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1.
NPJ Biofilms Microbiomes ; 10(1): 84, 2024 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-39266529

RESUMO

The role of mast cells (MCs) in ulcerative colitis (UC) development is controversial. FcεRI, the IgE high-affinity receptor, is known to activate MCs. However, its role in UC remains unclear. In our study, Anti-FcεRI showed highly diagnostic value for UC. FcεRIα knockout in mice ameliorated DSS-induced colitis in a gut microbiota-dependent manner. Increased Lactobacillus abundance in FcεRIα deficient mice showed strongly correlation with the remission of colitis. RNA sequencing indicated activation of the NLRP6 inflammasome pathway in FcεRIα knockout mice. Additionally, Lactobacillus plantarum supplementation protected against inflammatory injury and goblet cell loss, with activation of the NLRP6 inflammasome during colitis. Notably, this effect was absent when the strain is unable to produce lactic acid. In summary, colitis was mitigated in FcεRIα deficient mice, which may be attributed to the increased abundance of Lactobacillus. These findings contribute to a better understanding of the relationship between allergic reactions, microbiota, and colitis.


Assuntos
Sulfato de Dextrana , Microbioma Gastrointestinal , Receptores de IgE , Animais , Camundongos , Colite/prevenção & controle , Colite/microbiologia , Colite/induzido quimicamente , Colite Ulcerativa/microbiologia , Modelos Animais de Doenças , Inflamassomos/metabolismo , Lactobacillus , Lactobacillus plantarum/genética , Lactobacillus plantarum/fisiologia , Mastócitos/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Probióticos , Receptores de IgE/genética
2.
Arch Microbiol ; 206(10): 398, 2024 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-39254791

RESUMO

Increasing awareness regarding health promotion and disease prevention has driven inclusion of fermented foods and beverages in the daily diet. These are the enormous sources of beneficial microbes, probiotics. This study aims to isolate yeast strains having probiotic potential and effectivity against colitis. Initially, ninety-two yeast strains were isolated from Haria, an ethnic fermented beverage of West Bengal, India. Primary screening was done by their acid (pH 4) and bile salt (0.3%) tolerance ability. Four potent isolates were selected and found effective against Entamoeba histolytica, as this human pathogen is responsible to cause colitis. They were identified as Saccharomyces cerevisiae. They showed luxurious growth even at 37 oC, tolerance up to 5% of NaCl, resistance to gastric juice and high bile salt (2.0%) and oro-gastrointestinal transit tolerance. They exhibited good auto-aggregation and co-aggregation ability and strong hydrophobicity. Finally, heat map and principal component analysis revealed that strain Y-89 was the best candidate. It was further characterised and found to have significant protective effects against DSS-induced colitis in experimental mice model. It includes improvement in colon length, body weight and organ indices; reduction in disease activity index; reduction in cholesterol, LDL, SGPT, SGOT, urea and creatinine levels; improvement in HDL, ALP, total protein and albumin levels; decrease in coliform count and restoration of tissue damage. This study demonstrates that the S. cerevisiae strain Y-89 possesses remarkable probiotic traits and can be used as a potential bio-therapeutic candidate for the prevention of colitis.


Assuntos
Colite , Alimentos Fermentados , Probióticos , Saccharomyces cerevisiae , Probióticos/administração & dosagem , Probióticos/farmacologia , Animais , Camundongos , Índia , Colite/microbiologia , Colite/induzido quimicamente , Colite/prevenção & controle , Alimentos Fermentados/microbiologia , Modelos Animais de Doenças , Bebidas/microbiologia , Masculino , Entamoeba histolytica , Humanos , Fermentação
3.
Biomed Pharmacother ; 178: 117286, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39128189

RESUMO

Fat and sugar overconsumption is the cause of increasing worldwide incidence of gastrointestinal tract in inflammatory conditions. The intestinal pre-inflammatory alterations are partially reversible, simultaneously inhibiting the predisposition to colitis. Searching for an effective pharmacotherapy for treating inflammatory conditions in the intestine is essential. This study aimed to investigate the effect of cannabigerol (CBG) on the inflammation state in the colon tissue of rats subjected to high-caloric diet. The experiment was conducted on male Wistar rats subjected to a standard or a high-fat high-sucrose diets for six weeks. For the last 14 days, half of rats from both groups received intragastrically cannabigerol solution (30 mg/kg of body mass). The ratio of n-6/n-3 PUFA, the activity of n-6 and n-3 PUFA, and arachidonic acid (AA) content in selected lipid fractions were determined by gas-liquid chromatography. Immunoblotting examined the expression of proteins involved in inflammation development. ELISA kits measured the content of arachidonic acid derivatives. CBG treatment reduced the n-6/n-3 PUFA ratio in TAG fraction and increased the n-3 PUFA pathway activity in almost all lipid fractions. Cannabigerol supplementation decreased AA concentration in PL and TAG. CBG also caused diminishments in the expression of cPLA2, COX-1, COX-2, and 12/15-LOX, which was indirectly correlated with a decreased LTB4 level and an increased LXA4 level. We concluded that cannabigerol has a protective influence on the development of inflammation in the colon tissue under lipid and sugar overload condition, thereby favoring cancer initiation and progression.


Assuntos
Anti-Inflamatórios , Ácido Araquidônico , Colo , Dieta Hiperlipídica , Ratos Wistar , Animais , Masculino , Dieta Hiperlipídica/efeitos adversos , Ácido Araquidônico/metabolismo , Colo/efeitos dos fármacos , Colo/metabolismo , Colo/patologia , Anti-Inflamatórios/farmacologia , Ratos , Canabinoides/farmacologia , Ácidos Graxos Ômega-3/farmacologia , Ácidos Graxos Ômega-6/farmacologia , Colite/tratamento farmacológico , Colite/induzido quimicamente , Colite/metabolismo , Colite/prevenção & controle
4.
Microbiol Res ; 286: 127812, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38954992

RESUMO

Clostridioides difficile infection (CDI) poses a significant health threat due to high recurrence rates. Antimicrobial agents are commonly used to manage CDI-related diarrhoea; however, by aggravating intestinal dysbiosis, antibiotics enable C. difficile spores germination and production of toxins, the main virulence factors. Therefore, the binding of exotoxins using adsorbents represents an attractive alternative medication for the prevention and treatment of relapses. In this study, we provided evidence that the natural insoluble polysaccharides, named ABR119, extracted by plant cell cultures, effectively trap C. difficile toxins. In our experiments, ABR119 exhibited no cytotoxicity in vitro and was safely administered in vivo. In the animal model of C. difficile-associated colitis, ABR119 (50 mg/kg body weight) significantly reduced the colonic myeloperoxidase activity and severity of inflammation, preventing body weight loss. These effects were not evident when we treated animals with wheat bran polysaccharides. We did not detect bacterial killing effects of ABR119 against C. difficile nor against bacterial species of the normal gut microbiota. Moreover, ABR119 did not interfere in vitro with the antimicrobial activities of most clinically used antibiotics. In summary, ABR119 holds promise for treating and preventing C. difficile colitis by trapping the bacterial toxins, warranting further studies to assess the ABR119 potential in human infections caused by C. difficile.


Assuntos
Antibacterianos , Toxinas Bacterianas , Clostridioides difficile , Infecções por Clostridium , Colite , Modelos Animais de Doenças , Polissacarídeos , Polissacarídeos/farmacologia , Polissacarídeos/metabolismo , Clostridioides difficile/efeitos dos fármacos , Clostridioides difficile/patogenicidade , Animais , Colite/microbiologia , Colite/tratamento farmacológico , Colite/prevenção & controle , Colite/induzido quimicamente , Infecções por Clostridium/prevenção & controle , Infecções por Clostridium/microbiologia , Infecções por Clostridium/tratamento farmacológico , Toxinas Bacterianas/metabolismo , Antibacterianos/farmacologia , Humanos , Células Vegetais , Camundongos , Colo/microbiologia , Colo/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos
5.
Nutrients ; 16(11)2024 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-38892639

RESUMO

Compared to the general population, patients with inflammatory bowel disease (IBD) are less likely to be vaccinated, putting them at an increased risk of vaccine-preventable illnesses. This risk is further compounded by the immunosuppressive therapies commonly used in IBD management. Therefore, developing new treatments for IBD that maintain immune function is crucial, as successful management can lead to better vaccination outcomes and overall health for these patients. Here, we investigate the potential of recombinant banana lectin (rBanLec) as a supporting therapeutic measure to improve IBD control and possibly increase vaccination rates among IBD patients. By examining the therapeutic efficacy of rBanLec in a murine model of experimental colitis, we aim to lay the foundation for its application in improving vaccination outcomes. After inducing experimental colitis in C57BL/6 and BALB/c mice with 2,4,6-trinitrobenzene sulfonic acid, we treated animals orally with varying doses of rBanLec 0.1-10 µg/mL (0.01-1 µg/dose) during the course of the disease. We assessed the severity of colitis and rBanLec's modulation of the immune response compared to control groups. rBanLec administration resulted in an inverse dose-response reduction in colitis severity (less pronounced weight loss, less shortening of the colon) and an improved recovery profile, highlighting its therapeutic potential. Notably, rBanLec-treated mice exhibited significant modulation of the immune response, favoring anti-inflammatory pathways (primarily reduction in a local [TNFα]/[IL-10]) crucial for effective vaccination. Our findings suggest that rBanLec could mitigate the adverse effects of immunosuppressive therapy on vaccine responsiveness in IBD patients. By improving the underlying immune response, rBanLec may increase the efficacy of vaccinations, offering a dual benefit of disease management and prevention of vaccine-preventable illnesses. Further studies are required to translate these findings into clinical practice.


Assuntos
Colite , Modelos Animais de Doenças , Doenças Inflamatórias Intestinais , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Musa , Animais , Doenças Inflamatórias Intestinais/tratamento farmacológico , Camundongos , Musa/química , Colite/tratamento farmacológico , Colite/imunologia , Colite/prevenção & controle , Lectinas de Plantas/farmacologia , Ácido Trinitrobenzenossulfônico , Agentes de Imunomodulação/farmacologia , Feminino , Colo/efeitos dos fármacos , Colo/imunologia , Colo/patologia , Masculino
6.
J Hazard Mater ; 476: 134858, 2024 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-38905983

RESUMO

Endemic fluorosis has gained increasing attention as a public health concern, and the escalating risk of colitis resulting from excessive fluoride intake calls for effective mitigation strategies. This study aimed to investigate the potential mechanisms underlying the alleviation of fluoride-induced colitis by Tea polysaccharides (TPS). Under conditions of excessive fluoride intake, significant changes were observed in the gut microbiota of rats, leading to aggravated colitis. However, the intervention of TPS exerted a notable alleviating effect on colitis symptoms. Antibiotic intervention and fecal microbiota transplantation (FMT) experiments provided evidence that TPS-mediated relief of fluoride-induced colitis is mediated through its effects on the gut microbiota. Furthermore, TPS supplementation was found to modulate the structure of gut microbiota, enhance the relative abundance of Limosilactobacillus vaginalis in the gut microbiota, and promote the expression of short-chain fatty acid (SCFAs) receptors in colonic tissue. Notably, L. vaginalis played a significant role in alleviating fluoride-induced colitis and facilitating the absorption of butyric acid in the rat colon. Subsequent butyric acid intervention experiments confirmed its remarkable alleviating effect on fluoride-induced colitis. Overall, these findings provide a potential preventive strategy for fluoride-induced colitis by TPS intervention, which is mediated by L. vaginalis and butyric acid.


Assuntos
Ácido Butírico , Colite , Fluoretos , Microbioma Gastrointestinal , Polissacarídeos , Chá , Animais , Ácido Butírico/metabolismo , Fluoretos/toxicidade , Microbioma Gastrointestinal/efeitos dos fármacos , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/prevenção & controle , Polissacarídeos/farmacologia , Masculino , Chá/química , Ratos Sprague-Dawley , Colo/efeitos dos fármacos , Colo/metabolismo , Ratos
7.
J Helminthol ; 98: e41, 2024 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-38785193

RESUMO

Background: Inflammatory bowel disease is an autoimmune disease that affects the gut. T. spiralis larvae (E/S Ags) loaded on calcium-benzene-1,3,5-tricarboxylate metal-organic frameworks (Ca-BTC MOFs) were tested to determine whether they might prevent or cure acetic acid-induced murine colitis. Methods: T. spiralis larvae E/S Ags/Ca-BTC MOFs were used in prophylactic and therapeutic groups to either precede or follow the development of murine colitis. On the seventh day after colitis, mice were slaughtered. The effect of our target antigens on the progress of the colitis was evaluated using a variety of measures, including survival rate, disease activity index, colon weight/bodyweight, colon weight/length) ratios, and ratings for macroscopic and microscopic colon damage. The levels of inflammatory cytokines (interferon-γ and interleukin-4), oxidative stress marker malondialdehyde, and glutathione peroxidase in serum samples were evaluated. Foxp3 T-reg expression was carried out in colonic and splenic tissues. Results: T. spiralis larvae E/S Ags/Ca-BTC MOFs were the most effective in alleviating severe inflammation in murine colitis. The survival rate, disease activity index score, colon weight/length and colon weight/bodyweight ratios, and gross and microscopic colon damage scores have all considerably improved. A large decrease in proinflammatory cytokine (interferon-γ) and oxidative stress marker (malondialdehyde) expression and a significant increase in interleukin-4 and glutathione peroxidase expression were obtained. The expression of Foxp3+ Treg cells was elevated in colonic and splenic tissues. Conclusion: T. spiralis larvae E/S Ags/Ca-BTC MOFs had the highest anti-inflammatory, antioxidant, and cytoprotective capabilities against murine colitis and might be used to develop new preventative and treatment strategies.


Assuntos
Colite , Citocinas , Larva , Estruturas Metalorgânicas , Trichinella spiralis , Animais , Camundongos , Estruturas Metalorgânicas/química , Colite/prevenção & controle , Colite/induzido quimicamente , Colite/parasitologia , Trichinella spiralis/imunologia , Antígenos de Helmintos/imunologia , Modelos Animais de Doenças , Colo/parasitologia , Colo/patologia , Camundongos Endogâmicos BALB C , Feminino , Masculino
8.
Sci Rep ; 14(1): 11291, 2024 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-38760355

RESUMO

In the current study, we utilized molecular modeling and simulation approaches to define putative potential molecular targets for Burdock Inulin, including inflammatory proteins such as iNOS, COX-2, TNF-alpha, IL-6, and IL-1ß. Molecular docking results revealed potential interactions and good binding affinity for these targets; however, IL-1ß, COX-2, and iNOS were identified as the best targets for Inulin. Molecular simulation-based stability assessment demonstrated that inulin could primarily target iNOS and may also supplementarily target COX-2 and IL-1ß during DSS-induced colitis to reduce the role of these inflammatory mechanisms. Furthermore, residual flexibility, hydrogen bonding, and structural packing were reported with uniform trajectories, showing no significant perturbation throughout the simulation. The protein motions within the simulation trajectories were clustered using principal component analysis (PCA). The IL-1ß-Inulin complex, approximately 70% of the total motion was attributed to the first three eigenvectors, while the remaining motion was contributed by the remaining eigenvectors. In contrast, for the COX2-Inulin complex, 75% of the total motion was attributed to the eigenvectors. Furthermore, in the iNOS-Inulin complex, the first three eigenvectors contributed to 60% of the total motion. Furthermore, the iNOS-Inulin complex contributed 60% to the total motion through the first three eigenvectors. To explore thermodynamically favorable changes upon mutation, motion mode analysis was carried out. The Free Energy Landscape (FEL) results demonstrated that the IL-1ß-Inulin achieved a single conformation with the lowest energy, while COX2-Inulin and iNOS-Inulin exhibited two lowest-energy conformations each. IL-1ß-Inulin and COX2-Inulin displayed total binding free energies of - 27.76 kcal/mol and - 37.78 kcal/mol, respectively, while iNOS-Inulin demonstrated the best binding free energy results at - 45.89 kcal/mol. This indicates a stronger pharmacological potential of iNOS than the other two complexes. Thus, further experiments are needed to use inulin to target iNOS and reduce DSS-induced colitis and other autoimmune diseases.


Assuntos
Ciclo-Oxigenase 2 , Interleucina-1beta , Inulina , Simulação de Acoplamento Molecular , Óxido Nítrico Sintase Tipo II , Inulina/química , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo II/química , Ciclo-Oxigenase 2/metabolismo , Ciclo-Oxigenase 2/química , Interleucina-1beta/metabolismo , Animais , Simulação de Dinâmica Molecular , Colite/induzido quimicamente , Colite/metabolismo , Colite/prevenção & controle , Ligação Proteica , Ligação de Hidrogênio , Camundongos , Modelos Moleculares , Fator de Necrose Tumoral alfa/metabolismo
9.
Anaerobe ; 88: 102860, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38701912

RESUMO

OBJECTIVES: Clostridioides difficile infection (CDI) is the leading hospital-acquired infection in North America. We have previously discovered that antibiotic disruption of the gut microbiota decreases intestinal IL-33 and IL-25 and increases susceptibility to CDI. We further found that IL-33 promotes protection through type 2 Innate Lymphoid Cells (ILC2s), which produce IL-13. However, the contribution of IL-13 to disease has never been explored. METHODS: We used a validated model of CDI in mice, in which we neutralized via blocking antibodies, or administered recombinant protein, IL-13 to assess the role of this cytokine during infection using weight and clinical scores. Fluorescent activated cell sorting (FACS) was used to characterize myeloid cell population changes in response to IL-13 manipulation. RESULTS: We found that administration of IL-13 protected, and anti-IL-13 exacerbated CDI. Additionally, we observed alterations to the monocyte/macrophage cells following neutralization of IL-13 as early as day three post infection. We also observed elevated accumulation of myeloid cells by day four post-infection following IL-13 neutralization. Neutralization of the decoy receptor, IL-13Rα2, resulted in protection from disease, likely through increased available endogenous IL-13. CONCLUSIONS: Our data highlight the protective role of IL-13 in protecting from more severe CDI and the association of poor responses with a dysregulated monocyte-macrophage compartment. These results increase our understanding of type 2 immunity in CDI and may have implications for treating disease in patients.


Assuntos
Clostridioides difficile , Infecções por Clostridium , Modelos Animais de Doenças , Interleucina-13 , Animais , Camundongos , Clostridioides difficile/imunologia , Infecções por Clostridium/prevenção & controle , Infecções por Clostridium/imunologia , Infecções por Clostridium/microbiologia , Colite/imunologia , Colite/prevenção & controle , Colite/microbiologia , Interleucina-13/metabolismo , Interleucina-13/imunologia , Camundongos Endogâmicos C57BL , Masculino
10.
ACS Biomater Sci Eng ; 10(5): 3041-3056, 2024 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-38623037

RESUMO

Oral immunization is a promising strategy for preventing and treating gastrointestinal (GI) infections and diseases, as it allows for direct access to the disease site. To elicit immune responses within the GI tract, however, there are many obstacles that oral vaccines must surmount, including proteolytic degradation and thick mucus barriers. Here, we employed a modular self-assembling peptide nanofiber platform to facilitate oral immunization against both peptide and small molecule epitopes. Synthesizing nanofibers with d-amino acids rendered them resistant to proteases in vitro, whereas l-amino acid nanofibers were rapidly degraded. Additionally, the inclusion of peptide sequences rich in proline, alanine, and serine (PAS), increased nanofiber muco-penetration, and accelerated nanofiber transport through the GI tract. Oral immunization with PASylated nanofibers and mucosal adjuvant generated local and systemic immune responses to a peptide epitope but only for l-amino acid nanofibers. Further, we were able to apply this design to also enable oral immunization against a small molecule epitope and illustrated the therapeutic and prophylactic effectiveness of these immunizations in mouse models of colitis. These findings demonstrate that supramolecular peptide self-assemblies have promise as oral vaccines and immunotherapies.


Assuntos
Imunização , Nanofibras , Peptídeos , Animais , Administração Oral , Nanofibras/química , Peptídeos/imunologia , Peptídeos/química , Peptídeos/administração & dosagem , Camundongos , Imunização/métodos , Epitopos/imunologia , Feminino , Camundongos Endogâmicos C57BL , Colite/imunologia , Colite/prevenção & controle , Colite/induzido quimicamente
11.
Proc Natl Acad Sci U S A ; 121(18): e2319833121, 2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38648480

RESUMO

Sirt2 is a nicotinamide adenine dinucleotide (NAD+)-dependent protein lysine deacylase that can remove both acetyl group and long-chain fatty acyl groups from lysine residues of many proteins. It was reported to affect inflammatory bowel disease (IBD) symptoms in a mouse model. However, conflicting roles were reported, with genetic knockout aggravating while pharmacological inhibition alleviating IBD symptoms. These seemingly conflicting reports cause confusion and deter further efforts in developing Sirt2 inhibitors as a potential treatment strategy for IBD. We investigated these conflicting reports and elucidated the role of Sirt2 in the mouse model of IBD. We essentially replicated these conflicting results and confirmed that Sirt2 inhibitors' protective effect is not through off-targets as two very different Sirt2 inhibitors (TM and AGK2) showed similar protection in the IBD mouse model. We believe that the differential effects of inhibitors and knockout are due to the fact that the Sirt2 inhibitors only inhibit some but not all the activities of Sirt2. This hypothesis is confirmed by the observation that a PROTAC degrader of Sirt2 did not protect mice in the IBD model, similar to Sirt2 knockout. Our study provides an interesting example where genetic knockout and pharmacological inhibition do not align and emphasizes the importance of developing substrate-dependent inhibitors. Importantly, we showed that the effect of Sirt2 inhibition in IBD is through regulating the gut epithelium barrier by inhibiting Arf6-mediated endocytosis of E-cadherin, a protein important for the intestinal epithelial integrity. This mechanistic understanding further supports Sirt2 as a promising therapeutic target for treating IBD.


Assuntos
Colite , Mucosa Intestinal , Sirtuína 2 , Animais , Humanos , Camundongos , Caderinas/metabolismo , Caderinas/genética , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/prevenção & controle , Modelos Animais de Doenças , Furanos , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/patologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Quinolinas , Sirtuína 2/metabolismo , Sirtuína 2/antagonistas & inibidores , Sirtuína 2/genética
12.
Nutrients ; 16(7)2024 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-38613088

RESUMO

Probiotics, recognized as beneficial and active microorganisms, often face challenges in maintaining their functionality under harsh conditions such as exposure to stomach acid and bile salts. In this investigation, we developed probiotic microcapsules and assessed their protective effects and underlying mechanisms in a murine model of dextran sulfate sodium (DSS)-induced colitis using male C57BL/6J mice. The administration of the probiotic microcapsules significantly mitigated body weight loss, prevented colon length shortening, decreased the disease activity index scores, and reduced histopathological scores in mice with DSS-induced colitis. Concurrently, the microencapsulated probiotics preserved intestinal barrier integrity by upregulating the expressions of tight junction proteins ZO-1 and occludin, as well as the mucus layer component MUC-2. Moreover, the treatment with probiotic microcapsules suppressed the activation of the NLRP3 inflammasome signaling pathway in the context of DSS-induced colitis. In conclusion, these findings support the utilization of probiotic microcapsules as a potential functional food ingredient to maintain the permeability of the intestinal barrier and alleviate colonic inflammation in UC.


Assuntos
Colite , Lactobacillus plantarum , Masculino , Animais , Camundongos , Camundongos Endogâmicos C57BL , Cápsulas , Colite/induzido quimicamente , Colite/prevenção & controle , Inflamação
13.
mBio ; 15(4): e0029824, 2024 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-38441000

RESUMO

Observational evidence suggests that human milk oligosaccharides (HMOs) promote the growth of commensal bacteria in early life and adulthood. However, the mechanisms by which HMOs benefit health through modulation of gut microbial homeostasis remain largely unknown. 2'-fucosyllactose (2'-FL) is the most abundant oligosaccharide in human milk and contributes to the essential health benefits associated with human milk consumption. Here, we investigated how 2'-FL prevents colitis in adulthood through its effects on the gut microbial community. We found that the gut microbiota from adult mice that consumed 2'-FL exhibited an increase in abundance of several health-associated genera, including Bifidobacterium and Lactobacillus. The 2'-FL-modulated gut microbial community exerted preventive effects on colitis in adult mice. By using Bifidobacterium infantis as a 2'-FL-consuming bacterial model, exploratory metabolomics revealed novel 2'-FL-enriched secretory metabolites by Bifidobacterium infantis, including pantothenol. Importantly, pantothenate significantly protected the intestinal barrier against oxidative stress and mitigated colitis in adult mice. Furthermore, microbial metabolic pathway analysis identified 26 dysregulated metabolic pathways in fecal microbiota from patients with ulcerative colitis, which were significantly regulated by 2'-FL treatment in adult mice, indicating that 2'-FL has the potential to rectify dysregulated microbial metabolism in colitis. These findings support the contribution of the 2'-FL-shaped gut microbial community and bacterial metabolite production to the protection of intestinal integrity and prevention of intestinal inflammation in adulthood.IMPORTANCEAt present, neither basic research nor clinical studies have revealed the exact biological functions or mechanisms of action of individual oligosaccharides during development or in adulthood. Thus, it remains largely unknown whether human milk oligosaccharides could serve as effective therapeutics for gastrointestinal-related diseases. Results from the present study uncover 2'-FL-driven alterations in bacterial metabolism and identify novel B. infantis-secreted metabolites following the consumption of 2'-FL, including pantothenol. This work further demonstrates a previously unrecognized role of pantothenate in significantly protecting the intestinal barrier against oxidative stress and mitigating colitis in adult mice. Remarkably, 2'-FL-enhanced bacterial metabolic pathways are found to be dysregulated in the fecal microbiota of ulcerative colitis patients. These novel metabolic pathways underlying the bioactivities of 2'-FL may lay a foundation for applying individual oligosaccharides for prophylactic intervention for diseases associated with impaired intestinal homeostasis.


Assuntos
Colite Ulcerativa , Colite , Microbioma Gastrointestinal , Ácido Pantotênico/análogos & derivados , Adulto , Humanos , Animais , Camundongos , Leite Humano , Colite Ulcerativa/metabolismo , Oligossacarídeos/metabolismo , Colite/prevenção & controle , Inflamação
14.
BMC Microbiol ; 24(1): 91, 2024 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-38500062

RESUMO

BACKGROUND: Probiotics are a potentially effective therapy for inflammatory bowel disease (IBD); IBD is linked to impaired gut microbiota and intestinal immunity. However, the utilization of an antibiotic cocktail (Abx) prior to the probiotic intervention remains controversial. This study aims to identify the effect of Abx pretreatment from dextran sulfate sodium (DSS)-induced colitis and to evaluate whether Abx pretreatment has an enhanced effect on the protection of Clostridium butyricum Miyairi588 (CBM) from colitis. RESULTS: The inflammation, dysbiosis, and dysfunction of gut microbiota as well as T cell response were both enhanced by Abx pretreatment. Additionally, CBM significantly alleviated the DSS-induced colitis and impaired gut epithelial barrier, and Abx pretreatment could enhance these protective effects. Furthermore, CBM increased the benefit bacteria abundance and short-chain fatty acids (SCFAs) level with Abx pretreatment. CBM intervention after Abx pretreatment regulated the imbalance of cytokines and transcription factors, which corresponded to lower infiltration of Th1 and Th17 cells, and increased Th2 cells. CONCLUSIONS: Abx pretreatment reinforced the function of CBM in ameliorating inflammation and barrier damage by increasing beneficial taxa, eliminating pathogens, and inducing a protective Th2 cell response. This study reveals a link between Abx pretreatment, microbiota, and immune response changes in colitis, which provides a reference for the further application of Abx pretreatment before microbiota-based intervention.


Assuntos
Colite , Doenças Inflamatórias Intestinais , Probióticos , Humanos , Animais , Camundongos , Antibacterianos/efeitos adversos , Células Th2 , Células Th17 , Colite/induzido quimicamente , Colite/prevenção & controle , Probióticos/farmacologia , Inflamação , Imunidade , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças
15.
Biochem J ; 481(4): 295-312, 2024 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-38372391

RESUMO

Ketogenesis is considered to occur primarily in liver to generate ketones as an alternative energy source for non-hepatic tissues when glucose availability/utilization is impaired. 3-Hydroxy-3-methylglutaryl-CoA synthase-2 (HMGCS2) mediates the rate-limiting step in this mitochondrial pathway. Publicly available databases show marked down-regulation of HMGCS2 in colonic tissues in Crohn's disease and ulcerative colitis. This led us to investigate the expression and function of this pathway in colon and its relevance to colonic inflammation in mice. Hmgcs2 is expressed in cecum and colon. As global deletion of Hmgcs2 showed significant postnatal mortality, we used a conditional knockout mouse with enzyme deletion restricted to intestinal tract. These mice had no postnatal mortality. Fasting blood ketones were lower in these mice, indicating contribution of colonic ketogenesis to circulating ketones. There was also evidence of gut barrier breakdown and increased susceptibility to experimental colitis with associated elevated levels of IL-6, IL-1ß, and TNF-α in circulation. Interestingly, many of these phenomena were mostly evident in male mice. Hmgcs2 expression in colon is controlled by colonic microbiota as evidenced from decreased expression in germ-free mice and antibiotic-treated conventional mice and from increased expression in a human colonic epithelial cell line upon treatment with aqueous extracts of cecal contents. Transcriptomic analysis of colonic epithelia from control mice and Hmgcs2-null mice indicated an essential role for colonic ketogenesis in the maintenance of optimal mitochondrial function, cholesterol homeostasis, and cell-cell tight-junction organization. These findings demonstrate a sex-dependent obligatory role for ketogenesis in protection against colonic inflammation in mice.


Assuntos
Colite , Cetonas , Humanos , Camundongos , Masculino , Animais , Corpos Cetônicos , Colite/genética , Colite/prevenção & controle , Colo , Inflamação , Camundongos Endogâmicos C57BL , Sulfato de Dextrana
16.
Nutrients ; 16(4)2024 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-38398846

RESUMO

Dietary polyphenols are reported to alleviate colitis by interacting with gut microbiota which plays an important role in maintaining the integrity of the intestinal barrier. As a type of dietary polyphenol, whether ligustroside (Lig) could alleviate colitis has not been explored yet. Here, we aimed to determine if supplementation of ligustroside could improve colitis. We explored the influence of ligustroside intake with different dosages on colitis induced with dextran sulfate sodium (DSS). Compared to the DSS group, supplementation of ligustroside could reduce body weight (BW) loss, decrease disease activity indices (DAI), and relieve colon damage in colitis mice. Furthermore, ligustroside intake with 2 mg/kg could decrease proinflammatory cytokine concentrations in serum and increase immunoglobulin content and antioxidant enzymes in colon tissue. In addition, supplementation of ligustroside (2 mg/kg) could reduce mucus secretion and prevent cell apoptosis. Also, changes were revealed in the bacterial community composition, microbiota functional profiles, and intestinal metabolite composition following ligustroside supplementation with 2 mg/kg using 16S rRNA sequencing and non-targeted lipidomics analysis. In conclusion, the results showed that ligustroside was very effective in preventing colitis through reduction in inflammation and the enhancement of the intestinal barrier. Furthermore, supplementation with ligustroside altered the gut microbiota and lipid composition of colitis mice.


Assuntos
Colite , Glucosídeos , Piranos , Camundongos , Animais , Sulfato de Dextrana/toxicidade , RNA Ribossômico 16S/genética , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/prevenção & controle , Intestinos , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Colo/metabolismo
17.
Food Res Int ; 176: 113797, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38163708

RESUMO

Fermented soymilk (FSM) as a new plant-based yoghurt has attracted attention for its nutritional and health benefits. The aim of this research is to explore the effect of consuming FSM before and during inflammatory bowel disease (IBD) on intestinal immune response, and to assess whether fermentation and sucrose can improve the anti-inflammatory activity of soymilk (SM) and FSM, and finally clarify their effect on the gut microbiota and levels of short-chain fatty acids (SCFAs). Consuming FSM in advance can effectively alleviate weight loss and bloody stools in mice with colitis and is associated with a 27% colon length repair rate. It can also prevent spleen and liver enlargement, inhibit immune response and oxidative stress, and increase the expression of the tight junction protein occludin gene (60%). Meanwhile, intaking FSM during IBD reduced weight loss, prevented liver damage, and repaired colon injury. In addition, fermentation enhance the inhibitory effects of FSM on colitis, whereas adding 3% sucrose to FSM had no effect on its intervention in colitis. Analysis of the composition of the gut microbiota in mice showed that the intake of FSM reduced the relative abundance of the pathogenic bacteria Parasutterella, Turicibater, and Bacteroide by 75%, 62%, and 50%, respectively, and increased the relative abundance of the beneficial bacteria Akkermansiaceae, Lachnospiraceae, Alloprevotella, and Dubosella by 28%, 50%, 80%, and 63%, respectively. It further restored the levels of SCFAs in the mouse intestine. The results provide a scientific basis for FSM as a natural anti-inflammatory food that can improve inflammatory intestinal microbiota imbalance and promote gut health.


Assuntos
Colite , Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , Camundongos , Animais , Colite/induzido quimicamente , Colite/prevenção & controle , Imunidade , Redução de Peso , Anti-Inflamatórios/efeitos adversos , Sacarose/farmacologia
18.
Adv Sci (Weinh) ; 11(13): e2304716, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38247203

RESUMO

Structural repair of the intestinal epithelium is strongly correlated with disease remission in inflammatory bowel disease (IBD); however, ulcer healing is not addressed by existing therapies. To address this need, this study reports the use of a small molecule prolyl hydroxylase (PHD) inhibitor (DPCA) to upregulate hypoxia-inducible factor one-alpha (HIF-1α) and induce mammalian regeneration. Sustained delivery of DPCA is achieved through subcutaneous injections of a supramolecular hydrogel, formed through the self-assembly of PEG-DPCA conjugates. Pre-treatment of mice with PEG-DPCA is shown to protect mice from epithelial erosion and symptoms of dextran sodium sulfate (DSS)-induced colitis. Surprisingly, a single subcutaneous dose of PEG-DPCA, administered after disease onset, leads to accelerated weight gain and complete restoration of healthy tissue architecture in colitic mice. Rapid DPCA-induced restoration of the intestinal barrier is likely orchestrated by increased expression of HIF-1α and associated targets leading to an epithelial-to-mesenchymal transition. Further investigation of DPCA as a potential adjunctive or stand-alone restorative treatment to combat active IBD is warranted.


Assuntos
Colite , Doenças Inflamatórias Intestinais , Camundongos , Animais , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/prevenção & controle , Mucosa Intestinal/metabolismo , Modelos Animais de Doenças , Mamíferos
19.
Adv Sci (Weinh) ; 11(11): e2305893, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38189580

RESUMO

The integrity of the intestinal mucosal barrier is crucial for protecting the intestinal epithelium against invasion by commensal bacteria and pathogens, thereby combating colitis. The investigation revealed that the absence of TSP50 compromised the integrity of the intestinal mucosal barrier in murine subjects. This disruption facilitated direct contact between intestinal bacteria and the intestinal epithelium, thereby increasing susceptibility to colitis. Mechanistic analysis indicated that TSP50 deficiency in intestinal stem cells (ISCs) triggered aberrant activation of the TGF-ß signaling pathway and impeded the differentiation of goblet cells in mice, leading to impairment of mucosal permeability. By inhibiting the TGF-ß pathway, the functionality of the intestinal mucosal barrier is successfully restored and mitigated colitis in TSP50-deficient mice. In conclusion, TSP50 played a crucial role in maintaining the intestinal mucosal barrier function and exhibited the preventive effect against the development of colitis by regulating the TGF-ß signaling pathway.


Assuntos
Colite , Animais , Humanos , Camundongos , Colite/induzido quimicamente , Colite/prevenção & controle , Mucosa Intestinal , Intestinos , Fator de Crescimento Transformador beta/metabolismo
20.
Biol Trace Elem Res ; 202(2): 659-670, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37249802

RESUMO

Inflammatory bowel diseases (IBDs), including Crohn's disease and ulcerative colitis, are chronic relapsing inflammatory gastrointestinal tract diseases of uncertain origin, which are frequently associated with zinc deficiency. Animal models have a considerable value in elucidating the process of IBD. In this study, 50 male C57BL/6 J mice were randomly assigned to five groups: control group (Con), 2,4,6-trinitrobenzenesulfonic acid (TNBS) group, and three zinc supplementation groups, namely 160 ppm group, 400 ppm group, and 1000 ppm group. The results showed that supplementation of dietary zinc with zinc oxide could effectively relieve the severity of ulcerative colitis induced by TNBS in mice. We demonstrate that the protective mechanism involves the immunomodulation of dietary zinc by increasing CD3+, CD3+CD8+, and Th2 cells, suppressing Th1 and Th17 cells, and decreasing the production of serum IL-1ß and IL-18. The dietary zinc oxide seems to be able to suppress the NF-κB/NLRP3 signaling pathway by downregulating the mRNA and protein expression of NIK, IKK, NF-κB, and NLRP3. The results suggest that dietary supplementation of zinc oxide may protect against colitis, and proper daily zinc supplementation may reduce the risk of IBD.


Assuntos
Colite Ulcerativa , Colite , Doenças Inflamatórias Intestinais , Óxido de Zinco , Camundongos , Masculino , Animais , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR , Células Th17/metabolismo , Óxido de Zinco/farmacologia , Camundongos Endogâmicos C57BL , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/prevenção & controle , Transdução de Sinais , Zinco/efeitos adversos , Modelos Animais de Doenças
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