Colon Length Research Articles

Bisphenol S exposure induces intestinal inflammation via altering gut microbiome

Bisphenol S (BPS), a substitute for bisphenol A, is widely used in the manufacture of food packaging materials, raising concern over its toxicity. However, evidence is still lacking on whether gut microbiota involved in BPS induced intestinal inflammation in mammals, as well as its underlying mechanism. Using mouse BPS exposure model, we found intestinal inflammation characterized by shortened colon length, crypt distortion, macrophage accumulation and increased apoptosis. As for gut microbiota, 16s rRNA gene amplicon sequencing showed BPS exposure induced gut dysbiosis, including increased pro-inflammatory microbes such as Ileibacterium, and decreased anti-inflammatory genera such as Lactobacillus, Blautia and Romboutsia. Besides, LC-MS/MS-based untargeted metabolomic analysis indicated BPS impaired both bacteria and host metabolism. Additionally, transcriptome analysis of the intestine revealed abnormal gene expression in intestinal mucosal barrier and inflammation. More importantly, treating mice with antibiotics significantly attenuated BPS-induced gut inflammation via the regulation of both bacterial and host metabolites, indicating the role of gut microbiota. Collectively, BPS exposure induces intestinal inflammation via altering gut microbiota in mouse. This study provides the possibility of madecassic acid, an anti-inflammatory metabolite, to prevent BPS-induced intestinal inflammation and also new insights in understanding host-microbiota interaction in BPS toxicity.

Fut2 deficiency aggravates chronic colitis through 2-oxindole-AHR mediated cGAS-STING pathway

ObjectiveThis study aims to disclose how loss of fucosyltransferase 2 (Fut2) impacts intestinal inflammation through cGAS-STING pathway that is closely associated with gut microbiota, and which microbial metabolite improves colitis in Fut2 deficiency. MethodsChronic colitis was induced in intestinal epithelial Fut2 knock out mice (Fut2△IEC), whose intestinal inflammation and activity of cGAS-STING pathway were evaluated. 16S rRNA sequencing and metabolomics were performed using intestinal samples. 2-oxindole was used to treat RAW264.7 cells and Fut2△IEC mice with colitis (Fut2△IEC-DSS) to investigate the effect of 2-oxindole on cGAS-STING response and intestinal inflammation. ResultsFut2 loss exacerbated chronic colitis in mice, manifested by declined body weight, reduced colon length, increased disease activity index (DAI) and more colon injury in Fut2△IEC-DSS mice compared with WT-DSS (wild type mice with colitis). Lack of Fut2 promoted activation of cGAS-STING pathway. Fut2 deficiency had a primary impact on colonic microbiota, as shown by alteration of microbial diversity and structure, as well as decreased Lactobacillus. Metabolic structure and tryptophan metabolism in colonic luminal microbiota were also influenced by Fut2 loss. Fut2 deficiency also led to decreased levels of aryl hydrocarbon receptor (AHR) and its ligand 2-oxindole derived from tryptophan metabolism. 2-oxindole compromised cGAS-STING response through activating AHR in macrophages, and protected against intestinal inflammation and overactive cGAS-STING pathway in Fut2△IEC-DSS mice. ConclusionFut2 deficiency promotes cGAS-STING pathway through suppressing 2-oxindole-AHR axis, ultimately facilitating the susceptibility to chronic colitis.

Protective effects of Amauroderma rugosum on dextran sulfate sodium-induced ulcerative colitis through the regulation of macrophage polarization and suppression of oxidative stress

BackgroundAmauroderma rugosum (AR) is a medicinal mushroom commonly used to treat inflammation, gastric disorders, epilepsy, and cancers due to its remarkable anti-inflammatory and anti-oxidative properties. This study was designed to evaluate the pharmacological effects of AR and its underlying mechanism of action against ulcerative colitis (UC) in vitro and in vivo. MethodsA UC mouse model was established by administration of dextran sulfate sodium (DSS). AR extract was administered intragastrically to mice for 7 days. At the end of the experiment, histopathology, macrophage phenotype, oxidative stress, and inflammatory status were examined in vivo. Furthermore, RAW 264.7, THP-1, and Caco-2 cells were used to elucidate the mechanism of action of AR in vitro. ResultsAR extract (0.5–2 mg/mL) significantly suppressed lipopolysaccharide (LPS) and interferon-gamma (IFN-γ)-induced M1 macrophage (pro-inflammatory) polarization in both RAW 264.7 and THP-1 cells. LPS-induced pro-inflammatory mediators (nitric oxide, TNF-α, IL-1β, MCP-1, and IL-6) were reduced by AR extract in a concentration-dependent manner. Similarly, AR extract downregulated MAPK signaling activity in LPS-stimulated RAW 264.7 cells. AR extract elicited a concentration-dependent increase in the mRNA expression of M2 (anti-inflammatory) phenotype markers (CD206, Arg-1, Fizz-1, and Ym-1) in RAW 264.7 cells. Moreover, AR extract suppressed DSS-induced ROS generation and mitochondrial dysfunction in Caco-2 cells. The in vivo experiment revealed that AR extract (200 mg/kg) increased colon length compared to the DSS-treated group. In addition, disease activity index, spleen ratio, body weight, oxidative stress, and colonic inflammation were markedly improved by AR treatment in DSS-induced UC mice. Finally, AR suppressed M1 and promoted M2 macrophage polarization in UC mice. ConclusionThe AR extract protected against DSS-induced UC by regulating macrophage polarization and suppressing oxidative stress. These valuable findings suggest that adequate intake of AR can prevent and/or treat UC.

Raffinose Ameliorates DSS-Induced Colitis in Mice by Modulating Gut Microbiota and Targeting the Inflammatory TLR4-MyD88-NF-κB Signaling Pathway.

This study aimed to explore the protective effects of raffinose (Raf) against inflammatory bowel disease in mice with colitis. Mice were administered 100, 200, or 400 mg/kg Raf for 21 d, followed by drinking-water containing 3% dextran sulfate sodium salt (DSS) for 3 d. Thereafter, the phenotype, pathological lesions in the colon, cytokines levels, and gut microbiota were evaluated. Treatment with Raf reduced the severity of the pathological changes in the colon, mitigating the reduction in colon length. Following Raf intervention, serum levels of inflammatory cytokines (IL-2, IL-6, IL-1β, and TNF-α) tended to return to normal. These results suggest that the anti-inflammatory effects of Raf are associated with a reduction in TLR4-MyD88-NF-κB pathway expression in mouse colonic tissues. Analysis of gut microbiota abundance and its correlation with colitis parameters revealed that DSS-induced dysbiosis was partially mitigated by Raf. In conclusion, Raf exerts a protective effect in colitis by modulating the gut microbiota and TLR4-MyD88-NF-κB pathway.

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

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

Cu,Zn,I-Doped Carbon Dots with Boosted Triple Antioxidant Nanozyme Activity for Treatment of DSS-Induced Colitis.

Nanozyme-mediated antioxidative therapy is a promising star for treating a myriad of important diseases through eliminating excessive reactive oxygen species (ROS) such as O2·- and H2O2, a critical mechanism for inflammatory bowel disease (IBD). This work provides a high biocompatibility iodine-copper-zinc covalent doped carbon dots (Cu,Zn,I-CDs) with the catalase (CAT)-, superoxide dismutase (SOD)- and glutathione peroxidase (GPx)-like catalytic activities for treating ulcerative colitis (UC) by scavenging overproduced ROS. We found that I dopant aids in counteracting the positive charge at Cu,Zn dopants brought on by low pH, enabling Cu,Zn,I-CDs to process strong triple antioxidant nanozyme activities rather than Cu,Zn-CDs. Vitro experiments displayed that the Cu,Zn,I-CDs could scavenge the excessive ROS to protect cellular against oxidative stress and reduce the expression of proinflammatory cytokines, such as TNF-α, IL-1β, and IL-6. In sodium dextran sulfate (DSS)-induced colitis mice models, Cu,Zn,I-CDs with excellent biocompatibility could effectively relieve the inflammation of the colon, containing the reduction of the colon length, the damaged epithelium, the infiltration of inflammatory cells, and upregulation of antioxidant genes. Therefore, the therapy of Cu,Zn,I-CD antioxidant nanozymes is an effective approach and provides a novel strategy for UC treatment.

Anti-Inflammatory Effect of Korean Soybean Sauce (Ganjang) on Mice with Induced Colitis.

Inflammatory bowel disease (IBD), characterized by chronic inflammation of the gut, is caused by several factors. Among these factors, microbial factors are correlated with the gut microbiota, which produces short-chain fatty acids (SCFAs) via anaerobic fermentation. Fermented foods are known to regulate the gut microbiota composition. Ganjang (GJ), a traditional fermented Korean soy sauce consumed worldwide, has been shown to exhibit antioxidant, anticancer, anti-colitis, and antihypertensive activities. However, its effects on the gut microbiota remain unknown. In the present study, we aimed to compare the anti-inflammatory effects of GJ manufactured using different methods and investigate its effect on SCFA production in the gut. To evaluate the anti-inflammatory effects of GJ in the gut, we performed animal experiments using a mouse model of dextran sulfate sodium (DSS)-induced colitis. All GJ samples attenuated DSS-induced colitis symptoms, including reduced colonic length, by suppressing the expression of inflammatory cytokines. In addition, GJ administration modulated SCFA production in the DSS-induced colitis model. Overall, GJ exerted anti-inflammatory effects by reducing DSS-induced symptoms via regulation of inflammation and modulation of SCFA levels in a DSS-induced colitis model. Thus, GJ is a promising fermented food with the potential to prevent IBD.

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.

Atorvastatin improved ulcerative colitis in association with gut microbiota-derived tryptophan metabolism

AimsAtorvastatin is a commonly used cholesterol-lowering drug that possesses non-canonical anti-inflammatory properties. However, the precise mechanism underlying its anti-inflammatory effects remains unclear. Materials and methodsThe acute phase of ulcerative colitis (UC) was induced using a 5 % dextran sulfate sodium (DSS) solution for 7 consecutive days and administrated with atorvastatin (10 mg/kg) from day 3 to day 7. mRNA-seq, histological pathology, and inflammatory response were determined. Intestinal microbiota alteration, tryptophan, and its metabolites were analyzed through 16S rRNA sequencing and untargeted metabolomics. Key findingsAtorvastatin relieved the DSS-induced UC in mice, as evidenced by colon length, body weight, disease activity index score and pathological staining. Atorvastatin treatment reduced the level of pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α). Atorvastatin also relieved the intestinal microbiota disorder caused by UC and decreased the proliferation of pernicious microbiota such as Akkermansia and Bacteroides. Atorvastatin dramatically altered tryptophan metabolism and increased the fecal contents of tryptophan, indolelactic acid (ILA), and indole-3-acetic acid (IAA). Furthermore, atorvastatin enhanced the expression level of aryl hydrocarbon receptor (AhR) and interleukin-22 (IL-22) and further promoted the expression level of intestinal tight junction proteins, such as ZO-1 and occludin, in colitis mice. SignificanceThese findings indicated that atorvastatin could alleviate UC by regulating intestinal flora disorders, promoting microbial tryptophan metabolism, and repairing the intestinal barrier.

Green tea polyphenols reduced Porphyromonas gingivalis virulence and ameliorated aggravated gut inflammation by improving immunity and gut microbiota dysbiosis

Porphyromonas gingivalis (PG), a key periodontal pathogen, has been implicated in various systemic diseases, including colorectal cancer and cardiovascular diseases. However, its potential role in promoting gut inflammation and the underlying mechanisms remain unclear. Furthermore, multiple studies have reported an association between tea polyphenols and a reduced risk of periodontal disease and colitis, but it remains unclear whether they play a role in mitigating gut inflammation exacerbated by PG. In this study, we demonstrated that Tea polyphenols (TP) reduced the activity of PG and lowered the expression levels of virulence factors. Intervention with TP can prevent the worsening of gut inflammation exacerbated by PG, including body weight loss and shortened colon length. TP not only alleviated the differentiation of Th17 cells and the secretion of related cytokines but also promoted the enrichment of potentially beneficial bacteria like Ruminococcus and Lactobacillus. Metabolomics revealed that TP enriched potential beneficial microbial metabolites, such as secondary bile acids, and showed certain correlations with immune-related markers.

The immunomodulatory effects of paraprobiotic mixtures derived from novel probiotic isolates in dextran sodium sulfate-induced colitis in mice via MAPK pathway

IntroductionThe positive effects of paraprobiotic which are inviable components derived from probiotic strains, in a colitis model have been reported in some studies, although the precise mechanisms behind these effects have not been fully elucidated. Therefore, the objective of this study was to evaluate the beneficial anti-inflammatory effect of paraprobiotics derived from our native Bifidobacterium and Lactobacillus spp. In a colitis model as a safer product in comparison to probiotic, through the MAPK signaling pathway. MethodsColitis was induced by orally administering 2 % DSS to C57BL/6 mice. Alongside DSS, a mixture of paraprobiotics was administered via gavage. After two weeks, the mice were assessed using Disease Activity Index and histopathological scores. Moreover, the colonic specimens were analyzed to determine the expression of inflammatory markers using qRT-PCR. ResultsThe consumption of DSS resulted in alterations in body weight and the structure of the colon. However, the administration of the paraprobiotics mixture exhibited a significant improvement in DSS-induced colitis in mice through a reduction in body weight loss and an increase in the colon length. Furthermore, there were decreases in DAI and histopathological scores observed following this treatment. The administration of paraprobiotics led to a reduction in inflammation by downregulating the expression of MAPK-related genes that were induced by DSS. ConclusionThe findings demonstrate that presented paraprobiotic have a protective effect in a mouse model of DSS-induced colitis by mitigating the inflammatory response. The present study provides support for the development of paraprobiotics as a safe alternative therapeutic agent for IBD.

Chang'an decoction alleviates endoplasmic reticulum stress by regulating mitofusin 2 to improve colitis.

To evaluate the protective effects of Chang'an decoction (, CAD) on colitis, and investigate the potential mechanisms underlying these effects from the perspectives of endoplasmic reticulum (ER) stress induced by mitofusin 2 (MFN2). The composition of CAD was identified by liquid chromatography-mass spectrometry technology. A mice model of dextran sulfate sodium (DSS) induced colitis was established and therapeutic effects of CAD were determined by detecting body weight, disease activity index, colon length and histopathological changes. Then, the expression levels of MFN2, ER stress markers and Nucleotide-binding domain and leucine-rich repeat protein3 (NLRP3) relevant proteins were detected by polymerase chain reaction (PCR), Western blot, immunohistochemistry and immunofluorescence staining. Subsequently, knockdown and overexpression cell model were constructed to further investigate the underlying mechanism of MFN2 mediating ER stress and energy metabolism by PCR, Western blot, electron microscopy and reactive oxygen species (ROS) staining. Finally, inflammatory indicator and tight junction proteins were measured by PCR and immunofluorescence staining to evaluate the protective effects of CAD. Results showed that the indispensable regulatory role of MFN2 in mediating ER stress and mitochondrial damage was involved in the protective effects of CAD on colitis in mice fed with DSS. Network pharmacology analysis also revealed CAD may play a protective effect on colitis by affecting mitochondrial function. In addition, our data also suggested a causative role for MFN2 in the development of inflammatory responses and energy metabolic alterations by constructing a knockdown and overexpression cell model whereby alter proper ER-mitochondria interaction in Caco-2 cells. Furthermore, relative expression analyses of ER stress markers and NLRP3 inflammasome showed the onset of ER stress and activation of NLRP3 inflammasome, which is consistent with the above findings. In contrast, intervention of CAD could improve the mucosal barrier integrity and colonic inflammatory response effectively through inhibiting ER stress response mediated by MFN2. CAD could alleviate ER stress by regulating MFN2 to exert therapeutic effects on DSS-induced colitis, which might provide an effective natural therapeutic approach for the treatment of ulcerative colitis.

L.acidophilus HSCC LA042 and HKL suspension ameliorate DSS-induced ulcerative colitis in mice by improving the intestinal barrier inhibiting the NLRP3 inflammasome and pathogenic bacteria

Ulcerative Colitis(UC) is a chronic intestinal inflammation affecting the intestines, yet its underlying causes remain unclear. In recent decades, the global prevalence of UC has been on the rise, leading to an increasing demand for therapeutic drugs with minimal side effects. Huan Kui Le (HKL), a traditional Chinese medicine compound, has demonstrated promising efficacy when combined with Lactobacillus acidophilus (Lac.) for UC intervention. However, the precise therapeutic mechanism of this combination remains unknown. The study focused on understanding the mechanisms of UC by examining the effects of Lac. and HKL (LH) treatment. The outcomes discovered that the disruption of gut microbiota, triggered by the activation of the NLRP3 inflammasome, plays a crucial role in UC development. This disruption exacerbates UC symptoms by causing disturbances in inflammatory cytokines and mucosal permeability. We investigated the dynamic changes following the application of this treatment using 16S rRNA sequencing, HE, WB, IHC, and ELISA. Compared with the UC group, LH treatment reduced colon pathological injury, improved colon length, and decreased IL-1 β serum levels. Furthermore, it restored the expression of TJs and preserved mucosal barrier integrity. LH treatment also mitigated colon injury by attenuating the expression of pyroptosis-related genes and proteins, such as NLRP3 and Caspase-1. Additionally, LH treatment altered the gut microbiota's microecology, characterized by a reduction in pathogenic bacteria abundance like Escherichia-shigella and an increase in beneficial bacteria abundance like Akkermansia and Erysipelatoclostridium. Overall, our findings indicate that LH therapy may be associated with intestinal barrier repair, inflammasome inhibition, and gut microbiota regulation, suggesting its potential as a UC treatment.

Laparoscopic-Assisted Colonic Derotation in Patients With Hirschsprung Disease

BackgroundChildren with Hirschsprung disease (HSCR) proximal to the splenic flexure or those needing a redo pull-through (PT) are at risk for tension and ischemia of the PT which could result in leak, stricture, or loss of ganglionated bowel. Colonic derotation is a technique used to minimize tension and avoid duodenal obstruction. The aim of this study was to describe this technique and outcomes in a series of patients requiring this intervention. MethodsAll patients underwent initial diversion and colonic mapping. The derotation procedure involves mobilization of the remaining colon, counterclockwise rotation via the stoma closure site, placement of the pull through (the right colon) lying on the right of the pelvis, and ligation of the middle colic artery with preservation of the marginal branch running from the ileocolic artery. This maneuver prevents compression of the duodenum by the mesenteric vessels and allows for an isoperistaltic, tension-free anastomosis. Intraoperative indocyanine green fluorescence angiography (ICG-FA) was utilized in many of the cases to map the blood supply of the pull-through colon. We reviewed outcomes for all children with HSCR who underwent colonic derotation from 2014 to 2023. Descriptive statistics were performed. ResultsThere were 37 children included. Most were male (67.5%) with the original transition zone proximal to the rectosigmoid (81.1%). The median age at PT was 9.3 months [6.1–39.7]. Median operative time was 6.6 h [4.9–7.4] and 19 cases (51.4%) used ICG-FA. Most children had no 30-day postoperative complications (67.6%); in those who did develop complications, readmissions for electrolyte imbalance was most common (50.0%).There were zero cases of anastomotic leak at PT anastomosis. At long-term follow up, median 4.4 years [2.3–7.0], three children (8.1%) developed an anastomotic stricture, all were amenable to anal dilation, and five experienced episodes of enterocolitis (14.7%). Most children had between 1 and 4 stools per day (58.8%). ConclusionColonic derotation is a useful strategy to ensure well-perfused colonic length, protect the marginal artery blood supply, avoid duodenal compression, and ensure a tension-free anastomosis with minimal complications. Type of StudyOriginal research, retrospective cohort. Level of EvidenceIII.

Traditional medicine Xianglian pill suppresses high-fat diet-related colorectal cancer via inactivating TLR4/MyD88 by remodeling gut microbiota composition and bile acid metabolism

Ethnopharmacological relevancePrevious studies have revealed that a high-fat diet (HFD) promotes the progression of colorectal cancer (CRC) in close association with disturbances in the intestinal flora and metabolic disorders. Xianglian pill (XLP) is a well-established traditional prescription with unique advantages in controlling intestinal flora imbalance and inflammation. However, its therapeutic effects on HFD-related CRC remain largely unknown. Aim of the studyThe primary objective of this research was to investigate the anticancer mechanism of XLP in countering HFD-related CRC. Materials and methodsThe protective effect of XLP was evaluated using azoxymethane (AOM) and dextran sulfate sodium (DSS)-induced CRC model of mice exposed to a HFD. The degree of colorectal carcinogenesis, including body weight, colon length, and histopathology, was measured in mice treated with XLP and untreated mice. The effect of XLP on gut microbiota and its metabolites was detected using 16S rDNA and liquid chromatography/mass spectrometry analysis. Furthermore, a “pseudo-sterile” mouse model was constructed using antibiotics (Abx) to verify whether the gut microbiota and metabolites play a role in the pathogenesis of CRC. ResultsXLP inhibited colorectal tumorigenesis in a dose-dependent fashion. Our findings also highlighted that XLP protected the integrity of the intestinal barrier by reducing the expression of pro-inflammatory cytokines, such as IL-6 and TNF-α, as well as the infiltration of pro-inflammatory macrophages. Mechanistically, XLP inhibited the TLR4/MyD88 pathway. Notably, the XLP treatment increased the proportion of probiotics (particularly Akkermansia) and significantly reduced fecal deoxycholic acid (DCA), a microbiota-derived metabolite of bile acids (BA) closely related to Muribaculaceae. Furthermore, after Abx treatment, XLP showed no clear antitumor effects on CRC. Simultaneously, DCA-supplemented feedings promoted colorectal tumorigenesis and provoked obvious colonic inflammation, M1 macrophage infiltration, and colonic injury. In vitro, the results of RAW-264.7 macrophages and normal intestinal epithelial cells treated with DCA corroborated our in vivo findings, demonstrating consistent patterns in inflammatory responses and intestinal barrier protein expression. ConclusionOur findings suggest that XLP inhibits colorectal cancer associated with HFD via inactivating TLR4/MyD88 by remodeling gut microbiota composition and BA metabolism.

Desloratadine via its anti-inflammatory and antioxidative properties ameliorates TNBS-induced experimental colitis in rats

Background Intestinal mucosal immune cells, notably mast cells, are pivotal in ulcerative colitis (UC) pathophysiology. Its activation elevates tissue concentrations of histamine. Inhibiting colonic histamine release could be an effective therapeutic strategy for treating UC. Experimental model like 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats mimic human IBD, aiding treatment investigations. Drug repurposing is a promising strategy to explore new indications for established drugs. Desloratadine (DES) is second-generation antihistamine utilized for managing allergies by blocking histamine action in the body. It also has reported anti-inflammatory and antioxidant actions. Objective DES was investigated for its repurposing potential in UC by preclinical screening in TNBS-induced colitis in Wistar rats. Methods Therapeutic efficacy of DES was evaluated both individually and in combination with standard drug 5-aminosalicylicacid (5-ASA). Rats were orally administered DES (10 mg/kg), 5-ASA (25 mg/kg), and DES + 5-ASA (5 mg + 12.15 mg) following the induction of colitis. Parameters including disease activity score rate (DASR), colon/body weight ratio (CBWR), colon length, diameter, pH, histological injury, and scoring were evaluated. Inflammatory biomarkers such as IL-1β, TNF-α, along with reduced glutathione (GSH), and malondialdehyde (MDA) were assessed. Results Significant protective effects of DES, especially in combination with 5-ASA, against TNBS-induced inflammation were observed as evidenced by reduced DASR, CBWR, and improved colon morphology. Drugs significantly lowered plasma and colon histamine and, cytokines levels. GSH restoration, and decreased MDA content were also observed. Conclusion DES and DES + 5-ASA demonstrated potential in alleviating colonic inflammation associated with TNBS-induced colitis in rats. The effect can be attributed to its antihistamine, anticytokine, and antioxidative properties.

Total flavone of Abelmoschus manihot regulates autophagy through the AMPK/mTOR signaling pathway to treat intestinal fibrosis in Crohn's disease.

Drug therapy is the treatment of choice for Crohn's disease because it effectively controls or prevents intestinal inflammation. The purpose was to research the molecular mechanism of the total flavones of Abelmoschus manihot (TFA) on intestinal fibrosis in Crohn's disease. A 2,4,6-Trinitrobenzenesulfonic acid (TNBS)-induced colitis model and IGF-1-treated intestinal fibroblasts were established. Then, TFA, 3-MA, and compound C were used treatments. Hematoxylin and eosin, Masson, and Picrosirius red staining were performed to observe the colon tissue. Immunohistochemical staining was used to detect α-SMA expression. Flow cytometry, CCK8, wound healing, and Transwell assays were conducted to determine apoptosis, proliferation, invasion, and migration. Col1a1 and Col3a1 levels were detected using quantitative polymerase chain reaction. Proteins related to autophagy and apoptosis were detected using western blotting. TFA treated intestinal fibrosis in chronic Crohn's disease. Colon length was the shortest in the ethanol+TNBS group, and TFA treatment significantly improved the situation. Intestinal fibrosis and the percentage of collagen area decreased after TFA treatment. TFA reduced fibrosis by enhancing autophagy stimulation, whereas an autophagy inhibitor reversed the TFA effect. TFA also inhibited migration, proliferation, and collagen synthesis in intestinal fibroblasts. Moreover, it enhanced autophagy and apoptosis of intestinal fibroblasts. TFA upregulated p-AMPK expression and decreases p-mTOR levels. Compound C partially rescued the effect of TFA, indicating that TFA affected intestinal fibroblasts via the AMPK/mTOR pathway in vitro and in vivo. TFA also downregulated Col1a1 and Col3a1 expression. TFA regulates autophagy through AMPK/mTOR signaling pathway to treat intestinal fibrosis, which may provide a new therapy for Crohn's disease treatment.

Intervention with fructooligosaccharides, Saccharomyces boulardii, and their combination in a colitis mouse model.

To examine the effects of an intervention with fructooligosaccharides (FOS), Saccharomyces boulardii, and their combination in a mouse model of colitis and to explore the mechanisms underlying these effects. The effects of FOS, S. boulardii, and their combination were evaluated in a DSS-induced mouse model of colitis. To this end, parameters such as body weight, the disease activity index (DAI), and colon length were examined in model mice. Subsequently, ELISA was employed to detect the serum levels of proinflammatory cytokines. Histopathological analysis was performed to estimate the progression of inflammation in the colon. Gas chromatography was used to determine the content of short-chain fatty acids (SCFAs) in the feces of model mice. Finally, 16S rRNA sequencing technology was used to analyze the gut microbiota composition. FOS was slight effective in treating colitis and colitis-induced intestinal dysbiosis in mice. Meanwhile, S. boulardii could significantly reduced the DAI, inhibited the production of IL-1β, and prevented colon shortening. Nevertheless, S. boulardii treatment alone failed to effectively regulate the gut microbiota. In contrast, the combined administration of FOS/S. boulardii resulted in better anti-inflammatory effects and enabled microbiota regulation. The FOS/S. boulardii combination (109 CFU/ml and 107 CFU/ml) significantly reduced the DAI, inhibited colitis, lowered IL-1β and TNF-α production, and significantly improved the levels of butyric acid and isobutyric acid. However, FOS/S. boulardii 109 CFU/ml exerted stronger anti-inflammatory effects, inhibited IL-6 production and attenuated colon shortening. Meanwhile, FOS/S. boulardii 107 CFU/ml improved microbial regulation and alleviated the colitis-induced decrease in microbial diversity. The combination of FOS and S. boulardii significantly increased the abundance of Parabacteroides and decreased the abundance of Escherichia-Shigella. Additionally, it promoted the production of acetic acid and propionic acid. Compared with single administration, the combination can significantly increase the abundance of beneficial bacteria such as lactobacilli and Bifidobacteria and effectively regulate the gut microbiota composition. These results provide a scientific rationale for the prevention and treatment of colitis using a FOS/S. boulardii combination. They also offer a theoretical basis for the development of nutraceutical preparations containing FOS and S. boulardii.

Mogroside V reduced the excessive endoplasmic reticulum stress and mitigated the Ulcerative colitis induced by dextran sulfate sodium in mice

Ulcerative colitis (UC) is an idiopathic, chronic inflammatory condition of the colon, characterized by repeated attacks, a lack of effective treatment options, and significant physical and mental health complications for patients. The endoplasmic reticulum (ER) is a vital intracellular organelle in maintaining cellular homeostasis. Endoplasmic reticulum stress (ERS) is induced when the body is exposed to adverse external stimuli. Numerous studies have shown that ERS-induced apoptosis plays a vital role in the pathogenesis of UC. Mogroside V (MV), an active ingredient of Monk fruit, has demonstrated excellent anti-inflammatory and antioxidant effects. In this study, we investigated the therapeutic effects of MV on dextran sulfate sodium (DSS)-induced UC and its potential mechanisms based on ERS. The results showed that MV exerted a protective effect against DSS-induced UC in mice as reflected by reduced DAI scores, increased colon length, reduced histological scores of the colon, and levels of pro-inflammatory cytokines, as well as decreased intestinal permeability. In addition, the expression of ERS pathway including BIP, PERK, eIF2α, ATF4, CHOP, as well as the apoptosis-related protein including Caspase-12, Bcl-2 and Bax, was found to be elevated in UC. However, MV treatment significantly inhibited the UC and reversed the expression of inflammation signaling pathway including ERS and ERS-induced apoptosis. Additionally, the addition of tunicamycin (Tm), an ERS activator, significantly weakened the therapeutic effect of MV on UC in mice. These findings suggest that MV may be a therapeutic agent for the treatment of DSS-induced UC by inhibiting the activation of the ERS-apoptosis pathway, and may provide a novel avenue for the treatment of UC.

Punicalagin ameliorates DSS-induced colitis in mice through strengthening gut barrier, decreasing oxidative stress and downregulating inflammation via AMPK–NF–κB-STAT3 pathway

Inflammatory bowel disease is characterized by compromised epithelium barrier function and hyperactive intestinal inflammation. This study aims to investigate the effects of punicalagin, a bioactive ellagitannin in pomegranate, on dextran-sodium sulfate (DSS) - induced colitis in mice and to examine the underlying mechanisms involved. Oral administration of punicalagin (100 mg/kg/day) effectively mitigated the severity of experimental colitis in mice, evidenced by increased colon length, improved intestinal permeability, and decreased histological scores. Punicalagin up-regulated the mRNA expression level of Muc2 in and the protein expression of zonula occludens-1 (ZO-1) and Occludin in colitic mice. Moreover, punicalagin effectively decreased reactive oxygen species (ROS) levels in the colon, and in Caco-2 cells exposed to H2O2in vitro. Mechanistically, punicalagin attenuated inflammation by inhibiting the secretion of interleukin-6 (IL-6) and the phosphorylation of the NF-κB/STAT3 pathway. In addition, punicalagin increased adenosine monophosphate activated protein kinase (AMPK) phosphorylation in the colon of DSS-treated mice and lipopolysaccharide (LPS) -induced RAW 264.7 macrophages. Knocking down AMPKα by siRNA diminished punicalagin's anti-inflammatory function in RAW 264.7 macrophages exposed to LPS. Furthermore, molecular docking analysis, cellular thermal shift assay (CETSA), and drug affinity responsive target stability (DARTS) analysis supported the direct interaction between punicalagin and AMPK. In conclusion, punicalagin could mitigate DSS-induced colitis through enhancing intestinal epithelial barrier, alleviating oxidative stress, and attenuating inflammation partly through modulation of AMPK–NF–κB-STAT3 pathway.