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Gut microbiota provides an important insight into clarifying the mechanism of active substances with low bioavailability, but its specific action mechanism varied case by case and remained unclear. Dihydroquercetin (DHQ) is a bioactive flavonoid with low bioavailability, which showed beneficial effects on colitis alleviation and gut microbiota modulation. Herein, we aimed to explore the microbiota-dependent anticolitis mechanism of DHQ in sight of gut microbiota metabolites and their interactions with microRNAs (miRNAs). Dietary supplementation of DHQ alleviated dextran sulfate sodium-induced colitis phenotypes and improved gut microbiota dysbiosis. Fecal microbiota transplantation further revealed that the anticolitis activity of DHQ was mediated by gut microbiota. To clarify how the modulated gut microbiota alleviated colitis in mice, the tandem analyses of the microbiome and targeted metabolome were performed, and altered profiles of metabolite short-chain fatty acids (SCFAs) and bile acids and their producers were observed in DHQ-treated mice. In addition, SCFA treatment showed anticolitis activity compared to that of bile acids, along with the specific inhibition on the phosphoinositide-3-kinase (PI3K)-protein kinase B (Akt) pathway. Subsequently, the colonic miRNA profile of mice receiving SCFA treatment was sequenced, and a differentially expressed miR-10a-5p was identified. Both prediction analysis and dual-luciferase reporter assay indicated that miR-10a-5p directly bind to the 3'-untranslated regions of gene pik 3 ca , inhibit the PI3K-Akt pathway activation, and lead to colitis alleviation. Together, we proposed that gut microbiota mediated the anticolitis activity of DHQ through the SCFAs/miR-10a-5p/PI3K-Akt axis, and it provided a novel insight into clarifying the microbiota-dependent mechanism via the interaction between metabolites and miRNAs.

Mammalian milk exosomal miRNAs play an important role in maintaining intestinal immune homeostasis and protecting epithelial barrier function, but the specific miRNAs and whether miRNA-mediated mechanisms are responsible for these benefits remain a matter of investigation. This study isolated sheep milk-derived exosomes (sheep MDEs), identifying the enriched miRNAs in sheep MDEs, oar-miR-148a, and oar-let-7b as key components targeting TLR4 and TRAF1, which was validated by a dual-luciferase reporter assay. In dextran sulfate sodium-induced colitis mice, administration of sheep MDEs alleviated colitis symptoms, reduced colonic inflammation, and systemic oxidative stress, as well as significantly increased colonic oar-miR-148a and oar-let-7b while reducing toll-like receptor 4 (TLR4) and TNF-receptor-associated factor 1 (TRAF1) level. Further characterization in TNF-α-challenged Caco-2 cells showed that overexpression of these miRNAs suppressed the TLR4/TRAF1-IκBα-p65 pathway and reduced IL-6 and IL-12 production. These findings indicate that sheep MDEs exert gastrointestinal anti-inflammatory effects through the miRNA-mediated modulation of TLR4 and TRAF1, highlighting their potential in managing colitis.

Intestinal barrier hemostasis is the key to health. As a resveratrol analogue, pterostilbene (PT) has been reported to prevent dextran sodium sulfate (DSS)-induced intestinal barrier dysfunction mainly associated with the intestinal NF-κB signaling pathway. However, the exact underlying mechanisms are not yet well-defined yet. In this study, we performed RNA-sequencing analysis and unexpectedly found that alarmin S100A8 sensitively responded to DSS-induced intestinal injury. Accordingly, histologic assessments suggested that the high expression of S100A8 was accompanied by increased intestinal infiltration of macrophages, upregulated intestinal epithelial Toll-like receptor 4 (TLR-4), and activated NF-κB signaling pathway. Interestingly, the above phenomena were effectively counteracted upon the addition of PT. Furthermore, by using a coculture system of macrophage THP-1 cells and HT-29 colon cells, we identified macrophage-secreted S100A8 activated intestinal epithelial NF-κB signaling pathway through TLR-4. Taken together, these findings suggested that PT ameliorated DSS-induced intestinal barrier injury through suppression of the macrophage S100A8-intestinal epithelial TLR-4-NF-κB signaling cascade.

Taurine (Tau) is a semiessential amino acid in mammals with preventive and therapeutic effects on several intestinal disorders. However, the exact function of taurine in ulcerative colitis (UC) is still largely unclear. In this study, we used two taurine-deficient mouse models (CSAD -/- and TauT -/- mice) to explore the influence of taurine on the progression of UC in both dextran sulfate sodium (DSS)-induced colitis and LPS-stimulated Caco-2 cells. We found that cysteine sulfinic acid decarboxylase (CSAD) and taurine transporter (TauT) expressions and taurine levels were markedly reduced in colonic tissues of mice treated with DSS. The CSAD and TauT knockouts exacerbated DSS-induced clinical symptoms and pathological damage and aggravated the intestinal barrier dysfunction and the colonic mucosal inflammatory response. Conversely, taurine pretreatment enhanced the intestinal barrier functions by increasing goblet cells and upregulating tight junction protein expression. Importantly, taurine bound with TLR4 and inhibited the TLR4/NF-κB pathway, ultimately reducing proinflammatory factors (TNF-α and IL-6) and oxidative stress. Our findings highlight the essential role of taurine in maintaining the intestinal barrier integrity and inhibiting intestinal inflammation, indicating that taurine is a promising supplement for colitis treatment.

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.

Inflammatory bowel disease is a major health problem that can lead to prolonged damage to the digestive system. This study investigated the effects of an exopolysaccharide from genistein-stimulated Monascus purpureus (G-EMP) in a mouse model of colitis to clarify its molecular mechanisms and identified its structures. G-EMP ( Mw = 56.4 kDa) was primarily consisted of → 4)-α-D-Gal p -(1 →, → 2,6)-α-D-Glc p -(1→ and →2)-β-D-Man p -(1 → , with one of the branches being α-D-Manp-(1 →. G-EMP intervention reduced the loss of body weight, degree of colonic damage and shortening, disease activity index scores, and histopathology scores, while restoring goblet cell production and oxidative homeostasis, repairing colonic functions, and regulating inflammatory cytokines. RNA sequencing and Western blot analysis indicated that G-EMP exerts anti-inflammatory properties by suppressing the TLR4/MAPK/NF-κB inflammatory signaling pathway. G-EMP modulated the gut microbiota by improving its diversities, elevating the relative abundances of beneficial bacteria, declining the Firmicutes / Bacteroidota value, and regulating the level of short-chain fatty acids (SCFAs). Correlation analysis demonstrated strong links between SCFAs, gut microbiota, and the inflammatory response, indicating the potential of G-EMP to prevent colitis.

The aim of this study was to investigate the intervention effect of kefir supernatant (KS) on the initiation and progression of an ulcerative colitis (UC) murine model. We established an UC murine model by orally administrating with 10 9 CFUs of Fusobacterium nucleatum for 3 weeks and 3% dextran sulfate sodium (DSS) treatment in the third week. KS was used to intervene in this colitis model. Our results showed that KS supplementation ameliorated the symptoms, restrained the secretion of pro-inflammatory cytokines (TNF-α, IL-6, and IL-17F), promoted the release of anti-inflammatory cytokines (IL-4 and IL-10), and ameliorated oxidative stress. Furthermore, the increased number of goblet cells and upregulated expression of MUC2, occludin and claudin-1 indicated that the colon barrier was protected by KS. Additionally, KS supplementation mitigated gut microbiota dysbiosis in the UC murine model, leading to an increase in the abundance of Blautia and Akkermansia and a decrease in the level of Bacteroides . The altered gut microbiota also affected colon metabolism, with differential metabolites mainly associated with the biosynthesis of the l-arginine pathway. This study revealed that KS supplementation restored the community structure of gut microbiota, altered the biosynthesis of l-arginine, and thereby modulated the process of colonic inflammation.

In this study, we aimed to explore the protective effects of Bifidobacterium in colitis mice and the potential mechanisms. Results showed that Bifidobacterium breve ( B. breve ) effectively colonized the intestinal tract and alleviated colitis symptoms by reducing the disease activity index. Moreover, B. breve mitigated intestinal epithelial cell damage, inhibited the pro-inflammatory factors, and upregulated tight junction (TJ)-proteins. Gut microbiota and metabolome analysis found that B. breve boosted bile acid-regulating genera (such as Bifidobacterium and Clostridium sensu stricto 1), which promoted bile acid deconjugation in the intestine. Notably, cholic acid (CA) was closely associated with the expression levels of inflammatory factors and TJ-proteins ( p < 0.05). Our in vitro cell experiments further confirmed that CA (20.24 ± 4.53 pg/mL) contributed to the inhibition of lipopolysaccharide-induced tumor necrosis factor-α expression (49.32 ± 5.27 pg/mL) and enhanced the expression of TJ-proteins (Occludin and Claudin-1) and MUC2. This study suggested that B. breve could be a probiotic candidate for use in infant foods.

Lipid metabolism is closely related to obesity and its complications. Our previous study found that ginsenoside Rk3 (Rk3), a natural bioactive substance derived from ginseng, can effectively alleviate obesity-induced colitis, while its impact on the improvement of the lipid metabolism disorder remains unclear. Here, we demonstrated that Rk3 significantly alleviated inflammation, oxidative stress, and lipid dysregulation in high-fat diet-induced colitis C57BL/6 mice. The potential mechanism by which Rk3 mitigated colon inflammation in the context of obesity may involve the modulation of polyunsaturated fatty acid metabolism with specific attention to n-6 fatty acids, linoleic acid, and arachidonic acid. Rk3 intervention markedly reduced the production of pro-inflammatory factors (PGE2, PGD2, TXB2, HETE, and HODE) by inhibiting cyclooxygenase and lipoxygenase pathways, while enhancing the production of anti-inflammatory factors (EET and diHOME) via cytochrome P450 pathways. Our findings suggest that Rk3 is a potential anti-inflammatory natural drug that can improve obesity-induced intestinal inflammation by regulating lipid metabolism.

Previously, Lactobacillus paracasei VL8, a lactobacillus strain isolated from the traditional Finnish fermented dairy product Viili, demonstrated immunomodulatory and antibacterial effects. The prebiotic mannan-oligosaccharide (MOS) further promoted its antibacterial activity and growth performance, holding promise for maintaining intestinal health. However, this has not been verified in vivo. In this study, we elucidated the process by which L. paracasei VL8 and its synbiotc combination (SYN) with MOS repair the intestinal barrier function in dextran sodium sulfate (DSS)-induced colitis mice. SYN surpasses VL8 or MOS alone in restoring goblet cells and improving the tight junction structure. Omics analysis on gut microbiota reveals SYN's ability to restore Lactobacillus spp. abundance and promote tryptophan metabolism. SYN intervention also inhibits the DSS-induced hyperactivation of the Wnt/β-catenin pathway. Tryptophan metabolites from Lactobacillus induce intestinal organoid differentiation. Co-housing experiments confirm microbiota transferability, replicating intestinal barrier repair. In conclusion, our study highlights the potential therapeutic efficacy of the synbiotic combination of Lactobacillus paracasei VL8 and MOS in restoring the damaged intestinal barrier and offers new insights into the complex crosstalk between the gut microbiota and intestinal stem cells.

In this study, we investigated the protective mechanism of walnut-derived peptide LPLLR (LP-5) against cognitive impairment induced in a dextran sodium sulfate (DSS)-induced colitis mouse model, with emphasis on the microbiota-gut-brain axis (MGBA). The results revealed that LP-5 could improve the learning ability and memory of mice with cognitive impairment and mitigate colitis symptoms, including weight loss, bloody stools, colon shortening, and histopathological changes. Additionally, LP-5 protected the integrity of the intestinal barrier by promoting the expression of tight junction proteins (TJs) while attenuating colonic inflammation by suppressing proinflammatory cytokine and epithelial cell apoptosis. Western blotting indicated that LP-5 treatment suppressed the inflammatory NF-κB/MLCK/MLC signaling pathway activity. Furthermore, LP-5 ameliorated hippocampal neuron damage and protected blood-brain barrier (BBB) integrity by downregulating microglia marker protein Iba-1, increasing TJ protein expression, and restoring the deterioration of synaptic proteins. Importantly, 16S rRNA sequencing results indicated that LP-5 reshaped the abundance of a wide range of gut microbiota at the phylum and genus levels, with increased Prevotella and Akkermansia associated with tryptophan (TRP), 5-hydroxytryptamine (5-HT), and 5-hydroxyindoleacetic acid (5-HIAA). These findings suggest that LP-5 could maintain intestinal barrier and BBB integrity, reverse gut dysbiosis, and improve learning and memory ability in colitis mice, providing novel insights into alterations of gut microbes in colitis and a potential new mechanism by which it causes cognitive impairment.

The increasing incidence of colitis and the side effects of its therapeutic drugs have led to the search for compounds of natural origin, including phenolics, as new treatments for colitis. In this study, the potential mechanism of Dendrobium officinale leaf phenolics (DOP) on the relief of dextran sulfate sodium (DSS)-induced colitis was explored. The results showed that DOP treatment for 36 days reduced the symptoms of colitis caused by DSS, including reduction of the disease activity index and alleviation of colonic tissue damage. In addition, DOP downregulated the expression of key proteins of the TLR4/NF-κB signaling pathway and reduced the production of inflammatory cytokines. Furthermore, DOP could enhance the expression of tight junction proteins including ZO-1, Occludin, and Claudin-1 to restore intestinal mucosal barrier function. DOP also effectively regulates disordered intestinal flora and enhances the production of short-chain fatty acids, which is also beneficial in modulating gut internal environmental homeostasis, inhibiting inflammation, and restoring the intestinal barrier. These findings indicated that DOP can ameliorate DSS-induced chronic colitis by regulating gut microbiota, intestinal barrier, and inflammation, and it is a promising ingredient from D. officinale .

The potential biological function of tea and its active components on colitis has attracted wide attention. In this study, different tea active ingredients including tea polyphenols (TPPs), tea polysaccharides (TPSs), theabrownin (TB), and theanine (TA) have been compared in the intervention of dextran sulfate sodium (DSS)-induced colitis in mice. Specifically, TPP showed the greatest effect on colitis since it reduced 60.87% of disease activity index (DAI) compared to that of the DSS-induced colitis group, followed by the reduction of 39.13% of TPS and 28.26% of TB on DAI, whereas there was no obvious alleviative effect of TA on colitis. TPP, TPS, and TB could regulate the composition and abundance of gut microbiota to increase the content of short-chain fatty acids (SCFAs) and enhance intestinal barrier function. Further evidence was observed that TPP and TPS regulated the activation of Nrf2/ARE and the TLR4/MyD88/NF-κB P65 pathway to alleviate the colitis. Results of cell experiments demonstrated that TPP showed the greatest antiapoptosis and mitochondrial function protective capability among the tea ingredients via inhibiting the Cytc/Cleaved-caspase-3 signaling pathway. In summary, the superior anticolitis activity of TPP compared to TPS and TB is primarily attributed to its unique upregulation of the abundance of Akkermansia and its ability to regulate the mitochondrial function.

Vitexin, which exists in various medicinal plants and food sources, has recently received increasing attention because of its anti-inflammatory properties. This study aims to identify the protein target of vitexin that ameliorates dextran sulfate sodium (DSS)-induced colitis. The results showed that vitexin not only alleviated the clinical symptoms and colonic damage in mice with DSS-induced colitis but also suppressed the colonic production of inflammatory cytokines (IL-1β, IL-6, ICAM, and VCAM) and enhanced the expression of barrier-associated proteins (ZO-1, Occludin, and E-cadherin). Based on tissue thermal proteome profiling (Tissue-TPP) and molecular docking, OLA1 was creatively identified as a potential protein target for vitexin. Further siRNA-mediated knockdown of the OLA1 gene in Caco-2 cells demonstrated the ability of OLA1 to increase Nrf2 protein expression and, thus, mediated the anti-inflammatory effects of vitexin. Interaction of the OLA1-vitexin complex with Keap1 protein to disrupt the Keap1-Nrf2 interaction may be required for activating Nrf2. Our findings revealed a novel role for OLA1 as a protein target of vitexin that contributes to its anti-inflammatory action by activating Nrf2, which may provide a promising molecular mechanism for novel therapeutic strategies to treat colitis and the associated systemic inflammation.

Saffron petal (SP) is an agricultural byproduct in the process of the crude drug saffron, accounting for 90% of the dry weight of saffron flowers. To promote the utilization of SP in the food and pharmaceutical industries, its anti-inflammatory activities were evaluated on LPS-activated RAW 264.7 cells and DSS-challenged colitic mice. The results indicated that the SP extract had a notable effect in alleviating the clinical manifestations of colitis, such as reduction in body weight, improvement in disease activity index, mitigation of colon shortening, and alleviation of colon tissue damage. Moreover, SP extract significantly suppressed macrophage infiltration and activation, evidenced by a decrease in colonic F4/80 macrophages and suppression of the transcription and secretion of colonic tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in DSS-challenged colitic mice. In vitro , SP extract also significantly suppressed nitric oxide production, COX-2 and iNOS expressions, and TNF-α and IL-1β transcription of activated RAW 264.7 cells. Network pharmacology-guided research identified that SP extract significantly downregulated Akt, p38, ERK, and JNK phosphorylation in vivo and in vitro . In parallel, SP extract also effectively corrected microbial dysbiosis by increasing the abundance of Bacteroides acidifaciens , Bacteroides vulgatus , Lactobacillus murinus , and Lactobacillus gasseri . These findings indicate that the effectiveness of SP extract in treating colitis is demonstrated by its ability to reduce macrophage activation, inhibit the PI3K/Akt and MAPK pathways, and regulate gut microbiota, suggesting that SP extract holds great potential as a therapeutic option for colitis.

A high-fructose diet (HFrD) has been reported to exacerbate dextran sulfate sodium (DSS)-induced colitis. 2'-Fucosyllactose (FL) and galactooligosaccharide (GOS) have been shown, respectively, to have preventive and ameliorative effects on colitis, while limited research has explored whether GOS and FL may be equally protective or preventive in mice with HFrD. Here, we evaluated the protective effects of FL and GOS on colitis exacerbated by feeding HFrD and explored the underlying mechanisms. DSS-induced colitis was studied in four randomized C57BL/6J male mice ( n = 8 mice/group). Among them, three groups were fed with HFrD, and two received either GOS or FL treatment, respectively. Gut microbial composition was analyzed by 16S rDNA gene sequencing. Intestinal barrier integrity and inflammatory pathway expression were measured using qPCR, immunofluorescence, and Western blot methods. Compared to the HFrD group, GOS or FL treatment increased the α-diversity of the gut microbiota, reduced the relative abundance of Akkermansia , and increased the content of short-chain fatty acids (SCFAs), respectively. Compared with the HFrD group, GOS or FL treatment improved the loss of goblet cells and the reduction of tight junction protein expression, thereby improving intestinal barrier integrity. Also, GOS or FL inhibited the LPS/TLR4/NF-κB signaling pathway and oxidative stress to suppress the inflammatory cascade compared with the HFrD group. These findings suggest that GOS or FL intake can alleviate HFrD-exacerbated colitis, with no significant difference observed between GOS and FL treatments.

Western diet is thought to increase susceptibility to inflammatory bowel disease (IBD), and probiotics are a potential therapeutic agent for IBD. This study revealed the effects of Lactobacillus plantarum AR113 and L. plantarum AR113Δ bsh 1 on a dextran sulfate sodium (DSS)-induced colitis mouse model under the Western diet (WD). After four weeks of WD and low-sugar and low-fat diet (LD) intervention, induction with 3% DSS, and intragastric administration of probiotics, we found that L. plantarum AR113 could regulate blood glucose and lipid levels and have a certain protective effect on hepatocytes. Our results suggested that the L. plantarum AR113 alleviated DSS-induced colitis under the Western diet by improving dyslipidemia, repairing intestinal barrier dysfunction, and inhibiting the TLR4/Myd88/TRAF-6/NF-κB inflammatory pathway. However, these changes were not demonstrated in the L. plantarum AR113Δ bsh 1, and therefore, we reasoned that the presence of bsh 1 may play a crucial role in the L. plantarum AR113 exerting its anti-inflammatory function. The relationship between bile salt hydrolase (BSH) and colitis was worthy of further exploration.

The development and progression of colitis would detrimentally destroy the intestine barrier. However, there remains a paucity of evidence on whether ovalbumin (OVA) can be used as a nutritional food protein to repair the intestinal barrier. In this study, the repairing mechanism of OVA on intestinal barrier was thoroughly investigated by gut microbiota and untargeted metabolomics techniques. The findings demonstrated that OVA reduced intestinal permeability and restored mucin (0.75 ± 0.06) and tight junction (TJ) protein (0.67 ± 0.14) expression in colitis mice caused by 3% dextran sulfate sodium (DSS). In addition, the inflammation response and oxidative stress were also attenuated. The intake of OVA upregulated the abundance of Lactobacillaceae (7.60 ± 3.34%) and Akkermansiaceae (10.39 ± 5.97%). Furthermore, OVA upregulated the abundance of inosine (6.06 ± 0.36%), putrescine (4.14 ± 0.20%), and glycocholic acid (5.59 ± 0.23%) in colitis mice through ATP binding cassette (ABC) transporters and bile secretion pathways. In summary, our findings revealed that OVA could maintain intestinal health, which may provide crucial insights for preventing and treating intestinal diseases.

Shikimic acid (SA) is a compound extracted from the plant anise and has anti-inflammatory effects. However, any impact on intestinal inflammation or mechanisms involved has not been investigated. The present study used a dextran sulfate sodium (DSS)-induced mouse colitis model to investigate the effects of SA on intestinal inflammation. Intragastric administration of SA slowed DSS-induced weight loss, reduced disease activity index (DAI) score, enhanced the intestinal barrier, reduced the destruction of the colonic structure, inhibited the phosphorylation of key proteins in MAPK and NF-κB signaling pathways, inhibited the expression of inflammatory factors TNF-α, IL-1β, and MPO ( P < 0.05), decreased IFN-γ expression ( P < 0.05), and increased immunoglobulin IgG content ( P < 0.05). After 50 mg/kg SA treatment, the content of Bacteroidetes increased and Proteobacteria decreased in the cecal feces of mice with colitis ( P < 0.05) and the richness of gut species increased. In conclusion, SA could improve intestinal inflammation and enhance intestinal immunity, indicating its suitability as a therapeutic candidate.

The intracellular polysaccharides of Aspergillus cristatus (IPSs) from Fuzhuan brick tea have been demonstrated to improve immune function linked to modulating the gut microbiota. Herein, to further investigate the efficacy of IPSs to maintain gut homeostasis, the protection of the purified fraction of IPSs (IPSs-2) on the mice with colitis induced by dextran sulfate sodium (DSS) and the underlying mechanisms were explored in this study. The results revealed that IPSs-2 alleviated the typical symptoms of colitis and suppressed the excessive inflammatory mediators, regulating the genes related to inflammatory responses in the colon at the mRNA level. Meanwhile, IPSs-2 treatment reinforced the intestinal barrier function by ameliorating the DSS-induced histological injury, facilitating the differentiation of goblet cells to enhance Mucin-2 generation, and enhancing the expression of tight junction proteins to alleviate colitis. In addition, IPSs protected against colitis by promoting the production of short-chain fatty acids (SCFAs), the activation of SCFAs receptors, and the leverage of the gut microbiota via the enrichment of Bacteroides , Parabacteroides , Faecalibacterium , Flavonifractor&#95;plautii , and Butyricicoccus , linking with reducing inflammation and repairing intestinal barrier function. Overall, our research revealed the therapeutic potential of IPSs-2 as a prebiotic for attenuating inflammatory bowel disease and provided a rationale for future investigation.

The anti-inflammation effect of aqueous Phyllanthus emblica L. extract (APE) and its possible underlying mechanism in dextran sulfate sodium (DSS)-induced mice chronic colonic inflammation were studied. APE treatment significantly improved the colitic symptoms, including ameliorating the shortening of the colon, increasing the DSS-induced body weight loss, reducing the disease activity index, and reversing the condition of colon tissue damage of mucus lost and goblet cell reduction. Overproduction of serum pro-inflammatory cytokines were suppressed by the treatment of APE. Gut microbiome analysis showed that APE remodeled the structure of gut bacteria in phylum and genus levels, upregulating the abundance of phylum Bacteroidetes, family Muribaculaceae, and genus Bacteroides and downregulating the abundance of phylum Firmicutes. The reshaped gut microbiome caused metabolic functions and pathway change with enhanced queuosine biosynthesis and reduced polyamine synthesis pathway. Colon tissue transcriptome analysis further elucidated APE-inhibited mitogen-activated protein kinase (MAPK), cytokine-cytokine receptor interaction, and tumor necrosis factor (TNF) signaling pathways and the expressions of the genes that promote the progress of colorectal cancer. It turned out that APE reshaped the gut microbiome and inhibited MAPK, cytokine-cytokine receptor interaction, and TNF signaling pathways as well as the colorectal-cancer-related genes to exert its colitis protective effect.

Antimicrobial peptides (AMPs) play essential roles in maintaining intestinal health and have been suggested as possible therapeutic strategies against inflammatory bowel disease (IBD). However, the instability of AMPs in the process of transmission in vivo limits their application in the treatment of IBD. In this study, we constructed the mBD14-producing Lactococcus lactis NZ9000 ( L. lactis /mBD14) to achieve enteric delivery of mBD14 and evaluated its protective effect on dextran sodium sulfate (DSS)-induced colitis. Mice treated with L. lactis /mBD14 exhibited milder symptoms of colitis ( P < 0.01). Additionally, L. lactis /mBD14 treatment reversed DSS-induced epithelial dysfunction and reduced the production of pro-inflammatory cytokines in colon ( P < 0.01). Mechanistically, L. lactis /mBD14 significantly inhibited NOD-like receptor pyrin domain containing three inflammasome-mediated pro-inflammatory response ( P < 0.05) and regulated microbiota homeostasis by promoting the abundance of probiotic bacteria Akkermansia muciniphila and Faecalibacterium prausnitzii and decreasing the pathogenic Escherichia coli ( P < 0.01). Taken together, this study demonstrates the protective effect of L. lactis /mBD14 in DSS-induced colitis, and suggests that oral administration of L. lactis /mBD14 may represent a potential therapeutic strategy for IBD.

Oxidized triglyceride monomers are the main cytotoxic products of deep-frying oil. However, its impact on the intestinal barrier, the first health guardian, remains unknown. In this study, HPLC-MS/MS analysis revealed that the epoxy group is the main oxidation product, indicating that it may be the main cytotoxic factor. Therefore, 1-9,10-epoxystearic ester, 2,3-dioleic acid (EGT) and glycerol trioleate (GT) were used to reveal the effect of the epoxy group on the intestinal barrier of dextran sulfate sodium-induced colitis. Characteristics analysis showed that EGT could aggravate intestinal damage. The relative mRNA expression analysis suggested that EGT could activate Caspase-1/NLRP3/GSDMD, thereby inducing pyroptosis. The proinflammatory cytokines activated by pyroptosis and the cGAS-STING pathway were released through the pores, thus inducing the disintegration of the tight junction between the intestinal epithelial cells and enhancing intestinal permeability. Metabonomics further confirmed that EGT can change the composition and content of phospholipids on the cell membrane, indicating the morphological changes of the intestinal epithelial cell membrane. In conclusion, this study highlights that EGT induced intestinal dysfunction via Caspase-1/NLRP3/GSDMD and cGAS-STING pathways.

The etiology of inflammatory bowel diseases (IBDs) involves complex genetic and environmental factors such as mycotoxin contamination. Deoxynivalenol (DON), a well-known mycotoxin, contaminates food and feed and can induce intestinal injury and inflammatory response. The dose of DON in many foods is also below the limit, although the dose of DON exceeds the limit. The present study aims to evaluate the effects of the nontoxic dose of DON on colitis induced by dextran sodium sulfate (DSS) and the mechanism in mice. The results showed a nontoxic dose of DON at 50 μg/kg bw per day exacerbated DSS-induced colitis in mice as demonstrated by increased disease activity index, decreased colon length, increased morphological damage, decreased occludin and mucoprotein 2 expression, increased IL-1β and TNF-α expression, and decreased IL-10 expression. DON at 50 μg/kg bw per day enhanced JAK2/STAT3 phosphorylation induced by DSS. Adding JAK2 inhibitor AG490 attenuated the aggravating effects of DON on DSS-induced colitis by reversing the morphological damage, occludin and mucoprotein 2 expression increased, IL-1β and TNF-α expression increased, and IL-10 expression decreased. Taken together, a nontoxic dose of DON could aggravate DSS-induced colitis via the JAK2/STAT3 signaling pathway. This suggests that DON, below the standard limit dose, is also a risk for IBD and may be harmful to the health of humans and animals, which could provide the basis for establishing limits for DON.

Ulcerative colitis has been consistently associated with gut microbiota imbalance and disturbed immune system. Emerging research suggests a protective function of polyphenols on prevention and treatment of ulcerative colitis, yet underlying mechanisms remain unclear. Fu brick tea, a postfermented tea, contains abundant polyphenols with anti-inflammatory and antioxidant properties. In the present study, we found that prophylactic supplementation of polyphenols extracted from Fu brick tea (FBTP) dose-dependently alleviated colitis symptoms, immune cells infiltration, and pro-inflammatory cytokines secretion in mice suffering dextran sulfate sodium induced murine colitis. FBTP substantially reshaped gut microbiota and promoted microbial transformation of tryptophan into indole-3-acetic acid (I3A), thereafter leading to aryl hydrocarbon receptor (AHR)-mediated protection from colitis through enhanced expressions of IL-22 and tight junction proteins (i.e., ZO-1, occluding and claudin-1) in colon. Multiomics integration analyses revealed strong connections between I3A, tryptophan-metabolizing bacteria, AHR activity, and pathological phenotypes of colitis. Notably, FBTP failed to significantly alleviate colitis symptoms in the absence of gut microbiota, while intragastric administration of I3A could imitate benefits of FBTP on colitis alleviation and intestinal epithelial homeostasis through a direct enhancement in AHR activity in microbiota-depleted mice. These findings further determine the key role of gut microbiota controlled I3A-AHR signaling in mediating the FBTP on colitis alleviation. This study provides the first data proposing the FBTP as a natural prebiotic for colitis alleviation through the gut microbiota-dependent modulation of the AHR pathway. Most importantly, we also identified I3A as a key microbial metabolite targeted by FBTP for exhibiting health-promoting effects.

Fu-brick tea (FBT) has attracted the attention of researchers because of its unique nutritional value, but it remains unknown whether Eurotium cristatum , the critical fungus from FBT, is responsible for the observed anti-colitis effects of FBT. Herein, the effects of E. cristatum on dextran sulfate sodium (DSS)-induced ulcerative colitis was first discussed. The results illustrated that the oral administration of E. cristatum inhibited DSS-induced colon damage. Microbiota analysis revealed that E. cristatum improved the intestinal homeostasis of colitis mice, especially increased the proportion of Lactobacillus , followed by an obvious increase in fecal short-chain fatty acids (SCFAs). Besides, E. cristatum markedly promoted tryptophan metabolism and increased the fecal contents of tryptophan metabolites in colitis mice. Furthermore, E. cristatum drastically increased the content of colonic IL-22 and the expression of tight-junction proteins. Conclusively, these results suggest that E. cristatum can resist colon damage and other implications of colitis by regulating the microbiota and enhancing tryptophan metabolism to strengthen intestinal barriers.

Inflammatory bowel disease (IBD) is a global chronic disease with a long duration and repeated relapse. Currently, there is still a lack of effective approaches to prevent IBD. Food-derived oryzanol (ORY) possesses extensive biological activities, such as ameliorating bowel diseases, antioxidation, and antiobesity. However, the mechanism of ORY in preventing colitis remains unclear. The present research aims to explore the potential mechanism of ORY in dextran sulfate sodium (DSS)-stimulated colitis in a rat model. The results showed that the symptoms of colitis were significantly improved with the administration of ORY. Mechanismly, the expression levels of Zonula occludens-1 (ZO-1), Claudin-1, Occludin, MUC2, and TFF3 were elevated through ORY treatment, suggesting that oral ORY relieved the degree of gut barrier damage of colitis rats. Meanwhile, 16S sequencing results found that ORY supplementation increased the abundances of Alloprevotella , Roseburia , Treponema , Muribaculaceae , and Ruminococcus , which are associated with the synthesis of short-chain fatty acids (SCFAs). Moreover, GC-MS results confirmed that ORY supplementation reversed the DSS-induced reduction of acetic acid, butyric acid, and total acid. Further research indicated that ORY intervention downregulated the TLR4/NF-κB/NLRP3 pathway, which is closely linked to the expression of proinflammatory cytokines and colon injury. Taken together, ORY ameliorates DSS-stimulated gut barrier damage and inflammatory responses via the gut microbiota-TLR4/NF-κB/NLRP3 signaling axis.

Epigallocatechin gallate and tetrahydrocurcumin are aminated as colonic metabolites, preserving their bioactivities and improving their capabilities. We compared the bioactivities of unaminated (CUR) and aminated (AC) curcumin in inflammatory colitis-associated tumorigenesis. The anti-inflammatory and anticancer capabilities of CUR and AC were evaluated using RAW264.7 and HT29 cell lines, respectively. An azoxymethane/dextran sodium sulfate-induced colitis-associated carcinogenesis mouse model was used with CUR and two-dose AC interventions. AC had a greater anti-inflammatory effect but a similar anticancer effect as CUR in vitro. CUR and low-dose AC (LAC) significantly preserved colon length and reduced tumor number in vivo. Both CUR and LAC inhibited activation of the protein kinase B (AKT)/nuclear factor kappa B (NF-κB) signaling pathway, its downstream cytokines, and the interleukin (IL)-6/signal transducer and activator of transcription 3 (STAT3)/c-myelocytomatosis oncogene (c-MYC) pathway. However, only LAC significantly preserved E-cadherin, reduced N-cadherin, and facilitated beneficial gut microbial growth, including Akkermansia and Bacteroides , potentially explaining AC's better ameliorative effect at low than high doses.

The aim of this study was to evaluate the ability of the Saccharomyces cerevisiae strain with probiotic properties isolated from Tibetan kefir grains to ameliorate Fusobacterium nucleatum (Fn) infection and dextran sulfate sodium (DSS) treatment-induced murine model of colitis. The tolerance to simulated gastrointestinal conditions, hydrophobicity test, autoaggregation assay, and the antioxidant effect of strains was used to screen one strain with colonization and probiotic potential. The murine model of colitis was established by giving 10 9 cfu Fn 3 weeks by intragastric administration and 3% DSS in water 1 week before sacrifice. The results indicated that S. cerevisiae JKSP39 (SC) possessed optimal probiotic characteristics in vitro. Supplementation with SC increased the body weight and the expression of anti-inflammatory cytokines (IL-4 and IL-10), while decreasing the disease activity index score and expression of proinflammatory cytokines (TNF-α, IL-6, and IL-17F) in mice undergoing experimental colitis as compared with the colitis model group. Additionally, tight junction proteins and the number of goblet cells per crypt were significantly increased in the SC group, which indicated that the gut barrier was well repaired. The mechanism of SC ameliorating Fn-DSS-induced colitis could be related to the decreased levels of reactive oxygen species (myeloperoxidase, total superoxide dismutase, catalase, H 2 O 2 , and malondialdehyde) in the colon, the inhibition of endoplasmic reticulum stress, and the regulation of gut microbiota.

Inflammatory bowel disease (IBD), with increasing incidence, causes a range of gastrointestinal symptoms and brings distress and impact on the health and lives of patients. The aim of this study was to explore the protective effects of industrially produced rice protein peptides (RPP) on dextran sulfate sodium (DSS)-induced acute colitis in mice and the potential mechanisms. The results showed that RPP treatment alleviated the symptoms of colitis in mice, including weight loss, colon shortening, and injury, decreased the level of disease activity index (DAI), regulated the balance of inflammatory factors and oxidation, activated Kelch-like ECH-associating protein 1 (Keap1)-nuclear factor E2-related factor 2 (Nrf2) signaling pathway, regulated the expression of related antioxidant proteases, and promoted the expression of intestinal tight junction proteins. In addition, RPP maintained intestinal mucosal barrier function and alleviated acute colitis caused by DSS treatment in mice by increasing the value of F/B, increasing the relative abundance of beneficial bacteria such as Akkermansia , and regulating the level of short-chain fatty acids. In conclusion, RPP alleviated colitis symptoms through the Keap1-Nrf2 signaling pathway and regulating gut microbiota, which had the potential as dietary supplements or functional foods.

Patients with ulcerative colitis (UC) have been found to be frequently associated with secondary liver injury (SLI). In this study, we investigated the protective effect of GA on dextran sodium sulfate (DSS)-induced SLI in mice and its mechanism. The SLI was established by adding 4% DSS in the drinking water of mice, and the effects of GA (5, 20 mg/kg, p.o., once a day for 7 days) in hepatic tissues were analyzed. HepG2 cells were induced by lipopolysaccharide (LPS) to detect the effect of GA on ferroptosis and the underlying mechanism. Pathological damage was determined by H&E. Liver parameters (AST and ALT), antioxidant enzyme activities (MDA and SOD), and the level of Fe 2+ in the liver were detected by kits. Cytokine levels (TNF-α, IL-1β, and IL-6) and Gpx4 activity in the liver were detected by ELISA. Finally, the activation of nuclear factor erythroid 2-like 2 (Nrf2) was detected to explore the mechanism. The results indicated that GA significantly attenuated DSS-induced hepatic pathological damage, liver parameters, and cytokine levels and increased the antioxidant enzyme activities. Moreover, GA attenuated ferroptosis in DSS-induced liver injury and upregulated Gpx4 expression in DSS-induced mice. Mechanistic experiments revealed that GA activated Nrf2 in mice. Taken together, this study demonstrates that GA can alleviate ferroptosis in SLI in DSS-induced colitis mice, and its protective effects are associated with activating the Nrf2-Gpx4 signaling pathway.

Vitexin, one of the major active components in hawthorn, has been shown to possess multiple pharmacological activities. Here, we sought to investigate the effect of vitexin on an ameliorating dextran sodium sulfate (DSS)-induced ulcerative colitis (UC) mouse model and further explored its potential mechanism. The results indicated that vitexin administration could significantly alleviate the signs of colitis via suppressing body weight loss, reducing disease activity index (DAI) score, and mitigating colonic damage. Also, vitexin treatment in colitis mice markedly inhibited the production of pro-inflammation cytokines (such as IL-1β, IL-6, and TNF-α). Meanwhile, vitexin also could markedly down-regulate the phosphorylation levels of p65, IκB, and STAT1. Moreover, vitexin also dose-dependently increased the expressions of muc-2, ZO-1, and occludin proteins in colonic tissues of colitis mice. Further studies revealed that vitexin dramatically modulated the disturbed intestinal flora in colitis mice. Vitexin is beneficial for regulating abundances of some certain bacteria, such as Bacteroides , Helicobacter , Alistipes , Lachnospiraceae&#95;NK4A136&#95;group , and Lachnospiraceae&#95;UCG-006. Interestingly, the correlation analysis indicated that key microbes were strongly correlated with colitis features, such as pro-inflammatory cytokines and gut barrier. Collectively, these results demonstrated that vitexin treatment alleviated inflammation, intestinal barrier dysfunction, and intestinal flora dysbiosis in colitis mice. Vitexin is expected to be a promising compound for UC treatment.

The effectiveness of resveratrol (RES) on intestinal barrier dysfunction and colitis has been extensively studied. However, the specific effects of its microbial metabolites on gut barrier function remain unclear. Hence, we compared the protective effects of RES and its microbial metabolites dihydroresveratrol (DHR) and 3-(4-hydroxyphenyl)-propionic acid (4HPP) against intestinal barrier injury and colitis. Only 4HPP and RES significantly reduced paracellular permeability and the secretion of proinflammatory cytokines in lipopolysaccharides (LPS)-treated intestinal Caco-2 cells, which was consistent with the upregulation in tight junction (TJ) proteins. Furthermore, RES and 4HPP ameliorated intestinal barrier dysfunction and colonic inflammation in colitis mice, while DHR did not. In particular, the expressions of intestinal TJ proteins and Muc2 were restored by RES and 4HPP. The molecular mechanism involved the adenosine monophosphate-activated protein kinase (AMPK)-mediated activation of CDX2 and the regulation of the SIRT1/NF-κB pathway. These findings provide new insights into understanding the protective effects of RES against intestinal barrier damage and colitis.

Coffee cherry husks, the main byproduct of coffee production, contain an abundance of polyphenols. In this study, dextran sodium sulfate (DSS)-induced colitis mice were used to study the protective effects of polyphenolic extracts of coffee cherry husks (CCHP) on inflammation. The results indicated that CCHP administration alleviated the histological changes of DSS-induced colitis in mice and downregulated the mRNA level of TNF-α, IL-1β, IL-6 and Cox-2. Interestingly, CCHP inhibited the activation of microglia and suppressed neural inflammation in the brain. The TLR4/Myd88/NF-κB signaling pathway was examined and found to be inhibited by CCHP. Furthermore, a determination of the gut microbiota showed that an alteration of microbiota induced by DSS was restored by CCHP, including the decrease of the relative abundance of Proteobacteria and the increase of Bacteroidota . In conclusion, our results revealed the great potential of CCHP to alleviate brain inflammation in colitis mice by inhibiting the NF-κB signaling pathway and regulating gut microbiota.

Inflammatory bowel disease (IBD) poses a threat to health and compromises the immune system and gut microflora. The present study aimed to explore the effects of rice protein (RP) purified from rice dregs (RD) on acute colitis induced by dextran sulfate sodium (DSS) and the underlying mechanisms. Results showed that RP treatment could alleviate the loss of body weight, colon shortening and injury, and the level of disease activity index, repair colonic function (claudin-1, ZO-1 and occludin), regulate inflammatory factors, and restore oxidative balance (malondialdehyde (MDA), catalase (CAT), superoxide dismutase (SOD), and total antioxidant capability (T-AOC)) in mice. Also, RP treatment could activate the Kelch-like ECH-associating protein 1 (Keap1)-nuclear factor E2-related factor 2 (Nrf2) signaling pathway, mediate the expression of downstream antioxidant protease (NQO-1, HO-1, and Gclc), regulate gut microbiota by enhancing the relative abundance of Akkermansia and increasing the value of F/B, and adjust short-chain fatty acid levels to alleviate DSS-induced colitis in mice. Thus, RP may be an effective therapeutic dietary resource for ulcerative colitis.

Hydroxytyrosol (HT), a polyphenol derived from olive oil, was examined against dextran sulfate sodium (DSS)-induced colitis to study its potential in preventing colitis and the underlying mechanisms involved. The low dose and high dose of HT used in mice were 10 and 50 mg/kg, respectively. Research findings have shown that HT is effective in preventing colitis by alleviating the signs of colitis. HT intervention significantly reduces colitis markers such as myeloperoxidase (MPO) and proinflammatory cytokine (IL-6, IL-1β, and TNF-α). Also, mice treated with a high dose of HT showed increased secretion of antioxidant enzymes (heme oxygenase-1 (HO) and anti-inflammatory cytokine (IL-10) by 2.32- and 2.28-fold, respectively, in comparison to the DSS-treated group. Modulation effects of HT on the antioxidant signal pathway (NRF2) and the inflammatory pathway (NF-κB) were confirmed. Meanwhile, HT promoted the regeneration of the intestinal barrier and maintained intestinal functional homeostasis by boosting the regeneration of goblet cells and the expression of mucin protein (Muc2) and tight junction (TJ) proteins (claudin-1, occludin, and Zonula Occludens-1). Moreover, HT intervention obviously transformed the gut microbiota, leading to a lower abundance of inflammation-related microbes (e.g., Bacteroidaceae and Desulfovibrionaceae) and a higher level of short-chain fatty acids (SCFAs) producing bacteria (e.g., Lachnospiraceae, Muribaculaceae, ASF356, and Colidextribacter). Scientific evidence for the beneficial effect of the "Mediterranean diet" (MD) on intestinal health was achieved by elucidating the alleviation mechanism of hydroxytyrosol on colitis.

A comprehensive understanding of the relationships between the structure and function is critical for the targeted preparation of functional pectins. In this study, we compared the alleviating effects of five orange pectins (200 mg/kg) extracted using acid ( P2 ), alkali ( P10 ), cellulase ( C ), acid + cellulase ( P2 + C ), and alkali + cellulase ( P10 + C ) on dextran sodium sulfate-induced acute colitis. The physiological and histopathological indicators revealed that the alleviating effects were most significant for P10 + C , followed by P10 , P2 + C , P2 , and C . P10 + C increased the diversity and relative abundance of Akkermansia , leading to increased generation of colonic short-chain fatty acids as well as mRNA and protein expressions of GPR43, GPR109A, claudin-1, ZO-1, and occludin. Therefore, proinflammatory cytokines were decreased, and anti-inflammatory cytokines were increased. A compact conformation of P10 + C contributed to the alleviation effects on acute colitis. Alkali + cellulase-extracted orange pectin with a compact conformation has potential as adjuvant treatment for intestinal inflammation.

Non-nutritive sweeteners are the most widely used food additives designed to provide sweetness and reduce caloric intake. Studies have confirmed a link between sweeteners and colitis, yet supporting scientific data remain exiguous and controversial. In this study, three common sweeteners (Saccharin sodium, Stevioside, and Sucralose) in acceptable daily intake dosage were added to water in order to determine their effects on dextran sodium sulfate-induced colitis in mice. Our results show that the three sweeteners meliorate colitis to varying degrees─Saccharin exerts the most pronounced effect, followed by Stevioside and Sucralose. Intake of sweeteners alleviates colitis symptoms, alters gut microbiota, reshapes the TH17/Treg balance, protects the intestinal barrier, and reduces inflammation. Most significantly, sweeteners can enhance the abundance of Mucispirillum and Alistipes, which are conducive to colitis recovery, and upregulate the expression of E-cadherin through the miR-15b/RECK/MMP-9 axis to improve intestinal barrier integrity. Moreover, by inhibiting the MMP-9/AKT/NF-κB pathway, inflammation is relieved, as reflected in the restoration of the Th17/Treg balance. Our results link the consumption of sweeteners to the remission of colitis, which provides new scientific evidence for the safe use of sweeteners.

Hyperoside (HYP), a naturally occurring flavonoid compound, exerts multiple biological functions including myocardial protection, antiredox, and anti-inflammatory activities. However, the role of HYP on inflammatory bowel disease (IBD) and the underlying mechanism need to be further established. Here, we show that HYP treatment profoundly alleviated dextran sulfate sodium-induced ulcerative colitis in mice, characterized by reduced pathological scores, preserved tissue integrity, suppressed colonic inflammation, and balanced Th17/Treg response. Mechanistically, HYP was shown to restrain the expression of the E3 ubiquitin ligase, makorin ring finger protein 1 (MKRN1), which in turn promoted the ubiquitination and proteasomal degradation of peroxisome proliferator-activated receptor gamma (PPARγ), an essential regulator of Th17 and Treg differentiation. Consequently, HYP treatment enhanced PPARγ signaling and hence promoted Treg differentiation while suppressing Th17 cell development during colitis. Thus, our data indicate that HYP acts through the MKRN1/PPARγ axis to modulate the Th17/Treg axis and thereby confers protection against experimental colitis. The findings extend our understanding about HYP action and may provide a potential therapeutic target for IBD.

Dysbiosis leads to continuous progress of inflammatory bowel disease (IBD). However, current therapeutic approaches for IBD have limited efficacy and are associated with various side effects. This study focused on exploring the positive effect of a new Bacillus cereus ( B. cereus ) strain (HMPM18123) in a colitis mouse model and elucidate the underlying molecular mechanisms. The colitis symptoms were alleviated by the B. cereus administration as evidenced by decreased body weight loss, colon length shortening, disease activity index score, and histopathological score. The B. cereus mitigated intestinal epithelial barrier damage by upregulating tight junction protein expression. Moreover, B. cereus exerted anti-inflammatory effects by regulating macrophage polarization and suppressing the TLR4-NF-κB-NLRP3 inflammasome signaling pathways. B. cereus also rebalanced the damaged gut microbiota. Thus, the molecular mechanism of alleviating colitis by B. cereus treatment involved the regulation of the TLR4-NF-κB-NLRP3 inflammasome signaling pathways in intestinal mucosal barriers by modulating gut microbiota composition.

The present study revealed the phylactic effects of l-theanine on a DSS-induced colitis mice model. The results showed that 3% DSS treatment significantly induced intestinal damage as reflected by DAI, histopathological feature, and colon length, while l-theanine pretreatment markedly prevented these trends to exert protective effects. Meanwhile, l-theanine pretreatment decreased the levels of TNF-α, IL-1β, IL-6, iNOS, and COX2 on DSS-induced colitis. Notably, DSS inhibited the proliferation and promoted the apoptosis of intestinal epithelial cells, thereby damaging the integrity of the intestinal epithelial barrier, whereas l-theanine also played a protective role by attenuating these deteriorated effects. It was also observed that l-theanine treatment downregulated the levels of p-p65, p65, p-p53, p53, and p-AKT protein expression in acute DSS-induced colitis, which showed the protective function of l-theanine, mainly via the NF-κB signaling pathway. Furthermore, the results of lipid analysis and transcriptome analysis show that l-theanine reversed transcriptional profiles and lipid profiles of colitis models, mainly via the inflammatory reactivity-related pathway. Interestingly, the correlation analysis between transcriptional profiles and lipid profiles showed that inflammatory response-related genes were almost significantly correlated with differential lipid metabolites. In summary, l-theanine plays a protective role in DSS-induced colitis via downregulating the NF-κB signaling pathway and regulating lipid metabolism disorders.

Dietary ethanolamine plasmalogen (PlsEtn) has been reported to have several health benefits; however, its functional role during colon pathophysiology remains elusive. The present study investigated the anticolitis effect of dietary ethanolamine glycerophospholipids (EtnGpls) with high PlsEtn from ascidian muscle (86.2 mol %) and low PlsEtn from porcine liver (7.7 mol %) in dextran sulfate sodium (DSS)-induced colitis in mice. Dietary EtnGpls lowered myeloperoxidase activity, thiobarbituric acid-reactive substances, proinflammatory cytokines and proapoptosis-related protein levels in colon mucosa after 16 days of DSS treatment, with ascidian muscle (0.1% EtnGpl in diet) showing higher suppression than porcine liver (0.1% EtnGpl in diet). Moreover, dietary EtnGpls suppressed DSS symptoms after 38 days of DSS treatment as evidenced by increased body weight, colon length, and ameliorated colon mucosa integrity. Additionally, dietary EtnGpls elevated short-chain fatty acid production in DSS-treated mice. Altogether, these results indicate the potential of utilizing diets with abundant PlsEtn for the prevention of colon inflammation-related disorders.

Ripened pu-erh tea has the biological activity of antioxidation and anti-inflammation, which inhibits the related parameters of colitis. However, the role of storage-induced changes in bioactive ingredients of ripened pu-erh tea in colitis remains unclear. In this study, 3.5% dextran sulfate sodium-induced colitis mice were treated with 10 mg/kg bw/day extracts, aged 14 years (P2006) and unaged (P2020) ripened pu-erh tea, respectively, for 1 week. We found that ripened pu-erh tea, especially P2006, inhibited the intestinal oxidative stress-mediated inflammation pathway (TLR4/MyD88/ROS/p38MAPK/NF-κB p65), upregulated the expression of intestinal tight junction proteins (Mucin-2, ZO-1, occludin), promoted M2 polarization of macrophages, and in turn, improved the intestinal immune barrier, which stemmed from the reshaping of intestinal microbiota (e.g., increased Lachnospiraceae&#95;NK4A136&#95;group and Akkermansia levels). Our results speculate that drinking aged ripe pu-erh tea (10 mg/kg bw/day in mice, a human equivalent dose of 7 g/60 kg bw/day) has a practical effect on alleviating and preventing the development of intestinal inflammation.

The present study investigated the effect of eugenol (EUG) on dextran sulfate sodium (DSS)-induced colitis and explored the underlying mechanisms. C57BL/6 mice were intragastrically administered normal saline or EUG (20 mg/kg body weight) for 17 days, and colitis was induced by using 3% DSS from day 7. The results showed that EUG increased the body weight and reduced the disease activity index score and colon pathological scores in DSS-treated mice ( P < 0.05). Further, EUG preserved the proinflammatory cytokines (interleukin (IL)-6, -12, -21, and -23), lowered ( P < 0.05) colonic malondialdehyde (MDA), uncoupling protein 2 (UCP2) expression and p65 phosphorylation, and activated ( P < 0.05) colonic kelch-like ECH-associated protein 1 and nuclear factor (erythroid-derived 2)-like 2 expressions but did not affect the intestinal microbiota in DSS-treated mice. Furthermore, EUG ameliorated colitis in antibiotic-treated mice, while fecal microbiota transplantation from EUG preadministered mice failed to ameliorate colitis. In conclusion, EUG could alleviate colitis by attenuating colonic inflammation and oxidative stress independent of intestinal microbiota.

In this study, the preventive effect of tangeretin (TAN), a natural flavonoid derivative from citrus fruits, on the dextran sulfate sodium (DSS)-induced colitis in mice was evaluated. Our results showed that dietary TAN (0.04% and 0.08% w/w in the diet) significantly reduced the severity of colitis caused by DSS treatment in mice, evidenced by the increased colon length, the reduced disease activity index, and the attenuated colonic tissue damages. Moreover, dietary TAN inhibited the inflammatory response via down-regulating the overexpression of colonic inflammatory cytokines. Immunohistochemical analysis revealed that the intestinal barrier function was restored by TAN through enhancing claudin-1 and ZO-1 expressions. Additionally, dietary TAN modulated gut microbiota in colitic mice via enhancing gut microbiota diversity, ascending the level of beneficial bacteria, e.g., Lachnospiraceae and Lactobacillaceae , and descending the level of harmful bacteria, e.g., Enterobacteriaceae and Alistipes . Besides, dietary TAN promoted short-chain fatty acids production in DSS-treated mice. Altogether, these findings provided scientific evidence for the rational utilization of TAN as a preventive agent against colonic inflammation and related diseases.

The worldwide prevalence of obesity has significantly increased over the past few decades. It is currently believed that obesity is a risk factor for developing inflammatory bowel disease. Pterostilbene (PTS), a naturally occurring stilbene from blueberries, is known to have anticancer, anti-inflammation, antifibrosis, and antiobesity effects. The preventive effect of PTS on the susceptibility of high-fat diet (HFD) to dextran sulfate sodium (DSS)-induced colitis in mice was investigated. Beginning at 5 weeks of age, C57BL/6J mice were fed a normal diet, 50% HFD alone, or containing PTS, and DSS (2.5%, w/v) was given in drinking water at week 9 and week 11. The results demonstrated that PTS significantly attenuated HFD and DSS-induced plasma interleukin-6 accumulation. Moreover, PTS suppressed HFD/DSS-induced formation of aberrant crypt foci and reduced the colon weight-to-length ratio in HFD/DSS-induced colitis mice. Furthermore, PTS inhibited interleukin-1β (IL-1β), the C/EBP homologous protein (CHOP), cyclooxygenase-2, and transforming growth factor beta-1 (TGF-β1)/mothers against decapentaplegic homolog 2 expression and maintained mucin2 (Muc2) and E-cadherin expressions. In addition, post-treatment with PTS also decreased the colon weight-to-length ratio and loss of Muc2. Moreover, the CHOP, IL-1β, matrix metalloproteinase-2, and TGF-β1 expressions were significantly decreased in HFD/DSS-induced colitis mice after post-treatment with PTS. In conclusion, the results of the present study suggest that PTS is of significant interest for the prevention of HFD/DSS-induced colitis in C57BL/6J mice.

Intestinal barrier dysfunction and inflammatory cytokine secretion play crucial roles in inflammatory bowel disease (IBD). Herein, we investigated the protective effects of Tricholoma matsutake -derived peptides SDIKHFPF and SDLKHFPF against dextran sulfate sodium-induced colitis. Both peptides alleviated colitis signs, including diarrhea, weight loss, bloody stools, colon shortening, and histopathological changes, while reducing mucus destruction, goblet cell exhaustion, and intestinal permeability. SDIKHFPF and SDLKHFPF protected the barrier function by promoting the expression of tight junction (TJ) zonula occludens-1 and occludin within the colon, as well as attenuating colonic inflammation through myeloperoxidase and pro-inflammatory cytokine suppression. Western blotting indicated that the peptides suppressed myosin light chain kinase (MLCK) and nuclear factor kappa B (NF-κB) levels, inhibiting MLC phosphorylation. SDLKHFPF was more potent than SDIKHFPF. These findings suggest that peptide SDLKHFPF mitigates colitis by regulating TJ protein expression and pro-inflammatory cytokine production via NF-κB/MLCK/p-MLC signaling, improving the barrier function.

In this study, we evaluated the protective effect and molecular mechanism of a dominant phenanthrene, (6,7-dihydroxy-2,4-dimethoxyphenanthrene, CYP4), from Chinese yam peels on intestinal epithelial integrity. Three doses of Chinese yam phenolic extract (CYPE) and Chinese yam phenanthrene 4 (CYP4) were administered to BALB/c mice for 7 days before dextran sulfate sodium (DSS) treatment, with berberine hydrochloride as a positive control (PC). Results showed that both disease activity indexes (DAIs), histological damage score (HDS) and survival rate in DSS mice, were improved with preintervention of CYPE and CYP4, which exhibited better efficiency than PC. Further studies showed that administration of CYP4 downregulated the oxidative stress-associated factors, MPO and NO, and improved tight junction protein occludin. Besides, the CYP4 treatment substantially downregulated the caspase-3 expression and the apoptosis rate of intestinal epithelial cells. In addition, the CYP4 treatment ameliorated the production of inflammatory cytokines including TNF-α, IFN-γ, IL-10, and IL-23 in the colon. Furthermore, the protein expression of ERK1/2, NF-κB p65, pNF-κB, and COX-2 was suppressed in CYE4 groups as compared with that in model control (MC). These findings suggested that CHP4 could effectively inhibit the activation of NF-κB/COX-2 in an experimental UC model in vivo. It was demonstrated for the first time that CYPE and CYP4 protected intestinal mucosa from damage and prevented DSS-induced colitis in mice. CYP4 was one of the active principles obligatory for the biological effect of Chinese yam in protecting intestinal health. These findings indicated that CYP4 might be a promising and useful approach for treatment of UC in humans.

The preventive effect of lychee pulp phenolics (LPP) on dextran sulfate sodium (DSS)-induced colitis of mice and its underlying mechanisms were investigated in this research. LPP supplementation mitigated DSS-induced breakage of the gut barrier as evidenced by the increased tight junction proteins and the enhanced integrity of epithelial cells. Both LPP and 5-ASA treatments could downregulate the expressions of toll-like receptor 4 (TLR-4), NOD protein-like receptor 3 (NLRP3), and proinflammatory cytokines to normal levels. Notably, treatment with LPP at a dosage of 500 mg/kg/day effectively upregulated FFAR2 and FFAR3 expression and contents of short-chain fatty acids (SCFAs), suggesting the activation of the SCFA-FFAR (free fatty acid receptor) pathway. Consistently, the abundances of probiotic taxa and microbiota ( Akkermansia , Lactobacillus , Coprococcus , and Bacteroides uniformis ) associated with SCFA synthesis were elevated, whereas harmful bacteria ( Enterococcus and Aggregatibacter ) were suppressed. These data indicate that LPP ameliorates gut barrier damage, activates the microbiota-SCFA-FFAR signaling cascade, and suppresses the TLR4/NLRP3-NF-κB pathway, and therefore, LPP supplementation could be a promising way to protect the intestinal tract.

Obesity-induced colonic inflammation-stimulated colitis is one of the main causes of colorectal cancer. Dietary phytochemicals are considered to be an effective strategy for relieving obesity-induced inflammatory diseases such as diabetes and colitis. Ginsenoside Rk3 (Rk3) is the main bioactive component of ginseng. Our previous study has demonstrated that Rk3 can effectively alleviate obesity-induced type 2 diabetes, but whether it plays a beneficial role in obesity-induced colitis remains poorly understood. Here, we found that Rk3 intervention repaired the intestinal barrier dysfunction by increasing the expression of the tight junction proteins (zonula occludens-1, claudin, and occludin), and reduced colonic inflammatory cytokine levels, oxidative stress, and macrophage infiltration in high-fat diet-induced mice. Importantly, Rk3 effectively ameliorated the metabolic dysbiosis of intestinal flora with significantly decreased Firmicute / Bacteroidete ratios and suppressed the inflammatory cascade by inhibiting the TLR4/NF-κB signaling pathway. Taken together, our findings indicate that Rk3 can be used as a potential natural anti-inflammatory agent to reduce chronic obesity-induced colitis.