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1.
Int J Nanomedicine ; 19: 993-1016, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38299194

RESUMO

Background: The M1/M2 polarization of intestinal macrophages exerts an essential function in the pathogenesis of ulcerative colitis (UC), which can be adjusted to alleviate the UC symptoms. Purpose: A kind of pH-sensitive lipid calcium phosphate core-shell nanoparticles (NPs), co-loading with dexamethasone (Dex) and its water-soluble salts, dexamethasone sodium phosphate (Dsp), was constructed to comprehensively regulate macrophages in different states towards the M2 phenotype to promote anti-inflammatory effects. Methods: Dex and Dsp were loaded in the outer lipid shell and inner lipid calcium phosphate (Cap) core of the LdCaPd NPs, respectively. Then, the morphology of NPs and methods for determining drug concentration were investigated, followed by in vitro protein adsorption, stability, and release tests. Cell experiments evaluated the cytotoxicity, cellular uptake, and macrophage polarization induction ability of NPs. The in vivo distribution and anti-inflammatory effect of NPs were evaluated through a 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced BALB/c mice ulcerative colitis model. Results: The LdCaPd NPs showed a particle size of about 200 nm and achieved considerable loading amounts of Dex and Dsp. The in vitro and in vivo studies revealed that in the acidic UC microenvironment, the cationic lipid shell of LdCaPd underwent protonated dissociation to release Dex first for creating a microenvironment conducive to M2 polarization. Then, the exposed CaP core was further engulfed by M1 macrophages to release Dsp to restrict the pro-inflammatory cytokines production by inhibiting the activation and function of the nuclear factor kappa-B (NF-κB) through activating the GC receptor and the NF kappa B inhibitor α (I-κBα), respectively, ultimately reversing the M1 polarization to promote the anti-inflammatory therapy. Conclusion: The LdCaPd NPs accomplished the sequential release of Dex and Dsp to the UC site and the inflammatory M1 macrophages at this site, promoting the regulation of macrophage polarization to accelerate the remission of UC symptoms.


Assuntos
Colite Ulcerativa , Colite , Nanopartículas , Camundongos , Animais , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/patologia , Colite/induzido quimicamente , Colite/tratamento farmacológico , Macrófagos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Dexametasona/farmacologia , Dexametasona/uso terapêutico , Fosfatos de Cálcio/farmacologia , Lipídeos/efeitos adversos
2.
Gut Microbes ; 16(1): 2310894, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38312103

RESUMO

Gut microbiota and related metabolites are both crucial factors that significantly influence how individuals with Crohn's disease respond to immunotherapy. However, little is known about the interplay among gut microbiota, metabolites, Crohn's disease, and the response to anti-α4ß7-integrin in current studies. Our research utilized 2,4,6-trinitrobenzene sulfonic acid to induce colitis based on the humanized immune system mouse model and employed a combination of whole-genome shotgun metagenomics and non-targeted metabolomics to investigate immunotherapy responses. Additionally, clinical cases with Crohn's disease initiating anti-α4ß7-integrin therapy were evaluated comprehensively. Particularly, 16S-rDNA gene high-throughput sequencing and targeted bile acid metabolomics were conducted at weeks 0, 14, and 54. We found that anti-α4ß7-integrin therapy has shown significant potential for mitigating disease phenotypes in remission-achieving colitis mice. Microbial profiles demonstrated that not only microbial composition but also microbially encoded metabolic pathways could predict immunotherapy responses. Metabonomic signatures revealed that bile acid metabolism alteration, especially elevated secondary bile acids, was a determinant of immunotherapy responses. Especially, the remission mice significantly enriched the proportion of the beneficial Lactobacillus and Clostridium genera, which were correlated with increased gastrointestinal levels of BAs involving lithocholic acid and deoxycholic acid. Moreover, most of the omics features observed in colitis mice were replicated in clinical cases. Notably, anti-α4ß7 integrin provided sustained therapeutic benefits in clinical remitters during follow-up, and long-lasting remission was linked to persistent changes in the microbial-related bile acids. In conclusion, gut microbiota-mediated bile acid metabolism alteration could play a crucial role in regulating immunotherapy responses to anti-α4ß7-integrin in Crohn's disease. Therefore, the identification of prognostic microbial signals facilitates the advancement of targeted probiotics that activate anti-inflammatory bile acid metabolic pathways, thereby improving immunotherapy responses. The integrated multi-omics established in our research provide valuable insights into potential mechanisms that impact treatment responses in complex diseases.


Assuntos
Colite , Doença de Crohn , Microbioma Gastrointestinal , Animais , Camundongos , Doença de Crohn/tratamento farmacológico , Multiômica , Integrinas/genética , Integrinas/uso terapêutico , Colite/induzido quimicamente , Colite/terapia , Ácidos e Sais Biliares/uso terapêutico , Imunoterapia
3.
FASEB J ; 38(4): e23487, 2024 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-38345808

RESUMO

Increasing attention is being paid to the mechanistic investigation of exercise-associated chronic inflammatory disease improvement. Ulcerative colitis (UC) is one type of chronic inflammatory bowel disease with increasing incidence and prevalence worldwide. It is known that regular moderate aerobic exercise (RMAE) reduces the incidence or risk of UC, and attenuates disease progression in UC patients. However, the mechanisms of this RMAE's benefit are still under investigation. Here, we revealed that ß-hydroxybutyrate (ß-HB), a metabolite upon prolonged aerobic exercise, could contribute to RMAE preconditioning in retarding dextran sulfate sodium (DSS)-induced mouse colitis. When blocking ß-HB production, RMAE preconditioning-induced colitis amelioration was compromised, whereas supplementation of ß-HB significantly rescued impaired ß-HB production-associated defects. Meanwhile, we found that RMAE preconditioning significantly caused decreased colonic Th17/Treg ratio, which is considered to be important for colitis mitigation; and the downregulated Th17/Treg ratio was associated with ß-HB. We further demonstrated that ß-HB can directly promote the differentiation of Treg cell rather than inhibit Th17 cell generation. Furthermore, ß-HB increased forkhead box protein P3 (Foxp3) expression, the core transcriptional factor for Treg cell, by enhancing histone H3 acetylation in the promoter and conserved noncoding sequences of the Foxp3 locus. In addition, fatty acid oxidation, the key metabolic pathway required for Treg cell differentiation, was enhanced by ß-HB treatment. Lastly, administration of ß-HB without exercise significantly boosted colonic Treg cell and alleviated colitis in mice. Together, we unveiled a previously unappreciated role for exercise metabolite ß-HB in the promotion of Treg cell generation and RMAE preconditioning-associated colitis attenuation.


Assuntos
Colite Ulcerativa , Colite , Humanos , Camundongos , Animais , Linfócitos T Reguladores/metabolismo , Ácido 3-Hidroxibutírico/farmacologia , Ácido 3-Hidroxibutírico/metabolismo , Colite/induzido quimicamente , Colite/metabolismo , Colite Ulcerativa/metabolismo , Colo/metabolismo , Diferenciação Celular , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Células Th17/metabolismo , Sulfato de Dextrana/toxicidade , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças
4.
Clin Lab ; 70(2)2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38345994

RESUMO

BACKGROUND: Members of beta blockers drugs possess significant antioxidant activities. The current research is to assess the effect of the labetalol on acetic acid (AA-induced) colitis in rat model. METHODS: Forty adult Wistar rats were separated into 4 groups, including the negative control group, AA group, AA + sulfasalazine (100 mg/kg/day) group, and AA + labetalol (300 mg/kg/day) group. Colitis was induced in rats by the interrectal installation of 2 mL of 4% (v/v) AA. Sulfasalazine and labetalol were administered orally for 7 days after 2 hours of induction. The following parameters were measured: disease activity index (DAI), histopa-thological changes and colon tissue homogenate concentrations of proinflammatory mediators IL-1ß, adhesion molecules ICAM-1, and oxidative stress marker myeloperoxidase (MPO). RESULTS: The treatment with labetalol significantly reduced DAI and histopathological changes induced by AA. Also, labetalol markedly decreased the concentrations of IL-1ß, ICAM-1, and MPO in colonic tissue that were increased by AA. The effects of labetalol were significantly lower than that produced by sulfasalazine as standard drug. CONCLUSIONS: Labetalol exerts ameliorative effects on disease activity and histopathological features of AA-induced colitis in rats possibly through antioxidant effects and inhibition of inflammatory mediators.


Assuntos
Colite , Labetalol , Ratos , Animais , Labetalol/efeitos adversos , Molécula 1 de Adesão Intercelular/metabolismo , Sulfassalazina/efeitos adversos , Ratos Wistar , Colo/patologia , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/patologia , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Estresse Oxidativo , Ácido Acético/efeitos adversos , Ácido Acético/metabolismo
5.
Nat Commun ; 15(1): 1333, 2024 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-38351003

RESUMO

Commensal bacteria generate immensely diverse active metabolites to maintain gut homeostasis, however their fundamental role in establishing an immunotolerogenic microenvironment in the intestinal tract remains obscure. Here, we demonstrate that an understudied murine commensal bacterium, Dubosiella newyorkensis, and its human homologue Clostridium innocuum, have a probiotic immunomodulatory effect on dextran sulfate sodium-induced colitis using conventional, antibiotic-treated and germ-free mouse models. We identify an important role for the D. newyorkensis in rebalancing Treg/Th17 responses and ameliorating mucosal barrier injury by producing short-chain fatty acids, especially propionate and L-Lysine (Lys). We further show that Lys induces the immune tolerance ability of dendritic cells (DCs) by enhancing Trp catabolism towards the kynurenine (Kyn) pathway through activation of the metabolic enzyme indoleamine-2,3-dioxygenase 1 (IDO1) in an aryl hydrocarbon receptor (AhR)-dependent manner. This study identifies a previously unrecognized metabolic communication by which Lys-producing commensal bacteria exert their immunoregulatory capacity to establish a Treg-mediated immunosuppressive microenvironment by activating AhR-IDO1-Kyn metabolic circuitry in DCs. This metabolic circuit represents a potential therapeutic target for the treatment of inflammatory bowel diseases.


Assuntos
Colite , Firmicutes , Cinurenina , Humanos , Animais , Camundongos , Cinurenina/metabolismo , Lisina , Receptores de Hidrocarboneto Arílico/metabolismo , Colite/induzido quimicamente , Bactérias/metabolismo , Tolerância Imunológica , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo
6.
Sci Rep ; 14(1): 3472, 2024 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-38342939

RESUMO

MicroRNAs play a crucial role in regulating the epithelial barrier and immune response, which are implicated in the pathogenesis of ulcerative colitis (UC). This study aimed to investigate the role and molecular mechanism of miR-30c in the pathogenesis of UC using a dextran sulfate sodium salt (DSS)-induced colitis model, which is similar to ulcerative colitis. Wild-type (WT) and miR-30c knockout (KO) mice were assigned to either control or DSS-treated groups to evaluate the influence of aberrant miR-30c expression on UC pathogenesis. The disease activity index, inflammatory factors, and the extent of pathological and histological damage in colon tissues were analyzed. The effect of miR-30c on vasoactive intestinal peptide (VIP) gene expression was validated through luciferase reporter assay, qRT-PCR, Western blotting, and immunohistochemistry. The results showed that miR-30c KO mice with DSS-induced colitis model showed more severe phenotypes: significantly higher disease activity indices, significant body weight loss, reduced length of the colon of mice, increased number of aberrant crypt structures, reduced mucus secretion, and significant differences in inflammatory factors. These findings suggested that the absence of miR-30c might promote DSS-induced colitis, and the targe-regulatory effect of miR-30c on VIP might play an important role in the development of colitis.


Assuntos
Colite Ulcerativa , Colite , MicroRNAs , Camundongos , Animais , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/genética , Colite Ulcerativa/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Colite/induzido quimicamente , Camundongos Knockout , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Colo/patologia
7.
PLoS One ; 19(2): e0291543, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38354108

RESUMO

Our previous work demonstrated that the anisodamine (ANI) and neostigmine (NEO) combination produced an antiseptic shock effect and rescued acute lethal crush syndrome by activating the α7 nicotinic acetylcholine receptor (α7nAChR). This study documents the therapeutic effect and underlying mechanisms of the ANI/NEO combination in dextran sulfate sodium (DSS)-induced colitis. Treating mice with ANI and NEO at a ratio of 500:1 alleviated the DSS-induced colitis symptoms, reduced body weight loss, improved the disease activity index, enhanced colon length, and alleviated colon inflammation. The combination treatment also enhanced autophagy in the colon of mice with DSS-induced colitis and lipopolysaccharide/DSS-stimulated Caco-2 cells. Besides, the ANI/NEO treatment significantly reduced INF-γ, TNF-α, IL-6, and IL-22 expression in colon tissues and decreased TNF-α, IL-1ß, and IL-6 mRNA levels in Caco-2 cells. Meanwhile, the autophagy inhibitor 3-methyladenine and ATG5 siRNA attenuated these effects. Furthermore, 3-methyladenine (3-MA) and the α7nAChR antagonist methyllycaconitine (MLA) weakened the ANI/NEO-induced protection on DSS-induced colitis in mice. Overall, these results indicate that the ANI/NEO combination exerts therapeutic effects through autophagy and α7nAChR in a DSS-induced colitis mouse model.


Assuntos
Colite , Neostigmina , Alcaloides de Solanáceas , Camundongos , Animais , Humanos , Neostigmina/efeitos adversos , Fator de Necrose Tumoral alfa/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Interleucina-6/metabolismo , Células CACO-2 , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Autofagia , Sulfato de Dextrana/toxicidade , Colo/metabolismo , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças
8.
Food Funct ; 15(4): 2314-2326, 2024 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-38323473

RESUMO

Certain types of soluble dietary fibre, such as pectin and pectic oligosaccharides from different sources, have demonstrated protective effects against inflammation in DSS-induced colitis mouse models. In this work, we have evaluated the impact of a diet enriched in apple pomace (AP-diet), an agricultural by-product with a significant content of pectin and that previously demonstrated prebiotic properties in human fecal batch fermentation models, on the gut microbiota composition, intestinal damage and inflammation markers in a DSS-induced colitis model. We found that the apple pomace enriched diet (AP-diet), providing a significant amount of pectin with demonstrated prebiotic properties, was associated with a slower increase in the disease activity index, translating into better clinical symptomatology of the animals. Histological damage scoring confirmed less severe damage in those animals receiving an AP-diet before and during the DSS administration period. Some serum inflammatory markers, such as TNFα, also demonstrated lower levels in the group receiving the AP-diet, compared to the control diet. AP-diet administration is also associated with the modulation of key taxa in the colonic microbiota of animals, such as some Lachnospiraceae genera and Ruminococcus species, including commensal short chain fatty acid producers that could play a role in attenuating inflammation at the intestinal level.


Assuntos
Colite , Microbioma Gastrointestinal , Malus , Camundongos , Animais , Humanos , Colite/induzido quimicamente , Colite/patologia , Inflamação/patologia , Dieta , Colo/patologia , Pectinas/farmacologia , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL
9.
J Ethnopharmacol ; 319(Pt 3): 117365, 2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-38380568

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Fufangxiaopi Formula (FF) is a modified form of Sishen Wan, traditionally used for treating diarrhea. The application of FF for treating ulcerative colitis (UC) has achieved desirable outcomes in clinical settings. However, the underlying mechanism of the effect of FF on UC is yet to be determined. AIM OF STUDY: This study aimed to evaluate the protective effect and underlying mechanism of FF on mice with dextran sodium sulfate (DSS)-induced colitis. MATERIALS AND METHODS: In vivo, the efficacy of FF on the symptoms associated with DSS-induced colitis in mice was clarified by observing the body weight change, colon length, DAI score, and H&E staining. The release of inflammatory mediators in mouse colon tissues was detected by ELISA and MPO, and the contents of TLR4/NF-κB signaling pathway and MAPK signaling pathway-related proteins, as well as intestinal barrier-related proteins, were detected in mouse colon tissues by western blot method. Changes in the content of barrier proteins in mouse colon tissues were detected by immunofluorescence. 16S rRNA sequencing and FMT were performed to clarify the effects of FF on intestinal flora. In vitro, the effect of FF-containing serum on LPS-induced inflammatory mediator release from RAW264.7 cells were detected by qRT-PCR. The contents of TLR4/NF The effects of FF-containing serum on B signaling pathway and MAPK signaling pathway related proteins in RAW264.7 cells and intestinal barrier related proteins in Caco-2 cells were detected by western blot. The effects of FF-containing serum on LPS-induced nuclear translocation of p65 protein in RAW264.7 cells and barrier-associated protein in Caco-2 cells were detected by immunofluorescence. RESULTS: In vivo studies showed that FF could significantly alleviate the symptoms of UC, including reducing colon length, weight loss, clinical score, and colon tissue injury in mice. FF could significantly reduce the secretion of proinflammatory cytokines by suppressing the activation of the TLR4/NF-κB and MAPK signaling pathways. Moreover, FF could protect the integrity of intestinal barriers by significantly increasing claudin-3, occludin, and ZO-1 expression levels. 16S rRNA sequencing and FMT elucidate that FF can alleviate symptoms associated with colitis in mice by interfering with intestinal flora. In vitro studies showed that FF drug-containing serum could significantly inhibit proinflammatory responses and attenuate the secretion of iNOS, IL-1ß, TNF-α, IL-6, and COX-2 by suppressing the activation of TLR4/NF-κB and MAPK signaling pathways in RAW264.7 cells. Furthermore, FF could protect the Caco-2 cell epithelial barrier. CONCLUSION: FF could alleviate DSS-induced colitis in mice by maintaining the intestinal barrier, inhibiting the activation of TLR4/NF-κB and MAPK signaling pathways, reducing the release of proinflammatory factors, and regulating intestinal microecology.


Assuntos
Colite Ulcerativa , Colite , Humanos , Camundongos , Animais , NF-kappa B/metabolismo , RNA Ribossômico 16S , Receptor 4 Toll-Like/metabolismo , Lipopolissacarídeos/farmacologia , Células CACO-2 , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Inflamação/tratamento farmacológico , Colo , Sulfato de Dextrana , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças
10.
Nat Commun ; 15(1): 1673, 2024 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-38396052

RESUMO

The PD-1/PD-L1 pathway in mucosal immunity is currently actively explored and considered as a target for inflammatory bowel disease (IBD) treatment. However, systemic PD-L1 administration may cause unpredictable adverse effects due to immunosuppression. Here we show that reactive oxygen species (ROS)-responsive nanoparticles enhance the efficacy and safety of PD-L1 in a mouse colitis model. The nanoparticles control the accumulation and release of PD-L1 fused to Fc (PD-L1-Fc) at inflammatory sites in the colon. The nanotherapeutics shows superiority in alleviating inflammatory symptoms over systemic PD-L1-Fc administration and mitigates the adverse effects of PD-L1-Fc administration. The nanoparticles-formulated PD-L1-Fc affects production of proinflammatory and anti-inflammatory cytokines, attenuates the infiltration of macrophages, neutrophils, and dendritic cells, increases the frequencies of Treg, Th1 and Tfh cells, reshapes the gut microbiota composition; and increases short-chain fatty acid production. In summary, PD-L1-Fc-decorated nanoparticles may provide an effective and safe strategy for the targeted treatment of IBD.


Assuntos
Colite , Doenças Inflamatórias Intestinais , Camundongos , Animais , Antígeno B7-H1/metabolismo , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/metabolismo , Citocinas/metabolismo , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/metabolismo , Macrófagos/metabolismo , Modelos Animais de Doenças
11.
Int J Mol Sci ; 25(4)2024 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-38397074

RESUMO

We recently reported that transient receptor potential canonical (TRPC) 6 channel activity contributes to intracellular Zn2+ homeostasis in the heart. Zn2+ has also been implicated in the regulation of intestinal redox and microbial homeostasis. This study aims to investigate the role of TRPC6-mediated Zn2+ influx in the stress resistance of the intestine. The expression profile of TRPC1-C7 mRNAs in the actively inflamed mucosa from inflammatory bowel disease (IBD) patients was analyzed using the GEO database. Systemic TRPC3 knockout (KO) and TRPC6 KO mice were treated with dextran sulfate sodium (DSS) to induce colitis. The Zn2+ concentration and the mRNA expression levels of oxidative/inflammatory markers in colon tissues were quantitatively analyzed, and gut microbiota profiles were compared. TRPC6 mRNA expression level was increased in IBD patients and DSS-treated mouse colon tissues. DSS-treated TRPC6 KO mice, but not TRPC3 KO mice, showed severe weight loss and increased disease activity index compared with DSS-treated WT mice. The mRNA abundances of antioxidant proteins were basically increased in the TRPC6 KO colon, with changes in gut microbiota profiles. Treatment with TRPC6 activator prevented the DSS-induced colitis progression accompanied by increasing Zn2+ concentration. We suggest that TRPC6-mediated Zn2+ influx activity plays a key role in stress resistance against IBD, providing a new strategy for treating colitis.


Assuntos
Colite , Doenças Inflamatórias Intestinais , Humanos , Animais , Camundongos , Canal de Cátion TRPC6/genética , Canal de Cátion TRPC6/metabolismo , Colite/induzido quimicamente , Colite/genética , Colite/metabolismo , Intestinos , Doenças Inflamatórias Intestinais/metabolismo , RNA Mensageiro/metabolismo , Sulfato de Dextrana/efeitos adversos , Camundongos Endogâmicos C57BL , Colo/metabolismo , Modelos Animais de Doenças
12.
Int Immunopharmacol ; 129: 111645, 2024 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-38354512

RESUMO

Metabolic changes have been linked to the development of inflammatory bowel disease (IBD), which includes colitis. Allulose, an endogenous bioactive monosaccharide, is vital to the synthesis of numerous compounds and metabolic processes within living organisms. Nevertheless, the precise biochemical mechanism by which allulose inhibits colitis remains unknown. Allulose is an essential and intrinsic protector of the intestinal mucosal barrier, as it maintains the integrity of tight junctions in the intestines, according to the current research. It is also important to know that there is a link between the severity of inflammatory bowel disease (IBD) and colorectal cancer (CRC), chemically-induced colitis in rodents, and lower levels of allulose in the blood. Mice with colitis, either caused by dextran sodium sulphate (DSS) or naturally occurring colitis in IL-10-/- mice, had less damage to their intestinal mucosa after being given allulose. Giving allulose to a colitis model starts a chain of reactions because it stops cathepsin B from ejecting and helps lysosomes stick together. This system effectively stops the activity of myosin light chain kinase (MLCK) when intestinal epithelial damage happens. This stops the breakdown of tight junction integrity and the start of mitochondrial dysfunction. To summarise, the study's findings have presented data that supports the advantageous impact of allulose in reducing the advancement of colitis. Its ability to stop the disruption of the intestinal barrier enables this. Therefore, allulose has potential as a medicinal supplement for treating colitis.


Assuntos
Colite , Enterite , Frutose , Doenças Inflamatórias Intestinais , Doenças Mitocondriais , Humanos , Camundongos , Animais , Catepsina B/metabolismo , Células CACO-2 , Doenças Inflamatórias Intestinais/metabolismo , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/metabolismo , Mucosa Intestinal , Junções Íntimas , Doenças Mitocondriais/metabolismo , Sulfato de Dextrana/farmacologia , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças
13.
J Agric Food Chem ; 72(7): 3606-3621, 2024 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-38324392

RESUMO

Ulcerative colitis is closely associated with the dysregulation of gut microbiota. There is growing evidence that natural products may improve ulcerative colitis by regulating the gut microbiota. In this research, we demonstrated that bergenin, a naturally occurring isocoumarin, significantly ameliorates colitis symptoms in dextran sulfate sodium (DSS)-induced mice. Transcriptomic analysis and Caco-2 cell assays revealed that bergenin could ameliorate ulcerative colitis by inhibiting TLR4 and regulating NF-κB and mTOR phosphorylation. 16S rRNA sequencing and metabolomics analyses revealed that bergenin could improve gut microbiota dysbiosis by decreasing branched-chain amino acid (BCAA) levels. BCAA intervention mediated the mTOR/p70S6K signaling pathway to exacerbate the symptoms of ulcerative colitis in mice. Notably, bergenin greatly decreased the symbiotic bacteria Bacteroides vulgatus (B. vulgatus), and the gavage of B. vulgatus increased BCAA concentrations and aggravated the symptoms of ulcerative colitis in mice. Our findings suggest that gut microbiota-mediated BCAA metabolism plays a vital role in the protective effect of bergenin on ulcerative colitis, providing novel insights for ulcerative colitis prevention through manipulation of the gut microbiota.


Assuntos
Bacteroides , Benzopiranos , Colite Ulcerativa , Colite , Animais , Camundongos , Humanos , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Células CACO-2 , RNA Ribossômico 16S , Colite/induzido quimicamente , Colite/tratamento farmacológico , Aminoácidos de Cadeia Ramificada , Serina-Treonina Quinases TOR/genética , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Colo
14.
J Agric Food Chem ; 72(7): 3572-3583, 2024 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-38334304

RESUMO

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.


Assuntos
Bifidobacterium breve , Colite , Microbioma Gastrointestinal , Humanos , Lactente , Animais , Camundongos , Bifidobacterium breve/genética , Ácido Cólico/efeitos adversos , Colite/induzido quimicamente , Colite/genética , Colite/microbiologia , Mucosa Intestinal , Bifidobacterium , Inflamação , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Sulfato de Dextrana/efeitos adversos
15.
J Agric Food Chem ; 72(7): 3536-3548, 2024 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-38346349

RESUMO

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 109 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.


Assuntos
Colite Ulcerativa , Colite , Microbioma Gastrointestinal , Kefir , Humanos , Animais , Camundongos , Fusobacterium nucleatum , Modelos Animais de Doenças , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/genética , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/metabolismo , Citocinas/metabolismo , Metaboloma , Arginina/metabolismo , Sulfato de Dextrana/metabolismo , Colo/metabolismo , Camundongos Endogâmicos C57BL
16.
Eur J Pharmacol ; 967: 176318, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38309678

RESUMO

In this study, we used alkaloids from Sophora flavescens to inhibit the SASP, leading to fibroblast-into-myofibroblast transition (FMT) to maintain intestinal mucosal homeostasis in vitro and in vivo. We used western blotting (WB) and immunofluorescence staining (IF) to assess whether five kinds of alkaloids inhibit the major inflammatory pathways and chose the most effective compound (sophocarpine; SPC) to ameliorate colorectal inflammation in a dextran sulfate sodium (DSS)-induced UC mouse model. IF, Immunohistochemistry staining (IHC), WB, disease activity index (DAI), and enzyme-linked immunosorbent assay (ELISA) were conducted to investigate the mechanism of action of this compound. Next, we detected the pharmacological activity of SPC on the senescence-associated secretory phenotypes (SASP) and FMT in interleukin 6 (IL-6)-induced senescence-like fibroblasts and discussed the mucosal protection ability of SPC on a fibroblast-epithelium/organoid coculture system and organ-on-chip system. Taken together, our results provide evidence that SPC alleviates the inflammatory response, improves intestinal fibrosis and maintains intestinal mucosal homeostasis in vivo. Meanwhile, SPC was able to prevent IL-6-induced SASP and FMT in fibroblasts, maintain the expression of TJ proteins, and inhibit inflammation and genomic stability of colonic mucosal epithelial cells by activating SIRT1 in vitro. In conclusion, SPC treatment attenuates intestinal fibrosis by regulating SIRT1/NF-κB p65 signaling, and it might be a promising therapeutic agent for inflammatory bowel disease.


Assuntos
Alcaloides , Colite Ulcerativa , Colite , Matrinas , Camundongos , Animais , Interleucina-6/efeitos adversos , Miofibroblastos/metabolismo , Sirtuína 1 , Inflamação/tratamento farmacológico , Inflamação/patologia , Colo , Alcaloides/efeitos adversos , Fibroblastos/metabolismo , Fibrose , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças , Colite Ulcerativa/induzido quimicamente , NF-kappa B/metabolismo , Camundongos Endogâmicos C57BL , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/patologia
17.
Cytokine ; 176: 156537, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38325140

RESUMO

OBJECTIVE: Inflammatory bowel disease (IBD) is listed by the World Health Organization as one of the modern intractable diseases. High mobility histone box 1 (HMGB1), originally described as a non-histone nucleoprotein involved in transcriptional regulation, was later identified as a pro-inflammatory cytokine that may contribute to the pathogenesis of inflammatory diseases such as IBD. Neutrophil extracellular traps (NETs) play an important role in the pathophysiology of IBD The aim of this study was to investigate the role of HMGB1 in experimental colitis mice and its potential mechanisms of action. METHODS: We first constructed the experimental colitis mouse model. Intervention of mice by rhHMGB1 supplementation or HMGB1 inhibition. The pathological morphology of the colon was observed using HE staining. Apoptosis of colonic tissue intestinal epithelial cells was evaluated using Tunel assay. The expression of HMGB1, ZO-1 and occludin in colon tissue was detected by immunohistochemistry, ELISA and western-blot. We also assessed the effects of HMGB1 on colonic injury, NETs content, macrophage polarization and inflammatory cells in mice. The regulatory effect of HMGB1 inhibition on NETs was assessed by combining DNase I. RESULTS: Inhibition of HMGB1 significantly reduced the inflammatory model in experimental colitis mice, as evidenced by reduced body weight, increased colonic length, reduced DAI scores and apoptosis, reduced inflammatory response, and improved colonic histopathological morphology and intestinal mucosal barrier function. Meanwhile, inhibition of HMGB1 was able to reduce the expression of CD86, citH3 and MPO and increase the expression of CD206 in the colonic tissue of mice. In addition, DNase I intervention was also able to improve colonic inflammation in mice. And the best effect was observed when DNase I and inhibition of HMGB1 were intervened together. CONCLUSION: Inhibition of HMGB1 ameliorates IBD by mediating NETs and macrophage polarization.


Assuntos
Colite , Armadilhas Extracelulares , Proteína HMGB1 , Doenças Inflamatórias Intestinais , Animais , Camundongos , Proteína HMGB1/metabolismo , Armadilhas Extracelulares/metabolismo , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/metabolismo , Doenças Inflamatórias Intestinais/patologia , Modelos Animais de Doenças , Macrófagos/metabolismo , Desoxirribonuclease I , Camundongos Endogâmicos C57BL , Sulfato de Dextrana
18.
Nutrients ; 16(3)2024 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-38337648

RESUMO

Exclusive enteral nutrition (EEN) is an established dietary treatment for Crohn's disease (CD) by alleviating inflammation and inducing remission. However, the mechanisms of action of EEN are incompletely understood. As CD is associated with gut microbiome dysbiosis, we investigated the effect of EEN on the microbiome in a rat model of CD-like colitis. The rat model of CD-like colitis was established by an intracolonic instillation of TNBS at 65 mg/kg in 250 µL of 40% ethanol. Sham control rats were instilled with saline. Rats were fed ad libitum with either regular pellet food or EEN treatment with a clear liquid diet (Ensure). Rats were euthanized at 7 days. Fecal pellets were collected from the distal colon for 16S rRNA sequencing analysis of gut microbiota. In addition, colon tissues were taken for histological and molecular analyses in all the groups of rats. EEN administration to TNBS-induced CD rats significantly improved the body weight change, inflammation scores, and disease activity index. The mRNA expression of IL-17A and interferon-γ was significantly increased in the colonic tissue in TNBS rats when fed with regular food. However, EEN treatment significantly attenuated the increase in IL-17A and interferon-γ in TNBS rats. Our 16S rRNA sequencing analysis found that gut microbiota diversity and compositions were significantly altered in TNBS rats, compared to controls. However, EEN treatment improved alpha diversity and increased certain beneficial bacteria such as Lactobacillus and Dubosiella and decreased bacteria such as Bacteroides and Enterorhabdus in CD-like rats, compared to CD-like rats with the regular pellet diet. In conclusion, EEN treatment increases the diversity of gut microbiota and the composition of certain beneficial bacteria. These effects may contribute to the reduced inflammation by EEN in the rat model of CD-like colitis.


Assuntos
Colite , Doença de Crohn , Microbioma Gastrointestinal , Ratos , Animais , Doença de Crohn/microbiologia , Nutrição Enteral , RNA Ribossômico 16S/genética , Interleucina-17 , Interferon gama , Colite/induzido quimicamente , Colite/terapia , Bactérias , Inflamação/terapia , Indução de Remissão
19.
Carbohydr Polym ; 330: 121882, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38368089

RESUMO

Structurally defined arabinogalactan (LBP-3) from Lycium barbarum have effect on improving intestinal barrier function. However, whether its intestinal barrier function depended on the changes of intestinal mucin O-glycans have not been investigated. A dextran sodium sulfate-induced acute colitis mouse model was employed to test prevention and treatment with LBP-3. The intestinal microbiota as well as colonic mucin O-glycan profiles were analyzed. Supplementation with LBP-3 inhibited harmful bacteria, including Desulfovibrionaceae, Enterobacteriaceae, and Helicobacteraceae while significantly increased the abundance of beneficial bacteria (e.g., Lachnospiraceae, Ruminococcaceae, and Lactobacillaceae). Notably, LBP-3 augmented the content of neutral O-glycans by stimulating the fucosylation glycoforms (F1H1N2 and F1H2N2), short-chain sulfated O-glycans (S1F1H1N2, S1H1N2, and S1H2N3), and sialylated medium- and long-chain O-glycans (F1H2N2A1, H2N3A1, and F1H3N2A1). In summary, we report that supplement LBP-3 significantly reduced pathological symptoms, restored the bacterial community, and promoted the expression of O-glycans to successfully prevent and alleviate colitis in a mouse model, especially in the LBP-3 prevention testing group. The underlying mechanism of action was investigated using glycomics to better clarify which the structurally defined LBP-3 were responsible for its beneficial effect against ulcerative colitis and assess its use as a functional food or pharmaceutical supplement.


Assuntos
Colite , Galactanos , Lycium , Camundongos , Animais , Mucinas/metabolismo , Lycium/metabolismo , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/metabolismo , Polissacarídeos/efeitos adversos , Bactérias/metabolismo , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças
20.
Nutrients ; 16(4)2024 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-38398793

RESUMO

Lactobacillus species have been shown to alleviate gut inflammation and oxidative stress. However, the effect of different lactobacilli components on gut inflammation has not been well studied. This study aims to identify the differences in the effect and mechanisms of different forms and components of Limosilactobacillus mucosae (LM) treatment in the alleviation of gut inflammation using a colitis mouse model that is induced by dextran sodium sulfate (DSS). Seventy-two C57BL/6 mice were divided into six groups: control, DSS, live LM+DSS (LM+DSS), heat-killed LM+DSS (HKLM+DSS), LM cell-free supernatant + DSS (LMCS+DSS), and MRS medium + DSS (MRS+DSS). The mice were treated with different forms and components of LM for two weeks before DSS treatment. After that, the mice were sacrificed for an assessment of their levels of inflammatory cytokines, serotonin (5-HT) receptors (HTRs), and tryptophan metabolites. The results showed that, compared to other treatments, LMCS was more effective (p < 0.05) in the alleviation of DSS-induced body weight loss and led to an increase in the disease activity index score. All three forms and components of LM increased (p < 0.05) the levels of indole-3-acetic acid but reduced (p < 0.05) the levels of 5-HT in the colon. HKLM or LMCS reduced (p < 0.05) the percentages of CD3+CD8+ cytotoxic T cells but increased (p < 0.05) the percentages of CD3+CD4+ T helper cells in the spleen. LM or HKLM increased (p < 0.05) abundances of CD4+Foxp3+ regulatory T cells in the spleen. The LM and LMCS treatments reduced (p < 0.05) the expression of the pro-inflammatory cytokines Il6 and Il17a. The mice in the HKLM+DSS group had higher (p < 0.05) mRNA levels of the anti-inflammatory cytokine Il10, the cell differentiation and proliferation markers Lgr5 and Ki67, the 5-HT degradation enzyme Maoa, and HTRs (Htr1a, Htr2a, and Htr2b) in the colon. All three forms and components of LM reduced the phosphorylation of STAT3. The above findings can help to optimize the functionality of probiotics and develop new dietary strategies that aid in the maintenance of a healthy gut.


Assuntos
Colite , Serotonina , Animais , Camundongos , Serotonina/metabolismo , Temperatura Alta , Camundongos Endogâmicos C57BL , Colite/induzido quimicamente , Colite/terapia , Lactobacillus/metabolismo , Inflamação/metabolismo , Citocinas/metabolismo , Receptores de Serotonina/metabolismo , Imunidade , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças , Colo/metabolismo
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