Inflammatory bowel disease (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), can seriously impact patients' quality of life. Sodium butyrate (NaB), a product of dietary fiber fermentation, has been shown to alleviate IBD symptoms. Some studies have shown that it is related to ferroptosis. However, the precise mechanism linking NaB, IBD, and ferroptosis is not clear.

This study aimed to demonstrate that NaB suppresses ferroptosis, thereby alleviating inflammatory bowel disease (IBD) through modulation of the extracellular regulated protein kinases/signal transducer and activator of transcription 3 (ERK/STAT3) signaling pathway and intestinal flora.

An IBD model was established using 2.5% (w/v) dextran sulfate sodium (DSS). Mice were orally administered low-dose NaB, high-dose NaB , or 5-aminosalicylic acid (5-ASA). Ferroptosis-related molecules were measured using specific kits, and western blotting (WB) and real-time polymerase chain reaction (RT-qPCR) were used to determine the levels of the target molecules.

NaB alleviated symptoms in IBD mice, including reduced weight loss, prolonged colon length, reduced disease activity index (DAI), and reduced spleen index and mRNA expression of inflammatory factors. Additionally, NaB reduced the content of Fe2+ and myeloperoxidase (MPO) and increased the content of GSH and the activity of superoxide dismutase (SOD), which reflected NaB-inhibited ferroptosis. Moreover, western blotting showed that NaB enhanced STAT3 and ERK phosphorylation. In addition, NaB regulates the composition and functions of flora related to IBD.

NaB alleviates IBD by inhibiting ferroptosis and modulating ERK/STAT3 signaling and the intestinal flora.

Inflammatory bowel diseases (IBD), including ulcerative colitis and Crohn's disease, arise from various factors such as dietary, genetic, immunological, and microbiological influences. The gut microbiota plays a crucial role in the development and treatment of IBD, though the exact mechanisms remain uncertain. Current research has yet to definitively establish the beneficial effects of the microbiome on IBD. Bacteria and viruses (both prokaryotic and eukaryotic) are key components of the microbiome uniquely related to IBD. Numerous studies suggest that dysbiosis of the microbiota, including bacteria, viruses, and bacteriophages, contributes to IBD pathogenesis. Conversely, some research indicates that bacteria and bacteriophages may positively impact IBD outcomes. Additionally, plant metabolites play a crucial role in alleviating IBD due to their anti-inflammatory and microbiome-modulating properties. This systematic review discusses the role of the microbiome in IBD pathogenesis and evaluates the potential connection between plant metabolites and the microbiome in the context of IBD pathophysiology.

The current limitations of oral nanomedicines such as aminosalicylates, immunosuppressants, corticosteroids, and antibiotics include the toxic byproducts from nanocarrier synthesis, poor targeting and retention within the inflamed colon, delayed release at inflammation sites, susceptibility to gastric degradation, reduced efficacy under hypoxic conditions, MUC2 homeostasis disruption, and insufficiently addressing the disease's root causes. This research presents an innovative approach of using non-toxic, biodegradable, and biocompatible Maillard reaction-based nanoparticles (MPs) for targeted oral drug delivery in IBD therapy. Through the development of mucoadhevise chitosan-bovine serum albumin Maillard nanoparticles shielded with biocompatible, non-toxic, non-immunogenic, gastroprotective pectin (P@CMPs) encapsulating with chrysin, a flavonoid with anti-inflammatory and hyperoxia properties whose bioavailability is negatively affected by gastric degradation. P@CMPs had a spherical, uniform 300 nm hydrodynamic diameter, confirmed by TEM and FESEM. Chrysin encapsulation efficiency and loading capacity were ∼96 % and 16 %, respectively, demonstrating effective nanoparticle formulation The P@CMPs is designed to withstand the gastrointestinal environment, ensuring targeted delivery and prolonged retention in inflamed colonic regions. In a dextran sodium sulfate-induced colitis mouse model, P@CMPs markedly mitigated inflammation, suppressed proinflammatory cytokine levels, and augmented the expression of MUC2, a crucial factor for maintaining the integrity of the gut barrier. By employing non-toxic, biocompatible and biodegradable materials, our P@CMPs approach offers a promising avenue for advancing IBD treatment, addressing various challenges and precise oral delivery within the gastrointestinal system.

Ulcerative colitis (UC) is an inflammatory bowel disease characterized by the overproduction of reactive oxygen species (ROS) and the release of inflammatory mediators. Dihydroartemisinin (DHA) is a semi-synthetic active metabolite of artemisinin that has anti-inflammatory, antioxidant, and anti-fibrotic properties.

This study aimed to assess the therapeutic benefits of DHA on acetic acid(AA) -induced UC in rats, with particular emphasis on its anti-inflammatory effects and its influence on NFκB/TNF-α/RIPK1 necroptotic pathways.

Eighteen rats were allocated into control, acetic acid-induced colitis (AA), and DHA-treated (AA+DHA) groups. Colitis was caused by rectal instillation of 5 % acetic acid. DHA was supplied via intraperitoneal injection. Histological, biochemical studies of oxidative stress, inflammatory and anti-inflammatory mediators, Western blotting for TNF-α, RIPK1, and caspase 3, and immunohistochemical assessment of NFκB, TNF-α, and RIPK1, were conducted.

DHA treatment markedly diminished macroscopic damage, disease activity index, histopathology scores, and malondialdehyde (MDA) levels, enhancing glutathione (GSH) levels. Additionally, DHA decreased serum TNF-α and IL-6 and increased IL-10. Western blotting and immunohistochemistry investigations validated the reduced expression of TNF-α, RIPK1, and caspase 3 in DHA-treated rats.

DHA demonstrates protective properties against acetic acid-induced UC by decreasing oxidative stress and inflammation, modifying TNF-α activity to regulate apoptotic and necroptotic pathways. So, DHA may be a favorable therapeutic alternative for the management of ulcerative colitis.

Multimorbidity is the conjoint presence of multiple conditions in patients, which is a public health problem. Multimorbidity is like the elephant in the clinic room because it remains the unaddressed challenge we face in healthcare. Clinical health psychology has a role to play in this undertaking because it recognizes the intersection and interface of concurrent mental and/or behavioral problems and physical diseases. The current article will define multimorbidity, describe current statistics, how it differs from comorbidity, how to use the biopsychosocial model, and ways in which clinical health psychologists can manage and prevent it in their clinics. A model of how to address multimorbidity will be shared using the role of a clinical health psychologist working in a multidisciplinary pain clinic in a hospital setting serving patients who are socioeconomically disadvantaged.

Inflammatory bowel disease (IBD) is a chronic and relapsing immune-mediated disorder characterized by intestinal inflammation and epithelial injury. The underlying causes of IBD are not fully understood, but genetic factors have been implicated in genome-wide association studies, including CTLA-4, an essential negative regulator of T cell activation. However, establishing a direct link between CTLA-4 and IBD has been challenging due to the early lethality of CTLA-4 knockout mice. In this study, we identified zebrafish Ctla-4 homolog and investigated its role in maintaining intestinal immune homeostasis by generating a Ctla-4-deficient (ctla-4-/-) zebrafish line. These mutant zebrafish exhibited reduced weight, along with impaired epithelial barrier integrity and lymphocytic infiltration in their intestines. Transcriptomics analysis revealed upregulation of inflammation-related genes, disturbing immune system homeostasis. Moreover, single-cell RNA-sequencing analysis indicated increased Th2 cells and interleukin 13 expression, along with decreased innate lymphoid cells and upregulated proinflammatory cytokines. Additionally, Ctla-4-deficient zebrafish exhibited reduced diversity and an altered composition of the intestinal microbiota. All these phenotypes closely resemble those found in mammalian IBD. Lastly, supplementation with Ctla-4-Ig successfully alleviated intestinal inflammation in these mutants. Altogether, our findings demonstrate the pivotal role of Ctla-4 in maintaining intestinal homeostasis. Additionally, they offer substantial evidence linking CTLA-4 to IBD and establish a novel zebrafish model for investigating both the pathogenesis and potential treatments.

Inflammatory bowel disease (IBD) is a chronic and relapsing disease of the gastrointestinal tract. At present, antioxidant therapy is a promising strategy for IBD treatment. Since low-molecular-weight antioxidants (e.g., 2,2,6,6-tetramethylpiperidin-N-oxyl (TEMPO)) have a short in vivo half-life and inadequate cellular uptake, researchers have focused on loading antioxidants into nanostructures for improving their antioxidant and anti-inflammatory activities. As we know, in situ self-assembly with the formation of nanostructures under intracellular specific stimuli is a convenient delivery strategy to enhance the accumulation and retention of molecules at target sites in vivo. Herein, we developed an in situ self-assembled TEMPO probe TPP-FFYp-O to improve the antioxidant and anti-inflammatory effects of TEMPO in IBD. Compared to the control probe TPP-O without a self-assembly moiety, TPP-FFYp-O could successfully self-assemble into nanoparticles (NPs) under alkaline phosphatase (ALP)-guided dephosphorylation, with significantly enhanced antioxidant capacity in vitro. Cell experiments confirmed that intracellular formation of NPs by TPP-FFYp-O could improve the antioxidant and anti-inflammatory abilities of TEMPO and alleviate cellular damage. Moreover, TPP-FFYp-O exhibited good biocompatibility in vivo and significantly relieved pathological injury and inflammatory factors in the colon tissues of an IBD model compared to TPP-O. We envision that the in situ self-assembly platform can be used to load various active molecules for more applications in the future.

Developing oral drug delivery systems is promising for ulcerative colitis (UC). However, the key challenges, including formulation degradation under harsh gastric conditions, poor targeting efficiency, and limited colonic residence, lead to poor therapeutic efficacy that still needs to be tackled. Effective treatment requires a safe, efficacious, enzyme- and pH-responsive, biomucoadhesive oral drug delivery system to overcome these challenges. Therefore, we have developed chitosan-armored 1,2-dimyristoyl-sn-glycero-3-phosphoglycerol (DMPG) nanoliposomes amalgamated with synthesized beta-sitosterol-sinapic acid (Be-S) conjugate, further encapsulated with 3,4-methylenedioxy-β-nitrostyrene (MNS) as NLRP3 inhibitor, termed C@MN@DMBe-S, to overcome the limitation of free MNS and sinapic acid. Formulated by the thin-film hydration method and processed through extrusion, these unilamellar liposomes demonstrated structural stability and mucoadhesive properties due to chitosan coating. This configuration protected the nanoliposomes from the gastric acidic environment and allowed retention in the inflamed colon for 48 h. The enzyme-responsive C@MN@DMBe-S nanoliposome releases sinapic acid at the inflamed colonic site via esterase activity, providing sustained and controlled release of MNS. This synergistic action delivers antioxidant and anti-inflammatory effects while influencing the gut microbiota composition by releasing short-chain fatty acids. Moreover, therapeutic investigations revealed that C@MN@DMBe-S exhibited superior efficacy compared with free MNS when administered orally. The formulation effectively downregulated NF-κB, NLRP3, Caspase-1, and IL-1β expression while upregulating MUC5AC expression, indicating enhanced anti-inflammatory and protective effects and thereby promoting mucosal healing. In addition, C@MN@DMBe-S was found to regulate immune cell expression and effectively downregulate neutrophil infiltration. This armor- and enzyme-responsive strategy elucidates the impact of oral nanomedicines on mitigating UC and is demonstrated as an effective treatment.

Sini Decoction (SND), a time-honored formulation in traditional Chinese medicine, consists of three key ingredients: aconite, licorice, and ginger rhizome. It has been used for more than a thousand years to relieve symptoms associated with acute gastroenteritis, dyspepsia, and abdominal discomfort, but its therapeutic efficacy in ulcerative colitis (UC) and the mechanisms involved have not been validated. In this study, a comprehensive approach integrating network pharmacology, molecular docking, molecular dynamics simulation and experimentation was used to assess the efficacy of SND in the treatment of UC and to explore its molecular mechanisms.

The bioactive compounds associated with ulcerative colitis (UC) were identified using the TCMSP database, with potential targets predicted via the Swiss Target Prediction database. Protein-protein interaction networks were constructed using the STRING database and Cytoscape and the most important genes were identified. Subsequently, molecular docking was combined with molecular dynamics simulations using molecular docking to assess the binding affinity of the main active ingredient of SND to AKT1. To evaluate the therapeutic effects of SND, we utilized a dextran sodium sulfate-induced UC mouse model. Additionally, fecal samples were collected for analysis of the intestinal microbiota to explore the influence of SND on gut flora composition.

Fifteen bioactive components from SND were identified, and their activities were validated. The results indicated that AKT serine/threonine kinase 1 is a core target of SND for the treatment of UC. The anti-inflammatory, intestinal barrier-protective, and microbiota-regulating effects of SND were confirmed in animal models, alongside evidence of its inhibitory effect on AKT1.

The active ingredients of SND were screened, with a focus on AKT1 inhibition, to reduce inflammation in UC, protect the intestinal barrier, and regulate the intestinal microbiota, demonstrating significant therapeutic potential.

This study explores the impact of Faecalibacterium longum CM04-06 on inflammatory bowel disease (IBD) by regulating gut microbiota in mice.

We reanalyzed the distribution of the CM04-06 genome in the metagenome of the IBD cohort and observed a significantly higher abundance of CM04-06 in healthy individuals compared to patients with UC or CD. The prophylactic administration of CM04-06 was evaluated for its effects on intestinal microbial diversity and community composition after a two-week trial in mice. The intestinal microbiota was characterized using metagenomic sequencing of fecal samples on the DNBSEQ platform. CM04-06 treatment resulted in a significant reduction in the Disease Activity Index (DAI) and histological scores, as well as a decrease in the levels of pro-inflammatory cytokines, including IL-1β, IL-6, and TNF-α, in both the colon and serum of DSS-induced mice. Furthermore, supplementation with CM04-06 significantly reduced the levels of pro-inflammatory cytokines in both the colon and serum. Additionally, CM04-06 enhanced the integrity of the intestinal epithelial barrier by increasing the expression of tight junction proteins and mucin. Moreover, we observed greater abundances of Faecalibaculum rodentium, Alistipes onderdonkii, Alistipes shahii, and Bifidobacterium animalis after CM04-06 treatment.

CM04-06 prevents and alleviates intestinal inflammation by modulating the composition of the microbiota community, increasing the abundance of beneficial probiotics, and suppressing pro-inflammatory cytokine levels.

The multidimensional regulatory mechanism of the gut-brain-immune axis in the context of inflammatory bowel disease (IBD) has garnered significant attention, particularly regarding how intestinal microbiota finely regulates immune responses through immune cells and sensory neurons.

Metabolites produced by intestinal microbiota influence the phenotype switching of immune cells via complex signalling pathways, thereby modulating their anti-inflammatory and pro-inflammatory functions during intestinal inflammation. Furthermore, sensory neurons exhibit heightened sensitivity to microbial-derived signals, which is essential for preserving intestinal balance and controlling pathological inflammation by integrating peripheral environmental signals with local immune responses. The dynamic equilibrium between immune cells and the neuroimmunoregulation mediated by sensory neurons collectively sustains immune homeostasis within the intestine. However, this coordination mechanism is markedly disrupted under the pathological conditions associated with IBD.

An in-depth exploration of the interactions among immune cells, gut microbiota and sensory neurons may yield significant insights into the pathological mechanisms underlying IBD and guide the creation of new treatment approaches.

The gut microbiota regulates the gut-brain-immune axis, modulating neuroimmune interactions in IBD. Microbiota-derived metabolites influence immune cells, thereby affecting neurons. Neurons secrete mediators, enabling bidirectional neuroimmune communication essential for intestinal homeostasis. Disruptions contribute to IBD, offering therapeutic targets.

Recent systematic reviews and meta-analyses (SRMAs) have shown inconsistent effectiveness of FMT among patients with IBD. This study aimed to appraise the evidence for clinically relevant outcomes with FMT in patients with IBD using published SRMAs.

We searched major databases from inception through Nov 2023 to identify SRMAs assessing the effectiveness of FMT in patients with IBD. Primary outcomes included clinical remission, clinical response, endoscopic remission/response, a composite endpoint, and adverse effects. We included SRMAs investigating FMT's effect in patients with IBD using RCTs and observational studies data. Methodological quality and evidence certainty were assessed using AMSTAR 2 and GRADE.

Out of 106 citations, 16 SRMAs were included with varying study sizes (2 to 60 primary studies) and participants (112 to 1169 per SRMA). Five SRMAs assessed FMT in IBD, while 11 focused on Ulcerative Colitis (UC). Seven SRMAs included RCTs only, and nine included both RCTs and observational studies. Methodological quality was critically low in 9 SRMAs (56%) and low in 7 studies (44%). FMT showed clinical remission benefit in all 16 SRMAs, with varying certainty: 3 high, 4 moderate, 4 low, and 5 very low. Endoscopic remission/response was reported in 5 meta-analyses on UC, with 1 high, 3 moderate, and 1 very low certainty. Combined clinical remission and endoscopic response were reported in 3 SRMAs on UC, with 1 low and 2 moderate certainty. Adverse events were reported in 6 SRMAs, with 1 high, 3 moderate, 1 low, and 1 very low certainty.

Current evidence shows potential benefits of FMT in IBD, particularly UC, supported by significant associations in 16 meta-analyses. However, poor methodological quality and variability in evidence certainty call for high-quality RCTs to strengthen the evidence.

Disruption of the circadian clock is associated with the development of inflammatory bowel disease (IBD), but the underlying mechanisms remain unclear. Here, we observe that mice in the early active phase (Zeitgeber time 12, ZT12) of the circadian clock are more tolerant to dextran sodium sulfate (DSS)-induced colitis, compared to those in the early resting phase (ZT0). The expression of the circadian gene Bmal1 peaks in the early resting phase and declines in the early active phase. Bmal1 knockout in the intestinal epithelium reduces DSS-induced inflammatory symptoms. Mechanistically, BMAL1 promotes apoptosis by binding to apoptosis-related genes, including Bax, p53, and Bak1, and promotes their expression. Intriguingly, we observe circadian apoptotic rhythms in the homeostatic intestinal epithelium, while Bmal1 deletion reduces cell apoptosis. Consistently, reducing Bmal1 expression by the REV-ERBα agonist SR9009 has the best therapeutic efficacy against DSS-induced colitis at ZT0. Collectively, our data demonstrate that the Bmal1-centered circadian clock is involved in intestinal injury repair.

Current treatments for ulcerative colitis (UC), including mesalamine (Me) enemas, face limitations such as poor colonic retention, systemic side effects, and suboptimal patient compliance. To address these challenges, this study developed a thermo-responsive hydrogel combining hyaluronic acid-mesalamine (HA-Me) conjugates with methylcellulose (MC), providing a targeted and sustained drug delivery platform for UC treatment. HA-Me conjugates were synthesized via a nucleophilic addition-elimination reaction, with FT-IR and 1H-NMR confirming successful conjugation and a grafting ratio of 12.45%. Rheological analysis revealed a lower critical solution temperature (LCST) of 36.7-37.7 °C, ensuring gelation at body temperature when the MC concentration was 5-7 wt%. The optimized hydrogel exhibits intestinal retention properties, thereby improving drug bioavailability. The results confirmed that this hydrogel not only improved drug release time but also provided a protective barrier for inflamed wounds, facilitating wound healing, reducing the risk of reinfection, and improving medical compliance. Its mucoadhesive properties further supported effective drug delivery and localized therapeutic effects. This study highlights the potential of the MC/HA-Me hydrogel as a platform for overcoming the limitations of conventional UC treatments, offering opportunities for tailored therapeutic applications and future clinical development.

Inflammatory bowel disease (IBD), encompassing Crohn's disease and ulcerative colitis, is characterized by chronic intestinal inflammation and epithelial barrier disruption. Emerging evidence highlights mitochondrial dysfunction as a pivotal contributor to IBD pathogenesis, where impaired mitochondrial homeostasis in intestinal epithelial cells (IECs) disrupts redox balance, exacerbates oxidative stress, and triggers apoptosis, further compromising barrier integrity. This study investigated the therapeutic effects of Engeletin (Eng), a dihydroflavonoid from Smilax glabra Roxb., in dextran sulfate sodium (DSS)-induced colitis mice and colonic organoid models. Eng administration (10, 20, 40 mg/kg) significantly alleviated colitis symptoms, including weight loss, disease activity index (DAI) scores, and colon shortening, while restoring intestinal barrier integrity through the upregulation of tight junction proteins (ZO-1, claudin-1) and goblet cell preservation. Eng suppressed NF-κB-mediated inflammation and activated the Nrf2 antioxidant pathway, as well as reduced oxidative stress markers (MDA, CAT, GSH, and SOD). It attenuated epithelial apoptosis by balancing pro- and anti-apoptotic proteins (Bax/Bcl2, c-caspase3) and ameliorated mitochondrial dysfunction via enhanced ATP production, mtDNA levels, and complex I/IV activity. Mechanistically, Eng activated the AMPK/SIRT1/PGC-1α axis, and pharmacological inhibition of PGC-1α abolished its mitochondrial protective and anti-apoptotic effects. These findings demonstrate that Eng alleviates colitis by targeting mitochondrial homeostasis and oxidative stress through AMPK/SIRT1/PGC-1α signaling, offering a multitargeted strategy for IBD therapy.

Ulcerative colitis (UC) is a major form of inflammatory bowel disease (IBD) characterised by chronic immune-mediated inflammation. While serological biomarkers for IBD diagnosis and differentiation have been explored, autoantibody-based profiling remains underdeveloped. This study aimed to elucidate antibody signatures in manifested and pre-diagnostic UC patients compared to controls using a high-content protein microarray. Serum and plasma samples from manifested and pre-diagnostic UC cohorts were analysed using AIT's 16k protein microarray, presenting 6369 human proteins. The pre-diagnostic cohort, consisting of 33 UC cases and 33 controls, included longitudinal samples collected before diagnosis, while the severe UC cohort, comprising 49 severe UC patients and 23 controls, included individuals undergoing treatment. Immunoglobulin G (IgG) autoantibody reactivity was assessed to identify differentially reactive antigens (DIRAGs) linked to UC onset, disease progression, and activity. In manifested UC, 691 DIRAGs showed higher reactivity in cases. In the pre-diagnostic cohort, 966 DIRAGs were identified, with 803 antigens exhibiting increased reactivity in cases. Longitudinal analysis revealed 1371 DIRAGs, with 1185 showing increased reactivity closer to diagnosis when comparing samples collected 4-11 months before UC diagnosis to earlier time points 9-24 months prior, highlighting potential early biomarkers. A significant overlap of 286 antigens, corresponding to 41 percent of identified DIRAGs, was observed between severe and pre-diagnostic UC datasets, with an odds ratio of 3.8 and a p-value below 2.2 × 10-16, confirming reliability and biological relevance. Additionally, 21 antigens correlated with simple clinical colitis activity index (SCCAI) scores. Reactome pathway analysis identified 49 pathways associated with DIRAGs in pre-diagnostic UC, distinct from 24 pathways in manifested UC, with an overlap of five key pathways related to protein folding, immune regulation, and viral infection, reflecting differences in disease onset and manifestation. Autoantibody profiling reveals early immune signatures in UC, offering novel biomarkers for preclinical diagnosis and disease monitoring. The overlap between pre-diagnostic and manifested UC antigenic profiles reinforces their biological relevance, linking them to molecular pathology. These findings highlight antibody profiling as an additional omics layer, paving the way for new diagnostic and therapeutic strategies in UC management.

The gastrointestinal tract is a remarkable example of complex biology, with a constant dialogue between the intestinal epithelium, in close contact with the microbiota, and the immune cells that protect the gut from infection. Organoids have revolutionized our approach to modeling the intestinal cellular compartment and have opened new avenues for unraveling the mechanisms involved in intestinal homeostasis and chronic pathogenesis, such as inflammatory bowel disease. To date, few models have been established to explore the role of the colon, which is, however, the main site of inflammation in ulcerative colitis. Here, we used conditioned media produced by colon organoids from mice or humans (control patients and patients with ulcerative colitis) to investigate the relationship between macrophages and the colon epithelium. We addressed transcriptomic profiles of organoid conditioned media-stimulated bone marrow-derived macrophages and found that these cells exhibited a unique anti-inflammatory signature distinct from that of conventional in vitro IL-4/IL-13 M2-differentiated macrophages. In addition, organoid conditioned media induced a clear CD5 antigen-like-mediated immunoregulatory effect characterized by a significant reduction in lipopolysaccharide-induced inducible nitric oxide synthase expression. In line, organoid conditioned media from human colons inhibited lipopolysaccharide-dependent inflammatory cytokine expression in human monocyte-derived macrophages. Interestingly, the inflammatory marker CD68 was reduced by organoid conditioned media from control patients but not from patients with ulcerative colitis, suggesting epithelial dysfunction in patients with ulcerative colitis. Our results report new regulatory mechanisms in the colon and highlight the importance of developing new in vitro models to better characterize the relationship between the intestinal epithelium and immune mucosal cells.

Cell-free DNA (cfDNA) holds significant promise for diagnostic and therapeutic advancements in medicine. This review delineates the utility of cfDNA in diagnostics and its therapeutic potential through clearance mechanisms for an array of diseases. Damage-associated molecular patterns (DAMPs) are endogenous molecules released by host cells during stress, or injury. As a trigger for inflammatory responses via damage-associated molecular patterns (DAMPs), cfDNA's removal via nanotechnological approaches can attenuate inflammation and promote tissue repair. While the application of cfDNA clearance is particularly auspicious in cancer, sepsis, and inflammatory conditions, it is confronted with challenges including toxicity, specificity, and the rigors of clinical trial validation. Collectively, this review delineates novel therapeutic targets to inform the development of innovative treatment strategies.

Inflammatory bowel disease (IBD), a chronic, progressive, and recurrent gastrointestinal inflammatory disorder, poses a significant threat to global health and exerts an adverse effect on the quality of life. Currently, there is a lack of effective therapies for IBD. Developing novel targeted therapies for IBD, particularly orally effective therapeutics, is a vital need for IBD patients. Herein, we first demonstrate that BRD4/NF-κB signaling is aberrantly activated in the colons of human IBD biopsy samples compared to that of normal healthy controls. ZL0516, a potent, selective, and orally bioavailable BRD4 BD1 inhibitor, significantly inhibits the TNFα- and LPS-induced expression of inflammatory cytokines in human colonic epithelial cells (HCECs) and peripheral blood mononuclear cells (PBMCs) with low cytotoxicity. Intriguingly, when administered in a preventive mode, ZL0516 significantly blocks dextran sulfate sodium (DSS)-induced murine colitis. When used in a therapeutic mode, ZL0516 effectively suppresses colonic inflammation in several IBD-relevant animal models: DSS-, oxazolone (OXA)-, and flagellin (Cbir1) T cell-induced chronic murine colitis models of IBD. ZL0516 suppresses IBD inflammatory responses in vitro and in vivo by blocking the activation of the BRD4/NF-κB signaling pathway. Also, we found that RVX208, a selective BRD4 BD2 inhibitor in Phase III clinical development, only displayed marginal effects in these IBD animal models. Collectively, our results demonstrate that specific BRD4 BD1 inhibition is a novel therapeutic strategy for IBD-associated colonic inflammation, and orally effective inhibitor ZL0516 is a promising candidate for the development of a novel therapeutic regimen against IBD.

Fluxapyroxad, the most extensively utilized succinate dehydrogenase inhibitor (SDHI) fungicide, lacks comprehensive research on potential risks associated with chronic toxicity. To investigate its effects on chronic colonic inflammation and elucidate the underlying mechanisms, a mouse model was employed to assess oral exposure to fluxapyroxad at no observed adverse effect level (NOEL) for 13 weeks, in vitro and in silico models were utilized as well. The results revealed reduced body weight gain, colon length reduction, crypt damage, goblet cell loss in the colon, impaired intestinal barrier integrity, and an elevation of proinflammatory cytokines, including IL-6, IL-1β, and TNF-α following fluxapyroxad exposure in mice. These findings suggested that fluxapyroxad induced chronic colonic inflammation. Furthermore, fluxapyroxad decreased interleukin 22 levels and antibacterial peptide secretion by inhibiting Aryl hydrocarbon receptors (AhR) activation, which was confirmed in vitro experiments. Molecular docking analysis indicated that fluxapyroxad spontaneously formed halogen bonds and bound hydrophobic interactions with AhR, which might act as an AhR inhibitor. These results indicated that AhR inhibition may represent one of the primary mechanisms for chronic colonic inflammation induced by fluxapyroxad exposure. This study shed light on the association between low acute pesticide exposure to fluxapyroxad and chronic colonic inflammation development while contributing to pesticide safety assessment.

Autophagy is a conserved cellular recycling pathway that delivers damaged or superfluous cytoplasmic material to lysosomes for degradation. In response to cytotoxic stress or starvation, autophagy can also sequester bulk cytoplasm and deliver it to lysosomes to regenerate building blocks. In macroautophagy, a membrane cisterna termed phagophore that encloses autophagic cargo is generated. The formation of the phagophore depends on a conserved machinery of autophagy related proteins. The phosphatidylinositol(3)-phosphate binding protein WIPI2 facilitates the transition from phagophore initiation to phagophore expansion by recruiting the ATG12-ATG5-ATG16L1 complex to phagophores. This complex functions as an E3-ligase to conjugate ubiquitin-like ATG8 proteins to phagophore membranes, which promotes tethering of cargo to phagophore membranes, phagophore expansion, maturation and the fusion of autophagosomes with lysosomes. ATG16L1 also has important functions independently of ATG12-ATG5 in autophagy and beyond. In this review, we will summarize the functions of WIPI2 and ATG16L1 in selective and nonselective autophagy.

Inflammatory bowel disease (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC), is affecting a growing global population. Unlike UC, which is characterized by inflammation confined to the intestinal mucosa and submucosa, CD involves transmural inflammation of the intestine. Although the lymphatic system is believed to play a role in the pathogenesis of CD, its exact contribution remains poorly understood. Mesenteric lymphatics (MLs), which drain interstitial fluid and immune cells into mesenteric lymph nodes, have been implicated in this process. In the present study, we aimed to investigate the role of ML immune cells in TNBS-induced colitis in rats. Flow cytometry analysis revealed an increased ratio of B cells and altered B cell function in the MLs of colitis rats compared to controls. The adoptive transfer of mesenteric lymphatic B (MLB) cells isolated from colitis rats to recipient rats exacerbated colitis and was associated with the enhanced migration of MLB cells to the gut. RNA sequencing analysis demonstrated a significant upregulation of genes associated with inflammation and immune responses in MLB cells from colitis rats, particularly key molecules involved in T cell activation, such as cluster of differentiation 27 (Cd27) and cluster of differentiation 40 (Cd40), and the chemotactic receptor C-C motif chemokine receptor 8 (Ccr8), which mediates B cell migration in response to T cells. Mechanistically, MLB cells from colitis rats were recruited to the colon by intra-intestinal T cells through the Ccr8-C-C motif chemokine ligand 1 (Ccl1) axis, where they subsequently exacerbated inflammatory responses via enhanced differentiation. These observations indicate that the migration of MLB cells to the gut exacerbates TNBS-induced colitis in rats by modulating intestinal T cells.

The Wnt signaling pathway is critically involved in orchestrating cellular functions such as proliferation, migration, survival, and cell fate determination during development. Given its pivotal role in cellular communication, aberrant Wnt signaling has been extensively linked to the pathogenesis of various diseases. This review offers an in-depth analysis of the Wnt pathway, detailing its signal transduction mechanisms and principal components. Furthermore, the complex network of interactions between Wnt cascades and other key signaling pathways, such as Notch, Hedgehog, TGF-β, FGF, and NF-κB, is explored. Genetic mutations affecting the Wnt pathway play a pivotal role in disease progression, with particular emphasis on Wnt signaling's involvement in cancer stem cell biology and the tumor microenvironment. Additionally, this review underscores the diverse mechanisms through which Wnt signaling contributes to diseases such as cardiovascular conditions, neurodegenerative disorders, metabolic syndromes, autoimmune diseases, and cancer. Finally, a comprehensive overview of the therapeutic progress targeting Wnt signaling was given, and the latest progress in disease treatment targeting key components of the Wnt signaling pathway was summarized in detail, including Wnt ligands/receptors, β-catenin destruction complexes, and β-catenin/TCF transcription complexes. The development of small molecule inhibitors, monoclonal antibodies, and combination therapy strategies was emphasized, while the current potential therapeutic challenges were summarized. This aims to enhance the current understanding of this key pathway.

Inflammatory bowel disease (IBD) is a chronic relapsing immune-mediated inflammatory disorder of the alimentary tract without exact etiology. Mitochondrial reactive oxygen species (mtROS) derived from mitochondrial dysfunction impair intestinal barrier function, increase gut permeability, and facilitate immune cell invasion, and, therefore, are considered to have a pivotal role in the pathogenesis of IBD. Here, we reprogrammed regulatory T cell (Treg)-derived exosomes loaded with the antioxidant trace element selenium (Se) and decorated them with the synthetic mitochondria-targeting SS-31 tetrapeptide via a peptide linker. This linker can be cleaved by matrix metalloproteinases (MMPs) in inflammatory lesions. This actively targetable exosome-derived delivery system is protected from intestinal inflammation by scavenging excessive mtROS and preventing immunologically programmed cell death pyroptosis, necroptosis, and apoptosis, known as PANoptosis. Our results suggest that this engineered exosome delivery platform represents a promising targeted therapeutic strategy for the treatment of IBDs.

As the target of therapy in Ulcerative colitis (UC) has changed from symptomatic relief to mucosal healing, endoscopic visualization is mandatory. Colon capsule endoscopy (CCE) may serve as a less invasive and more tolerable alternative to standard colonoscopy (SC) for the monitoring of UC.

To evaluate the diagnostic accuracy, adverse events and tolerability for CCE compared to SC.

Systematic review.

A systematic literature search was conducted in PubMed, Embase and Web of Science.

Search results were imported into Covidence and screened. Included studies underwent risk of bias assessment using Methodological Index for Non-Randomized Studies (MINORS), and relevant data, including completeness of the procedure, type of bowel preparation and adverse events, was extracted. Pooled estimates of diagnostic accuracy were calculated from the studies providing the necessary data.

Out of 2804 articles, six studies were eligible for inclusion. Three provided the necessary data to calculate pooled estimates of diagnostic accuracy in recognizing mucosal inflammation: pooled sensitivity of 93%, specificity of 68.8%, positive predictive value of 89.4%, and negative predictive value of 78.6%. The adverse events, such as nausea and abdominal distension, were predominantly related to bowel preparation regimens.

CCE has the potential for monitoring UC. However, the specificity and NPV must be improved. Bowel preparation regimens must be optimized to improve patient experience and the effectiveness of CCE.

Prospero ID CRD42023450210.

Inflammatory bowel disease (IBD) is an inflammatory disorder in which intestinal homeostasis is disrupted for some reason. Among them, ulcerative colitis (UC) and Crohn's disease (CD) are frequently referred to as IBD in the narrow sense, characterized by relapse episodes and remission periods. The differential diagnosis of IBD involves a broad spectrum of inflammatory or infectious diseases that mimic UC and/or CD, as well as others that may complicate existing IBD. Accordingly, these differential diseases and modifying factors should be considered in their pathological diagnosis, and a careful diagnosis should be made in close collaboration with clinicians. Here, we provide a pathological overview of UC, CD, and their differential diseases, as well as IBD-associated cancers, demonstrating their typical gross and histological features. Further, we introduce a pathological scoring system for biopsy specimens to diagnose IBD that may potentially be integrated into clinical practice.

Artificial intelligence (AI) is being increasingly studied and implemented in gastroenterology. In inflammatory bowel disease (IBD), numerous AI models are being developed to assist with IBD diagnosis, standardization of endoscopic and radiologic disease activity, and predicting outcomes. Further prospective, multicenter studies representing diverse populations and novel applications are needed prior to routine implementation in clinical practice and expected improved outcomes for clinicians and patients.

Inflammatory bowel disease (IBD) is a chronic recurrent IBD, whose cause involves the interaction between genetic and environmental factors. Although there is a recognized link between immune response and IBD, the causal relationship between circulating immune cell counts and IBD remains controversial. This study aimed to elucidate the causal relationship between genetically predicted circulating immune cell counts and IBD. We conducted a bidirectional 2-sample Mendelian randomization (MR) study using aggregated statistics from genome-wide association studies. The causal relationship between 5 circulating leukocytes cells (monocytes, lymphocytes, eosinophils, basophils and neutrophils) counts and IBD, including ulcerative colitis (UC) and Crohn disease (CD) was analyzed. Horizontal pleiotropy test and heterogeneity test were used to ensure the stability of the results. Our findings indicated that monocytes, lymphocytes, eosinophils, and basophils count were not significantly associated with IBD, however, elevated circulating neutrophils count was significantly associated with higher risk of IBD [odds ratio (OR) = 1.0017; 95% confidence interval (CI) = 1.0004-1.003; P = .009] and UC [OR = 2.465; 95% CI = 1.236-4.916; P = .01]. In addition, we also found that IBD [OR: 12.07; 95% CI = 1.909-76.316; P = .008] and CD [OR = 1.014; 95% CI = 1.004-1.023; P = .005] were significantly associated with higher circulating neutrophils count in reverse MR. This MR study provides genetic evidence for the causal relationship between the genetically predicted increase in circulating neutrophils count and the risk of IBD (UC and CD). This finding stresses the need for further exploring physiological functions of neutrophils in order to develop effective strategies against IBD.

Colonic mucus forms a first line of defense against bacterial invasion while providing nutrition to support coinhabiting microbes in the gut. Mucus is composed of polymeric networks of mucin proteins, which are heavily modified post-translationally. The full compendium of enzymes responsible for these modifications and their roles in health and disease remain incompletely understood. Herein, we determine the biochemical function of NXPE1, a gene implicated in ulcerative colitis (UC), and demonstrate that it encodes an acetyltransferase that modifies mucin glycans. Specifically, NXPE1 utilizes acetyl-CoA to regioselectively modify the mucus sialic acid, 5-N-acetylneuraminic acid (Neu5Ac), at the 9-OH group to generate 9-O-acetylated Neu5Ac (Neu5,9Ac2). We further demonstrate that colonic organoids derived from donors harboring the missense variant NXPE1 G353R, which is protective against UC, exhibit severely impaired acetylation of Neu5Ac on mucins. Together, our findings support a model in which NXPE1 masks the alcohols of mucus sialoglycans via acetylation, which is important for modulating mucus barrier properties that limit interactions with commensal microbes.

Although oral delivery of therapeutic agents offers numerous benefits, its application is limited due to the digestive tract's harsh conditions (e.g., strong acidity and high osmolarity), which impair activity and create challenges in achieving targeted release into the intestine. Here, we present multicompartmental hydrogel microspheres equipped with a concentric oil layer to significantly enhance the oral drug delivery efficiency for treating inflammatory bowel disease (IBD). These microspheres are created through the utilization of triple-emulsion droplets, featuring intermediate oil layers that distinctively separate two prepolymer phases, allowing us to fine-tune the composition of each compartment through a tailored polymerization strategy. We demonstrate that the oil layer can protect the encapsulated material by preventing exposure to the acidic environment of the stomach during the digestive process. Unlike aqueous core capsules, the core is composed of hydrogel, which provides high stability even under high osmolarity conditions in the stomach. By fine-tuning the shell's composition, we can develop capsules that release selectively in response to the gut's pH conditions. We demonstrate the system's efficacy by preserving the anti-inflammatory activities of 5-aminosalicylic acid (5-ASA) and Lys-Pro-Val (KPV) under stomach conditions and maintaining their therapeutic effects on colonic epithelial cell migration and proliferation.

Citrinin (CTN) is commonly found in animal feed and stored grains and poses a serious threat to human and animal health. Formation of the IP3R1-GRP75-VDAC1 complex has been shown to play a key role in intestinal defense against harmful stimuli, but the mechanism of its action in CTN-exposure-induced enterotoxicity is not clear. Therefore, the aim of this study was to investigate the role of the IP3R1-GRP75-VDAC1 complex in CTN-exposure-induced intestinal and IPEC-J2 monolayer cell damage in mice. It was shown that CTN exposure triggered intestinal cell pyroptosis and increased IP3R1-GRP75-VDAC1 complex formation as well as mitochondrial levels of calcium ions and mitochondrial reactive oxygen species (mtROS). And mtROS is considered to be a key factor in cellular pyroptosis. Therefore, the removal of mtROS by using Mito-Tempo was found to attenuate CTN-exposure-induced cellular pyroptosis but failed to attenuate mitochondrial calcium ion overload. However, silencing of GRP75 alleviated CTN-exposure-induced increases in the level of mtROS, mitochondrial calcium ions, and subsequent cellular pyroptosis. Therefore, this study confirms that CTN exposure induces cellular juxtaposition in intestinal tissues and points out that mitochondrial oxidative stress mediated by the IP3R1-GRP75-VDAC1 complex is a key mechanism by which CTN exposure triggers intestinal cellular pyroptosis.

Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs), especially, exosomes are considered to have diverse therapeutic effects for various significant diseases. MSC-derived exosomes (MSCex) offer substantial advantages over MSCs due to their long-term preservation, stability, absence of nuclei and fewer adverse effects such as infusion toxicity, thereby paving the way towards regenerative medicine and cell-free therapeutics. These exosomes harbor several cellular contents such as DNA, RNA, lipids, metabolites, and proteins, facilitating drug delivery and intercellular communication. MSCex have the ability to immunomodulate and trigger the anti-inflammatory process hence, playing a key role in alleviating inflammation and enhancing tissue regeneration. In this review, we addressed the anti-inflammatory effects of MSCex and the underlying immunomodulatory pathways. Moreover, we discussed the recent updates on MSCex in treating specific inflammatory diseases, including arthritis, inflammatory bowel disease, inflammatory eye diseases, and respiratory diseases such as asthma and acute respiratory distress syndrome (ARDS), as well as neurodegenerative and cardiac diseases. Finally, we highlighted the challenges in using MSCex as the successful therapeutic tool and discussed future perspectives.

Bacteroides fragilis toxin (BFT), produced by enterotoxigenic B. fragilis (ETBF), is crucial for ETBF-induced colitis. This study aims to investigate the impact of BFT-host interactions on N6-methyladenosine (m6A) modification of host mRNA and its underlying mechanisms.

Single-cell sequencing was employed to identify the cell types involved in ETBF-induced colitis in inflammatory bowel disease patients and dextran sodium sulfate-induced colitis mice. An ETBF strain with the bft gene deleted (ETBF[Δbft]) was utilized to investigate the role of ETBF components. The biological functions and mechanisms of BFT-induced m6A modifications, as well as the target genes, were explored in vitro and in vivo.

Inflammatory macrophages are enriched in the intestinal mucosal tissue of both inflammatory bowel disease patients and mice with high levels of ETBF. Additionally, ETBF triggers the activation of inflammatory macrophages, subsequently inducing downstream inflammatory responses. Remarkably, BFT secreted by ETBF reduced METTL3 transcription by inhibiting FOXD3 expression and induced a dramatic reduction of m6A modifications in inflammatory macrophages. Moreover, BFT promotes the expression of its target ITGA5 expression by diminishing YTHDF2-dependent mRNA degradation. Targeting integrin subunit alpha 5 using Cilengitide significantly alleviated ETBF-induced colitis by decreasing the level of inflammatory factors in macrophages.

Our study reveals that BFT produced by ETBF leads to a reduction of m6A modifications by reducing METTL3 transcription and promotes ITGA5 expression in inflammatory macrophages. These findings provide new insights into the modulation of human m6A epitranscriptome in macrophages by gut microbiota and its significance in inflammatory bowel disease progression.

Interleukin-1 receptor 2 (IL1R2) and C-C motif chemokine receptor 2 (CCR2) as critical mediators of immune modulation and inflammation. This study aims to evaluate their functions in dextran sulfate sodium (DSS)-induced intestinal injury.

A DSS-induced intestinal injury model was established in C57BL/6 mice. Pharmacological inhibitors targeting IL1R2 or CCR2 were administered. Adipose-derived mesenchymal stem cell (ADMSC)-derived exosomes were isolated and loaded with IL1R2-siRNA, which were then administered to intestinal epithelial cells (IEC-6) or DSS-challenged mice.

IL1R2 and CCR2 were upregulated in DSS-treated colon tissues. Pharmacological inhibition of IL1R2 or CCR2 improved body weight, restored colon length, reduced serum TNF-α and IL-6 levels, and preserved epithelial integrity in mice. miR-128-3p enriched in ADMSC-derived exosomes significantly reduced CCR2 expression in IEC-6 cells. Further loading of an IL1R2 siRNA in these exosomes led to a simultaneous inhibition of IL1R2. These exosomes reduced lipopolysaccharide-induced apoptosis and inflammation in IEC-6 cells and improved histological outcomes in DSS-challenged mice.

IL1R2 and CCR2 are key mediators of inflammation in DSS-induced intestinal injury. Dual inhibition of IL1R2 and CCR2 holds great promise for alleviating inflammatory responses and improving histological presentations in inflammatory bowel disease.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease. UC treatments are limited by significant adverse effects associated with non-specific drug delivery, such as systematic inhibition of the host immune system. Endoscopic delivery of a synthetic hydrogel material with biocompatible gelation that can efficiently cover irregular tissue surfaces provides an effective approach for targeted drug delivery at the gastrointestinal (GI) tract. An ideal integration of synthetic material with intestinal epithelium entails an integrated and preferable chemically bonded interface between the hydrogel and mucosal surface. In this study, a photo-triggered coupling reaction is leveraged as the crosslinking platform to develop a mucosal-adhesive hydrogel, which is compatible with endoscope-directed drug delivery for UC treatment. The results demonstrated superior spatiotemporal specificity and drug pharmacokinetics with this delivery system in vivo. Delivery of different drugs with the hydrogel leads to greatly enhanced therapeutic efficacy and significantly reduced systemic drug exposure with rat colitis models. The study presents a strategy for targeted and persistent drug delivery for UC treatment.