BACKGROUND:Oral 5-aminosalicylic acid (5-ASA) preparations were intended to avoid the adverse effects of sulfasalazine (SASP) while maintaining its therapeutic benefits. It was previously found that 5-ASA drugs in doses of at least 2 g/day were more effective than placebo but no more effective than SASP for inducing remission in ulcerative colitis (UC). This review is an update of a previously published Cochrane Review. OBJECTIVES:To assess the efficacy, dose-responsiveness and safety of oral 5-ASA compared to placebo, SASP, or 5-ASA comparators (i.e. other formulations of 5-ASA) for induction of remission in active UC. A secondary objective was to compare the efficacy and safety of once-daily dosing of oral 5-ASA versus conventional dosing regimens (two or three times daily). SEARCH METHODS:We searched MEDLINE, Embase and the Cochrane Library on 11 June 2019. We also searched references, conference proceedings and study registers to identify additional studies. SELECTION CRITERIA:We considered randomized controlled trials (RCTs) including adults (aged 18 years or more) with active UC for inclusion. We included studies that compared oral 5-ASA therapy with placebo, SASP, or other 5-ASA formulations. We also included studies that compared once-daily to conventional dosing as well as dose-ranging studies. DATA COLLECTION AND ANALYSIS:Outcomes include failure to induce global/clinical remission, global/clinical improvement, endoscopic remission, endoscopic improvement, adherence, adverse events (AEs), serious adverse events (SAEs), withdrawals due to AEs, and withdrawals or exclusions after entry. We analyzed five comparisons: 5-ASA versus placebo, 5-ASA versus sulfasalazine, once-daily dosing versus conventional dosing, 5-ASA (e.g. MMX mesalamine, Ipocol, Balsalazide, Pentasa, Olsalazine and 5-ASA micropellets) versus comparator 5-ASA (e.g. Asacol, Claversal, Salofalk), and 5-ASA dose-ranging. We calculated the risk ratio (RR) and 95% confidence interval (95% CI) for each outcome. We analyzed data on an intention-to-treat basis, and used GRADE to assess the overall certainty of the evidence. MAIN RESULTS:We include 54 studies (9612 participants). We rated most studies at low risk of bias. Seventy-one per cent (1107/1550) of 5-ASA participants failed to enter clinical remission compared to 83% (695/837) of placebo participants (RR 0.86, 95% CI 0.82 to 0.89; 2387 participants, 11 studies; high-certainty evidence). We also observed a dose-response trend for 5-ASA. There was no difference in clinical remission rates between 5-ASA and SASP. Fifty-four per cent (150/279) of 5-ASA participants failed to enter remission compared to 58% (144/247) of SASP participants (RR 0.90, 95% CI 0.77 to 1.04; 526 participants, 8 studies; moderate-certainty evidence). There was no difference in remission rates between once-daily dosing and conventional dosing. Sixty per cent (533/881) of once-daily participants failed to enter clinical remission compared to 61% (538/880) of conventionally-dosed participants (RR 0.99, 95% CI 0.93 to 1.06; 1761 participants, 5 studies; high-certainty evidence). Eight per cent (15/179) of participants dosed once daily failed to adhere to their medication regimen compared to 6% (11/179) of conventionally-dosed participants (RR 1.36, 95% CI 0.64 to 2.86; 358 participants, 2 studies; low-certainty evidence). There does not appear to be any difference in efficacy among the various 5-ASA formulations. Fifty per cent (507/1022) of participants in the 5-ASA group failed to enter remission compared to 52% (491/946) of participants in the 5-ASA comparator group (RR 0.94, 95% CI 0.86 to 1.02; 1968 participants, 11 studies; moderate-certainty evidence). There was no evidence of a difference in the incidence of adverse events and serious adverse events between 5-ASA and placebo, once-daily and conventionally-dosed 5-ASA, and 5-ASA and comparator 5-ASA formulation studies. Common adverse events included flatulence, abdominal pain, nausea, diarrhea, headache and worsening UC. SASP was not as well tolerated as 5-ASA. Twenty-nine per cent (118/411) of SASP participants experienced an AE compared to 15% (72/498) of 5-ASA participants (RR 0.48, 95% CI 0.36 to 0.63; 909 participants, 12 studies; moderate-certainty evidence). AUTHORS' CONCLUSIONS:There is high-certainty evidence that 5-ASA is superior to placebo, and moderate-certainty evidence that 5-ASA is not more effective than SASP. Considering relative costs, a clinical advantage to using oral 5-ASA in place of SASP appears unlikely. High-certainty evidence suggests 5-ASA dosed once daily appears to be as efficacious as conventionally-dosed 5-ASA. There may be little or no difference in efficacy or safety among the various 5-ASA formulations.

Inflammatory bowel disease (IBD), as a representative inflammatory disease, currently has multiple effective treatment options available and new therapeutic strategies are being actively explored to further increase the treatment options for patients with IBD. Furthermore, biologic agents and small molecule drugs developed for ulcerative colitis (UC) and Crohn's disease (CD) have evolved toward fewer side effects and more accurate targeting. Novel inhibitors that target cytokines (such as IL-12/23 inhibitors, PDE4 inhibitors), integrins (such as integrin inhibitors), cytokine signaling pathways (such as JAK inhibitors, SMAD7 blocker) and cell signaling receptors (such as S1P receptor modulator) have become the preferred treatment choice for many IBD patients. Conventional therapies such as 5-aminosalicylic acid, corticosteroids, immunomodulators and anti-tumor necrosis factor agents continue to demonstrate therapeutic efficacy, particularly in combination with drug therapy. This review integrates research from chemical, biological and adjuvant therapies to evaluate current and future IBD therapies, highlighting the mechanism of action of each therapy and emphasizing the potential of development prospects.

BACKGROUND:Ulcerative colitis (UC) is a type of inflammatory bowel disease primarily affecting the colon and rectum. The clinical symptoms of UC include persistent diarrhea, abdominal pain, and rectal bleeding, with chronic inflammation often limited to the mucosal layer of the colon. Macrophages play a significant role in the pathogenesis of UC in response to the presence of gut microbiota. Puerarin is an active compound derived from the root of pueraria lobata, a traditional Chinese herbal medicine, and exhibits potent anti-inflammatory properties in various diseases and disease models including UC-like colitis in mice. However, how the molecule achieves its therapeutic effect in colitis by re-polarizing macrophages remains poorly understood. PURPOSE:Utilizing in vivo and in vitro experimental methods along with multi-omics analysis, we aimed to elucidate the potential mechanism by which puerarin targets macrophages to treat colitis. METHODS:The inflammation induced by DSS was assessed both locally in the gut and systemically, and the anti-inflammatory effect of puerarin was evaluated using molecular and histological assays such as H&E staining, qPCR, ELISA, Western blot, and immunofluorescence. Intestinal permeability parameters were measured by in vivo imaging, immunofluorescence, Western blot, qPCR, and PAS staining. The central role of macrophages in colitis was investigated through macrophage depletion/infusion using cytological methods. The direct effects of puerarin on the macrophages were examined by CCK8, flow cytometry, and qPCR in vitro. Additionally, 16S rRNA sequencing and metabolomics analysis of gut contents were conducted. Identification of key pathogenic flora was facilitated by a trans-omic approach and validated both in vitro and in vivo. RESULTS:Puerarin exerted a direct and robust suppression of M1-like polarization of macrophages in vitro, which was sufficient to confer therapeutic benefits in terms of colonic lesions and systemic inflammation in DSS mice. Puerarin also reduced the abundance of Akkermansia muciniphila in the gut, which was significantly upregulated in DSS mice in our experimental context. Further study demonstrated that puerarin effectively suppressed M1-like macrophage activation induced by Akkermansia muciniphila secreted protein Amuc_2172, thereby altering the pathology in the DSS model. CONCLUSION:Our data suggest that the pathogenesis of DSS colitis is mediated by host cellular responses to toxic foreign molecules and the gut microbiota, and targeting specific cell populations, such as macrophages, with puerarin holds potential therapeutic value.

Background:Ulcerative colitis (UC) and atherosclerosis (AS) are closely related. However, the pathologic mechanisms underlying the co-occurrence of UC and AS are not well understood. Objects:To reveal the hub molecule and mechanism involved in the co-occurrence of UC and AS. Methods:Differentially expressed genes (DEGs) of UC and AS were obtained, and the shared DEGs of UC and AS were explored for biological function. Next, the hub genes were explored using the cytoHubba plugin. The predictive ability of the hub genes was measured by constructing the receiver operating characteristic curve. Analyses of immune infiltration and the single-gene gene set enrichment analysis (GSEA) for the hub genes were further carried out. Results:Identification of 59 DEGs (55 were upregulated and four were downregulated) shared by both UC and AS was performed. Enriched pathways of the shared DEGs were mainly related to immunity and inflammation. Protein tyrosine phosphatase, receptor type, C (PTPRC) was identified as the hub crosstalk gene for the comorbidity of UC and AS. The upregulation of PTPRC was correlated with mast cells resting, T cells CD4 memory resting, macrophages M0, and macrophages M1. Pathways of immune and inflammatory processes, including NF-kappa B, viral protein interaction with cytokine and cytokine receptor, and cytokine-cytokine receptor interaction, were significantly correlated with high expression of PTPRC in UC and AS. Conclusion:At the transcriptional level, our study reveals that imbalanced inflammatory and immune responses are the key pathological mechanisms underlying the comorbidity of UC and AS and that PTPRC is a key biomarker for the comorbidity of UC and AS.

Probiotics can effectively improve ulcerative colitis (UC), but the mechanism is still unclear. Here, shotgun metagenome and transcriptome analyses were performed to explore the therapeutic effect and the mechanism of the probiotic Lactobacillus plantarum HNU082 (Lp082) on UC. The results showed that Lp082 treatment significantly ameliorated dextran sulfate sodium (DSS)-induced UC in mice, which was manifested as increases in body weight, water intake, food intake, and colon length and decreases in disease activity index (DAI), immune organ index, inflammatory factors, and histopathological scores after Lp082 intake. An in-depth study discovered that Lp082 could improve the intestinal mucosal barrier and relieve inflammation by cooptimizing the biological barrier, chemical barrier, mechanical barrier, and immune barrier. Specifically, Lp082 rebuilt the biological barrier by regulating the intestinal microbiome and increasing the production of short-chain fatty acids (SCFAs). Lp082 improved the chemical barrier by reducing intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule (VCAM) and increasing goblet cells and mucin2. Lp082 ameliorated the mechanical barrier by increasing zonula occludens-1 (ZO-1), zonula occludens-2 (ZO-2), and occludin while decreasing claudin-1 and claudin-2. Lp082 optimized the immune barrier by reducing the content of interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), myeloperoxidase (MPO), and interferon-γ (IFN-γ) and increasing IL-10, transforming growth factor-β1 (TGF-β1), and TGF-β2, inhibiting the NF-κB signaling pathway. Taken together, probiotic Lp082 can play a protective role in a DSS-induced colitis mouse model by protecting the intestinal mucosal barrier, attenuating the inflammatory response, and regulating microbial imbalance. This study provides support for the development of probiotic-based microbial products as an alternative treatment strategy for UC. Many studies have focused on the therapeutic effect of probiotics on ulcerative colitis (UC), but few studies have paid attention to the mechanism of probiotics, especially the therapeutic effect. This study suggests that Lp082 has a therapeutic effect on colitis in mice. Its mechanisms of action include protecting the mucosal barrier and actively modulating the gut microbiome, modulating inflammatory pathways, and reducing neutrophil infiltration. Our study enriches the mechanism and provides a new prospect for probiotics in the treatment of colitis, helps to deepen the understanding of the intestinal mucosal barrier, and provides guidance for the future probiotic treatment of human colitis.

Imbalance of gut microbiota homeostasis is related to the occurrence of ulcerative colitis (UC), and probiotics are thought to modulate immune microenvironment and repair barrier function. Here, in order to reveal the interaction between UC and gut microbiota, we screened a new probiotic strain by 16S rRNA sequencing from Dextran Sulfate Sodium (DSS)-induced colitis mice, and explored the mechanism and clinical relevance. (), as a potential anti-inflammatory bacterium was decreased colonization in colitis mice. Gavage could alleviate colitis by specifically increasing the proportion of intestinal macrophages and the secretion of Il-10 with macrophages depleted model and in mice. We identified this subset of immune cells activated as CD206 macrophages. Mechanistically, supplementation enhanced the mobilization of CD206 macrophages through the activation of STAT3 and . In addition, we revealed that TLR1/2 was essential for the activation of STAT3 and the recognition of by macrophages. Clinically, there was positive correlation between the abundance of and the expression level of and in UC tissues. could activate native macrophages into CD206 macrophages and release IL-10 through TLR1/2-STAT3 pathway to relieve experimental colitis. may serve as an immunomodulator and anti-inflammatory therapeutic target for UC.

Given the complex nature of ulcerative colitis, combination therapy targeting multiple pathogenic genes and pathways of ulcerative colitis may be required. Unfortunately, current therapeutic strategies are usually based on independent chemical compounds or monoclonal antibodies, and the full potential of combination therapy has not yet been realized for the treatment of ulcerative colitis. Here, we develop a synthetic biology strategy that integrates the naturally existing circulating system of small extracellular vesicles with artificial genetic circuits to reprogram the liver of male mice to self-assemble multiple siRNAs into secretory small extracellular vesicles and facilitate in vivo delivery siRNAs through circulating small extracellular vesicles for the combination therapy of mouse models of ulcerative colitis. Particularly, repeated injection of the multi-targeted genetic circuit designed for simultaneous inhibition of TNF-α, B7-1 and integrin α4 rapidly relieves intestinal inflammation and exerts a synergistic therapeutic effect against ulcerative colitis through suppressing the pro-inflammatory cascade in colonic macrophages, inhibiting the costimulatory signal to T cells and blocking T cell homing to sites of inflammation. More importantly, we design an AAV-driven genetic circuit to induce substantial and lasting inhibition of TNF-α, B7-1 and integrin α4 through only a single injection. Overall, this study establishes a feasible combination therapeutic strategy for ulcerative colitis, which may offer an alternative to conventional biological therapies requiring two or more independent compounds or antibodies.

The intestine constantly encounters and adapts to the external environment shaped by diverse dietary nutrients. However, whether and how gut adaptability to dietary challenges is compromised in ulcerative colitis is incompletely understood. Here, we show that a transient high-fat diet exacerbates colitis owing to inflammation-compromised bile acid tolerance. Mechanistically, excessive tumor necrosis factor (TNF) produced at the onset of colitis interferes with bile-acid detoxification through the receptor-interacting serine/threonine-protein kinase 1/extracellular signal-regulated kinase pathway in intestinal epithelial cells, leading to bile acid overload in the endoplasmic reticulum and consequent apoptosis. In line with the synergy of bile acids and TNF in promoting gut epithelial damage, high intestinal bile acids correlate with poor infliximab response, and bile acid clearance improves infliximab efficacy in experimental colitis. This study identifies bile acids as an "opportunistic pathogenic factor" in the gut that would represent a promising target and stratification criterion for ulcerative colitis prevention/therapy.

Obesity has reached epidemic proportions, but little is known about its influence on the intestinal immune system. Here we show that the gut immune system is altered during high-fat diet (HFD) feeding and is a functional regulator of obesity-related insulin resistance (IR) that can be exploited therapeutically. Obesity induces a chronic phenotypic pro-inflammatory shift in bowel lamina propria immune cell populations. Reduction of the gut immune system, using beta7 integrin-deficient mice (Beta7(null)), decreases HFD-induced IR. Treatment of wild-type HFD C57BL/6 mice with the local gut anti-inflammatory, 5-aminosalicyclic acid (5-ASA), reverses bowel inflammation and improves metabolic parameters. These beneficial effects are dependent on adaptive and gut immunity and are associated with reduced gut permeability and endotoxemia, decreased visceral adipose tissue inflammation, and improved antigen-specific tolerance to luminal antigens. Thus, the mucosal immune system affects multiple pathways associated with systemic IR and represents a novel therapeutic target in this disease.

Crohn's disease and ulcerative colitis, phenotypically comprising a spectrum of inflammatory bowel diseases (IBDs), spread globally during the westernization of lifestyle and dietary habits over the past few decades. Here, we review experimental and clinical evidence for the metabolic nature of gut inflammation in IBD and delineate distinct parallels to the inflammatory state in metabolic diseases. Experimental evidence indicates that excessive intake of specific macronutrients in a Western diet fuels an inflammatory response in the gut by exploiting sensors of innate immunity and perturbation of gut microbial metabolism. Genetic IBD risk partly affects metabolism and stress signalling of innate immunity, and immunometabolism controls susceptibility to gut inflammation. Epidemiological and clinical studies indicate that specific nutrients in the Western diet pose a risk for the development of IBD and a poor disease course. Translational studies in IBD indicate perturbation of energy metabolism in immune cells and perturbation of gut microbial metabolism, which can be shaped by diet. In turn, dietary restriction by exclusive enteral nutrition induces remission in patients with IBD. Collectively, these studies support a metabolic underpinning of gut inflammation in IBD as described for metabolic inflammation in obesity and related disorders.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease of unknown aetiology affecting the colon and rectum. Multiple factors, such as genetic background, environmental and luminal factors, and mucosal immune dysregulation, have been suggested to contribute to UC pathogenesis. UC has evolved into a global burden given its high incidence in developed countries and the substantial increase in incidence in developing countries. An improved understanding of the mechanisms underlying UC has led to the emergence of new treatments. Since the early 2000s, anti-tumour necrosis factor (TNF) treatment has significantly improved treatment outcomes. Advances in medical treatments have enabled a paradigm shift in treatment goals from symptomatic relief to endoscopic and histological healing to achieve better long-term outcomes and, consequently, diagnostic modalities have also been improved to monitor disease activity more tightly. Despite these improvements in patient care, a substantial proportion of patients, for example, those who are refractory to medical treatment or those who develop colitis-associated colorectal dysplasia or cancer, still require restorative proctocolectomy. The development of novel drugs and improvement of the treatment strategy by implementing personalized medicine are warranted to achieve optimal disease control. However, delineating the aetiology of UC is necessary to ultimately achieve disease cure.

Ulcerative colitis is a lifelong inflammatory disease affecting the rectum and colon to a variable extent. In 2023, the prevalence of ulcerative colitis was estimated to be 5 million cases around the world, and the incidence is increasing worldwide. Ulcerative colitis is thought to occur in people with a genetic predisposition following environmental exposures; gut epithelial barrier defects, the microbiota, and a dysregulated immune response are strongly implicated. Patients usually present with bloody diarrhoea, and the diagnosis is based on a combination of clinical, biological, endoscopic, and histological findings. The aim of medical management is, first, to induce a rapid clinical response and normalise biomarkers and, second, to maintain clinical remission and reach endoscopic normalisation to prevent long-term disability. Treatments for inducing remission include 5-aminosalicylic acid drugs and corticosteroids. Maintenance treatments include 5-aminosalicylic acid drugs, thiopurines, biologics (eg, anti-cytokines and anti-integrins), and small molecules (Janus kinase inhibitors and sphingosine-1-phosphate receptor modulators). Although the therapeutic options are expanding, 10-20% of patients still require proctocolectomy for medically refractory disease. The keys to breaking through this therapeutic ceiling might be the combination of therapeutics with precision and personalised medicine.