NF-κB pathway. We further investigated its therapeutic effects in a dextran sodium sulfate (DSS)-induced colitis model and explored its impact on gut microbiota regulation and the underlying molecular mechanisms. Our results showed that BZA significantly reduced DSS-induced colitis symptoms in mice, evidenced by decreased colon length shortening, lower histological scores, and increased expression of intestinal mucosal barrier-associated proteins, such as Claudin 1, Occludin, Zo-1, Mucin 2 (Muc2), and E-cadherin. Used independently, BZA showed therapeutic effects comparable to those of infliximab (IFX). In addition, BZA modulated the abundance of gut microbiota especially Bifidobacterium pseudolongum, and influenced microbial metabolite production. Crucially, BZA's alleviation of DSS-induced colitis in mice was linked to change in gut microbiota composition, as evidenced by in vivo gut microbiota depletion and fecal microbiota transplantation (FMT) mice model. Molecularly, BZA inhibited STAT3 and NF-κB activation in DSS-induced colitis in mice. In general, BZA significantly reduced DSS-induced colitis in mice through modulating the gut microbiota and inhibiting STAT3 and NF-κB activation, and its independent use demonstrated a therapeutic potential comparable to IFX. This study highlights gut microbiota's role in IBD drug development, offering insights for BZA's future development and its clinical applications.

Pregnancy period and early-life risk factors for inflammatory bowel disease: a Northern Finland birth cohort 1966 study

BackgroundThe pathogenesis of inflammatory bowel disease (IBD) has not been fully elucidated. The aim of this study was to analyze the pregnancy period, perinatal period, and infancy period risk factors for IBD in a well-characterized birth cohort from Northern Finland.MethodsThe Northern Finland Birth Cohort 1966 (NFBC1966) population comprises mothers living in the two northernmost provinces of Finland, Oulu, and Lapland, with dates of delivery between Jan 1st and Dec 31st, 1966 (12 055 mothers, 12 058 live-born children, 96.3% of all births during 1966). IBD patients were identified using hospital registries (from 1966 to 2020) and Social Insurance Institution (SII) registry reimbursement data for IBD drugs (from 1978 to 2016). The data were analyzed by Fisher’s exact test and logistic regression.ResultsIn total, 6972 individuals provided informed consent for the use of combined SII and hospital registry data. Of those, 154 (2.1%) had IBD (113 [1.6%] had ulcerative colitis (UC), and 41 (0.6%) had Crohn’s disease (CD)). According to multivariate analysis, maternal smoking > 10 cigarettes/day during pregnancy was associated with a nearly 6-fold increased risk of CD in the offspring (OR 5.78, 95% CI 1.70–17.3). Breastfeeding (OR = 0.18, 95% CI 0.08–0.44) and iron supplementation during the first year of life (OR = 0.43, 95% CI 0.21–0.89) were negatively associated with CD.ConclusionsSmoking during pregnancy was associated with the risk of CD while Breastfeeding and oral iron supplementation at infancy were negatively associated with the risk of CD later in life.

Research advancements and perspectives of inflammatory bowel disease: A comprehensive review.

Inflammatory bowel disease (IBD) is a chronic inflammatory disease with increasing incidence, such as Crohn's disease and ulcerative colitis. The accurate etiology and pathogenesis of IBD remain unclear, and it is generally believed that it is related to genetic susceptibility, gut microbiota, environmental factors, immunological abnormalities, and potentially other factors. Currently, the mainstream therapeutic drugs are amino salicylic acid agents, corticosteroids, immunomodulators, and biological agents, but the remission rates do not surpass 30-60% of patients in a real-life setting. As a consequence, there are many studies focusing on emerging drugs and bioactive ingredients that have higher efficacy and long-term safety for achieving complete deep healing. This article begins with a review of the latest, systematic, and credible summaries of the pathogenesis of IBD. In addition, we provide a summary of the current treatments and drugs for IBD. Finally, we focus on the therapeutic effects of emerging drugs such as microRNAs and lncRNAs, nanoparticles-mediated drugs and natural products on IBD and their mechanisms of action.

A Gastroenterologist's guide to drug interactions of small molecules for inflammatory bowel disease.

Small molecule drugs are becoming increasingly used in the treatment of inflammatory bowel diseases (IBD). However, unlike monoclonal antibody drugs, which have few interactions with other medications, the pharmacokinetics of small molecule drugs are complex and may be influenced by a myriad of drug-drug interactions (DDI) as well as by patient characteristics and food intake. This review aims to provide a concise practical guide to small molecule drug interactions for the use of IBD physicians. It starts with a brief overview of the main metabolizing enzymes and transporters involved in drug interactions and the Food and Drug Administration's (FDA) approach to determining drug-interaction hazard thresholds. It is then followed by a more detailed review of the pharmacokinetics of five novel small molecules approved in IBD: Tofacitinib, Upadacitinib, Filgotinib, Ozanimod, and Etrasimod, including their known interactions and specific warnings. This review will also inform readers on challenges in determining the actual magnitude of interactions and their clinical relevance, including the arbitrary nature of some hazard thresholds, the inference of the impact on metabolizing enzymes and transporters from single-drug assays which may not reflect poly-pharmaceutical regimens, and other challenges in this field which the IBD physician needs to be cognizant of. In practice, before administering a small molecule drug, it is advisable to evaluate any potential interactions with other medications the patient is receiving. An increased awareness by health care professionals and patients, may reduce the possible risks associated with DDI of small molecule IBD drugs.

Curcumin@Fe/Tannic Acid Complex Nanoparticles for Inflammatory Bowel Disease Treatment.

Inflammatory bowel disease (IBD) is a serious public health issue because of its chronic and incurable nature. Common IBD drugs have limited efficacy and produce adverse effects, leading to an urgent need to develop new drugs and drug delivery systems. Curcumin (Cur) is a natural and nontoxic drug that is increasingly used in the treatment of IBD owing to its anti-inflammatory and antioxidant effects. Metal-polyphenol networks constructed from metal ions and polyphenols exhibit biological functionality while acting as an adhesive nanomaterial to encapsulate nano-Cur, thereby improving its solubility and drug release behavior. In this study, we prepared a Cur@Fe&TA nanodrug delivery system by constructing an Fe3+/tannic acid (TA) metal-polyphenol network with encapsulated Cur. The Cur@Fe&TA nanodrug exhibited good stability, drug release behavior, and biocompatibility. Based on the anti-inflammatory and antioxidant effects of Cur@Fe&TA, the gastrointestinal cytopathology in an IBD mouse model was effectively improved. The proposed Cur@Fe&TA nanomedicine delivery system has promising application and research value for the treatment of IBD by regulating levels of antioxidants and inflammatory cytokines.

Changes in HLA-B27 Transgenic Rat Fecal Microbiota Following Tofacitinib Treatment and Ileocecal Resection Surgery: Implications for Crohn's Disease Management.

The therapeutic management of Crohn's disease (CD), a chronic relapsing-remitting inflammatory bowel disease (IBD), is highly challenging. Surgical resection is sometimes a necessary procedure even though it is often associated with postoperative recurrences (PORs). Tofacitinib, an orally active small molecule Janus kinase inhibitor, is an anti-inflammatory drug meant to limit PORs in CD. Whereas bidirectional interactions between the gut microbiota and the relevant IBD drug are crucial, little is known about the impact of tofacitinib on the gut microbiota. The HLA-B27 transgenic rat is a good preclinical model used in IBD research, including for PORs after ileocecal resection (ICR). In the present study, we used shotgun metagenomics to first delineate the baseline composition and determinants of the fecal microbiome of HLA-B27 rats and then to evaluate the distinct impact of either tofacitinib treatment, ileocecal resection or the cumulative effect of both interventions on the gut microbiota in these HLA-B27 rats. The results confirmed that the microbiome of the HLA-B27 rats was fairly different from their wild-type littermates. We demonstrated here that oral treatment with tofacitinib does not affect the gut microbial composition of HLA-B27 rats. Of note, we showed that ICR induced an intense loss of bacterial diversity together with dramatic changes in taxa relative abundances. However, the oral treatment with tofacitinib neither modified the alpha-diversity nor exacerbated significant modifications in bacterial taxa induced by ICR. Collectively, these preclinical data are rather favorable for the use of tofacitinib in combination with ICR to address Crohn's disease management when considering microbiota.

RETROSPECTIVE, SINGLE-CENTER, REAL-WORLD ANALYSIS OF BIOLOGIC AND IMMUNOMODULATOR THERAPY DISCONTINUATION IN ELDERLY IBD PATIENTS

Abstract BACKGROUND The population of elderly inflammatory bowel disease (IBD) patients is increasing each year, however use of immunomodulators and biologic therapy in this population remains low. Clinical IBD drug trials limit enrollment of elderly patients. This leads to poor understanding of medication adverse effects and long-term outcomes in this population. Medication sustainability reflects drug efficacy and safety of drugs, which lead to better adherence. The primary aim of this study was to compare the discontinuation rates of various IBD therapies in a cohort of elderly patients and provide some guidance on positioning therapies within this population. METHODS This was a single-center retrospective study conducted at an academic institution. Elderly IBD patients 60 years or older followed between 2016-2022 were included in the study. Patients had to be on either immunomodulator and/or biologic therapy. Chart review was performed to extract demographic data, duration of IBD therapy, and reasons for discontinuation. A Kaplan-Meier survival curve was generated per IBD therapy to depict drug sustainability stratified by reason for discontinuation. Statistical analysis was performed to assess for significant differences across survival curves. RESULTS A total of 224 elderly IBD patients were included in the study analysis. The cohort was comprised of 97 (43.3%) patients with ulcerative colitis (UC) and 127 (56.7%) patients with Crohn’s disease (CD). For both CD and UC, there were no significant differences in biologic drug discontinuation rates due to inadequate disease control (p=0.26 for CD; p=0.74 for UC). There was a significantly increased risk of elderly IBD patients stopping anti-TNF therapy due to medication adverse event compared to those on anti-integrin therapy (p=0.002) and immunomodulator therapy (p=0.003). CONCLUSIONS While the number of biologics used to treat IBD has increased in the last few decades, there is a paucity of studies examining real world sustainability of biologics particularly in elderly patients. With regards to effectiveness, our study showed that there was no significant difference among the three classes of biologics being discontinued due to poorly controlled disease. However, results of our study suggest that anti-TNF therapy is less sustainable in elderly IBD patients compared to other biologics and immunomodulator therapy due to patient experienced adverse events. Our results are pertinent to clinical practice as prescribing biologics other than anti-TNF therapy may increase an elderly patient’s therapy longevity and lead to optimized clinical outcomes. Figure 1 shows time to biologic discontinuation due uncontrolled disease by IBD subtype. For both Crohn’s disease and ulcerative colitis, there was no significant difference in drug survival per biologic with regards to discontinuation due to inadequately controlled disease. Figure 2 shows time to therapy discontinuation due to patient experienced adverse events. This included infections, infusion reactions, systemic reactions, laboratory abnormalities, financial burden, and non-compliance. There was a significantly increased risk of elderly IBD patients stopping anti-TNF over time due to adverse events compared to those on anti-integrin and immunomodulator therapy.

P1170 Long-term outcomes of newly diagnosed Inflammatory Bowel Disease (IBD) patients: results from the nationwide EpidemIBD study of GETECCU

Abstract Background Aims: 1) To describe the main epidemiological and clinical characteristics of patients at IBD diagnosis and the long-term outcomes; 2) to analyse the use of drugs for IBD, and the need of hospitalisations and surgeries; 3) to compare IBD management based on the type of disease and the resources of the hospitals. Methods Prospective, population-based nationwide registry. Adult patients diagnosed with IBD, Crohn’s Disease (CD), Ulcerative Colitis (UC) or IBD unclassified, during 2017 in the 17 Spanish regions were included. Patients who consented were followed-up for 5 years (yr) after diagnosis. Treatment was grouped into 5 categories: mesalamine (oral or topical), steroids (intravenous, oral, or topical), immunomodulators (thiopurines, methotrexate or cyclosporine), biologics (anti-TNF, vedolizumab, ustekinumab) or JAK inhibitors (JAKi), and surgery. Hospitals were classified into high resources and low resources ones. Cumulative incidence of exposure to each of the studied treatments was estimated by Kaplan-Meier curves; curves were compared with log-rank test. Results 3,301 incident cases of IBD diagnosed during 2017 in 108 hospitals, covering over 22 million inhabitants in Spain (about 50% of the population), were enrolled into the follow-up study. Main characteristics of the cohort are summarised in table 1. Median diagnosis delayed was 3.5 months (5.6 in CD and 2.7 in UC, p<0.001). During the 5-yr follow-up, 25% of UC patients progressed to more extensive involvement, while 8% of CD patients with inflammatory behaviour progressed to either stricturing or fistulising behaviour. Most of the patients who received mesalamine, corticosteroids, or immunomodulators initiated treatment within the first 2 years after diagnosis (figure 1). However, the cumulative incidence of biologics/JAKi usage steadily increased over time, reaching 49% by the 5-yr timepoint in CD. In terms of surgeries, a progressive increase in cumulative incidence was observed in CD; the incidence of colectomy remained stable in UC from the 2nd year post-diagnosis. A higher cumulative incidence of biologics/JAKi usage, hospitalisations, and surgeries was observed in CD at high resources hospitals; no differences were observed in the use of other therapeutic resources or the management of UC. Conclusion In the EpidemIBD large-scale epidemiological study, we have observed that the delay in diagnosing IBD is shorter than previously described. Approximately 50% of patients with CD and 20% of patients with UC ended up receiving biologics/JAKi in the first 5 yrs following diagnosis. The percentage of patients undergoing surgery was lower than previously reported; in the case of UC, the majority of colectomies occurred within the first 2 yrs after diagnosis.

P868 Patients with inflammatory bowel disease who are intolerant to thiopurine treatment

Abstract Background Approximately 15-40% of patients with inflammatory bowel disease (IBD) treated with thiopurines experience side-effects that leads to drug withdrawal. The aim of this retrospective observational study was to compare patients who stop thiopurine treatment due to side effects with patients who tolerate thiopurine treatment in the use of other IBD treatments, the risk of surgery and in the chance of reaching remission (a median faecal calprotectin level < 200 mg/g). Methods We included all patients in our clinic who were born after 1956 and diagnosed with Ulcerative colitis (UC) and with Crohn´s disease (CD) after the year of 2006 (n=698). In the patients who at least once started thiopurine treatment, prescription of IBD drugs, surgery and f-calprotectin values were noted for the first five years after start of thiopurine treatment. Patients who stopped treatment due to intolerance (side effects) was compared to patients who were tolerant to thiopurine treatment (no side-effects reported). Results The proportion of patients with IBD who initiated thiopurine treatment at our clinic was 44% (32% UC and 64% CD). For patients who started thiopurine treatment 31% (n=94) had to stop treatment within five years due to side effects. Patients who stopped thiopurine treatment due to intolerance were significantly older (median age 32 vs 25 years, p=0.002), were significantly more often on steroids (89% vs 76%, p=0.009) and used to a lesser extent TNF inhibitors at the start of thiopurine treatment (3% vs 9%, p=0.062). There were no statistically significant differences in the proportion of patients that at least once yearly used steroids, TNF-inhibitors or surgery in the first five years after initiated thiopurine treatment between the group of patients who stopped due to intolerance and the group of patients who were tolerant to thiopurine treatment. Budesonide treatment and non TNF-inhibitor biologic therapy was significantly more common used in the patients that stopped thiopurine treatment due to side-effects. The proportion of patients with a median faecal calprotectin >200 mg/g was significantly higher in the patients with UC who stopped thiopurine treatment due to side effects (Figure). Conclusion Patients who stopped thiopurines due to side-effects did not in general differ in the use of other treatment for IBD the first five year after initiated thiopurine treatment, except for the use of budesonides and non-TNF inhibitor biologics which was more commonly used in patients who stopped thiopurines due to side-effects. Patients with UC who stopped treatment due to side-effects had higher faecal calprotectin levels at follow-up than patients who tolerated thiopurines.

Therapeutic Applications of Extracellular Vesicles in Inflammatory Bowel Disease.

The treatment landscape for inflammatory bowel disease (IBD) has undergone substantial advancements with the introduction of biologics. However, a considerable number of patients either show an immediate lack of response or lose responsiveness over time, necessitating the development of innovative and effective treatment approaches. Extracellular vesicles (EVs) are small lipid bilayer-enclosed structures that facilitate cell-to-cell molecular transfer and are integral to the pathogenesis of IBD. They play pivotal roles in maintaining the integrity of the intestinal epithelial barrier and the expulsion of cellular metabolites. The potential use of EVs as drug carriers or therapeutic agents has opened up a plethora of clinical applications. This review investigates the creation and content of EVs, their role in IBD development, and advances in their isolation and analytical techniques. Furthermore, the therapeutic promise they hold for IBD is explored, along with the latest research on their roles as IBD drug delivery systems.

Acid-base transformative HADLA micelles alleviate colitis by restoring adaptive immunity and gut microbiome

Inflammatory bowel disease (IBD) is a worldwide public health issue with an increasing number of patients annually. However, there is no curative drug for IBD, and the present medication for IBD generally focuses on suppressing hyperactive immune responses, which can only delay disease progression but inevitably induce off-target side effects, including infections and cancers. Herein, late-model orally administered nanotherapeutic micelles (HADLA) were developed based on a conjugate of hyaluronic acid (HA) and dehydrolithocholic acid (DLA), which was simple to achieve and obtained satisfactory therapeutic efficacy in a murine colitis model with a full safety profile. HADLA is capable of targeting inflammatory colon tissues, restoring intestinal barrier function and reducing intestinal epithelial cell death. Moreover, it modulates the adaptive immune system by inhibiting the activation of pathogenic T helper 17 (Th17) cells, and it exhibits more remarkable effects in preventing colitis than DLA alone. Finally, HADLA exhibits a remarkable ability to modulate dysregulated gut microbiomes by increasing beneficial probiotics and decreasing pathogenic bacteria, such as Turicibacter. Compared with the current systemic or subcutaneous administration of biologics, this study opens new avenues in the oral delivery of immune-modulating nanomedicine and introduces DLA as a new medication for IBD treatment.

Cardiovascular manifestations of inflammatory bowel diseases and the underlying pathogenic mechanisms.

Inflammatory bowel disease (IBD), consisting of ulcerative colitis and Crohn's disease, mainly affects the gastrointestinal tract but is also known to have extraintestinal manifestations because of long-standing systemic inflammation. Several national cohort studies have found that IBD is an independent risk factor for the development of cardiovascular disorders. However, the molecular mechanisms by which IBD impairs the cardiovascular system are not fully understood. Although the gut-heart axis is attracting more attention in recent years, our knowledge of the organ-to-organ communication between the gut and the heart remains limited. In patients with IBD, upregulated inflammatory factors, altered microRNAs and lipid profiles, as well as dysbiotic gut microbiota, may induce adverse cardiac remodeling. In addition, patients with IBD have a three- to four times higher risk of developing thrombosis than people without IBD, and it is believed that the increased risk of thrombosis is largely due to increased procoagulant factors, platelet count/activity, and fibrinogen concentration, in addition to decreased anticoagulant factors. The predisposing factors for atherosclerosis are present in IBD and the possible mechanisms may involve oxidative stress system, overexpression of matrix metalloproteinases, and changes in vascular smooth muscle phenotype. This review focuses mainly on 1) the prevalence of cardiovascular diseases associated with IBD, 2) the potential pathogenic mechanisms of cardiovascular diseases in patients with IBD, and 3) adverse effects of IBD drugs on the cardiovascular system. Also, we introduce here a new paradigm for the gut-heart axis that includes exosomal microRNA and the gut microbiota as a cause for cardiac remodeling and fibrosis.

Wielding the double-edged sword: Redox drug delivery systems for inflammatory bowel disease.

The etiology of inflammatory bowel disease (IBD) is extremely complex and related to an excessive immune response that results in the pathologically release of reactive oxygen species (ROS) via tissue injury and chronic inflammation. Generally, excessive ROS production is one of the essential mediators for inflammatory pathogenesis. Targeting cumulate ROS to interrupt pathological inflammatory responses has been recognized as a feasible strategy for inflammatory suppression of IBD. Correspondingly, the overexpression of ROS can also trigger the drug release of novel drug delivery systems to alleviate IBD symptoms. In this review, we summarized the pathological production of endogenous ROS in IBD, discussed the enormous potential of multiple kinds of ROS-scavenging and ROS-triggering novel delivery systems for the treatment of IBD, including enzymology, metal, polyphenols, natural pigments, nitroxide radicals-contained and sulfide-loaded drug delivery systems, and other novel ROS-responsive materials to synthesize ROS-based drug delivery systems. We also summarized the immunomodulatory effects of ROS-targeted drug delivery systems for the treatment of IBD. Besides, based on the requirements of clinical applications and industrialization development, the challenges faced in the evolution of redox drug delivery systems were also discussed. Collectively, this review provides a reliable reference to the development of ROS-scavenging and ROS-triggering drug delivery systems for the medical intervention of IBD.

The Influence of Apremilast-Induced Macrophage Polarization on Intestinal Wound Healing.

There is compelling evidence suggesting a pivotal role played by macrophages in orchestrating intestinal wound healing. Since macrophages display significant plasticity and heterogeneity, exhibiting an either classically activated (M1-like) or alternatively activated (M2-like) phenotype, they can aggravate or attenuate intestinal wound healing. Growing evidence also demonstrates a causal link between impaired mucosal healing in inflammatory bowel disease (IBD) and defects in the polarization of pro-resolving macrophages. By targeting the switch from M1 to M2 macrophages, the phosphodiesterase-4 inhibitor Apremilast has gained recent attention as a potential IBD drug. However, there is a gap in our current knowledge regarding the impact of Apremilast-induced macrophages' polarization on intestinal wound healing. The THP-1 cells were differentiated and polarized into M1 and M2 macrophages, and subsequently treated with Apremilast. Gene expression analysis was performed to characterize macrophage M1 and M2 phenotypes, and to identify possible target genes of Apremilast and the involved pathways. Next, intestinal fibroblast (CCD-18) and epithelial (CaCo-2) cell lines were scratch-wounded and exposed to a conditioned medium of Apremilast-treated macrophages. Apremilast had a clear effect on macrophage polarization, inducing an M1 to M2 phenotype switch, which was associated with NF-κB signaling. In addition, the wound-healing assays revealed an indirect influence of Apremilast on fibroblast migration. Our results support the hypothesis of Apremilast acting through the NF-κB-pathway and provide new insights into the interaction with fibroblast during intestinal wound healing.

Inflammatory bowel disease (IBD)-specific immune cell recruitment and response can be modulated with anti-TNF-α therapies in the human Colon Intestine-Chip

Abstract Objective: Inflammatory bowel disease (IBD) is a complex inflammatory disease, for which few effective therapies exist. The goal of our current work was to show: i) that such a complex, immune cell-driven pathogenesis could be captured on Emulate’s human Colon Intestine-Chips; and ii) that this could be used as a novel human-centric system to support IBD drug development including anti-TNF-α antibodies. Methods: PBMCs were perfused through the vascular (bottom) channel in untreated ‘resting’ or cytokine-‘primed’ Colon Intestine-Chips. Clinically relevant IBD drugs, including anti-TNF-α antibodies (Humira and Cimzia), as well as dexamethasone and AJM300 were administered through the vascular channel during PBMC administration. Total cell recruitment, effluent biomarker secretion (cytokines, calprotectin, C-reactive protein), and barrier function were analyzed for 72 hours. Results: α4β7 +‘gut-tropic’ PBMCs (monocytes, CD4 +, CD8 +, and NK cells) preferentially adhered and transmigrated in a cytokine priming-dependent manner. These PBMCs released clinically relevant IBD cytokines and biomarkers and induced barrier disruption, a hallmark of IBD. Anti-TNF-α antibodies and AJM300 caused reduced PBMC recruitment, inflammatory response and barrier disruption >90%. Dexamethasone had more modest effects, as expected. Conclusion: The human Colon Intestine-Chip can both model complex immune cell-driven IBD and validate effects of clinically relevant IBD drugs. This system could provide predictive validity for pre-clinical development of new IBD drugs.

Risk-Benefit of IBD Drugs: A Physicians and Patients Survey.

Treatment choices for patients with inflammatory bowel disease (IBD) are based on the balance between risks and benefits. Our AI was to compare the perspectives of patients and physicians in evaluating the risks and benefits before initiating therapy for IBD. An anonymous survey was conducted between March and August 2022. All patients with confirmed IBD and all physicians who attended an IBDscope webinar were invited to participate. In total, 367 patients and 146 physicians participated. For most patients (71.4%) and physicians (89.0%), efficacy and safety were equally important. Clinical improvement and clinical remission were the most relevant outcomes for patients (90.9 and 88.4), while clinical remission and endoscopic remission were for physicians (90.0 and 87.6). The main factors in the benefit-risk assessment were quality of life (95.1%), disease activity (87.5%), and presence of comorbidities (84.5%) for patients, and presence of comorbidities (99.3%), disease activity (97.9%), and prior failure to biologics/small molecules (96.6%) for physicians. Based on patients' and physicians' opinions, the risk of serious infections, malignancies, cardiovascular events, death, relapse, all infections, surgery, and hospitalization should be included in the benefit-risk assessment. Physicians and patients have different priorities in evaluating the benefit-risk balance of a new therapy.

Medicinal plant-based drug delivery system for inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic recurrent intestinal disease. The incidence rate of IBD is increasing year by year, which seriously endangers human health worldwide. More and more studies have shown that medicinal plants or their main phytochemicals have great potential in the treatment of intestinal diseases. However, the disadvantages of low oral absorption rate, low biological distribution and low systemic bioavailability limit their clinical application to a certain extent. In recent years, the application of nanotechnology has made it possible to treat IBD. Nanoparticles (NPs) drug delivery system has attracted special attention in the treatment of IBD due to its small size, low immunogenicity, surface modification diversity, targeting and other advantages. Synthetic nanoparticles and extracellular vehicles (EVs) can deliver drug components to colon, and play a role in anti-inflammation, regulation of oxidative stress, improvement of intestinal flora, etc. In addition, some medicinal plants can secrete EVs by themselves, and carry biological molecules with therapeutic effects to act on the intestine. Some clinical trials to evaluate the safety, tolerance, toxicity and effectiveness of EVs-loaded drugs in IBD are also progressing steadily. This review introduces that synthetic nanoparticles and medicinal plants derived EVs can play an important role in the treatment of IBD by carrying the effective active phytochemicals of medicinal plants, and discuss the limitations of current research and future research needs, providing a scientific and reliable basis and perspective for further clinical application and promotion.