Estrogen deprivation and estrogen receptor α antagonism decrease DSS colitis in female mice.

The association of hormonal contraception with increased risk of inflammatory bowel disease (IBD) observed in females suggests involvement of ovarian hormones, such as estradiol, and the estrogen receptors in the progression of intestinal inflammation. Here, we investigated the effects of prophylactic SERM2 and estradiol supplementation in dextran sulfate sodium-induced colitis using mice with intact ovaries and ovariectomized (OVX) female mice. We found that graded colitis score was threefold reduced in the OVX mice, compared to mice with intact ovaries. Estradiol supplementation, however, aggravated the colitis in OVX mice, increasing the colitis score to a similar level than what was observed in the intact mice. Further, we observed that immune infiltration and gene expression of inflammatory interleukins Il1b, Il6, and Il17a were up to 200-fold increased in estradiol supplemented OVX colitis mice, while a mild but consistent decrease was observed by SERM2 treatment in intact animals. Additionally, cyclo-oxygenase 2 induction was increased in the colon of colitis mice, in correlation with increased serum estradiol levels. Measured antagonist properties of SERM2, together with the other results presented here, indicates an exaggerating role of ERα signaling in colitis. Our results contribute to the knowledge of ovarian hormone effects in colitis and encourage further research on the potential use of ER antagonists in the colon, in order to alleviate inflammation.

Neohesperidin Dihydrochalcone Ameliorates Experimental Colitis via Anti-Inflammatory, Antioxidative, and Antiapoptosis Effects.

Neohesperidin dihydrochalcone (NHDC) is a citrus-originated, seminatural sweetener. There is no investigation concerning the effect of NHDC on ulcerative colitis. The purpose of this study was to determine the therapeutic and protective effects of NHDC in Wistar Albino rats. NHDC was given for 7 days after or before colitis induction. The results showed that NHDC significantly reduced the interleukin-6 (IL-6), interleukin-10 (IL-10), transforming growth factor-ß1 (TGF-ß1), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) levels. Catalase levels did not show a significant difference between the groups. NHDC provided a remarkable decrease in the expression levels of cyclooxygenase-2 (COX-2), myeloperoxidase (MPO), malondialdehyde (MDA), 8-hydroxy-2'-deoxyguanosine (8-OHdG), and nuclear factor kappa B (NF-κB). Total antioxidant status (TAS) levels were significantly elevated in NHDC treatment groups, while total oxidant status (TOS) and oxidative stress index (OSI) levels were significantly decreased. NHDC provided remarkable improvement in histological symptoms such as epithelial erosion, edema, mucosal necrosis, inflammatory cell infiltration, and hemorrhage. Also, caspase-3 expression levels were statistically decreased in NHDC treatment groups. The results indicated that NHDC might be a protection or alternative treatment for ulcerative colitis.

Interfacial-engineered living drugs with "ON/OFF" switching for oral delivery.

Living drugs offer a new frontier in medicine, paving the way for personalized and potentially curative treatments. A customized living drug generally requires specialized technologies for highly effective and selective delivery to lesion locations. In this study, we explored an interfacial engineering method for living drugs by wrapping them with a "stealth coating", achieving "ON/OFF" switching of the communications between probiotics and the gastrointesinal (GI) tract. This maximized the bioactivity of living drugs following oral administration to exempt acidic insults and then significantly improved the retention through the gastrointestinal tract. With the notable ability to improve oral availability, the interfacial-engineered living drugs represent remarkable effects for enhanced oral delivery and treatment efficacy in the dextran sulfate sodium (DSS)-induced acute colitis model. We believe that this work has the potential to revolutionize medicine by precisely targeting and increasing curative activity in the future of disease treatment.

Orally administrated liquid metal agents for inflammation-targeted alleviation of inflammatory bowel diseases.

Rapid drug clearance and off-target effects of therapeutic drugs can induce low bioavailability and systemic side effects and gravely restrict the therapeutic effects of inflammatory bowel diseases (IBDs). Here, we propose an amplifying targeting strategy based on orally administered gallium (Ga)-based liquid metal (LM) nano-agents to efficiently eliminate reactive oxygen and nitrogen species (RONS) and modulate the dysregulated microbiome for remission of IBDs. Taking advantage of the favorable adhesive activity and coordination ability of polyphenol structure, epigallocatechin gallate (EGCG) is applied to encapsulate LM to construct the formulations (LM-EGCG). After adhering to the inflamed tissue, EGCG not only eliminates RONS but also captures the dissociated Ga to form EGCG-Ga complexes for enhancive accumulation. The detained composites protect the intestinal barrier and modulate gut microbiota for restoring the disordered enteral microenvironment, thereby relieving IBDs. Unexpectedly, LM-EGCG markedly decreases the Escherichia_Shigella populations while augmenting the abundance of Akkermansia and Bifidobacterium, resulting in favorable therapeutic effects against the dextran sulfate sodium-induced colitis.

Therapeutic potential of the secreted Kazal-type serine protease inhibitor SPINK4 in colitis.

Mucus injury associated with goblet cell (GC) depletion constitutes an early event in inflammatory bowel disease (IBD). Using single-cell sequencing to detect critical events in mucus dysfunction, we discover that the Kazal-type serine protease inhibitor SPINK4 is dynamically regulated in colitic intestine in parallel with disease activities. Under chemically induced colitic conditions, the grim status in Spink4-conditional knockout mice is successfully rescued by recombinant murine SPINK4. Notably, its therapeutic potential is synergistic with existing TNF-α inhibitor infliximab in colitis treatment. Mechanistically, SPINK4 promotes GC differentiation using a Kazal-like motif to modulate EGFR-Wnt/ß-catenin and -Hippo pathways. Microbiota-derived diacylated lipoprotein Pam2CSK4 triggers SPINK4 production. We also show that monitoring SPINK4 in circulation is a reliable noninvasive technique to distinguish IBD patients from healthy controls and assess disease activity. Thus, SPINK4 serves as a serologic biomarker of IBD and has therapeutic potential for colitis via intrinsic EGFR activation in intestinal homeostasis.

Ginkgetin improved experimental colitis by inhibiting intestinal epithelial cell apoptosis through EGFR/PI3K/AKT signaling.

Excessive apoptosis of intestinal epithelial cells leads to intestinal barrier dysfunction, which is not only one of the pathological features of inflammatory bowel disease (IBD) but also a therapeutic target. A natural plant extract, Ginkgetin (GK), has been reported to have anti-apoptotic activity, but its role in IBD is unknown. This study aimed to explore whether GK has anti-colitis effects and related mechanisms. An experimental colitis model induced by dextran sulfate sodium (DSS) was established, and GK was found to relieve colitis in DSS-induced mice as evidenced by improvements in weight loss, colon shortening, Disease Activity Index (DAI), macroscopic and tissue scores, and proinflammatory mediators. In addition, in DSS mice and TNF-α-induced colonic organoids, GK protected the intestinal barrier and inhibited intestinal epithelial cell apoptosis, by improving permeability and inhibiting the number of apoptotic cells and the expression of key apoptotic regulators (cleaved caspase 3, Bax and Bcl-2). The underlying mechanism of GK's protective effect was explored by bioinformatics, rescue experiments and molecular docking, and it was found that GK might directly target and activate EGFR, thereby interfering with PI3K/AKT signaling to inhibit apoptosis of intestinal epithelial cells in vivo and in vitro. In conclusion, GK inhibited intestinal epithelial apoptosis in mice with experimental colitis, at least in part, by activating EGFR and interfering with PI3K/AKT activation, explaining the underlying mechanism for ameliorating colitis, which may provide new options for the treatment of IBD.

Discovery of a Series of 4-Amide-thiophene-2-carboxyl Derivatives as Highly Potent P2Y14 Receptor Antagonists for Inflammatory Bowel Disease Treatment.

The P2Y14 receptor has been proven to be a potential target for IBD. Herein, we designed and synthesized a series of 4-amide-thiophene-2-carboxyl derivatives as novel potent P2Y14 receptor antagonists based on the scaffold hopping strategy. The optimized compound 39 (5-((5-fluoropyridin-2-yl)oxy)-4-(4-methylbenzamido)thiophene-2-carboxylic acid) exhibited subnanomolar antagonistic activity (IC50: 0.40 nM). Moreover, compound 39 demonstrated notably improved solubility, liver microsomal stability, and oral bioavailability. Fluorescent ligand binding assay confirmed that 39 has the binding ability to the P2Y14 receptor, and molecular dynamics (MD) simulations revealed the formation of a unique intramolecular hydrogen bond (IMHB) in the binding conformation. In the experimental colitis mouse model, compound 39 showed a remarkable anti-IBD effect even at low doses. Compound 39, with a potent anti-IBD effect and favorable druggability, can be a promising candidate for further research. In addition, this work lays a strong foundation for the development of P2Y14 receptor antagonists and the therapeutic strategy for IBD.

Inflammation assessment and therapeutic monitoring based on highly sensitive and multi-level electrochemical detection of PGE2.

Prostaglandin E2 (PGE2), an eicosane, regulates the physiological activity of inflammatory cells and represents a potential therapeutic target for facilitating tissue repair in vivo. In our work, an electrochemical immunosensor employing Ketjen black-Au nanoparticles (KB-Au) and poly tannic acid nanospheres conjugated with anti-PGE2 polyclonal antibody (PTAN-Ab) was designed to ultra-sensitively analyze PGE2 levels secreted by living cells and tissues. Antibody assembly strategies were explored to achieve signal amplification. Moreover, we studied the therapy effects of docosahexaenoic acid (DHA), arachidonic acid (AA), hyaluronic acid (HA), and small molecule 15-hydroxyprostaglandin dehydrogenase inhibitor (SW033291) on inflammation and evaluated the protective functions of HA and SW033291 in a murine model subjected to colitis induced by dextran sulfate sodium (DSS) using the developed sensor. The sensor exhibited a linear range of 10-5-106 fg/mL and a detection limit (LOD) of 10-5 fg/mL. Fetal bovine serum (FBS) samples were used to achieve high recovery of target analytes. This study not only presents an effective strategy for ultra-sensitively monitoring PGE2 but also provides valuable insights into assessing the degree of inflammation and the therapeutic effect of related drugs. Research on human health monitoring and regenerative medicine could greatly benefit from the findings.

Insoluble polysaccharides produced in plant cell cultures protect from Clostridioides difficile colitis.

Clostridioides difficile infection (CDI) poses a significant health threat due to high recurrence rates. Antimicrobial agents are commonly used to manage CDI-related diarrhoea; however, by aggravating intestinal dysbiosis, antibiotics enable C. difficile spores germination and production of toxins, the main virulence factors. Therefore, the binding of exotoxins using adsorbents represents an attractive alternative medication for the prevention and treatment of relapses. In this study, we provided evidence that the natural insoluble polysaccharides, named ABR119, extracted by plant cell cultures, effectively trap C. difficile toxins. In our experiments, ABR119 exhibited no cytotoxicity in vitro and was safely administered in vivo. In the animal model of C. difficile-associated colitis, ABR119 (50 mg/kg body weight) significantly reduced the colonic myeloperoxidase activity and severity of inflammation, preventing body weight loss. These effects were not evident when we treated animals with wheat bran polysaccharides. We did not detect bacterial killing effects of ABR119 against C. difficile nor against bacterial species of the normal gut microbiota. Moreover, ABR119 did not interfere in vitro with the antimicrobial activities of most clinically used antibiotics. In summary, ABR119 holds promise for treating and preventing C. difficile colitis by trapping the bacterial toxins, warranting further studies to assess the ABR119 potential in human infections caused by C. difficile.

Corrigendum to: Mechanism of HSP90 Inhibitor in the Treatment of DSS-induced Colitis in Mice by Inhibiting MAPK Pathway and Synergistic Effect of Compound Sophorae Decoction.

A typographical error appeared in the title of the article "Mechanism of HSP90 Inhibitor in the Treatment of DSS-induced Colitis in Mice by Inhibiting MAPK Pathway and Synergistic Effect of Compound Sophora Decoction", published in Current Pharmaceutical Design, 2022; 28(42): 3456-3468 [1]. Details of the error and a correction are provided below. Original: Mechanism of HSP90 Inhibitor in the Treatment of DSS-induced Colitis in Mice by Inhibiting MAPK Pathway and Synergistic Effect of Compound Sophora Decoction Corrected: Mechanism of HSP90 Inhibitor in the Treatment of DSS-induced Colitis in Mice by Inhibiting MAPK Pathway and Synergistic Effect of Compound Sophorae Decoction We regret the error and apologize to readers. The original article can be found online at: https://www.eurekaselect.com/article/127740.

Qing Hua Chang Yin ameliorates chronic colitis in mice by inhibiting PERK-ATF4-CHOP pathway of ER stress and the NF-κB signalling pathway.

CONTEXT: Ulcerative colitis has been clinically treated with Qing Hua Chang Yin (QHCY), a traditional Chinese medicine formula. However, its precise mechanisms in mitigating chronic colitis are largely uncharted. OBJECTIVE: To elucidate the therapeutic efficiency of QHCY on chronic colitis and explore its underlying molecular mechanisms. MATERIALS AND METHODS: A total ion chromatogram fingerprint of QHCY was analysed. Chronic colitis was induced in male C57BL/6 mice using 2% dextran sodium sulphate (DSS) over 49 days. Mice were divided into control, DSS, DSS + QHCY (0.8, 1.6 and 3.2 g/kg/d dose, respectively) and DSS + mesalazine (0.2 g/kg/d) groups (n = 6). Mice were intragastrically administered QHCY or mesalazine for 49 days. The changes of disease activity index (DAI), colon length, colon histomorphology and serum pro-inflammatory factors in mice were observed. RNA sequencing was utilized to identify the differentially expressed transcripts (DETs) in colonic tissues and the associated signalling pathways. The expression of endoplasmic reticulum (ER) stress-related protein and NF-κB signalling pathway-related proteins in colonic tissues was detected by immunohistochemistry staining. RESULTS: Forty-seven compounds were identified in QHCY. Compared with the DSS group, QHCY significantly improved symptoms of chronic colitis like DAI increase, weight loss, colon shortening and histological damage. It notably reduced serum levels of IL-6, IL-1ß and TNF-α. QHCY suppressed the activation of PERK-ATF4-CHOP pathway of ER stress and NF-κB signalling pathways in colonic tissues. DISCUSSION AND CONCLUSIONS: The findings in this study provide novel insights into the potential of QHCY in treating chronic colitis patients.

Matrine Ameliorates DSS-Induced Colitis by Suppressing Inflammation, Modulating Oxidative Stress and Remodeling the Gut Microbiota.

Matrine (MT) possesses anti-inflammatory, anti-allergic and antioxidative properties. However, the impact and underlying mechanisms of matrine on colitis are unclear. The purpose of this research was to examine the protective impact and regulatory mechanism of matrine on dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice. MT alleviated DSS-induced UC by inhibiting weight loss, relieving colon shortening and reducing the disease activity index (DAI). Moreover, DSS-induced intestinal injury and the number of goblet cells were reversed by MT, as were alterations in the expression of zonula occludens-1 (ZO-1) and occludin in colon. Simultaneously, matrine not only effectively restored DSS-induced oxidative stress in colonic tissues but also reduced the production of inflammatory cytokines. Furthermore, MT could treat colitis mice by regulating the regulatory T cell (Treg)/T helper 17 (Th17) cell imbalance. We observed further evidence that MT alleviated the decrease in intestinal flora diversity, reduced the proportion of Firmicutes and Bacteroidetes, decreased the proportion of Proteobacteria and increased the relative abundance of Lactobacillus and Akkermansia in colitis mice. In conclusion, these results suggest that MT may mitigate DSS-induced colitis by enhancing the colon barrier integrity, reducing the Treg/Th17 cell imbalance, inhibiting intestinal inflammation, modulating oxidative stress and regulating the gut microbiota. These findings provide strong evidence for the development and application of MT as a dietary treatment for UC.

Peiminine ameliorates Crohn's disease-like colitis by enhancing the function of the intestinal epithelial barrier through Nrf2/HO1 signal.

BACKGROUND AND AIMS: Impaired intestinal barrier function is key in maintaining intestinal inflammation in Crohn's disease (CD). However, no targeted treatment in clinical practice has been developed. Peiminine (Pm) strongly protects the epithelial barrier, the purpose of this study is to investigate whether Pm affects CD-like colitis and potential mechanisms for its action. METHODS: Trinitro-benzene-sulfonic acid (TNBS)-induced mice and Il-10-/- mice were used as CD animal models. Colitis symptoms, histological analysis, and intestinal barrier permeability were used to assess the Pm's therapeutic effect on CD-like colitis. The colon organoids were induced by TNF-α to evaluate the direct role of Pm in inhibiting apoptosis of the intestinal epithelial cells. Western blotting and small molecule inhibitors were used to investigate further the potential mechanism of Pm in inhibiting apoptosis of intestinal epithelial cells. RESULTS: Pm treatment reduced body weight loss, disease activity index (DAI) score, and inflammatory score, demonstrating that colonic inflammation in mice were alleviated. Pm decreased the intestinal epithelial apoptosis, improved the intestinal barrier function, and prevented the loss of tight junction proteins (ZO1 and claudin-1) in the colon of CD mice and TNF-α-induced colonic organoids. Pm activated Nrf2/HO1 signaling, which may protect intestinal barrier function. CONCLUSIONS: Pm inhibits intestinal epithelial apoptosis in CD mice by activating Nrf2/HO1 pathway. This partially explains the potential mechanism of Pm in ameliorating intestinal barrier function in mice and provides a new approach to treating CD.

Gut microbiota and D-ribose mediate the anti-colitic effect of punicalagin in DSS-treated mice.

Background: Inflammatory bowel disease (IBD) is an increasing health burden worldwide. Punicalagin, a bioactive component rich in pomegranate rind, has been shown to attenuate chemical or bacteria-induced experimental colitis in mice, but whether punicalagin exerts its function through modulating gut microbiota and metabolites remains unexplored. Results: Punicalagin (100 mg per kg per day) administered orally to mice alleviated dextran-sodium sulfate (DSS)-induced colitis. Gut microbiota analyzed by 16S rRNA sequencing showed that punicalagin altered gut microbiota by increasing the Lachnospiraceae_NK4A136_group and Bifidobacterium abundance. To evaluate the effect of punicalagin-modulated microbiota and its metabolites in colitis mice, we transplanted fecal microbiota and sterile fecal filtrate (SFF) to mice treated with oral antibiotics. The results of fecal microbiota transplantation (FMT) demonstrated that punicalagin's anti-colitic effect is transferable by transplanting punicalagin-modulated gut microbiota and its metabolites. Additionally, we discovered that punicalagin-modulated sterile fecal filtrate also exhibits anti-colitis effects, as evidenced by improved intestinal barrier integrity and decreased inflammation. Subsequently, fecal metabolites were analyzed using liquid chromatography-mass spectrometry (LC-MS). The analysis revealed that punicalagin significantly increased the level of D-ribose. In vitro experiments showed that D-ribose has both anti-inflammatory and antioxidant properties. Furthermore, D-ribose significantly mitigated DSS-induced colitis symptoms in mice. Conclusions: Overall, this study demonstrated that gut microbiota and its metabolites partly mediate the protective effect of punicalagin against DSS-induced colitis in mice. D-ribose is a key metabolite that contributes to the anti-colitic effect of punicalagin in mice.

Low-dose dimethylfumarate attenuates colitis-associated cancer in mice through M2 macrophage polarization and blocking oxidative stress.

Colitis-associated cancer (CAC) is an aggressive subtype of colorectal cancer that can develop in ulcerative colitis patients and is driven by chronic inflammation and oxidative stress. Current chemotherapy for CAC, based on 5-fluorouracil and oxalipltin, is not fully effective and displays severe side effects, prompting the search for alternative therapies. Dimethylfumarate (DMF), an activator of the nuclear factor erythroid 2-related factor 2 (NRF2), is a potent antioxidant and immunomodelatrory drug used in the treatment of multiple sclerosis and showed a strong anti-inflammatory effect on experimental colitis. Here, we investigated the chemotherapeutic effect of DMF on an experimental model of CAC. Male NMRI mice were given two subcutaneous injections of 1,2 Dimethylhydrazine (DMH), followed by three cycles of dextran sulfate sodium (DSS). Low-dose (DMF30) and high-dose of DMF (DMF100) or oxaliplatin (OXA) were administered from the 8th to 12th week of the experiment, and then the colon tissues were analysed histologically and biochemically. DMH/DSS induced dysplastic aberrant crypt foci (ACF), oxidative stress, and severe colonic inflammation, with a predominance of pro-inflammatory M1 macrophages. As OXA, DMF30 reduced ACF multiplicity and crypt dysplasia, but further restored redox status, and reduced colitis severity by shifting macrophages towards the anti-inflammatory M2 phenotype. Surprisingly, DMF100 exacerbated ACF multiplicity, oxidative stress, and colon inflammation, likely through NRF2 and p53 overexpression in colonic inflammatory cells. DMF had a dual effect on CAC. At low dose, DMF is chemotherapeutic and acts as an antioxidant and immunomodulator, whereas at high dose, DMF is pro-oxidant and exacerbates colitis-associated cancer.

Cinnamaldehyde, A Bioactive Compound from the Leaves of Cinnamomum osmophloeum Kaneh, Ameliorates Dextran Sulfate Sodium-Induced Colitis in Mice by Inhibiting the NLRP3 Inflammasome.

Inflammatory bowel disease (IBD) comprises a group of idiopathic intestinal disorders, including ulcerative colitis and Crohn's disease, significantly impacting the quality of life for affected individuals. The effective management of these conditions remains a persistent challenge. The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, a complex molecular structure, regulates the production of pro-inflammatory cytokines such as interleukin-1ß. Abnormal activation of the NLRP3 inflammasome plays a pivotal role in the development of IBD, making it a compelling target for therapeutic intervention. Our research revealed that cinnamaldehyde (CA), a major bioactive compound found in the leaves of Cinnamomum osmophloeum kaneh, demonstrated a remarkable ability to alleviate colitis induced by dextran sulfate sodium (DSS) in a mouse model. This effect was attributed to CA's ability to downregulate the activation of the NLRP3 inflammasome and reduce the expression of pro-inflammatory mediators in the colon. In the mechanism study, we observed that CA inhibited the NLRP3 inflammasome in macrophages, at least partially, by enhancing the autophagic response, without reducing mitochondrial damage. These findings collectively suggest that CA holds significant potential as a therapeutic agent for enhancing the management of IBD, offering a promising avenue for further research and development.

Endogenous stem cell mobilization and localized immunosuppression synergistically ameliorate DSS-induced Colitis in mice.

BACKGROUND: Stem cell therapy is a promising alternative for inflammatory diseases and tissue injury treatment. Exogenous delivery of mesenchymal stem cells is associated with instant blood-mediated inflammatory reactions, mechanical stress during administration, and replicative senescence or change in phenotype during long-term culture in vitro. In this study, we aimed to mobilize endogenous hematopoietic stem cells (HSCs) using AMD-3100 and provide local immune suppression using FK506, an immunosuppressive drug, for the treatment of inflammatory bowel diseases. METHODS: Reactive oxygen species (ROS)-responsive FK506-loaded thioketal microspheres were prepared by emulsification solvent-evaporation method. Thioketal vehicle based FK506 microspheres and AMD3100 were co-administered into male C57BL6/J mice with dextran sulfate sodium (DSS) induced colitis. The effect of FK506-loaded thioketal microspheres in colitis mice were evaluated using disease severity index, myeloperoxidase activity, histology, flow cytometry, and gene expression by qRT-PCR. RESULTS: The delivery of AMD-3100 enhanced mobilization of HSCs from the bone marrow into the inflamed colon of mice. Furthermore, targeted oral delivery of FK506 in an inflamed colon inhibited the immune activation in the colon. In the DSS-induced colitis mouse model, the combination of AMD-3100 and FK506-loaded thioketal microspheres ameliorated the disease, decreased immune cell infiltration and activation, and improved body weight, colon length, and epithelial healing process. CONCLUSION: This study shows that the significant increase in the percentage of mobilized hematopoietic stem cells in the combination therapy of AMD and oral FK506 microspheres may contribute to a synergistic therapeutic effect. Thus, low-dose local delivery of FK506 combined with AMD3100 could be a promising alternative treatment for inflammatory bowel diseases.

Stable Dietary Ora-Curcumin Formulation Protects from Experimental Colitis and Colorectal Cancer.

Inflammatory bowel disease (IBD) is a chronic gut disorder that also elevates the risk of colorectal cancer (CRC). The global incidence and severity of IBD are rising, yet existing therapies often lead to severe side effects. Curcumin offers potent anti-inflammatory and chemotherapeutic properties. However, its clinical translation is hindered by rapid metabolism, as well as poor water solubility and stability, which limits its bioavailability. To address these challenges, we developed OC-S, a water-soluble and colon-targeted curcumin formulation that protects against colitis in mice. The current study advances OC-S as a dietary supplement by establishing its stability and compatibility with various commercial dietary products. Further, OC-S exhibited specific binding to inflamed colon tissue, potentially aiding in targeted drug retention at the inflammation site in colitis with diarrhea symptoms. We further investigated its efficacy in vivo and in vitro using a murine model of colitis and tumoroids from APCmin mice. OC-S significantly reduced colitis severity and pro-inflammatory cytokine expression compared with curcumin, even at very low doses (5 mg/kg/day). It also demonstrated higher anti-proliferative activity in CRC cells and colon cancer tumoroids vs. curcumin. Overall, this study demonstrated that OC-S effectively targets and retains water-soluble curcumin at the inflamed colon sites, while showing promise in addressing both colitis and colorectal cancer, which potentially paves the way for OC-S to advance into clinical development as a dietary product for both IBD and CRC.

Quorum-Sensing Signal DSF Inhibits the Proliferation of Intestinal Pathogenic Bacteria and Alleviates Inflammatory Response to Suppress DSS-Induced Colitis in Zebrafish.

The imbalance of gut microbiota is an important factor leading to inflammatory bowel disease (IBD). Diffusible signal factor (DSF) is a novel quorum-sensing signal that regulates bacterial growth, metabolism, pathogenicity, and host immune response. This study aimed to explore the therapeutic effect and underlying mechanisms of DSF in a zebrafish colitis model induced by sodium dextran sulfate (DSS). The results showed that intake of DSF can significantly improve intestinal symptoms in the zebrafish colitis model, including ameliorating the shortening of the intestine, reducing the increase in the goblet cell number, and restoring intestinal pathological damage. DSF inhibited the upregulation of inflammation-related genes and promoted the expression of claudin1 and occludin1 to protect the tightness of intestinal tissue. The gut microbiome analysis demonstrated that DSF treatment helped the gut microbiota of the zebrafish colitis model recover to normal at the phylum and genus levels, especially in terms of pathogenic bacteria; DSF treatment downregulated the relative abundance of Aeromonas hydrophila and Staphylococcus aureus, and it was confirmed in microbiological experiments that DSF could effectively inhibit the colonization and infection of these two pathogens in the intestine. This study suggests that DSF can alleviate colitis by inhibiting the proliferation of intestinal pathogens and inflammatory responses in the intestine. Therefore, DSF has the potential to become a dietary supplement that assists in the antibiotic and nutritional treatment of IBD.

Yerba Mate (Ilex paraguariensis) Reduces Colitis Severity by Promoting Anti-Inflammatory Macrophage Polarization.

Yerba Mate (YM) (Ilex paraguariensis) is a natural herbal supplement with a well-described anti-inflammatory capacity and beneficial effects in different inflammatory contexts such as insulin resistance or obesity. However, whether YM could improve other inflammatory conditions such as colitis or the immune cell population that can be modulated by this plant remains elusive. Here, by using 61 male and female C57BL/6/J wild-type (WT) mice and the dextran sodium sulfate (DSS)-induced acute colitis model, we evaluated the effect of YM on colitis symptoms and macrophage polarization. Our results showed that the oral administration of YM reduces colitis symptoms and improves animal survival. Increasing infiltration of anti-inflammatory M2 macrophage was observed in the colon of the mice treated with YM. Accordingly, YM promoted M2 macrophage differentiation in vivo. However, the direct administration of YM to bone marrow-derived macrophages did not increase anti-inflammatory polarization, suggesting that YM, through an indirect mechanism, is able to skew the M1/M2 ratio. Moreover, YM consumption reduced the Eubacterium rectale/Clostridium coccoides and Enterobacteriaceae groups and increased the Lactobacillus/Lactococcus group in the gut microbiota. In summary, we show that YM promotes an immunosuppressive environment by enhancing anti-inflammatory M2 macrophage differentiation, reducing colitis symptoms, and suggesting that YM consumption may be a good cost-effective treatment for ulcerative colitis.