scholarly journals Tamoxifen-induced, intestinal-specific deletion of Slc5a6 in adult mice leads to spontaneous inflammation: involvement of NF-κB, NLRP3, and gut microbiota

2019 ◽  
Vol 317 (4) ◽  
pp. G518-G530 ◽  
Author(s):  
Subrata Sabui ◽  
Jonathan Skupsky ◽  
Rubina Kapadia ◽  
Kyle Cogburn ◽  
Nils W. Lambrecht ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Proinflammatory Cytokines ◽  
Nlrp3 Inflammasome ◽  
Intestinal Inflammation ◽  
Uptake System ◽  
Biotin Deficiency ◽  
Transport Pathway ◽  
Adult Mice ◽  
Reduced Body ◽  
Tnf Α

The sodium-dependent multivitamin transporter (SMVT; SLC5A6) is involved in intestinal absorption of vitamin B7 (biotin). We have previously shown that mice with an embryonic intestinal-specific SMVT knockout (KO) develop biotin deficiency and severe spontaneous intestinal inflammation in addition to growth retardation, developmental delays, and death within the first 6–7 wk of life. The profound morbidity and mortality associated with the SMVT-KO has limited our ability to further characterize the intestinal inflammation and other sequelae of this deletion in adult mice with a mature gut microbiota. To overcome this limitation, we generated an intestine-specific, tamoxifen-inducible, conditional SMVT-KO (SMVT-icKO). Our results showed that adult SMVT-icKO mice have reduced body weight, biotin deficiency, shorter colonic length, and bloody diarrhea compared with age- and sex-matched control littermates. All SMVT-icKO mice also developed spontaneous intestinal inflammation associated with induction of calprotectin (S100a8/S100a9), proinflammatory cytokines (IL-1β, TNF-α, IFN-γ, and IL-6), and an increase in intestinal permeability. Additionally, the intestines of SMVT-icKO showed activation of the NF-κB pathway and the nucleotide-binding domain and leucine-rich repeat pyrin 3 domain (NLRP3) inflammasome. Notably, administration of broad-spectrum antibiotics reduced lethality and led to normalization of intestinal inflammation, proinflammatory cytokines, altered mucosal integrity, and reduced expression of the NLRP3 inflammasome. Overall, these findings support our conclusion that the biotin transport pathway plays an important role in the maintenance of intestinal homeostasis, and that NF-κB and the NLRP3 inflammasome, as well as gut microbiota, drive the development of intestinal inflammation when SMVT is absent. NEW & NOTEWORTHY This study demonstrates that deletion of the intestinal biotin uptake system in adult mice leads to the development of spontaneous gut inflammation and that luminal microbiota plays a role in its development.

scholarly journals Intestinal inflammation downregulates smooth muscle CPI-17 through induction of TNF-α and causes motility disorders

2007 ◽  
Vol 292 (5) ◽  
pp. G1429-G1438 ◽  
Author(s):  
Takashi Ohama ◽  
Masatoshi Hori ◽  
Eiichi Momotani ◽  
Yoichiro Iwakura ◽  
Fengling Guo ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Muscle Tissue ◽  
Proinflammatory Cytokines ◽  
Knockout Mice ◽  
Intestinal Inflammation ◽  
In Vivo Model ◽  
Dependent Manner ◽  
Smooth Muscle Tissue ◽  
Motility Disorders ◽  
Tnf Α

Motility disorders are frequently observed in intestinal inflammation. We previously reported that in vitro treatment of intestinal smooth muscle tissue with IL-1β decreases the expression of CPI-17, an endogenous inhibitory protein of smooth muscle serine/threonine protein phosphatase, thereby inhibiting contraction. The present study was performed to examine the pathophysiological importance of CPI-17 expression in the motility disorders by using an in vivo model of intestinal inflammation and to define the regulatory mechanism of CPI-17 expression by proinflammatory cytokines. After the induction of acute ileitis with 2,4,6,-trinitrobenzensulfonic acid, CPI-17 expression declined in a time-dependent manner. This decrease in CPI-17 expression was parallel with the reduction of cholinergic agonist-induced contraction of smooth muscle strips and sensitivity of permeabilized smooth muscle fibers to Ca2+. Among the various proinflammatory cytokines tested, TNF-α and IL-1β were observed to directly inhibit CPI-17 expression and contraction in cultured rat intestinal tissue. Moreover, both TNF-α and IL-1β inhibited CPI-17 expression and contraction of smooth muscle tissue isolated from wild-type and IL-1α/β double-knockout mice. However, IL-1β treatment failed to inhibit CPI-17 expression and contraction in TNF-α knockout mice. In β-escin-permeabilized ileal tissues, pretreatment with anti-phosphorylated CPI-17 antibody inhibited the carbachol-induced Ca2+ sensitization in the presence of GTP. These findings suggest that CPI-17 was downregulated during intestinal inflammation and that TNF-α plays a central role in this process. Downregulation of CPI-17 may play a role in motility impairments in inflammation.

scholarly journals Study on the mechanism of Indigo naturalis and its two main compounds (indigo and indirubin) in the treatment of ulcerative colitis based on TLR4/MyD88/NF-κB pathway and intestinal microorganisms

2020 ◽  
Author(s):  
Qi-yue Yang ◽  
Ya-nan He ◽  
Le-le Ma ◽  
Run-chun Xu ◽  
Nan Li ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Gut Microbiota ◽  
Intestinal Inflammation ◽  
Activity Index ◽  
Disease Activity Index ◽  
Pathological Section ◽  
Inflammatory Cytokine Production ◽  
Tnf Α ◽  
Indigo Naturalis ◽  
Inflammation Cytokines

Abstract Background: Indigo naturalis is a natural dye extracted from plants and has a good anti-inflammatory effect. Clinical studies have shown that it can improve ulcerative colitis (UC), but the active constituents and the mechanism are unclear. Methods: The anti-UC activity of Indigo naturalis and its two main compounds (indigo and indirubin) were investigated in dextran sulfate sodium (DSS)-induced UC mice. Indigo naturalis, indigo and indirubin were administrated to DSS-induced UC rats by oral gavage for 1 weeks. The anti-UC effect was evaluated by pathological section, inflammatory cytokine production, western blotting, and gut microbiota analysis via 16S rRNA sequencing. Results: Indigo naturalis, indigo and indirubin can improve the UC induced by DSS. Their effect intensity is Indigo naturalis > indirubin > indigo based on disease activity index, body weight, colon length and pathological section. Indigo naturalis, indigo and indirubin also decrease the expression of NF-κB，TLR4 and MYD88 proteins, thus reducing the level of related inflammation cytokines (IL-1β, IL-6 and TNF-α) both in serum and tissue. In addition, Indigo naturalis and indigo improved symptoms of gut microbial disturbance, and decreased Firmicutes/Bacteroidetes ratio and the significantly increased probiotics such as Lactobacillus. Indirubin has little effect on the regulation of gut microbial. Conclusions: Indigo naturalis could attenuate the DSS-induced UC in mice, by means of ameliorating intestinal inflammation, improving intestinal mucosa, and regulating the disturbed gut microbiota. Indigo and indirubin could also attenuate the DSS-induced UC in mice, but their comprehensive effect is not as good as Indigo naturalis.

scholarly journals Signaling Through Purinergic Receptor P2Y2 Enhances Macrophage IL-1β Production

2020 ◽  
Vol 21 (13) ◽  
pp. 4686
Author(s):  
Gonzalo de la Rosa ◽  
Ana I. Gómez ◽  
María C. Baños ◽  
Pablo Pelegrín
Keyword(s):  
Proinflammatory Cytokines ◽  
Nlrp3 Inflammasome ◽  
Purinergic Receptor ◽  
Peritoneal Macrophages ◽  
Pharmacological Inhibition ◽  
Inflammatory Conditions ◽  
Low Concentrations ◽  
Tnf Α ◽  
Il1b Gene ◽  
Inflammatory Effect

The release of nucleotides during necrosis or apoptosis has been described to have both proinflammatory and anti-inflammatory effect on the surrounding cells. Here we describe how low concentrations of UTP and ATP applied during macrophage priming enhance IL-1β production when subsequently the NLRP3 inflammasome is activated in murine resident peritoneal macrophages. Deficiency or pharmacological inhibition of the purinergic receptor P2Y2 reverted the increase of IL-1β release induced by nucleotides. IL-1β increase was found dependent on the expression of Il1b gene and probably involving JNK activity. On the contrary, nucleotides decreased the production of a different proinflammatory cytokines such as TNF-α. These results suggest that nucleotides could shape the response of macrophages to obtain a unique proinflammatory signature that might be relevant in unrevealing specific inflammatory conditions.

scholarly journals Effect of Extracellular Vesicles Derived From Lactobacillus plantarum Q7 on Gut Microbiota and Ulcerative Colitis in Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Haining Hao ◽  
Xinyi Zhang ◽  
Lingjun Tong ◽  
Qiqi Liu ◽  
Xi Liang ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Gut Microbiota ◽  
Lactobacillus Plantarum ◽  
Extracellular Vesicles ◽  
Intestinal Inflammation ◽  
Body Weight Loss ◽  
Tnf Α ◽  
Cytokine Levels ◽  
Anti Inflammatory ◽  
Inflammatory Effect

Probiotics plays an important role in regulating gut microbiota and maintaining intestinal homeostasis. Extracellular vesicles (EVs) derived from probiotics have emerged as potential mediators of host immune response and anti-inflammatory effect. However, the anti-inflammatory effect and mechanism of probiotics derived EVs on inflammatory bowel disease (IBD) remains unclear. In this study, the effect of Lactobacillus plantarum Q7-derived extracellular vesicles (Q7-EVs) on gut microbiota and intestinal inflammation was investigated in C57BL/6J mice. The results showed that Q7-EVs alleviated DSS-induced colitis symptoms, including colon shortening, bleeding, and body weight loss. Consumption of Q7-EVs reduced the degree of histological damage. DSS-upregulated proinflammatory cytokine levels including IL-6, IL-1β, IL-2 and TNF-α were reduced significantly by Q7-EVs (p < 0.05). 16S rRNA sequencing results showed that Q7-EVs improved the dysregulation of gut microbiota and promoted the diversity of gut microbiota. It was observed that the pro-inflammatory bacteria (Proteobacteria) were reduced and the anti-inflammatory bacteria (Bifidobacteria and Muribaculaceae) were increased. These findings indicated that Q7-EVs might alleviate DSS-induced ulcerative colitis by regulating the gut microbiota.

scholarly journals The Anti-Inflammatory Effect and Mucosal Barrier Protection of Clostridium butyricum RH2 in Ceftriaxone-Induced Intestinal Dysbacteriosis

2021 ◽  
Vol 11 ◽  
Author(s):  
Yuyuan Li ◽  
Man Liu ◽  
He Liu ◽  
Xue Sui ◽  
Yinhui Liu ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Intestinal Inflammation ◽  
Clostridium Butyricum ◽  
Mucosal Barrier ◽  
Inflammatory Factors ◽  
High Dose ◽  
Intestinal Integrity ◽  
Tnf Α ◽  
Anti Inflammatory

This study aimed at determining the beneficial effect of Clostridium butyricum (CB) RH2 on ceftriaxone-induced dysbacteriosis. To this purpose, BALB/c mice were exposed to ceftriaxone (400 mg/ml) or not (control) for 7 days, and administered a daily oral gavage of low-, and high-dose CB RH2 (108 and 1010 CFU/ml, respectively) for 2 weeks. CB RH2 altered the diversity of gut microbiota, changed the composition of gut microbiota in phylum and genus level, decreased the F/B ratio, and decreased the pro-inflammatory bacteria (Deferribacteres, Oscillibacter, Desulfovibrio, Mucispirillum and Parabacteroides) in ceftriaxone-treated mice. Additionally, CB RH2 improved colonic architecture and intestinal integrity by improving the mucous layer and the tight junction barrier. Furthermore, CB RH2 also mitigated intestinal inflammation through decreasing proinflammatory factors (TNF-α and COX-2) and increasing anti-inflammatory factors (IL-10). CB RH2 had direct effects on the expansion of CD4+ T cells in Peyer’s patches (PPs) in vitro, which in turn affected their immune response upon challenge with ceftriaxone. All these data suggested that CB RH2 possessed the ability to modulate the intestinal mucosal and systemic immune system in limiting intestinal alterations to relieve ceftriaxone-induced dysbacteriosis.

scholarly journals Lactobacillus rhamnosus GG Derived Extracellular Vesicles Modulate Gut Microbiota and Attenuate Inflammatory in DSS-Induced Colitis Mice

Nutrients ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 3319
Author(s):  
Lingjun Tong ◽  
Xinyi Zhang ◽  
Haining Hao ◽  
Qiqi Liu ◽  
Zihan Zhou ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Extracellular Vesicles ◽  
Intestinal Inflammation ◽  
Lactobacillus Rhamnosus ◽  
Underlying Mechanism ◽  
Lactobacillus Rhamnosus Gg ◽  
Tnf Α ◽  
Rrna Sequencing ◽  
Clinical Benefits ◽  
Pro Inflammatory Cytokines

Ulcerative colitis (UC) is a relapsing and remitting inflammatory disease. Probiotics have a potential beneficial effect on the prevention of UC onset and relapse in clinical trials. Lactobacillus rhamnosus GG (L. rhamnosus GG) have shown clinical benefits on UC patients, however, the precise mechanisms are unknown. The aim of this study is to explore the effect of extracellular vesicles released from L. rhamnosus GG (LGG-EVs) on dextran sulfate sodium (DSS)-induced colitis and propose the underlying mechanism of LGG-EVs for protecting against colitis. The results showed that LGG-EVs could prevent colonic tissue damage and shortening of the colon (p < 0.01), and ameliorate intestinal inflammation by inhibiting TLR4-NF-κB-NLRP3 axis activation. Consistently, the pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-2) were suppressed effectively upon LGG-EVs treatment (p < 0.05). The 16S rRNA sequencing showed that LGG-EVs administration could reshape the gut microbiota in DSS-induced colitis mice, which further alters the metabolism pathways of gut microbiota. These findings propose a novel perspective of L. rhamnosus GG in attenuating inflammation mediated by extracellular vesicles and offer consideration for developing oral gavage of LGG-EVs for colitis therapies.

scholarly journals Rosiglitazone ameliorates radiation-induced intestinal inflammation in rats by inhibiting NLRP3 inflammasome and TNF-α production

2020 ◽  
Vol 61 (6) ◽  
pp. 842-850
Author(s):  
Liqiong Hu ◽  
Hao Chen ◽  
Xingliang Zhang ◽  
Zhencheng Feng ◽  
Haifeng Zhang ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Intestinal Inflammation ◽  
Intestinal Injury ◽  
Receptor Protein ◽  
Inflammasome Activation ◽  
Caspase 1 ◽  
Pparγ Agonist ◽  
Tnf Α ◽  
Radiation Induced

Abstract Radiation-induced acute intestinal injury is a common and serious occurrence following abdominal and pelvic irradiation. The Nod-like receptor protein 3 (NLRP3)-dependant inflammasome and inflammation activation is crucial in this process. In a pre-experimental design of radiation-induced intestinal injury, we found that rosiglitazone inhibited caspase-1 which is a key marker of inflammasome activation. The purpose of the present study was to clarify the inhibitory effect of rosiglitazone on the NLRP3 inflammasome both in vivo and in vitro. Radiation-induced intestinal injury after rosiglitazone treatment, and the expression of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), caspase-1 and NLRP3 in a radiation-induced intestinal injury model in a rat and macrophages were observed. We found that rosiglitazone ameliorated radiation-induced intestinal injury in rats by suppressing the expression of caspase-1, NLRP3, IL-1β and TNF-α. Treatment with rosiglitazone in vitro reduced the expression of NLRP3, and the NLRP3 activator monosodium urate (MSU) reversed the inhibition of IL-1β and TNF-α by rosiglitazone in macrophages. MSU reversed the protective effect of rosiglitazone on radiation-induced intestinal injury in rats by reversing the rosiglitazone-induced inhibition of IL-1β and TNF-α. Taken together, these findings indicate that the peroxisome proliferator-activated receptor gamma (PPARγ) agonist, rosiglitazone, ameliorates radiation-induced intestine inflammation in rats via inhibiting the induction of the NLRP3-dependent inflammasome in macrophages.

scholarly journals Do proinflammatory cytokines play a role in clozapine-associated glycometabolism disorders?

2021 ◽  
Author(s):  
Tongtong Zhao ◽  
Kai Zhang ◽  
Yelei Zhang ◽  
Yating Yang ◽  
Xiaoshuai Ning ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Side Effects ◽  
Proinflammatory Cytokines ◽  
Peripheral Blood ◽  
Animal Experiments ◽  
Pancreatic Tissue ◽  
Mouse Serum ◽  
Healthy Controls ◽  
Immunological Mechanisms ◽  
Tnf Α

Abstract Rationale and objective Clozapine (CLZ) is the most effective drug for treatment-resistant schizophrenia but is associated with many side effects, including glycometabolism disorders. Immunological mechanisms may be involved in the development of clozapine side effects. Research relating the immunomodulatory effects of clozapine and its early markers to clinically relevant adverse events is needed to reduce the harmful side effects of clozapine. This study aimed to investigate the role of proinflammatory cytokines in clozapine-associated glycometabolism disorders. Methods We measured the effect of a range of doses of clozapine on glycometabolism-related parameters and proinflammatory cytokines levels in mice peripheral blood. We also examined the differences between these indicators in the peripheral blood of clozapine-treated schizophrenia patients and healthy controls. Furthermore, we detected proinflammatory cytokines expression in mice pancreatic tissue. Results Following clozapine administration, glucagon significantly decreased in mouse serum, and proinflammatory cytokine IL-β levels markedly increased. Clozapine reliably increased proinflammatory cytokines (IL-1β, IL-6, and TNF-α) expression in murine pancreatic tissue. Compared with healthy controls, clozapine-treated patients’ BMI, blood glucose, and proinflammatory cytokines (IL-1β, IL-6, and TNF-α) increased significantly. In clozapine-treated patients, a higher clozapine daily dosage was associated with higher levels of the proinflammatory cytokines IL-1β and IL-6, and a significant positive correlation was observed between blood glucose levels and the proinflammatory cytokines IL-6 and TNF-α. Conclusion Findings from animal experiments and clinical trials have shown clear evidence that clozapine has a regulatory effect on immune-related proinflammatory cytokines and influences glycometabolism indicators.

scholarly journals Role of Dietary Nutritional Treatment on Hepatic and Intestinal Damage in Transplantation with Steatotic and Non-Steatotic Liver Grafts from Brain Dead Donors

Nutrients ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 2554
Author(s):  
Marc Micó-Carnero ◽  
Araní Casillas-Ramírez ◽  
Albert Caballeria-Casals ◽  
Carlos Rojano-Alfonso ◽  
Alfredo Sánchez-González ◽  
...  
Keyword(s):  
Growth Factor ◽  
Gut Microbiota ◽  
Intestinal Inflammation ◽  
Mucosal Damage ◽  
Hepatic Damage ◽  
Intestinal Damage ◽  
Edema Formation ◽  
Steatotic Liver ◽  
Damage And Failure

Herein, we investigate whether: (1) the administration of glucose or a lipid emulsion is useful in liver transplantation (LT) using steatotic (induced genetically or nutritionally) or non-steatotic livers from donors after brain death (DBDs); and (2) any such benefits are due to reductions in intestinal damage and consequently to gut microbiota preservation. In recipients from DBDs, we show increased hepatic damage and failure in the maintenance of ATP, glycogen, phospholipid and growth factor (HGF, IGF1 and VEGFA) levels, compared to recipients from non-DBDs. In recipients of non-steatotic grafts from DBDs, the administration of glucose or lipids did not protect against hepatic damage. This was associated with unchanged ATP, glycogen, phospholipid and growth factor levels. However, the administration of lipids in steatotic grafts from DBDs protected against damage and ATP and glycogen drop and increased phospholipid levels. This was associated with increases in growth factors. In all recipients from DBDs, intestinal inflammation and damage (evaluated by LPS, vascular permeability, mucosal damage, TLR4, TNF, IL1, IL-10, MPO, MDA and edema formation) was not shown. In such cases, potential changes in gut microbiota would not be relevant since neither inflammation nor damage was evidenced in the intestine following LT in any of the groups evaluated. In conclusion, lipid treatment is the preferable nutritional support to protect against hepatic damage in steatotic LT from DBDs; the benefits were independent of alterations in the recipient intestine.

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