Dextran Sulfate Sodium-induced Colitis In Mice Research Articles

Anti-inflammation mechanisms of a homogeneous polysaccharide from Phyllanthus emblica L. on DSS induced colitis mice via the gut microbiota and metabolites alteration

Phyllanthus emblica L. offers promising therapeutic potential for inflammatory diseases. This study revealed the molecular structure of a homogeneous polysaccharide purified from Phyllanthus emblica L. (PEP-1) and evaluated its anti-inflammatory effects on ulcerative colitis (UC) in mice. In the in vivo experiment, administered in varying dosages to dextran sulfate sodium (DSS)-induced UC models, PEP-1 significantly alleviated colonic symptoms, histological damages and reshaped the gut microbiota. Notably, it adjusted the Firmicutes/Bacteroidetes ratio and reduced pro-inflammatory species, closely aligning with shifts in the fecal metabolites and metabolic pathways such as the metabolism of pyrimidine, beta-alanine, and purine. These findings underscore the potential of PEP-1 as a therapeutic agent for UC, providing insights into the mechanisms through gut microbiota and metabolic modulation.

A Traditional Chinese Medicine, Zhenqi Granule, Potentially Alleviates Dextran Sulfate Sodium-Induced Mouse Colitis Symptoms.

Ulcerative colitis (UC) is an inflammatory bowel disease that causes chronic inflammation in the large intestine. The etiology of UC is complex and incompletely understood, with potential contributing factors including genetic susceptibility, environmental influences, immune dysregulation, and gut barrier dysfunction. Despite available therapeutic drugs, the suboptimal cure rate for UC emphasizes the necessity of developing novel therapeutics. Traditional Chinese Medicine (TCM) has attracted great interest in the treatment of such chronic inflammatory diseases due to its advantages, such as multi-targets and low side effects. In this study, a mouse model of Dextran Sulfate Sodium (DSS)-induced acute colitis was established and the efficacy of Zhenqi Granule, a TCM preparation composed of the extractives from Astragali Radix and Fructus Ligustri Lucidi, was evaluated. The results showed that treatment with Zhenqi Granule prior to or post-DSS induction could alleviate the symptoms of colitis, including weight loss, diarrhea, hematochezia, colon length shortening, and pathological damage of colon tissues of the DSS-treated mice. Further, network pharmacology analysis showed that there were 98 common targets between the active components of Zhenqi Granule and the targets of UC, and the common targets were involved in the regulation of inflammatory signaling pathways. Our results showed that Zhenqi Granule had preventive and therapeutic effects on acute colitis in mice, and the mechanism may be that the active components of Zhenqi Granule participated in the regulation of inflammatory response. This study provided data reference for further exploring the mechanism of Zhenqi Granule and also provided potential treatment strategies for UC.

Lactiplantibacillus plantarum-Derived Indole-3-lactic Acid Ameliorates Intestinal Barrier Integrity through the AhR/Nrf2/NF-κB Axis.

Our previous studies have shown that Lactiplantibacillus plantarum DPUL-S164-derived indole-3-lactic acid (ILA) ameliorates intestinal epithelial cell barrier injury by activating aryl hydrocarbon receptor (AhR) and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathways and promoting tight junction protein expression. This study further explored the crucial substances of L. plantarum DPUL-S164 in alleviating intestinal barrier damage in mice through a dextran sodium sulfate-induced ulcerative colitis mouse model. Compared to dead L. plantarum DPUL-S164 (D-S164), live L. plantarum DPUL-S164 (S164) and its tryptophan metabolite, ILA, showed an effective ameliorating effect on the intestinal barrier injury of mice treated by antibiotic cocktail and sodium dextran sulfate, suggesting that the crucial substances of L. plantarum DPUL-S164 ameliorating intestinal barrier injury are its extracellular metabolites. Furthermore, S164 and its tryptophan metabolite, ILA, ameliorate intestinal barrier injury and suppress intestinal inflammation by activating the AhR-Nrf2 pathway and inhibiting the nuclear factor kappa-B (NF-κB) pathway. These results suggest that L. plantarum DPUL-S164 ameliorates intestinal epithelial barrier damage in mice, primarily by producing ILA as a ligand to activate the AhR pathway.

So Shiho Tang Reduces Inflammation in Lipopolysaccharide-Induced RAW 264.7 Macrophages and Dextran Sodium Sulfate-Induced Colitis Mice.

So Shiho Tang (SSHT) is a traditional herbal medicine commonly used in Asian countries. This study evaluated the anti-inflammatory effect of SSHT and the associated mechanism using lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages and murine dextran sodium sulfate (DSS)-induced ulcerative colitis models. Pre-treatment of RAW 264.7 macrophages with SSHT significantly reduced LPS-induced inflammation by decreasing nitrite production and regulating the mitogen-activated protein kinase pathway. Meanwhile, in mice, DSS-induced colitis symptoms, including colon shortening and body weight loss, were attenuated by SSHT. Moreover, representative compounds of SSHT, including glycyrrhizic acid, ginsenoside Rb1, baicalin, saikosaponin A, and saikosaponin B2, were quantified, and their effects on nitrite production were measured. A potential anti-inflammatory effect was detected in LPS-induced RAW 264.7 cells. Our findings suggest that SSHT is a promising anti-inflammatory agent. Its representative components, including saikosaponin B2, ginsenoside Rb1, and baicalin, may represent the key active compounds responsible for eliciting the anti-inflammatory effects and can, therefore, serve as quality control markers in SSHT preparations.

Geraniin Alleviates Inflammation in Caco-2 Cells and Dextran Sulfate Sodium-Induced Colitis Mice by Targeting IL-1β.

IL-1β is an important cytokine implicated in the progression of inflammatory bowel disease (IBD) and intestinal barrier dysfunction. The polyphenolic compound, geraniin, possesses bioactive properties, such as antitumor, antioxidant, anti-inflammatory, antihypertensive, and antiviral activities; however, its IL-1β-targeted anticolitis activity remains unclear. Here, we evaluated the inhibitory effect of geraniin in IL-1β-stimulated Caco-2 cells and a dextran sulfate sodium (DSS)-induced colitis mouse model. Geraniin blocked the interaction between IL-1β and IL-1R by directly binding to IL-1β and inhibited the IL-1β activity. It suppressed IL-1β-induced intestinal tight junction damage in human Caco-2 cells by inhibiting IL-1β-mediated MAPK, NF-kB, and MLC activation. Moreover, geraniin administration effectively reduced colitis symptoms and attenuated intestinal barrier injury in mice by suppressing elevated intestinal permeability and restoring tight junction protein expression through the inhibition of MAPK, NF-kB, and MLC activation. Thus, geraniin exhibits anti-IL-1β activity and anticolitis effect by hindering the IL-1β and IL-1R interaction and may be a promising therapeutic anti-IL-1β agent for IBD treatment.

HSPA9 reduction exacerbates symptoms and cell death in DSS-Induced inflammatory colitis

Inflammatory bowel disease (IBD) is a chronic inflammatory condition that is influenced by various factors, including environmental factors, immune responses, and genetic elements. Among the factors that influence IBD progression, macrophages play a significant role in generating inflammatory mediators, and an increase in the number of activated macrophages contributes to cellular damage, thereby exacerbating the overall inflammatory conditions. HSPA9, a member of the heat shock protein 70 family, plays a crucial role in regulating mitochondrial processes and responding to oxidative stress. HSPA9 deficiency disrupts mitochondrial dynamics, increasing mitochondrial fission and the production of reactive oxygen species. Based on the known functions of HSPA9, we considered the possibility that HSPA9 reduction may contribute to the exacerbation of colitis and investigated its relevance. In a dextran sodium sulfate-induced colitis mouse model, the downregulated HSPA9 exacerbates colitis symptoms, including increased immune cell infiltration, elevated proinflammatory cytokines, decreased tight junctions, and altered macrophage polarization. Moreover, along with the increased mitochondrial fission, we found that the reduction in HSPA9 significantly affected the superoxide dismutase 1 levels and contributed to cellular death. These findings enhance our understanding of the intricate mechanisms underlying colitis and contribute to the development of novel therapeutic approaches for this challenging condition.

Structural characteristics of steamed Polygonatum cyrtonema polysaccharide and its bioactivity on colitis via improving the intestinal barrier and modifying the gut microbiota

Steamed Polygonatum cyrtonema has been commonly used clinically for its gaining effect, whose main active ingredient is a polysaccharide. A water-soluble polysaccharide named PSP-W-1 was isolated from steamed Polygonatum cyrtonema. PSP-W-1 was characterized as a galactan having a backbone consisting predominately of 1,4-β-linked Galp branched at the C-6 position by T-β-linked Galp with a molecular weight of 14.4 kDa. PSP-W-1 could inhibit the overproduction of inflammatory factors and inflammatory mediators (iNOS, IL-6, COX-2) in dextran sodium sulfate-induced colitis mice. Oral administration of PSP-W-1 dramatically alleviated colonic pathological damage, repaired the intestinal barrier (occludin and ZO-1) and regulated the intestinal microbiota by increasing the abundance of norank_f_Muribaculaceae, Lactobacillus and norank_f_norank_o_Clostridia UCG-014, while decreasing the abundance of Bacteroides and Escherichia-Shigella to alleviate colitis symptoms. Overall, our findings suggest that PSP-W-1 might be a therapeutic option for both the prevention and treatment of colitis.

Shen-Ling-Bai-Zhu-San alleviates the imbalance of intestinal homeostasis in dextran sodium sulfate-induced colitis mice by regulating gut microbiota and inhibiting the NLRP3 inflammasome activation

Ethnopharmacological relevanceShen-Ling-Bai-Zhu-San (SLBZS) is a classic formula for strengthening the spleen and dispelling dampness, which has shown excellent efficacy in inflammatory bowel disease (IBD) in traditional Chinese medicine clinical studies. However, its exact pharmacological mechanism needs to be further elucidated. Aim of the studyThis study aims to investigate the restorative effect and mechanism of SLBZS on disturbed intestinal homeostasis in DSS-induced colitis mice. Materials and methodsA colitis model was induced by 3% dextran sulfate sodium (DSS) for seven days, and SLBZS was administered by gavage. The influence of SLBZS on DSS-induced clinical symptoms and disease activity index (DAI) was monitored and analyzed. Alcian blue and fluorescein isothiocyanate-conjugated wheat germ agglutinin (FITC-WGA) staining were used to assess intestinal mucus changes. The expression of intestinal barrier function indexes and immune-associated indexes were determined by H&E staining, real-time quantitative PCR (RT-qPCR), and Western blot. And gut microbiota changes were detected by 16S rDNA sequencing technology. The antibiotic experiment was used to explore the role of gut microbiota in SLBZS treatment. ResultsThe results showed that SLBZS significantly improved the physiological indexes including body weight, DAI score, and colon length of colitis mice. We focused on the effects of SLBZS on intestinal homeostasis in colitis mice. First, SLBZS could enhance the secretion of intestinal mucin and the expression levels of tight junctions and adhesive junctions. Second, SLBZS inhibited the expression level of inflammatory factors and reduced the protein expression level of NLRP3 inflammasome. Third, 16S rDNA sequencing analysis revealed that SLBZS repaired the dysfunctional gut microbiota of colitis mice, such as enhancing the abundance of short-chain fatty acid-producing bacteria including Faecalibaculum, Colidextribacter, and Coprococcus. Further, by gut microbiota-depleted mice, we found that SLBZS could not exert an anti-colitis effect when gut microbiota was absent. ConclusionsSLBZS restored intestinal environmental homeostasis by enhancing intestinal barrier function, inhibiting NLRP3 inflammasome, and restoring disturbed gut microbiota. And SLBZS could not ameliorate colitis mice with depleted gut microbiota. Our finding provided a theoretical basis for the clinical application of SLBZS in IBD.

Gastrointestinal Microenvironment Responsive Nanoencapsulation of Probiotics and Drugs for Synergistic Therapy of Intestinal Diseases.

The gut microbiota are prominent in preserving intestinal environmental homeostasis and managing human health, and their dysbiosis has been directly related to many kinds of intestinal diseases. Probiotics-based therapy appears as a promising approach for the treatment of gut microbiota dysbiosis, while it always suffers from limited bioavailability and therapeutic effect after oral administration. Herein, we presented a facile and safe strategy to treat colitis by nanoencapsulation of probiotics and an anti-inflammatory agent, 5-aminosalicylic acid (5-ASA), within the gastrointestinal microenvironment responsive alginate polysaccharide. Because of acid resistance, the alginate-based coating protected probiotics from the harsh gastric condition. The coating could be disintegrated to release probiotics and 5-ASA upon arriving in the intestinal tract, where the pH is normally higher than 5. In the dextran sulfate sodium-induced colitis mouse model, probiotics recovered their bioactivities and acted together with anti-inflammatory 5-ASA to alleviate colitis by upregulating microbiota richness and diversity, reducing expression of proinflammatory cytokines, and restoring intestinal barriers. This work demonstrated the synergistic therapy of intestinal diseases based on alginate-encapsulated probiotics and a clinical drug, which provided an extensive method to improve the therapeutic effect of oral microecologics.

Gastric vagal afferent signaling to the basolateral amygdala mediates anxiety-like behaviors in experimental colitis mice.

Inflammatory bowel disease (IBD) is a relapsing-remitting disorder characterized by chronic inflammation of the gastrointestinal (GI) tract. Anxiety symptoms are commonly observed in patients with IBD, but the mechanistic link between IBD and anxiety remains elusive. Here, we sought to characterize gut-to-brain signaling and brain circuitry responsible for the pathological expression of anxiety-like behaviors in male dextran sulfate sodium-induced (DSS-induced) experimental colitis mice. We found that DSS-treated mice displayed increased anxiety-like behaviors, which were prevented by bilateral GI vagal afferent ablation. The locus coeruleus (LC) is a relay center connecting the nucleus tractus solitarius to the basolateral amygdala (BLA) in controlling anxiety-like behaviors. Chemogenetic silencing of noradrenergic LC projections to the BLA reduced anxiety-like behaviors in DSS-treated mice. This work expands our understanding of the neural mechanisms by which IBD leads to comorbid anxiety and emphasizes a critical role of gastric vagal afferent signaling in gut-to-brain regulation of emotional states.

MiR-29c-3p Accelerates Mucosal Injury in Dextran Sodium Sulfate-induced Ulcerative Colitis Mice through the KDM6B/ H3K27me3/LDHA axis.

Ulcerative colitis (UC) is an inflammatory intestinal disorder featured by mucosal injury. MicroRNAs (miRNAs) play a role in the pathogenesis underlying UC. This study was conducted to investigate the role of miR-29c-3p in a dextran sodium sulfate (DSS)-induced UC mouse model and provide targets for UC treatment. The UC mouse model was established by DSS induction. The expression levels of miR-29c-3p, lysine-specific demethylase 6B (KDM6B), zonula occludens-1 (ZO-1), Occludin, and lactate dehydrogenase A (LDHA) were detected by real-time quantitative polymerase chain reaction or Western blot assays. The mucosal injury was evaluated by disease activity index (DAI), colon length, Hematoxylin-Eosin staining, and fluorescein isothiocyanate-glucan permeability test. The binding between miR-29c-3p and KDM6B and the occupation of KDM6B or trimethylated H3 lysine 27 (H3K27me3) on the LDHA promoter were analyzed by the dual-luciferase and chromatin-immunoprecipitation assays. miR-29c-3p was downregulated while KDM6B and LDHA were upregulated in DSS mice. miR-29c-3p overexpression reduced DAI and inflammatory cell infiltration while increasing colon length, intestinal permeability, and levels of ZO-1 and Occludin. miR-29c-3p inhibited KDM6B expression and increased H3K27me3 occupation on the LDHA promoter, thus inhibiting LDHA transcription. Overexpression of KDM6B or LDHA averted the protective role of miR-29c-3p upregulation in mucosal injury. miR-29c-3p limited KDM6B expression and increased the H3K27me3 occupation on the LDHA promoter to enhance LDHA transcription, moderating mucosal injury and delaying UC progression.

The improvement of intestinal dysbiosis and hepatic metabolic dysfunction in dextran sulfate sodium-induced colitis mice: effects of curcumin.

Curcumin may have promising application in the prevention and amelioration of inflammatory bowel disease (IBD). However, the underlying mechanisms underpinning the ability of curcumin to interact with the gut and liver in IBD remains to be defined, which is the exploration aim of this study. Mice with dextran sulfate sodium salt (DSS)-induced acute colitis were treated either with 100mg/kg of curcumin or phosphate buffer saline (PBS). Hematoxylin-eosin (HE) staining, 16S rDNA Miseq sequencing, proton nuclear magnetic resonance (1 H NMR) spectroscopy, and liquid chromatography-tandem mass spectrometry (LC-MS/MS) were applied for analysis. Spearman's correlation coefficient (SCC) was utilized to assess the correlation between the modification of intestinal bacteria and hepatic metabolite parameters. Curcumin supplementation not only prevented further loss of body weight and colon length in IBD mice but also improved diseases activity index (DAI), colonic mucosal injury, and inflammatory infiltration. Meanwhile, curcumin restored the composition of the gut microbiota, significantly increased Akkermansia, Muribaculaceae_unclassified, and Muribaculum, and significantly elevated the concentration of propionate, butyrate, glycine, tryptophan, and betaine in the intestine. For hepatic metabolic disturbances, curcumin intervention altered 14 metabolites, including anthranilic acid and 8-amino-7-oxononanoate while enriching pathways related to the metabolism of bile acids, glucagon, amino acids, biotin, and butanoate. Furthermore, SCC analysis revealed a potential correlation between the upregulation of intestinal probiotics and alterations in liver metabolites. The therapeutic mechanism of curcumin against IBD mice occurs by improving intestinal dysbiosis and liver metabolism disorders, thus contributing to the stabilization of the gut-liver axis.

Quercetin serves as the major component of Xiang-lian Pill to ameliorate ulcerative colitis via tipping the balance of STAT1/PPARγ and dictating the alternative activation of macrophage

Ethnopharmacological relevanceThe traditional Chinese herbal formula, Xiang-lian Pill (XLP), is commonly prescribed for ulcerative colitis (UC) patients to relieve their clinical symptom. Nonetheless, the underlying cellular and molecular mechanisms of XLP's anti-UC effect remain incompletely understood. Aim of the studyTo evaluate the therapeutic effect and elucidate the possible working mechanisms of XLP in UC treatment. The major active component of XLP was also characterized. Materials and methodsColitis was induced in C57BL/6 mice with 3% dextran sulfate sodium (DSS) dissolved in drinking water for 7 consecutive days. The UC mice were grouped and treated with XLP (3640 mg/kg) or vehicle orally during the procedure of DSS induction. Mouse body weight, disease activity index (DAI) score and colon length were recorded. Histopathological changes and inflammatory cell infiltration were evaluated by pathological staining and flow cytometric analysis (FACS). Network pharmacology, bioinformatic analysis, widely targeted and targeted metabolomics analysis were performed to screen the potential effective ingredients and key targets. Bone marrow derived macrophages (BMDMs), peripheral blood mononuclear cells (PBMCs), RAW264.7 and THP-1 cells were used to dissect the anti-inflammatory effect of XLP. ResultsOral administration of XLP ameliorated DSS induced mouse colitis, as evidenced by reduced DAI and colonic inflammatory destruction. FACS results demonstrated that XLP treatment effectively restored immune tolerance in colon, inhibited the generation of monocyte derived macrophages and skewed macrophage polarization into M2 phenotype. Network pharmacology analysis suggested that innate effector modules related to macrophage activation comprise the major targets of XLP, and the counter-regulatory STAT1/PPARγ signaling possibly serves as the critical downstream pathway. Subsequent experiments unveiled an imbalance of STAT1/PPARγ signaling in monocytes derived from UC patients, and validated that XLP suppressed LPS/IFN-γ induced macrophage activation (STAT1 mediated) but facilitated IL-4 induced macrophage M2 polarization (PPARγ dependent). Meanwhile, our data showed that quercetin served as the major component of XLP to recapitulate the regulatory effect on macrophages. ConclusionOur findings revealed that quercetin serves as the major component of XLP that regulates macrophage alternative activation via tipping the balance of STAT1/PPARγ, which provides a mechanistic explanation for the therapeutic effect of XLP in UC treatment.

Network pharmacology-based identification of bioavailable anti-inflammatory agents from Psoralea corylifolia L. in an experimental colitis model

Ethnopharmacological relevanceIn traditional oriental medicine, the dried seeds of Psoralea corylifolia L. (PC) have been used to treat various diseases, including gastrointestinal, urinary, orthopedic, diarrheal, ulcer, and inflammatory disorders. Aim of the studyAlthough its various biological properties are well-known, there is no information on the therapeutic effects and bioavailable components of PC against inflammatory bowel disease. Therefore, we focused on the relationship between hydroethanolic extract of PC (EPC) that ameliorates colitis in mice and bioactive constituents of EPC that suppress pro-inflammatory cytokines in macrophages. Materials and methodsWe investigated the therapeutic effects of EPC in a dextran sulfate sodium-induced colitis mouse model and identified the orally absorbed components of EPC using UPLC-MS/MS analysis. In addition, we evaluated and validated the mechanism of action of the bioavailable constituents of EPC using network pharmacology analysis. The effects on nitric oxide (NO) and inflammatory cytokines were measured by Griess reagent and enzyme linked immunosorbent assay in lipopolysaccharide (LPS)-induced macrophages. ResultsIn experimental colitis, EPC improved body weight loss, colon length shortening, and disease activity index. Moreover, EPC reduced the serum levels of pro-inflammatory cytokines and histopathological damage to the colon. Network pharmacological analysis identified 13 phytochemicals that were bioavailable following oral administration of EPC, as well as their potential anti-inflammatory effects. 11 identified EPC constituents markedly reduced the overproduction of NO, tumor necrosis factor-α, and/or interleukin-6 in macrophages induced by LPS. The LPS-induced expression of the nuclear factor kappa-light-chain-enhancer of activated B cells reporter gene was reduced by the 4 EPC constituents. ConclusionsThe results indicate that the protective activity of EPC against colitis is a result of the additive effects of each constituent on the expression of inflammatory cytokines. Therefore, it suggests that 11 bioavailable phytochemicals of EPC could aid in the management of intestinal inflammation, and also provides useful insights into the clinical application of PC for the treatment of inflammatory bowel diseases.

Enhancing oral delivery of plant-derived vesicles for colitis

Plant-derived vesicles (PDVs) are attractive for therapeutic applications, including as potential nanocarriers. However, a concern with oral delivery of PDVs is whether they would remain intact in the gastrointestinal tract. We found that 82% of cabbage PDVs were destroyed under conditions mimicking the upper digestive tract. To overcome this limitation, we developed a delivery method whereby lyophilized Eudragit S100–coated cabbage PDVs were packaged into a capsule (Cap-cPDVs). Lyophilization and suspension of PDVs did not have an appreciable impact on PDV structure, number, or therapeutic effect. Additionally, packaging the lyophilized Eudragit S100-coated PDVs into capsules allowed them to pass through the upper gastrointestinal tract for delivery into the colon better than did suspension of PDVs in phosphate-buffered saline. Cap-cPDVs showed robust therapeutic effect in a dextran sulfate sodium-induced colitis mouse model. These findings could have broad implications for the use of PDVs as orally delivered nanocarriers of natural therapeutic plant compounds or other therapeutics.

Abstract 2720: Enhancing oral delivery of plant-derived vesicles

Abstract Plant-derived vesicles (PDVs) were attractive for therapeutic applications, including as potential nanocarriers. However, a concern with oral delivery of PDVs is whether they would remain intact in the gastrointestinal tract. We found that 82% of cabbage PDVs were destroyed under conditions mimicking the upper digestive tract. To overcome this limitation, we developed a delivery method whereby lyophilized Eudragit S-100-coated cabbage PDVs were packaged into a capsule (Cap-cPDVs). Lyophilization and suspension of PDVs in phosphate-buffered saline did not have an appreciable effect on PDV structure, number of PDVs, or therapeutic effect. However, packaging the lyophilized Eudragit S-100-coated PDVs into capsules allowed them to pass through the upper gastrointestinal tract for delivery into the colon better than did suspension of PDVs in phosphate-buffered saline. Cap-cPDVs demonstrated robust therapeutic effect in a dextran sulfate sodium-induced colitis mouse model. These findings could have broad implications for oral delivery of PDVs. Citation Format: Yuan Liu, Adrian Lankenau-Ahumada, Emine Bayraktar, Paul Schwartz, Mamur Chowdhury, Sixiang Shi, Manu M. Sebastian, Htet Khant, Natalia De Val, Zuliang Jie, Nicholas B. Jennings, Cristian Rodriguez-Aguayo, Jody Swain, Elaine Stur, Lingegowda S. Mangala, Yutuan Wu, Supriya Nagaraju, Brooke Erimas, Chun Li, Gabriel Lopez-Berestein, Janet Braam, Anil K. Sood. Enhancing oral delivery of plant-derived vesicles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2720.

Coprococcus eutactus, a Potent Probiotic, Alleviates Colitis via Acetate-Mediated IgA Response and Microbiota Restoration.

Inflammatory bowel disease (IBD) is a complex disease characterized by relapsing episodes of inflammation of the colonic mucosa. Research into IBD suggests that this disease condition is caused by alterations in resident mucosal bacterial populations. Our previous study showed that Coprococcus was significantly elevated during the improvement of IBD. Human metagenome database GMrepo also indicates Coprococcus, in particular, Coprococcus eutactus (C. eutactus), which was negatively associated with IBD. The current study implied the alleviated effects and mechanisms of C. eutactus on dextran sodium sulfate-induced experimental colitis mice. Gavage with C. eutactus-ameliorated acute colitis, as evidenced, relieved weight loss, decreased concentrations of proinflammatory cytokines TNF-α, IL-1β, and IL-6, and increased anti-inflammatory factors, IL-4, IL-5, and IL-10. In addition, C. eutactus enhanced the maturation of goblet cells and the expressions of mucins and restored the expressions of tight junction proteins such as claudin-1, occludin, and ZO-1. As a short-chain fatty acid-producing bacterium, C. eutactus mainly generates acetic acid. Interestingly, not only high levels of secretory immunoglobulin A (SIgA) but also increased IgA-producing plasma cells were observed in colitis mice during the administration of C. eutactus. Importantly, our data demonstrated that colonic SIgA is specifically coated on pathogens of Enterobacteriaceae. Owing to the selective binding effect of SIgA on microorganisms, the microbial diversity in the intestinal lumen and mucosa of C. eutactus-treated colitis mice was significantly restored, and the microbiota structure was remodeled. These findings provide substantial insight that C. eutactus as a promising probiotic can ameliorate colitis. In conclusion, our findings may deliver a novel approach to the prevention and biotherapy of IBD.

Antioxidant properties of fermented soymilk and its anti-inflammatory effect on DSS-induced colitis in mice.

Lactic acid-fermented soymilk as a new plant-based food has aroused extensive attention because of its effects on nutrition and health. This study was conducted to delve into the antioxidative and anti-inflammatory activities of lactic acid-fermented soymilk. To elucidate the key factors that affect the antioxidant properties of fermented soymilk, the strains and preparation process were investigated. Findings show that the fermented soymilk prepared using hot-water blanching method (BT-80) demonstrated a better antioxidant activity than that using conventional method (CN-20). Besides, a huge difference was observed among the soymilks fermented with different strains. Among them, the YF-L903 fermented soymilk demonstrated the highest ABTS radical scavenging ability, which is about twofold of that of unfermented soymilk and 1.8-fold of that of L571 fermented soy milk. In vitro antioxidant experiments and the analysis of H2O2-induced oxidative damage model in Caco-2 cells showed that lactic acid-fermentation could improve the DPPH radical scavenging ability, ABTS radical scavenging ability, while reducing the content of reactive oxygen species (ROS) and malondialdehyde (MDA) in Caco-2 cells induced by H2O2, and increasing the content of superoxide dismutase (SOD). Consequently, cells are protected from the damage caused by active oxidation, and the repair ability of cells is enhanced. To identify the role of fermented soymilk in intestinal health, we investigate its preventive effect on dextran sodium sulfate-induced colitis mouse models. Results revealed that the fermented soymilk can significantly improve the health conditions of the mice, including alleviated of weight loss, relieved colonic injury, balanced the spleen-to-body weight ratio, reduced the disease index, and suppressed the inflammatory cytokines and oxidant indexes release. These results suggest that YF-L903 fermented soymilk is a promising natural antioxidant sources and anti-inflammatory agents for the food industry. We believe this work paves the way for elucidating the effect of lactic acid-fermented soymilk on intestinal health, and provides a reference for the preparation of fermented soymilk with higher nutritional and health value.

Atractylodin Ameliorates Colitis via PPARα Agonism.

Atractylodin is a major compound in the rhizome of Atractylodes lancea, an oriental herbal medicine used for the treatment of gastrointestinal diseases, including dyspepsia, nausea, and diarrhea. Recent studies have shown that atractylodin exerts anti-inflammatory effects in various inflammatory diseases. Herein, we investigated the anti-colitis effects of atractylodin and its molecular targets. We determined the non-cytotoxic concentration of atractylodin (50 μM) using a cell proliferation assay in colonic epithelial cells. We found that pretreatment with atractylodin significantly inhibits tumor necrosis factor-α-induced phosphorylation of nuclear factor-κ-light-chain-enhancer of activated B in HCT116 cells. Through docking simulation analysis, luciferase assays, and in vitro binding assays, we found that atractylodin has an affinity for peroxisome proliferator-activated receptor alpha (PPARα). Daily administration of atractylodin (40 mg/kg) increased the survival rate of mice in a dextran sodium sulfate-induced colitis mouse model. Thus, atractylodin can be a good strategy for colitis therapy through inducing PPARα-dependent pathways.

Anti-inflammatory effect and signaling mechanism of 8-shogaol and 10-shogaol in a dextran sodium sulfate-induced colitis mouse model

Ethnopharmacological relevanceGinger (Zingiber officinale Roscoe) has been used for food and applied in Ayurvedic medicine in India for thousands of years. With a reputation for strong anti-inflammatory properties, it has been used for to treat colds, migraines, nausea, arthritis, and high blood pressure in China and Southeast Asia. The physiological activity of ginger is attributed to its functional components, including gingerol and shogaol, and their derivatives. Aim of the studyWe aimed to investigate the effects of 8- and 10-shogaol and their bioactive signaling mechanisms in a dextran sodium sulfate (DSS)-induced colitis mouse model. The anti-colitis efficacy of 6-, 8-, and 10-derivatives of gingerol and shogaol was comparatively analyzed. Materials and methodsColitis was induced by providing mice with drinking water containing 5% DSS (w/v) for 8 days. The 6-, 8-, and 10-derivatives of gingerol and shogaol were orally administered for two weeks at a dose of 30 mg/kg. Changes in body weight and disease activity index were measured. The levels of pro-inflammatory cytokines, iNOS and COX-2, as well as the phosphorylation of NF-κB were analyzed using ELISA, PCR, or western blotting. Mucin expression and mRNA levels were measured using alcian blue staining and PCR, respectively. The tight-junction-associated proteins occludin and ZO-1 were assessed using immunohistological staining. ResultsThe 6-, 8-, and 10-derivatives of gingerol and shogaol exhibited anti-inflammatory effects by regulating NF-κB signaling. Among the compounds administered, 10-shogaol was the most effective against DSS-induced inflammation. Comparative analysis of the chemical structure showed that shogaol, a dehydrated analog of gingerol, was more effective. 6- and 10-shogaol showed similar effects on DSS-induced morphological changes in the colonic mucus layer, mucin expression, and tight junction proteins. Conclusions6-, 8-, and 10-Gingerol and 6-, 8-, and 10-shogaol significantly improved the clinical symptoms and intestinal epithelial barrier damage in DSS-induced colitis in mice. The derivatives effectively inhibited DSS-induced inflammation through the regulation of NF-κB signaling. Moreover, 10-shogaol showed the most potent anti-inflammatory effect among the six compounds used in this study. The results indicate that 8- and 10-shogaol, both main ingredients in ginger, may serve as therapeutic candidates for the treatment of colitis.