Therapy For Ulcerative Colitis Research Articles

An ROS/DAMP dual-scavenging nanomedicine for normalizing macrophage polarization and microbiome in colitis

Treatment for ulcerative colitis (UC) remains a clinical challenge as conventional approaches mostly use immunosuppressive agents to ameliorate pro-inflammatory colonic immune responses, which often induce severe side effects. Herein, we report the development of zeolitic imidazolate framework coated cerium dioxide core-shell nanoparticles for drug-free UC therapy. In compliance with clinical standards, the nanomedicine could be administered through oral or enema route for treating UC. The nanomedicine could cooperatively scavenge the excessive reactive oxygen species (ROS) and damage-associated molecular patterns (DAMPs) in intestinal macrophages and promote their repolarization into anti-inflammatory M2 phenotypes, thus normalizing the pro-inflammatory immune composition in inflamed colons. Owing to the anti-inflammatory performance, the nanoparticles also successfully abolished the UC-related gut-microbiota disorders and restored the normal mucosal structures and functions, thus completely reversing the UC-induced intestinal damage. Our work provides a potential candidate for drug-free UC treatment in the clinics.

Age is just a number with ulcerative colitis therapies

Age is just a number with ulcerative colitis therapies

Practical Primer Addressing Real-World Use Scenarios of Subcutaneous Vedolizumab in Ulcerative Colitis and Crohn's Disease: Post Hoc Analyses of VISIBLE Studies.

Vedolizumab, an anti-α4β7 integrin approved for intravenous (IV) treatment of moderately to severely active ulcerative colitis (UC) and Crohn's disease (CD), was evaluated as a subcutaneous (SC) formulation in maintenance therapy for UC and CD in phase 3 VISIBLE 1, 2, and open-label extension studies, and recently approved in Europe, Australia, and Canada. Our aim was to evaluate efficacy and safety of IV and SC vedolizumab in clinically relevant UC and CD scenarios. Post hoc data analyses from VISIBLE trials examined: (1) whether baseline characteristics predict clinical response to 2 vs 3 IV vedolizumab induction doses; (2) efficacy and safety of switching during maintenance vedolizumab IV to SC in patients with UC; (3) vedolizumab SC after treatment interruption of 1-46 weeks; (4) increasing dose frequency of vedolizumab SC from every 2 weeks (Q2W) to every week (QW) after disease worsening. No baseline characteristics were identified as strong predictors of response to 2 vs 3 vedolizumab infusions. Most patients achieved clinical response after 2 or 3 doses of IV vedolizumab maintained with SC treatment. Clinical remission and response rates were maintained in patients transitioned from maintenance vedolizumab IV to SC treatment. Of patients with UC, ≥75% achieved response following resumption after dose interruption. Escalation to QW dosing resulted in ≥45% of patients regaining response after loss while receiving vedolizumab Q2W. Clinical real-world scenarios with vedolizumab SC were reviewed using VISIBLE studies data. Vedolizumab SC provides an additional dosing option for patients with UC and CD.

Design of mesalamine loaded micro-particles: Preparation, in vitro and in-vivo characterization

The goal of this study was to develop mesalamine (MS) microparticles that could be ingested by the colon without first passing via the stomach and small intestines. Without resorting to the time-consuming and laborious double emulsion solvent diffusion method, microparticles were successfully fabricated using the Box-Behnken Design method. Microparticle production was optimized, and the effects of many parameters were analyzed (X1: Eudragit S100, X2: Span 80 and X3: agitation speed). Using the Box-Behnken design (BBD), we compared the chosen optimized microparticles to the pure drug solution utilizing in vivo pharmacokinetic study for particle size (Y1), entrapment efficiency (Y2), and drug-release (Y3). It was simple to create spherical, free-flowing, smooth-surfaced microparticles with a zeta potential of −36.52 mV and a size distribution of 264.35 ± 6.28–652.34 ± 6.49 nm. Coefficients of 264.35 ± 6.28–652.34 ± 6.49%, 42.31 ± 2.43–89.74 ± 2.17%, and 52.31 ± 0.43–93.51 ± 0.33% from a quadratic model best fit the observed values of dependent variables. Formulation F4 was selected as the best option because it prevented the drug from being released in the upper GIT before it was ready and instead released it only in the colon, where the pH is optimal. The formulation had a particle size of 266.597 μm, an entrapment efficiency of 93.735%, a cumulative drug release of 95.578 percent, and a desirability factor of 0.998. In comparison to drug solution pharmacokinetics, microparticle pharmacokinetics showed a 6.35-fold decrease in Cmax and MS with an appropriately increased half-life of 8.13 h. (13.67 and 3.46). This enhanced bioavailability of MS released from microparticles is probably due to an increase in the half-life, mean residence time (MRT), and area under the concentration–time curve (AUC0-24) of MS. Over a long length of time with no increase in plasma MS level, it became clear that the novel method of MS-loaded microparticles would provide successful therapy for ulcerative colitis. A pharmacodynamic study found that mesalamine-loaded microparticles dramatically decreased colon edema, necrosis, and bleeding compared to free drug solution. Results from this study suggest that mesalamine-loaded microparticles may be an effective pharmaceutical delivery strategy for the management of ulcerative colitis.

In moderately to severely active UC, etrasimod increased remission at 12 and 52 wk but increased adverse events.

Sandborn WJ, Vermeire S, Peyrin-Biroulet L, et al. Etrasimod as induction and maintenance therapy for ulcerative colitis (ELEVATE): two randomised, double-blind, placebo-controlled, phase 3 studies. Lancet. 2023;401:1159-1171. 36871574.

Molecular Mechanisms of the Antitumor Effects of Mesalazine and Its Preventive Potential in Colorectal Cancer

Chemoprevention is one of the ways to fight colorectal cancer, which is a huge challenge in oncology. Numerous pieces of evidence indicate that chronic inflammation in the course of Crohn’s disease or ulcerative colitis (UC) is a significant cancer risk factor. Epidemiologic studies suggest that long-term use of non-steroidal anti-inflammatory drugs (NSAIDs), including mesalazine, has beneficial effects on colitis-associated colorectal cancer. Mesalazine is a first-line therapy for UC and is also widely used for maintaining remission in UC. Data showed that mesalazine has antiproliferative properties associated with cyclooxygenase (COX) inhibition but can also act through COX-independent pathways. This review summarizes knowledge about mesalazine’s molecular mechanisms of action and chemopreventive effect by which it could interfere with colorectal cancer cell proliferation and survival.

Mirikizumab as Induction and Maintenance Therapy for Ulcerative Colitis

BackgroundMirikizumab, a p19-directed antibody against interleukin-23, showed efficacy in the treatment of ulcerative colitis in a phase 2 trial.MethodsWe conducted two phase 3, randomized, double-blind, placebo-controlled trials of mirikizumab in adults with moderately to severely active ulcerative colitis. In the induction trial, patients were randomly assigned in a 3:1 ratio to receive mirikizumab (300 mg) or placebo, administered intravenously, every 4 weeks for 12 weeks. In the maintenance trial, patients with a response to mirikizumab induction therapy were randomly assigned in a 2:1 ratio to receive mirikizumab (200 mg) or placebo, administered subcutaneously, every 4 weeks for 40 weeks. The primary end points were clinical remission at week 12 in the induction trial and at week 40 (at 52 weeks overall) in the maintenance trial. Major secondary end points included clinical response, endoscopic remission, and improvement in bowel-movement urgency. Patients who did not have a response in the induction trial were allowed to receive open-label mirikizumab during the first 12 weeks of the maintenance trial as extended induction. Safety was also assessed.ResultsA total of 1281 patients underwent randomization in the induction trial, and 544 patients with a response to mirikizumab underwent randomization again in the maintenance trial. Significantly higher percentages of patients in the mirikizumab group than in the placebo group had clinical remission at week 12 of the induction trial (24.2% vs. 13.3%, P<0.001) and at week 40 of the maintenance trial (49.9% vs. 25.1%, P<0.001). The criteria for all the major secondary end points were met in both trials. Adverse events of nasopharyngitis and arthralgia were reported more frequently with mirikizumab than with placebo. Among the 1217 patients treated with mirikizumab during the controlled and uncontrolled periods (including the open-label extension and maintenance periods) in the two trials, 15 had an opportunistic infection (including 6 with herpes zoster infection) and 8 had cancer (including 3 with colorectal cancer). Among the patients who received placebo in the induction trial, 1 had herpes zoster infection and none had cancer.ConclusionsMirikizumab was more effective than placebo in inducing and maintaining clinical remission in patients with moderately to severely active ulcerative colitis. Opportunistic infection or cancer occurred in a small number of patients treated with mirikizumab. (Funded by Eli Lilly; LUCENT-1 and LUCENT-2 ClinicalTrials.gov numbers, NCT03518086 and NCT03524092, respectively.)

Protective Effect and Mechanisms of Eckol on Chronic Ulcerative Colitis Induced by Dextran Sulfate Sodium in Mice.

The use of functional foods and their bioactive components is receiving increasing attention as a complementary and alternative therapy for chronic ulcerative colitis (UC). This study explored the protective effect and mechanisms of Eckol, a seaweed-derived bioactive phlorotannin, on the dextran sodium sulfate (DSS)-induced chronic UC in mice. Eckol (0.5-1.0 mg/kg) reduced DSS-enhanced disease activity indexes, and alleviated the shortening of colon length and colonic tissue damage in chronic UC mice. The contents of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 were significantly decreased, and the level of anti-inflammatory IL-10 was enhanced in the serum and colonic tissues collected from Eckol-treated mice compared with the DSS controls. Eckol administration significantly reduced the number of apoptotic cells and the expression of cleaved Caspase-3, and increased the B-cell lymphoma-2 (Bcl-2)/B-cell lymphoma-2- associated X (Bax) ratio in DSS-challenged colons. There were more cluster of differentiation (CD)11c+ dendritic cells and CD8+ T cells, and less CD4+ T cells infiltrated to inflamed colonic tissues in the Eckol-treated groups. Expression of colonic Toll-like receptor 4 (TLR4), nuclear factor kappa-B (NF-κB) p65, phosphorylated-signal transducer and activator of transcription (pSTAT)3 was significantly down-regulated by Eckol compared with the DSS-challenged group. In conclusion, our data suggest that Eckol appeared to be a potential functional food ingredient for protection against chronic UC. The anti-colitis mechanisms of Eckol might be attributed to the down-regulation of the TLR4/NF-κB/STAT3 pathway, inhibition of inflammation and apoptosis, as well as its immunoregulatory activity.

Oral Delivery of Transformable Bilirubin Self-Assembled System for Targeted Therapy of Colitis.

Ulcerative colitis (UC) is a high incidence disease worldwide and clinically presents as relapsing and incurable inflammation of the colon. Bilirubin (BR), a natural antioxidant with significant anti-colitic effects, is utilized in preclinical studies as an intestinal disease therapy. Due to their water-insolubility, the design of BR-based agents usually involves complicated chemosynthetic processes, introducing various uncertainties in BR development. After screening numerous materials, it is identified that chondroitin sulfate can efficiently mediate the construction of BR self-assembled nanomedicine (BSNM) via intermolecular hydrogen bonds between dense sulfate and carboxyl of chondroitin sulfate and imino groups of BR. BSNM exhibits pH sensitivity and reactive oxygen species responsiveness, enabling targeted delivery to the colon. After oral administration, BSNM significantly inhibits colonic fibrosis and apoptosis of colon and goblet cells; it also reduces the expression of inflammatory cytokines. Moreover, BSNM maintains the normal level of zonula occludens-1 and occludin to sustain the integrity of intestinal barrier, regulates the macrophage polarization from M1 to M2 type, and promotes the ecological recovery of intestinal flora. Collectively, the work provides a colon-targeted and transformable BSNM that is simple to prepare and is useful as an efficient targeted UC therapy.

Lack of Benefit for Early Escalation to Advanced Therapies in Ulcerative Colitis: Critical Appraisal of Current Evidence.

Although ulcerative colitis [UC] shares many common pathways and therapeutic options with Crohn's disease [CD], CD patients are four times more likely to undergo surgery 10 years into their disease in the biological era and are more likely to have extraintestinal manifestations than UC patients. Early treatment in CD has been demonstrated to modify the natural history of the disease and potentially delay surgery. Previous reviews on this topic have borrowed their evidence from CD to make UC-specific recommendations. This review highlights the emergence of UC-specific data from larger cohort studies and a comprehensive individual patient data systemic review and meta-analysis to critically appraise evidence on the utility of early escalation to advanced therapies with respect to short-, medium-, and long-term outcomes. In UC, the utility of the early escalation concept for the purposes of changing the natural history, including reducing colectomy and hospitalizations, is not supported by the available data. Data on targeting clinical, biochemical, endoscopic, and histological outcomes are needed to demonstrate that they are meaningful with regard to achieving reductions in hospitalization and surgery, improving quality of life, and minimizing disability. Analyses of different populations of UC patients, such as those with 'relapsing & remitting' disease or with severe or complicated disease course, are urgently needed. The costs and risk/benefit profile of some of the newer advanced therapies should be carefully considered. In this clinical landscape, it appears premature to advocate an indiscriminate 'one size fits all' approach to escalating to advanced therapies early during the course of UC.

In situ gel-forming oil as rectally delivering platform of hydrophobic therapeutics for ulcerative colitis therapy

Because of their poor water-soluble properties and non-specific distribution, most hydrophobic therapeutics had limited benefit for patients with ulcerative colitis. Herein, an in-situ oil-based gel has been developed as a rectal delivery vehicle for these therapeutics. In situ gel-forming oil (BBLG) was composed of soybean phosphatidyl choline (40%, w/w), glyceryl dioleate (50%, w/w), and ethanol (10%, w/w). The hydrophobic laquinimod (LAQ) as a model drug was easily dissolved in gel-forming oil and its solubility was reaching to 7 ± 0.1 mg/mL. Importantly, upon contact with the colonic fluids, the gel-forming oil was quickly transited to a semi-solid gel, adhering to the inflamed colon mucosa and forming a protective barrier. Transmission Electron Microscopy showed that the gel network was arranged by the connected lipid spheres and LAQ was non-crystally encapsulated into the lipid spheres. Moreover, the universal adhesive test showed that the adhesive force and the adhesive energy of BBLG toward fresh colon tissues were 711 ± 12 mN and 25 ± 2 J/m2, which was 2.14-fold and 5-fold higher than that of the marketed Poloxamer 407 gel, respectively. Meanwhile, in vivo imaging confirmed that the retention time of BBLG in the colon lumen was more than 8 h after rectal administration. In vivo animal studies showed that BBLG also greatly enhanced the therapeutic impact of LAQ on TNBS-treated rats with ulcerative colitis, as evidenced by reduced disease activity index (DAI) scores and weight loss. Moreover, the colonic inflammation was significantly alleviated and the goblet cells were obliviously restored after treatment. Importantly, the gut mucosa barrier was largely repaired without any formation of fibrosis remodeling. Conclusively, in situ liquid gel may be a potential delivery system of hydrophobic medicines for ulcerative colitis.

Cyclosporine A-loaded colon-targeted oral nanomicelles self-assembly by galactosylated carboxymethyl chitosan for efficient ulcerative colitis therapy

An oral galactosylated carboxymethyl chitosan polymeric nanomicelles (Gal-N-CMCS NPs) embedded in chitosan-alginate hydrogel (CA-Gel) was developed to load cyclosporine A (CyA) as therapeutic agents against ulcerative colitis (UC). Galactose modified CMCS with macrophage targeting characteristic and CyA via a simple ultrasonication method to form Gal-N-CMCS/CyA NPs, and mixed CA-Gel to acquire the final formulation (Gal-N-CMCS/CyA Gel). The generated Gal-N-CMCS/CyA NPs displayed a desirable particle size (206.8 nm), negative surface charge (-19.5 mV), and high encapsulating efficiency (89.6 %). The morphology and release profiles were also charactered by transmission electron microscope [1] and dialysis method, respectively. Strikingly, the mucus penetration of Gal-N-CMCS/CyA NPs exceeded 90 % within 90 min. The Gal-N-CMCS NPs internalized by macrophages were 3.3-fold higher than CMCS-N NPs, thereby, enhancing the anti-inflammatory activities of NPs. Meanwhile, these NPs exhibited excellent biocompatibility, reduced the toxic effect of CyA, and targeting ability on inflammatory macrophages both in vitro and in vivo. Most importantly, in vivo studies revealed that CyA NPs could efficiently target the inflamed colon, remarkably alleviate inflammation, repair mucosal and reconstructed colonic epithelial barriers in UC mice induced by dextran sulfate sodium (DSS) via Toll-like receptor 4 -Nuclear factor kappa-B (TLR4-NF-κB) pathway. Our findings suggest that these high-performance and facilely fabricated Gal-N-CMCS/CyA NPs could be developed as a promising drug carrier for oral UC treatment.

The immunomodulatory effects of probiotics and azithromycin in dextran sodium sulfate-induced ulcerative colitis in rats via TLR4-NF-κB and p38-MAPK pathway

Ulcerative colitis (UC), a chronic autoimmune disease of the gut with a relapsing and remitting nature, considers a major health-care problem. DSS is a well-studied pharmacologically-induced model for UC. Toll-Like Receptor 4 (TLR4) and its close association with p-38-Mitogen-Activated Protein Kinase (p-38 MAPK) and nuclear factor kappa B (NF-κB) has important regulatory roles in inflammation and developing UC. Probiotics are gaining popularity for their potential in UC therapy. The immunomodulatory and anti-inflammatory role of azithromycin in UC remains a knowledge need. In the present rats-established UC, the therapeutic roles of oral probiotics (60 billion probiotic bacteria per kg per day) and azithromycin (40 mg per kg per day) regimens were evaluated by measuring changes in disease activity index, macroscopic damage index, oxidative stress markers, TLR4, p-38 MAPK, NF-κB signaling pathway in addition to their molecular downstream; tumor necrosis factor alpha (TNFα), interleukin (IL)1β, IL6, IL10 and inducible nitric oxide synthase (iNOS). After individual and combination therapy with probiotics and azithromycin regimens, the histological architecture of the UC improved with restoration of intestinal tissue normal architecture. These findings were consistent with the histopathological score of colon tissues. Each separate regimen lowered the remarkable TLR4, p-38 MAPK, iNOS, NF-κB as well as TNFα, IL1β, IL6 and MDA expressions and elevated the low IL10, glutathione and superoxide dismutase expressions in UC tissues. The combination regimen possesses the most synergistic beneficial effects in UC that, following thorough research, should be incorporated into the therapeutic approach in UC to boost the patients’ quality of life.

A natural chalcone cardamonin inhibits necroptosis and ameliorates dextran sulfate sodium (DSS)-induced colitis by targeting RIPK1/3 kinases

Necroptosis, a new form of programmed cell death, is involved in the pathogenesis of ulcerative colitis (UC). Inhibition of necroptosis represents an attractive strategy for UC therapy. Herein, cardamonin, a natural chalcone isolated from Zingiberaceae family, was firstly identified as a potent necroptosis inhibitor. In vitro, cardamonin significantly inhibited necroptosis in TNF-α plus Smac mimetic and z-VAD-FMK (TSZ)-, cycloheximide plus TZ (TCZ)-, or lipopolysaccharide plus SZ (LSZ)-stimulated HT29, L929, or RAW264.7 cell lines. Furthermore, TSZ-induced elevated population of necrotic cells, release of LDH and HMGB1 also could be inhibited by cardamonin in HT29 cells. Cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS) assay combined with molecular docking demonstrated that cardamonin interacted with RIPK1/3. Furthermore, cardamonin blocked the phosphorylation of RIPK1/3, thereby disrupting RIPK1-RIPK3 necrosome formation and MLKL phosphorylation. In vivo, orally administration of cardamonin attenuated dextran sulfate sodium (DSS)-induced colitis, which mainly manifested as mitigated intestinal barrier damage, suppressed necroinflammation, and reduced phosphorylation of MLKL. Taken together, our findings revealed that dietary cardamonin is a novel necroptosis inhibitor and has great potential for UC therapy by targeting RIPK1/3 kinases.

Responsive nanosystems for targeted therapy of ulcerative colitis: Current practices and future perspectives

The pharmacological approach to treating gastrointestinal diseases is suffering from various challenges. Among such gastrointestinal diseases, ulcerative colitis manifests inflammation at the colon site specifically. Patients suffering from ulcerative colitis notably exhibit thin mucus layers that offer increased permeability for the attacking pathogens. In the majority of ulcerative colitis patients, the conventional treatment options fail in controlling the symptoms of the disease leading to distressing effects on the quality of life. Such a scenario is due to the failure of conventional therapies to target the loaded moiety into specific diseased sites in the colon. Targeted carriers are needed to address this issue and enhance the drug effects. Conventional nanocarriers are mostly readily cleared and have nonspecific targeting. To accumulate the desired concentration of the therapeutic candidates at the inflamed area of the colon, smart nanomaterials with responsive nature have been explored recently that include pH responsive, reactive oxygen species responsive (ROS), enzyme responsive and thermo – responsive smart nanocarrier systems. The formulation of such responsive smart nanocarriers from nanotechnology scaffolds has resulted in the selective release of therapeutic drugs, avoiding systemic absorption and limiting the undesired delivery of targeting drugs into healthy tissues. Recent advancements in the field of responsive nanocarrier systems have resulted in the fabrication of multi-responsive systems i.e. dual responsive nanocarriers and derivitization that has increased the biological tissues and smart nanocarrier’s interaction. In addition, it has also led to efficient targeting and significant cellular uptake of the therapeutic moieties. Herein, we have highlighted the latest status of the responsive nanocarrier drug delivery system, its applications for on–demand delivery of drug candidates for ulcerative colitis, and the prospects are underpinned.

Inflammation responsive tofacitinib loaded albumin nanomedicine for targeted synergistic therapy in ulcerative colitis

Inflammation responsive tofacitinib loaded albumin nanomedicine for targeted synergistic therapy in ulcerative colitis

Long-term disease course, cost and prognosis of inflammatory bowel disease: epidemiological studies of a European and a Danish inception cohort.

Long-term disease course, cost and prognosis of inflammatory bowel disease: epidemiological studies of a European and a Danish inception cohort.

Paeoniflorin promotes intestinal stem cell-mediated epithelial regeneration and repair via PI3K-AKT-mTOR signalling in ulcerative colitis

Ulcerative colitis (UC) is a chronic and immune-mediated inflammatory disorder characterized by abdominal pain, diarrhoea, and haematochezia. The goal of clinical therapy for UC is mucosal healing, accomplished by regenerating and repairing the intestinal epithelium. Paeoniflorin (PF) is a natural ingredient extracted from Paeonia lactiflora that has significant anti-inflammatory and immunoregulatory efficacy. In this study, we investigated how PF could regulate the renewal and differentiation of intestinal stem cells (ISCs) to improve the regeneration and repair of the intestinal epithelium in UC. Our experimental results showed that PF significantly alleviated colitis induced by dextran sulfate sodium (DSS) and ameliorated intestinal mucosal injury by regulating the renewal and differentiation of ISCs. The mechanism by which PF regulates ISCs was confirmed to be through PI3K-AKT-mTOR signalling. In vitro, we found that PF not only improved the growth of TNF-α-induced colon organoids but also increased the expression of genes and proteins related to the differentiation and regeneration of ISCs. Furthermore, PF promoted the repair ability of lipopolysaccharide (LPS)-induced IEC-6 cells. The mechanism by which PF regulates ISCs was further confirmed and was consistent with the in vivo results. Overall, these findings demonstrate that PF accelerates epithelial regeneration and repair by promoting the renewal and differentiation of ISCs, suggesting that PF treatment may be beneficial to mucosal healing in UC patients.

Structurally dynamic self-healable hydrogel cooperatively inhibits intestinal inflammation and promotes mucosal repair for enhanced ulcerative colitis treatment

Hydrogels are a class of biocompatible materials with versatile functions that have been increasing explored for the localized treatment of ulcerative colitis (UC), but various mechanical stimuli may cause premature hydrogel breakage and detachment, impeding their further clinical translation. Here we report a multifunctional mechanically-resilient self-healing hydrogel for effective UC treatment, which is synthesized through the host-guest interaction between dopamine/β-cyclodextrin-modified hyaluronic acid (HA-CD-DA) and amantadine-modified carboxymethyl chitosan (CMCS-AD). The excessive β-CD cavities allow the incorporation of dexamethasone (DEX), while the porous hydrogel network potentiates the encapsulation of basic fibroblast growth factor (bFGF) and L-alanyl-l-glutamine (ALG). DA moieties in HA components allow firm adhesion of the hydrogel to the ulcerative lesions after in-situ implantation, while the reversible host-guest interaction between CD and AD could enhance the persistence of hydrogel. The hydrogel demonstrated favorable biocompatibility and could continuously release DEX to induce M1-to-M2 repolarization of mucosal macrophages through inhibiting the toll-like receptor 4 (TLR4)-nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) axis. Furthermore, the co-delivered bFGF and ALG facilitates the regeneration of ulcerative mucosa and restore its barrier functions to ameliorate UC symptoms. The mechanically resilient hydrogel offers an integrative approach for UC therapy in the clinics.

Responsiveness to Vedolizumab Therapy in Ulcerative Colitis is Associated With Alterations in Immune Cell-Cell Communications.

Ulcerative colitis (UC) and Crohn's disease are 2 types of inflammatory bowel disease (IBD), a group of chronic digestive disorders caused by aberrant immune responses to intestinal microbes. Although changes in the composition of immune cell subsets in the context of IBD have been previously described, the interactions and communication among cells are less well understood. Moreover, the precise mechanisms of action underlying many biologic therapies, including the anti-α4β7 integrin antagonist vedolizumab, remain incompletely understood. Our study aimed to explore possible additional mechanisms through which vedolizumab acts. We performed cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) on peripheral blood and colon immune cells derived from patients with ulcerative colitis treated with the anti-α4β7 integrin antagonist vedolizumab. We applied a previously published computational approach, NicheNet, to predict immune cell-cell interactions, revealing putative ligand-receptor pairs and key transcriptional changes downstream of these cell-cell communications (CCC). We observed decreased proportions of T helper 17 (TH17) cells in UC patients who responded to vedolizumab and therefore focused the study on identifying cell-cell communications and signals of TH17 cells with other immune cells. For example, we observed that colon TH17 cells from vedolizumab nonresponders were predicted to have a greater degree of interactions with classical monocytes compared with responders, whereas colon TH17 cells from vedolizumab responders exhibited more interactions with myeloid dendritic cells compared with nonresponders. Overall, our results indicate that efforts to elucidate cell-cell communications among immune and nonimmune cell types may increase the mechanistic understanding of current and investigational therapies for IBD.