RESUMEN
Plant-derived exosome-like nanoparticles (ELNs) have drawn considerable attention for oral treatment of colonic diseases. However, the roles of ELNs derived from garlic on colitis remain unclear. Here, we demonstrate that garlic ELNs (GELNs), with desirable particle sizes (79.60 nm) and trafficking large amounts of functional proteins and microRNAs, stably roam in the gut and confer protection against ulcerative colitis (UC). In mice with DSS-induced colitis, orally administered GELNs effectively ameliorated bloody diarrhea, normalized the production of proinflammatory cytokines, and prevented colonic barrier impairment. Mechanistically, GELNs were taken up by gut microbes and reshaped DSS-induced gut microbiota dysbiosis, in which Bacteroides was the dominant respondent genus upon GELNs treatment. Notably, GELNs-enriched peu-MIR2916-p3 specifically promoted the growth of Bacteroides thetaiotaomicron, an intestinal symbiotic bacterium with palliative effects on colitis. Our findings provide new insights into the medicinal application of GELNs and highlight their potential as natural nanotherapeutic agents for preventing and treating UC.
Asunto(s)
Bacteroides thetaiotaomicron , Colitis Ulcerosa , Colitis , Exosomas , Ajo , Microbioma Gastrointestinal , Ratones , Animales , Exosomas/metabolismo , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Colitis/metabolismo , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/microbiología , Colon , Sulfato de Dextran/farmacología , Modelos Animales de Enfermedad , Ratones Endogámicos C57BLRESUMEN
The intestine requires a great deal of energy to maintain its health and function; thus, energy deficits in the intestinal mucosa may lead to intestinal damage. Aspartate (Asp) is an essential energy source in the intestinal mucosa and plays a vital part in gut health. In the current study, we hypothesized that dietary supplementation of Asp could alleviate DSS-induced colitis via improvement in the colonic morphology, oxidative stress, cell apoptosis, and microbiota composition in a mouse model of dextran. Asp administration decreased the disease activity index, apoptosis, myeloperoxidase, eosinophil peroxidase, and proinflammatory cytokine (IL-1ß and TNF-α) concentrations in the colonic tissue, but improved the body weight, average daily food intake, colonic morphology, and antioxidant-related gene (GPX1 and GPX4) expression in DSS-treated mice. Expression levels of RIPK1 and RIPK3 were increased in the colon following Asp administration in the DSS-induced mice, whereas the MLKL protein expression was decreased. 16S rRNA sequencing showed that Asp treatment increased the abundance of Lactobacillus and Alistipes at the gene level, and Bacteroidetes at the phylum level, but decreased the abundance of Actinobacteria and Verrucomicrobia at the phylum level. Asp may positively regulate the recovery of DSS-induced damage by improving the immunity and antioxidative capacity, regulating RIPK signaling and modulating the gut microbiota composition.
Asunto(s)
Colitis Ulcerosa , Colitis , Microbioma Gastrointestinal , Animales , Antioxidantes/metabolismo , Ácido Aspártico/metabolismo , Colitis/inducido químicamente , Colitis Ulcerosa/microbiología , Colon/metabolismo , Citocinas/genética , Sulfato de Dextran , Modelos Animales de Enfermedad , Peroxidasa del Eosinófilo/metabolismo , Ratones , Ratones Endogámicos C57BL , Peroxidasa/metabolismo , ARN Ribosómico 16S/genética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Both tea polysaccharides and selenium have certain remission potential for ulcerative colitis (UC), but few reports focused on natural selenium-containing tea polysaccharides. The purpose of this study was to isolate a selenium-containing tea polysaccharide (ASeTP) and determine its structure and effects on UC. Results showed that ASeTP was primarily composed of three purified, ß-pyranoside-linked, protein-binding polysaccharides (SeTP-1, SeTP-2, and SeTP-3) with SeOC, OSeO, and SeO linkages. Specifically, SeTP-1 was a neutral heteropolysaccharide principally composed of mannose, glucose, galactose, xylose, and arabinose, while SeTP-2 and SeTP-3 were acidic heteropolysaccharides due to the existence of glucuronic acid. ASeTP effectively alleviated the symptoms of weight loss, colon shortens, and disease activity index scores increase in dextran sodium sulfate (DSS)-induced colitis mice. ASeTP attenuated the histological damage and maintained the colonic mucosal barrier via up-regulating the expression of occludin, claudin-1, and zona occludens-1 (ZO-1). ASeTP suppressed the levels of pro-inflammatory cytokines and enhanced the antioxidant capacity of colon tissue. Besides, ASeTP beneficially increased the selenium content of the colon. Furthermore, ASeTP remodeled the gut microbiota by accelerating the proliferation of beneficial bacteria and inhibiting pathogenic microorganisms. Thus, ASeTP has the potential to be a functional food against colitis.
Asunto(s)
Colitis Ulcerosa , Colitis , Microbioma Gastrointestinal , Selenio , Animales , Colitis/inducido químicamente , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/microbiología , Colon , Sulfato de Dextran/efectos adversos , Modelos Animales de Enfermedad , Ratones , Ratones Endogámicos C57BL , Polisacáridos/metabolismo , Selenio/metabolismo , Selenio/farmacología , Té/metabolismoRESUMEN
CONTEXT: Chinese herb Huangqin decoction (HQD) can regulate intestinal flora in ulcerative colitis (UC) mice. OBJECTIVE: Our study clarifies the mechanism of HQD in regulating the intestinal flora of UC mice. MATERIALS AND METHODS: Male C57BL/6 mice were randomly divided into six groups: Control, Model (3% DSS), Sulfasalazine (500 mg/kg), HQD-L (250 mg/kg), HQD-M (500 mg/kg), and HQD-H (1000 mg/kg) groups. Measurement of body weight, colon length, DAI, and haematoxylin-eosin staining were conducted. FISH and 16S rDNA detected colonic bacterial infiltration and intestinal flora changes. The expression of RegIIIγ and PRRs (NOD2, TLR5, TLR4) were detected by FCM and WB, respectively. In addition, WB, qPCR, or IHC were used to detect the expression of NOD2, MyD88, RIP2, and NF-κB p65 in the colon. ELISA was used to determine cytokines. RESULTS: Compared with the model group (DAI score, 2.38 ± 0.05; histological score, 4.08 ± 0.54), HQD treatment significantly reduced the DAI score (L, 2.16 ± 0.09; M, 1.45 ± 0.05; H, 1.18 ± 0.05) and histological score (L, 3.16 ± 0.82; M, 2.50 ± 0.81; H, 1.51 ± 0.76); restored the weight, the colonic length (p < 0.05). 16S rDNA identification showed HQD regulated the balance of intestinal flora. Moreover, HQD suppressed the expression of RegIIIγ (p < 0.05) and prevented colonic bacterial infiltration. Furthermore, WB results showed NOD2, and TLR4 were inhibited by HQD, especially NOD2 (p < 0.01). The data of WB, qPCR, and IHC demonstrated that the NOD2-dependent pathway was inhibited by HQD (p < 0.01). DISCUSSION AND CONCLUSIONS: HQD (1000 mg/kg) regulates the intestinal flora of colitis mice, mainly characterized as inhibition of the NOD2-dependent pathway. These results indicate that HQD has potential.
Asunto(s)
Colitis Ulcerosa/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Microbioma Gastrointestinal/efectos de los fármacos , Scutellaria baicalensis/química , Animales , Colitis Ulcerosa/microbiología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Medicamentos Herbarios Chinos/administración & dosificación , Fármacos Gastrointestinales/administración & dosificación , Fármacos Gastrointestinales/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Proteína Adaptadora de Señalización NOD2/metabolismo , Transducción de Señal/efectos de los fármacos , Sulfasalazina/farmacologíaRESUMEN
The mucin2 (MUC2) mucus barrier acts as the first barrier that prevents direct contact between intestinal bacteria and colonic epithelial cells. Bacterial factors related to the MUC2 mucus barrier play important roles in the response to changes in dietary patterns, MUC2 mucus barrier dysfunction, contact stimulation with colonic epithelial cells, and mucosal and submucosal inflammation during the occurrence and development of ulcerative colitis (UC). In this review, these underlying mechanisms are summarized and updated, and related interventions for treating UC, such as dietary adjustment, exogenous repair of the mucus barrier, microbiota transplantation and targeted elimination of pathogenic bacteria, are suggested. Such interventions are likely to induce and maintain a long and stable remission period and reduce or even avoid the recurrence of UC. A better mechanistic understanding of the MUC2 mucus barrier and its related bacterial factors may help researchers and clinicians to develop novel approaches for treating UC.
Asunto(s)
Colitis Ulcerosa/metabolismo , Microbioma Gastrointestinal , Mucina 2/metabolismo , Antibacterianos/uso terapéutico , Colitis Ulcerosa/microbiología , Colitis Ulcerosa/patología , Colitis Ulcerosa/terapia , Terapia Combinada , Suplementos Dietéticos , Trasplante de Microbiota Fecal , Humanos , Mucosa Intestinal/patologíaRESUMEN
The gut microbiome has been implicated in a range of diseases and there is a rapidly growing understanding of this ecosystem's importance in inflammatory bowel disease. We are yet to identify a single microbe that causes either ulcerative colitis (UC) or pouchitis, however, reduced microbiome diversity is increasingly recognised in active UC. Manipulating the gut microbiome through dietary interventions, prebiotic and probiotic compounds and faecal microbiota transplantation may expand the therapeutic landscape in UC. Specific diets, such as the Mediterranean diet or diet rich in omega-3 fatty acids, may reduce intestinal inflammation or potentially reduce the risk of incident UC. This review summarises our knowledge of gut microbiome therapies in UC and pouchitis.
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Colitis Ulcerosa/terapia , Microbioma Gastrointestinal , Reservoritis/terapia , Colitis Ulcerosa/microbiología , Dieta Mediterránea , Ácidos Grasos Omega-3/uso terapéutico , Trasplante de Microbiota Fecal/métodos , Humanos , Enfermedades Inflamatorias del Intestino/terapia , Microbiota , Reservoritis/microbiología , Prebióticos/administración & dosificación , Probióticos/uso terapéuticoRESUMEN
As an effective drug against acute enteritis diarrhea, Gegen Qinlian decoction (GQD) has a history of 2000 years. However, the potential molecular mechanism through which GQD could protect intestinal barrier from ulcerative colitis (UC) still remains undefined. As an important part of the homeostasis of the colon, gut microbiota is closely related to the dynamic evolution of the surrounding environment and the adjustment of dietary structure. At present, the effectiveness and mechanism of Jiawei Gegen Qinlian decoction against UC in different dietary environments are not clear. Here, the main active components of Jiawei Gegen Qinlian Decoction (PBM), were selected to construct a reasonable and effective compound scheme. We adopted "5% dextran sulfate sodium (DSS)" and "high temperature and humidity + high sugar and high fat + alcohol + 5%DSS" to induce UC rat models in general environment and UC rat models in Lingnan area, respectively. Then, we examined the therapeutic effects of PBM (89.96 mg/kg and 179.92 mg/kg) on two kinds of UC rats. The role of gut microbiota in the anti-UC effect of PBM was identified by intestinal flora consumption and fecal microbiota transplantation (FMT) experiments. Subsequently, we monitored the alterations of gut microbiota and fecal metabolism in the rat colon by 16Sr DNA technique and targeted metabonomics, respectively. The colon inflammation of the PBM-treated and the FMT-treated rats both showed significant relief, as evidenced by a reduction in body weight loss, bloody stool, diarrhea, disease activity index (DAI) score, shortening of colon length as well as decreased colon histology damage. Interestingly enough, the depletion of intestinal flora took away the protective effect of PBM, confirming the importance of intestinal flora in the anti-UC effect of PBM. Then our findings suggested that PBM could not only regulate the gut microbiota by increasing Akkermansia and Romboutsia but also decrease Escherichia-Shigella. More importantly, PBM could increase the production of propionate and total short-chain fatty acids (SCFAs) in colitis rats, regulate medium and long chain fatty acids (M-LCFAs), maintain bile acids (BAs) homeostasis, and regulate amino acids (AAs) metabolism. The transformation of intestinal environment might be related to the upregulation of anti-inflammation, anti-oxidation and tight junction protein expression in colonic mucosa. In summary, PBM showed potential for anti-UC activity through gut microbiota dependence and was expected to be a complementary and alternative medicine herb therapy.
Asunto(s)
Antiinflamatorios/farmacología , Bacterias/efectos de los fármacos , Colitis Ulcerosa/tratamiento farmacológico , Colon/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Fármacos Gastrointestinales/farmacología , Microbioma Gastrointestinal/efectos de los fármacos , Animales , Bacterias/crecimiento & desarrollo , Bacterias/metabolismo , Colitis Ulcerosa/metabolismo , Colitis Ulcerosa/microbiología , Colitis Ulcerosa/patología , Colon/metabolismo , Colon/microbiología , Colon/patología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Disbiosis , Femenino , Mediadores de Inflamación/metabolismo , Masculino , Estrés Oxidativo/efectos de los fármacos , Ratas Sprague-DawleyRESUMEN
Juglone, mainly isolates from the green walnut husks of Juglans mandshurica, exhibits anti-cancer and anti-inflammaroty activities. But its protection on ulcerative colitis (UC) has never been explored. In this study, we first evaluated whether juglone ameliorated UC, and investigated its effects on gut microbiota and Th17/Treg balance in DSS-induced UC mice model. The model was established by administrating 2.7% DSS for seven days. Juglone was given daily by gavage for ten days, once a day. The disease activity index (DAI) decrease and pathological characteristics improvement demonstrated that the UC in mice was alleviated by juglone. Juglone treatment significantly inhibited the protein levels of IL-6, TNF-α and IL-1ß, improved the protein expression of IL-10. In addition, juglone altered microbial diversity and gut microbiota composition, including the enhancement of the ratio of Firmicutes to Bacteroidota and the abundance of Actinobacteriota, and decrease of the abundance of Verrucomicrobiota. Juglone treatment also inhibited the protein expressions of IL-6, STAT3 and RORγt, meanwhile improved the protein level of FOXP3. Furthermore, juglone inhibited Th17 development and increased Treg generation, beneficial to Th17/Treg balance. Together, we herein provided the first evidence to support that juglone, especially the high dose, possibly protected mice against UC by modulating gut microbiota and restoring Th17/Treg homeostasis.
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Colitis Ulcerosa/tratamiento farmacológico , Microbioma Gastrointestinal/efectos de los fármacos , Naftoquinonas/farmacología , Linfocitos T Reguladores/efectos de los fármacos , Células Th17/efectos de los fármacos , Animales , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/inmunología , Colitis Ulcerosa/microbiología , Colon/efectos de los fármacos , Colon/inmunología , Colon/microbiología , Sulfato de Dextran/administración & dosificación , Sulfato de Dextran/toxicidad , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Microbioma Gastrointestinal/inmunología , Humanos , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/inmunología , Mucosa Intestinal/microbiología , Masculino , Ratones , Naftoquinonas/uso terapéutico , Linfocitos T Reguladores/inmunología , Células Th17/inmunologíaRESUMEN
ß-Carotene displays antioxidant and anti-inflammatory activities and prevents the development of cancer. Ulcerative colitis (UC) is a kind of inflammatory bowel disease that is accompanied by a certain risk of colon cancer. However, the role of ß-carotene in the modulation of gut microbiota and UC improvement is unclear. In this research, the properties of ß-carotene on anti-inflammatory and the composition of gut microbiota were evaluated in a rat model of UC induced by dextran sulfate sodium (DSS). The results revealed that ß-carotene significantly (p < 0.05) decreased the severity of colitis in rats, as assessed using body weight (6.00 ± 1.73%), colon length (22.23 ± 0.53%), and disease activity index, and improved the structure of the colon damaged. Moreover, colonic levels of proinflammatory cytokines were significantly lower following ß-carotene supplementation. ß-Carotene intervention also lowered the expression levels of phosphorylated p65 (0.60 ± 0.02), p38 (0.57 ± 0.00), Erk (0.63 ± 0.04), and JNK (0.70 ± 0.00). The result of the relative abundance of gut microbiota showed that DSS administration significantly changed the microbial structure at the phylum and genus levels of rats. Furthermore, ß-carotene treatment significantly increased the abundance of Faecalibacterium, the levels of which negatively correlated with the levels of inflammatory cytokines. Faecalibacterium may be a potential target in the alleviation of DSS-induced UC. ß-Carotene can alleviate DSS-induced UC through the regulation of gut microbiota. This study provides a reference for the rational use of ß-carotene in the treatment of UC. PRACTICAL APPLICATION: ß-Carotene can relieve ulcerative colitis and regulate the gut microbiota; the nutritional intervention of ß-carotene enhancing animal health.
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Antiinflamatorios/farmacología , Colitis Ulcerosa/tratamiento farmacológico , Sulfato de Dextran/toxicidad , Modelos Animales de Enfermedad , Microbioma Gastrointestinal/efectos de los fármacos , beta Caroteno/farmacología , Animales , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/microbiología , Citocinas/metabolismo , Masculino , Provitaminas/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) induced by dysregulation of the immune response in the intestinal mucosa. Although the underlying mechanisms of UC development are not fully understood, disruption of gut microbiota, "dysbiosis", is thought to lead to the development of IBD. Persimmon (Ebenaceae Diospyros kaki Thunb.)-derived tannin, which is a condensed polymeric tannin consisting of catechin groups, has antioxidant, anti-inflammatory, and antimicrobial activities. In this study, we assessed the effect of persimmon-derived tannin on a murine model of UC established by dextran sulfate sodium-induced colitis in female mice. Dietary supplementation of tannin significantly decreased disease activity and colon inflammation. A hydrolysate of tannin directly suppressed expression of inflammatory genes in macrophages in vitro. In faecal microbiota, the relative abundance of Bacteroides was increased significantly by tannin supplementation. Alpha-diversity indices in colitis-induced mice were significantly higher in the tannin diet group compared with the control diet group. Additionally, expansion of Enterobacteriaceae and Enterococcus, which is associated with disease progression of IBD, was remarkably suppressed in the tannin diet group. These results suggest that persimmon-derived tannin ameliorates colon inflammation in UC through alteration of the microbiota composition and immune response, which may be a promising candidate for IBD therapy.
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Antiinflamatorios/uso terapéutico , Colitis Ulcerosa/tratamiento farmacológico , Microbioma Gastrointestinal/efectos de los fármacos , Taninos/uso terapéutico , Animales , Antiinflamatorios/administración & dosificación , Antiinflamatorios/farmacología , Células Cultivadas , Colitis Ulcerosa/microbiología , Suplementos Dietéticos , Diospyros/química , Femenino , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Ratones Endogámicos BALB C , Taninos/administración & dosificación , Taninos/farmacologíaRESUMEN
BACKGROUND: Inflammatory bowel disease (IBD) includes ulcerative colitis (UC) and Crohn's disease (CD), which is a common idiopathic digestive disease without a specific cure or treatment for improvement. Because Polygoni multiflori Radix has a traditional medicinal use to treat intestinal diseases, and the water extract of this herbal medicine had a positive influence on dextran sulfate sodium (DSS) induced UC model in our study. Meanwhile 2,3,5,4'-tetrahydroxystilbene-2-O-ß-D-glucoside (TSG) as the major component of the water extract of Polygoni multiflori Radix with yield of more than 10% exhibited the remarkable anti-inflammatory activity in vivo and in vitro, we predicted that TSG may contribute to benefit intestinal tract presented by the water extract of Polygoni multiflori Radix. Therefore, the present study aims to explore the pharmacological effect of this compound on UC model and its possible mechanism to regulate intestinal function through gut microbiota. METHODS: Ulcerative colitis model was established in BALb/c mice by continuously administrating 3% (w/v) DSS aqueous solution for one week. The disease activity index (DAI), colon length, histopathological examination by H&E and the levels of tight junction proteins (TJP) by immunofluorescence staining were performed in ulcerative colitis model following the protocol. Furthermore, the levels of main inflammatory factors like TNF-α, IL-ß, IL-6, and IL-10 were analyzed by the ELIZA kits for the further confirmation of anti-inflammatory activity of TSG on ulcerative colitis model. Finally, 16S rDNA sequencing technology was conducted to explore the composition and relative abundance of gut microbiota of different treatment groups. RESULTS: TSG treatments effectively increased body weight about 5% of those in DSS group (p < 0.001) as well remarkably reduced the DAI scores to the 50% of those in DSS group (p < 0.001) in the UC model. TSG treatments of either 25 mg/kg (TSG-25) or 100 mg/kg (TSG-100) dosage restored epithelial barrier structure and exhibited obviously intact colon histology with reduced signs of inflammatory cells infiltration, preserved epithelia barrier, restored crypt structure, and increased numbers of goblet cells. TSG treatments could markedly lessen the histopathologic score two or three times than those in DSS group (p < 0.001). Especially for TSG-100 treatment, the fluorescence intensity of ZO-1 and Occludin were nearly back to 80% of those in normal group, and were 1.5 times more than those in the DSS group (p < 0.001). Additionally, direct evidence pointed to TSG as a therapeutically active molecule in the prevention and treatment of UC by significantly reducing the production of these pro-inï¬ammatory cytokines like TNF-α, IL-1ß, and IL-6 (p < 0.05-0.001) and increasing the levels of anti-inï¬ammatory cytokine IL-10 (p < 0.05-0.001). Finally, it was found TSG treatments significantly raised the relative abundances of Firmicutes and Bacteroidetes with a dose-dependently and improved the homeostasis of the gut microbiota composition which disrupted by DSS through increasing genus level Lachnospiraceae_NK4A136 and decreasing genus level of Helicobacter, Bacteroides, Parabacteroides. CONCLUSION: The present results suggested that TSG treatments had a desirable pharmacological effect on acute colitis induced by DSS in the mice as well showed the possible mechanism relate to improve the intestinal function through balancing the gut microbiota of intestinal flora.
Asunto(s)
Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/prevención & control , Sulfato de Dextran , Microbioma Gastrointestinal/efectos de los fármacos , Glucósidos/farmacología , Estilbenos/farmacología , Animales , Antiinflamatorios/farmacología , Colitis Ulcerosa/microbiología , Colon/patología , Citocinas/metabolismo , ADN Bacteriano/aislamiento & purificación , Heces/microbiología , Glucósidos/química , Masculino , Ratones , Ratones Endogámicos BALB C , Extractos Vegetales , Plantas Medicinales/química , ARN Ribosómico 16S/química , ARN Ribosómico 16S/genética , Estilbenos/química , Proteínas de Uniones Estrechas/metabolismoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Inflammatory bowel disease (IBD) is a chronic and relapsing inflammatory disease of the gastrointestinal tract, consisting of ulcerative colitis (UC) and Crohn's disease (CD). Gut microbiota and their metabolites may play a role in the pathogen of IBD, especially of the UC. Qingchang Huashi Formula (QHF), a traditional Chinese medicine formula, has shown therapeutic effect on treating UC based on the clinical practice without clear pharmacological mechanism. AIM OF THE STUDY: The aim of this study was to clearly define the effect of QHF and its components, Baitouweng (PBR) and Baizhi (ADR) on treating UC. MATERIALS AND METHODS: Pharmacodynamic effects of QHF and single herb were evaluated in dextran sulfate sodium (DSS) induced acute or chronic colitis mice. Body weight loss, disease activity index (DAI) and colon length were estimated. Histological changes were observed by H&E staining. The number and abundance of gut microbiota were measured with 16S rRNA sequencing. LC-MS and GC-MS were used to detect the concentration of metabolites (e.g., bile acids (BAs) and short chain fatty acids (SCFAs)). The goblet cell was observed by Alcian blue/periodic acid-Schiff (AB/PAS) straining and the crypt stem cell was estimated by immunohistochemical analyses. The colorectal tissues were used to detect levels of IL-1ß, IL-6 and TNF-α by ELISA or qRT-PCR. The expression of NLRP3, Caspase 1 and IL-1ß were examined by western blotting. RESULTS: QHF significantly inhibited colitis, protected mice from the loss of body weight and colon shorten. Comparatively, ADR and PBR showed strong efficacy in inhibiting DSS-induced colitis. We verified that while ADR was responsible for QHF's effect on maintaining gut microbiota homeostasis and metabolism, PBR was more prominent in keeping crypt stem cells proliferation and colonic goblet cells function. Moreover, we demonstrated that the alleviation of colitis by QHF was associated with the restoration of gut microbiota-metabolism homeostasis, protection of intestinal epithelial barrier and regulation of NLRP3/IL-1ß pathway. CONCLUSIONS: The finding of the present study suggested that QHF is curative in DSS-induced colitis by restoring gut microbiota-metabolism homeostasis and goblet cells function. An optimized QHF was constituted by ADR and PBR, which showed comparable efficacy on colitis to that of QHF. Our work probed out the active constitutes as well as the relevant pharmacological mechanisms of QHF, shedding light on potential new drug combination for the treatment of IBD.
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Colitis Ulcerosa/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Microbioma Gastrointestinal/efectos de los fármacos , Células Caliciformes/efectos de los fármacos , Animales , Colitis Ulcerosa/microbiología , Colitis Ulcerosa/patología , Colon/efectos de los fármacos , Colon/microbiología , Colon/patología , Sulfato de Dextran , Modelos Animales de Enfermedad , Células Caliciformes/patología , Homeostasis/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , ARN Ribosómico 16SRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Ulcerative colitis (UC) is a relapsing inflammatory disease that still demands for effective remedies due to various adverse effects of the current principal treatments. Centella asiatica is a traditional medical herb with long application history in anti-inflammation. AIM OF THE STUDY: To explore the anti-inflammatory effect and possible mechanism of C. asiatica ethanol extract (CA) in a murine colitis model induced by dextran sulfate sodium (DSS). MATERIALS AND METHODS: CA was analyzed by high performance liquid chromatograph (HPLC). The colitis model was induced by free access to 3% DSS in distilled water for 7 days. CA (100, 200, and 400â¯mg/kg) and 5-aminosalicylic acid (5-ASA, 400 mg/kg) were administrated by gavage during the 7-day DSS challenge. At the end of experiment, mice were sacrificed and the brain, colon and cecum contents were harvested for analysis. Colitis was evaluated by disease activity index (DAI), colon length and colon lesion macroscopic score with hematoxylin-eosin staining. Myeloperoxidase (MPO) activity in colon and 5-hydroxytryptamine (5-HT) in brain were determined by ELISA. Tight junction protein expressions (ZO-1, E-Cadherin, Claudin-1) and c-Kit in colon were assessed by western blot and immunohistochemistry, respectively. Microbiota of cecum content was analyzed by 16S rRNA sequencing. RESULTS: Data showed that with recovery on the colon length and histological structure, CA prominently decreased DAI and macroscopic score for lesion in the suffering mice. CA relieved the colitis by suppressing inflammatory cell infiltration with decreased MPO activity in the colon, and up-regulated the expression of tight junction protein (ZO-1, E-cadherin) to enhance the permeability of intestinal mucosa. Moreover, CA restored intestinal motility by promoting c-Kit expression in the colon and 5-HT in the brain. Moreover, CA was able to reshape the gut microbiota in the suffering mice. It increased the α-diversity and shifted the community by depleting the colitis-associated genera, Helicobacter, Jeotgalicoccus and Staphylococcus, with impact on several metabolism signaling pathways, which possibly contributes to the renovation on the impaired intestinal mucosal barrier. CONCLUSIONS: CA displayed the anti-inflammatory activity against the DSS-induced colitis, which would possibly rely on the restoration on mucosa barrier and gut microbiota homeostasis, highlights a promising application of C. asiatica in the clinical treatment of UC.
Asunto(s)
Antiinflamatorios/farmacología , Bacterias/efectos de los fármacos , Colitis Ulcerosa/prevención & control , Colon/efectos de los fármacos , Fármacos Gastrointestinales/farmacología , Microbioma Gastrointestinal/efectos de los fármacos , Mucosa Intestinal/efectos de los fármacos , Extractos Vegetales/farmacología , Triterpenos/farmacología , Animales , Bacterias/crecimiento & desarrollo , Centella , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/metabolismo , Colitis Ulcerosa/microbiología , Colon/metabolismo , Colon/microbiología , Colon/patología , Sulfato de Dextran , Modelos Animales de Enfermedad , Etanol/química , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Mucosa Intestinal/patología , Masculino , Ratones Endogámicos BALB C , Permeabilidad , Serotonina/metabolismo , Solventes/química , Proteínas de Uniones Estrechas/metabolismoRESUMEN
BACKGROUND: Feiyangchangweiyan capsule (FYC) is a traditional Chinese medicine formulation used in the clinical treatment of acute and chronic gastroenteritis and bacterial dysentery. However, the effect of FYC on ulcerative colitis (UC) and the mechanism thereof remains unknown. PURPOSE: To investigate the protective effect of FYC on UC mice induced by dextran sulfate sodium and illustrate the potential mechanism of this effect. METHODS: Here, we established a model of UC mice by dextran sulfate sodium and administered with FYC. The disease activity index (DAI), colon length, myeloperoxidase (MPO) content in serum, pathological structure and ultrastructural changes, and inflammatory cell infiltration of colon tissue were evaluated. Transcriptome and 16S rDNA sequencing were employed to illuminate the mechanism of FYC in the protection of UC mice. RESULTS: FYC significantly alleviates the pathological damage and the infiltration of inflammatory cells in colon tissue of dextran sulfate sodium induced UC mice, rescues shortened colon length, reduces DAI score, MPO content in serum, and pro-inflammatory factors including IL-1ß, IL-6, CCL11, MCP-1 and MIP-2, and increases anti-inflammatory factors such as IL-10. Transcriptomics revealed that Oncostatin M (OSM) and its receptor (OSMR) are the critical pathway for UC treatment by FYC. OSM and OSMR increased in UC mice compared to control mice, and decreased with FYC, which was verified via measurement of OSM and OSMR mRNA and protein levels. Furthermore, we observed that FYC modulates intestinal microbiome composition (e.g., the proportion of Barnesiella/Proteobacteria) by affecting the inflammatory factors. CONCLUSION: FYC exerts an effect on UC by inhibiting the OSM/OSMR pathway and regulating inflammatory factors to improve the intestinal flora.
Asunto(s)
Colitis Ulcerosa/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Microbioma Gastrointestinal/efectos de los fármacos , Subunidad beta del Receptor de Oncostatina M/metabolismo , Oncostatina M/metabolismo , Animales , Antiinflamatorios no Esteroideos/farmacología , Cápsulas , Quimiocinas/sangre , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/microbiología , Colon/efectos de los fármacos , Colon/metabolismo , Colon/patología , Colon/ultraestructura , Citocinas/sangre , Sulfato de Dextran/toxicidad , Modelos Animales de Enfermedad , Microbioma Gastrointestinal/genética , Masculino , Ratones Endogámicos C57BL , Oncostatina M/genética , Subunidad beta del Receptor de Oncostatina M/genética , Sustancias Protectoras/farmacologíaRESUMEN
Inflammatory bowel disease (IBD), which consists of ulcerative colitis (UC) and Crohn's disease (CD), is a chronic inflammatory disorder of the gastrointestinal tract. Occurrence and development of UC have been associated with multiple potential causative factors, which include fungal dysbiosis. Growing evidence reveals that Candida albicans-associated dysbiosis is correlated with clinical deterioration in UC. Paeonol (PAE) is a commonly used traditional medicine with multiple reported properties including effective alleviation of UC. In this study, a murine UC model was established by colonizing mice with additional C. albicans via gavage prior to dextran sodium sulfate (DSS) administration. Effects of PAE treatment were also assessed at initiation and in preestablished C. albicans-associated colitis. The results showed that C. albicans supplementation could aggravate disease activity index (DAI), compromise mucosal integrity, exacerbate fecal and tissue fungal burdens, increase serum ß-glucan and anti-Saccharomyces cerevisiae antibody (ASCA) levels, promote serum and colonic tissue pro-inflammatory cytokine secretion (tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, and IL-8) and decrease the anti-inflammatory cytokine IL-10 level. It also stimulated Dectin-1, TLR2 and TLR4 as well as expression of their downstream effector NF-κB in colonic tissue. After PAE treatment, the adverse impacts of C. albicans on colitis were relieved, via decreased receptor-associated local and systemic inflammation. Our study suggests that PAE should be a candidate for treatment of fungal dysbiosis-associated UC and may act through the Dectin-1/NF-κB pathway in collaboration with TLR2 and TLR4. LAY SUMMARY: Candida albicans is believed to be an important stimulator in ulcerative colitice (UC) development. Suppressing the growth of intestinal C. albicans can be contributory to the amelioration of UC. Paeonol (PAE) is a commonly used traditional medicine with multiple biological functions. In this study, we observed that PAE could alleviate symptoms in mice UC model accompanying with burden reduction of C. albicans. Therefore, we suppose that PAE can be a candidate in the treatment of C. albicans-associated UC.
Asunto(s)
Acetofenonas/uso terapéutico , Candida albicans/efectos de los fármacos , Colitis Ulcerosa/prevención & control , Disbiosis/microbiología , Inflamación/tratamiento farmacológico , Animales , Candida albicans/patogenicidad , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/microbiología , Citocinas/análisis , Citocinas/inmunología , Dextranos/administración & dosificación , Modelos Animales de Enfermedad , Femenino , Medicina Tradicional China , Ratones , Ratones Endogámicos C57BL , Extractos Vegetales/inmunología , Extractos Vegetales/uso terapéutico , Transducción de Señal/efectos de los fármacos , Sulfatos/administración & dosificaciónRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Baitouweng (BTW) decoction, a Chinese traditional medicine prescription, has been used to treat ulcerative colitis (UC) over hundreds of years. In this study, we investigated the anti-inflammatory effects of BTW and intestinal flora of dextran sulfate sodium (DSS)-induced UC mice, and we investigated the mechanism of BTW in the preliminary treatment of UC. AIM OF STUDY: The aim of this study was to elucidate the mechanism of BTW in treating UC through molecular biology and high-throughput sequencing. METHODS: DSS-induced UC mice were established and randomly divided into the following four groups: control group, DSS group, BTW group and sulfasalazine (SASP) group. Except for the control group, 3% DSS drinking water was given to each group for 7 days, and the other two groups were intragastrically administered with BTW and SASP. Mice were sacrificed after gavage for 10 days. Body weight loss, disease activity index (DAI), colon length, colon histopathology and the expression of inflammatory cytokines were measured. Intestinal content samples were collected, and intestinal flora differences were analyzed by 16 S rDNA sequencing. RESULTS: BTW effectively reduced the symptoms and histopathological score of UC mice, and it reduced the production of IL-6, IL-1ß and TNF-α. Activation of the IL-6/STAT3 pathway was also suppressed by BTW treatment. Moreover, 16 S rDNA sequencing showed that the intestinal flora of mice in the DSS group was disordered compared to the control group. After treatment with BTW, the diversity of intestinal flora was significantly improved. At the phylum level, the proportion of Firmicutes to Bacteroidetes was decreased, and the ratio of Proteobacteria was decreased. At the genus level, the relative abundance of Escherichia-Shigella was decreased, but that of Lactobacillus and Akkermansia were increased. CONCLUSION: BTW significantly improved the inflammatory symptoms of mice with acute colitis, and the latent mechanism of BTW may be related to various signaling pathways, including the modulation of intestinal microflora and inflammatory signaling pathways, such as IL-6/STAT3.
Asunto(s)
Colitis Ulcerosa/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Microbioma Gastrointestinal/efectos de los fármacos , Extractos Vegetales/farmacología , Animales , Antiinflamatorios/aislamiento & purificación , Antiinflamatorios/farmacología , Colitis Ulcerosa/microbiología , Colitis Ulcerosa/patología , Sulfato de Dextran , Modelos Animales de Enfermedad , Ensayos Analíticos de Alto Rendimiento , Interleucina-6/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
The incidence of ulcerative colitis (UC) is high. Despite the availability of various therapeutic agents for the treatment of UC, the routine treatment has limitations and serious side effects. Therefore, a new drug that safely and effectively treats UC is urgently needed. Polysaccharides from natural resources have recently become a hot topic of study for their therapeutic effects on UC. These effects are associated with the regulation of inflammatory cytokines, intestinal flora, and immune system and protection of the intestinal mucosa. This review focuses on the recent advances of polysaccharides from natural resources in the treatment of UC. The mechanisms and practicability of polysaccharides, including pectin, guar gum, rhamnogalacturonan, chitosan, fructan, psyllium, glycosaminoglycan, algal polysaccharides, polysaccharides from fungi and traditional Chinese medicine, and polysaccharide derivatives, are discussed in detail. The good efficacy and safety of polysaccharides make them promising drugs for treating UC.
Asunto(s)
Colitis Ulcerosa/tratamiento farmacológico , Medicina Tradicional China , Polisacáridos/uso terapéutico , Productos Biológicos/química , Productos Biológicos/aislamiento & purificación , Productos Biológicos/uso terapéutico , Colitis Ulcerosa/inmunología , Colitis Ulcerosa/microbiología , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/aislamiento & purificación , Medicamentos Herbarios Chinos/uso terapéutico , Microbioma Gastrointestinal , Humanos , Estructura Molecular , Polisacáridos/química , Polisacáridos/aislamiento & purificaciónRESUMEN
The aim of this study was to investigate the effect of a polysaccharide from Scutellaria baicalensis Georgi on UC. Gut microbiota dysbiosis is a worldwide problem associating with ulcerative colitis. One homogeneous polysaccharide, named SP2-1, was isolated from Scutellaria baicalensis Georgi. SP2-1 comprised mannose, ribose, rhamnose, glucuronic acid, glucose, xylose, arabinose, fucose in the molar ratio of 5.06:21.24:1.00:20.25:3.49:50.90:228.77:2.40, with Mw of 3.72 × 106 Da. SP2-1 treatment attenuated body weight loss, reduced DAI, ameliorated colonic pathological damage, and decreased MPO activity of UC mice induced by DSS. SP2-1 also suppressed the levels of proinflammatory cytokines. Additionally, the intestinal barrier was repaired due to the up-regulated expressions of ZO-1, Occludin and Claudin-5. SP2-1 remarkably enhanced the levels of acetic acid, propionic acid, and butyric acid in DSS-treated mice. Furthermore, as compared with model group, the abundance of Firmicutes, Bifidobacterium, Lactobacillus, and Roseburia were significantly increased with SP2-1 treatment. And SP2-1 could significantly inhibit the levels of Bacteroides, Proteobacteria and Staphylococcus. In conclusion, SP2-1 might serve as a novel drug candidate against UC.
Asunto(s)
Colitis Ulcerosa/tratamiento farmacológico , Microbioma Gastrointestinal/efectos de los fármacos , Extractos Vegetales/uso terapéutico , Polisacáridos/uso terapéutico , Scutellaria baicalensis/química , Proteínas de Uniones Estrechas/metabolismo , Animales , Colitis Ulcerosa/etiología , Colitis Ulcerosa/microbiología , Citocinas/genética , Citocinas/metabolismo , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Extractos Vegetales/química , Extractos Vegetales/farmacología , Polisacáridos/química , Polisacáridos/farmacología , Dodecil Sulfato de Sodio/toxicidad , Proteínas de Uniones Estrechas/genéticaRESUMEN
Ulcerative colitis (UC) is an inflammatory bowel disease, and intestinal bacteria are implicated in the pathogenesis of this disorder. The administration of aminosalicylates (5-ASA) is a conventional treatment that targets the mucosa, while fecal microbial transplantation (FMT) is a novel treatment that directly targets the gut microbiota. The aim of this study was to identify changes in fecal bacterial composition after both types of treatments and evaluate clinical responses. Sixteen patients with active left-sided UC underwent enema treatment using 5-ASA (n = 8) or FMT (n = 8) with a stool from a single donor. Fecal microbiota were analyzed by 16S rDNA high-throughput sequencing, and clinical indices were used to assess the efficacy of treatments. 5-ASA therapy resulted in clinical remission in 50% (4/8) of patients, but no correlation with changes in fecal bacteria was observed. In FMT, remission was achieved in 37.5% (3/8) of patients and was associated with a significantly increased relative abundance of the families Lachnospiraceae, Ruminococcaceae, and Clostridiaceae of the phylum Firmicutes, and Bifidobacteriaceae and Coriobacteriaceae of the phylum Actinobacteria. At the genus level, Faecalibacterium, Blautia, Coriobacteria, Collinsela, Slackia, and Bifidobacterium were significantly more frequent in patients who reached clinical remission. However, the increased abundance of beneficial taxa was not a sufficient factor to achieve clinical improvement in all UC patients. Nevertheless, our preliminary results indicate that FMT as non-drug-using method is thought to be a promising treatment for UC patients.
Asunto(s)
Colitis Ulcerosa/microbiología , Colitis Ulcerosa/terapia , Trasplante de Microbiota Fecal , Microbioma Gastrointestinal , Mesalamina/administración & dosificación , Mesalamina/uso terapéutico , Administración Tópica , Adulto , Anciano , Bacterias/clasificación , Biodiversidad , Colitis Ulcerosa/tratamiento farmacológico , Análisis Discriminante , Heces/microbiología , Femenino , Microbioma Gastrointestinal/efectos de los fármacos , Humanos , Masculino , Mesalamina/farmacología , Persona de Mediana Edad , Análisis de Componente Principal , Donantes de TejidosRESUMEN
The colonic mucus barrier serves as a primary defense against enteric pathogens; destruction of this mucus layer has been observed in ulcerative colitis patients. This study aims to investigate the possibility of rebuilding the colon mucus layer through puerarin supplementation, which can stimulate mucin secretion and goblet cells differentiation. After puerarin supplementation, the thickness of colon mucus layer was increased and the permeability was reduced. The erosion of intestinal epithelium by bacteria was blocked, and the loss of epithelial integrity was alleviated. Puerarin also altered the composition of mucin-utilizing bacteria, which influenced the mucus permeability. Levels of short-chain fatty acids (SCFAs) were increased after puerarin supplementation, which as a direct source of energy for the proliferation of epithelia and goblet cells. This study demonstrated that enhancement of mucin secretion to relieve ulcerative colitis (UC) by puerarin supplementation is feasible, and the regulation of mucin-utilizing bacteria and the increased levels of SCFAs may be the main reasons.