High-Fat Diet Promotes DSS-Induced Ulcerative Colitis by Downregulated FXR Expression through the TGFB Pathway

Ulcerative colitis is one of the IBD which cause a chronic intestinal inflammation and dysfunctional of the mucosal barrier. For now, the incident of UC was steadily increased all over the world. It has become a novel independent risk factor of several severe diseases especially colon-rectal cancer. However, the etiology of UC was still obscure. Previous studies show that high-fat diet contributed to the pathogenesis of immune system dysregulation, and farnesoid X receptor (FXR) was also implicated in the pathogenesis of various inflammatory symptoms. Yet, their inner roles in the pathogenesis of UC have not been mentioned. In this study, we aim to investigate the role of FXR in UC. High-fat diet (HFD) promotes the progression of DSS-induced UC, shows an increasing secretion of bile acid in serum, and leads to a downregulation of FXR target genes (FXRα, Shp, and lbabp). Adding FXR agonist FexD rescues the phenotype induced by high-fat diet, whereas TGFBRI inhibitor SB431542 abrogates the restoration by FexD in DSS-induced UC mice. To further verify the relationship between the FXR and TGFB signaling pathway, we made a UC-HFD model in the Caco2 cell line. Results shows the same conclusion that FXR mitigate UC inflammation through a TGFB-dependent pathway. These results expand the role of FXR in ulcerative colitis and suggest that FXR activation may be considered a therapeutic strategy for UC.

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Maternal Exposure to High-Fat Diet Induces Long-Term Derepressive Chromatin Marks in the Heart

Nutrients ◽

10.3390/nu12010181 ◽

2020 ◽

Vol 12 (1) ◽

pp. 181 ◽

Cited By ~ 1

Author(s):

Guillaume Blin ◽

Marjorie Liand ◽

Claire Mauduit ◽

Hassib Chehade ◽

Mohamed Benahmed ◽

...

Keyword(s):

Dna Methylation ◽

Heart Development ◽

High Fat Diet ◽

Target Genes ◽

Critical Role ◽

Maternal Exposure ◽

High Fat ◽

Cardiac Alterations

Heart diseases are a leading cause of death. While the link between early exposure to nutritional excess and heart disease risk is clear, the molecular mechanisms involved are poorly understood. In the developmental programming field, increasing evidence is pointing out the critical role of epigenetic mechanisms. Among them, polycomb repressive complex 2 (PRC2) and DNA methylation play a critical role in heart development and pathogenesis. In this context, we aimed at evaluating the role of these epigenetic marks in the long-term cardiac alterations induced by early dietary challenge. Using a model of rats exposed to maternal high-fat diet during gestation and lactation, we evaluated cardiac alterations at adulthood. Expression levels of PRC2 components, its histone marks di- and trimethylated histone H3 (H3K27me2/3), associated histone mark (ubiquitinated histone H2A, H2AK119ub1) and target genes were measured by Western blot. Global DNA methylation level and DNA methyl transferase 3B (DNMT3B) protein levels were measured. Maternal high-fat diet decreased H3K27me3, H2Ak119ub1 and DNA methylation levels, down-regulated the enhancer of zeste homolog 2 (EZH2), and DNMT3B expression. The levels of the target genes, isl lim homeobox 1 (Isl1), six homeobox 1 (Six1) and mads box transcription enhancer factor 2, polypeptide C (Mef2c), involved in cardiac pathogenesis were up regulated. Overall, our data suggest that the programming of cardiac alterations by maternal exposure to high-fat diet involves the derepression of pro-fibrotic and pro-hypertrophic genes through the induction of EZH2 and DNMT3B deficiency.

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Colonic dysmotility and inflammation associated with high fat diet-induced obesity: role of the enteric glia

Proceedings of The Nutrition Society ◽

10.1017/s0029665120004425 ◽

2020 ◽

Vol 79 (OCE2) ◽

Author(s):

Matteo Fornai ◽

Carolina Pellegrini ◽

Vanessa D'Antongiovanni ◽

Laura Benvenuti ◽

Nunzia Bernardini ◽

...

Keyword(s):

High Fat Diet ◽

Mucosal Barrier ◽

Tlr4 Expression ◽

High Fat ◽

Glucose Levels ◽

Diet Induced Obesity ◽

Epididymal Fat ◽

Junction Protein ◽

Colonic Dysmotility

AbstractIntroductionEnteric glial cells (EGCs) contribute to the regulation of bowel motility, and have been implicated in the onset and development of several digestive disorders. However, the involvement of EGCs in obesity-related intestinal dysmotility is unknown. Accordingly, this study examined the role of EGCs in colonic neuromuscular dysfunctions in a mouse model of diet-induced obesity.Materials and MethodsC57BL/6 male mice (n = 6 per group) were fed with standard diet (SD) or high fat diet (HFD) for 8 weeks. Body and epididymal fat weight, and blood fasting glucose levels were evaluated the day before sacrifice. Colonic longitudinal muscle strips were set up in organ baths with Krebs solution and connected to isometric transducers. The effects of fluorocitrate (FC, gliotoxin) were tested on contractile responses mediated by NK1 tachykininergic receptors upon application of electrical stimuli (0.5 ms, 28 V, 10 Hz) [incubation with atropine, guanethidine, L-NAME, GR159897 and SB218795 (NK2 and NK3 antagonists, respectively)] or exogenous substance P (SP). Colonic levels of interleukin (IL)-1β, IL-6, malondialdehyde (MDA) and occludin (a tight junction protein involved the maintenance of mucosal barrier) were measured. Cultured rat EGCs were exposed to palmitate and lipopolysaccharide (LPS), either alone or in combination, to mimic the exposure to HFD. IL-1β and SP levels were then assessed in cell supernatants, while toll-like receptor 4 (TLR4) expression was evaluated in cell lysates.ResultsHFD-mice displayed increments of body weight, epididymal fat weight and blood glucose levels. In in vitro experiments, electrically induced colonic tachykininergic contractions were enhanced in HFD mice, as compared with SD animals. No differences were observed when comparing contractions to exogenous SP. The increase in electrically evoked tachykininergic contractions was blunted upon incubation with the gliotoxin FC. Exogenous SP-induced contractions were not affected by FC. HFD mice displayed an increase in colonic IL-1β, IL-6 and MDA levels and a reduced occludin expression, as compared with SD mice. Exposure of EGCs to palmitate, alone or in combination with LPS, resulted in a significant increase in TLR4 expression, while LPS alone was without effects. The combination of palmitate and LPS increased significantly IL-1β and SP levels in cell supernatants, while single treatments were without effects.DiscussionHFD is characterized by colonic dysmotility along with bowel inflammation, oxidative stress, and an impairment of mucosal barrier integrity. In this setting, the hyperactivation of EGCs, likely via TLR4, appears to contribute to inflammation and colonic tachykininergic motor dysfunctions.

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Microbiota-Immune Interactions in Ulcerative Colitis and Colitis Associated Cancer and Emerging Microbiota-Based Therapies

International Journal of Molecular Sciences ◽

10.3390/ijms222111365 ◽

2021 ◽

Vol 22 (21) ◽

pp. 11365

Author(s):

Jelena Popov ◽

Valentina Caputi ◽

Nandini Nandeesha ◽

David Avelar Rodriguez ◽

Nikhil Pai

Keyword(s):

Ulcerative Colitis ◽

Intestinal Inflammation ◽

Autoimmune Disorder ◽

Mucosal Barrier ◽

Host Immune System ◽

Intestinal Dysbiosis ◽

Inflammatory Bowel ◽

Genetic And Environmental Factors

Ulcerative colitis (UC) is a chronic autoimmune disorder affecting the colonic mucosa. UC is a subtype of inflammatory bowel disease along with Crohn’s disease and presents with varying extraintestinal manifestations. No single etiology for UC has been found, but a combination of genetic and environmental factors is suspected. Research has focused on the role of intestinal dysbiosis in the pathogenesis of UC, including the effects of dysbiosis on the integrity of the colonic mucosal barrier, priming and regulation of the host immune system, chronic inflammation, and progression to tumorigenesis. Characterization of key microbial taxa and their implications in the pathogenesis of UC and colitis-associated cancer (CAC) may present opportunities for modulating intestinal inflammation through microbial-targeted therapies. In this review, we discuss the microbiota-immune crosstalk in UC and CAC, as well as the evolution of microbiota-based therapies.

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The Role of Cytokines in Inflammatory Bowel Disease

Mediators of Inflammation ◽

10.1155/s0962935194000013 ◽

1994 ◽

Vol 3 (1) ◽

pp. 3-9 ◽

Cited By ~ 2

Author(s):

G. Radford-Smith ◽

D. P. Jewell

Keyword(s):

Ulcerative Colitis ◽

Inflammatory Bowel Disease ◽

Intestinal Inflammation ◽

Inflammatory Lesions ◽

Immunoregulatory Cytokines ◽

Current Thinking ◽

Inflammatory Bowel ◽

Chronic Intestinal Inflammation ◽

Th1 And Th2

Cytokines play an important role in the development and persistence of the inflammatory lesions seen in Crohn's disease and ulcerative colitis. This review discusses the current thinking of the role of cytokines in chronic intestinal inflammation including the involvement of immunoregulatory cytokines within the Th1 and Th2 subsets.

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A Novel Combination Therapy Using Rosuvastatin and Lactobacillus Combats Dextran Sodium Sulfate-Induced Colitis in High-Fat Diet-Fed Rats by Targeting the TXNIP/NLRP3 Interaction and Influencing Gut Microbiome Composition

Pharmaceuticals ◽

10.3390/ph14040341 ◽

2021 ◽

Vol 14 (4) ◽

pp. 341

Author(s):

Sameh Saber ◽

Eslam E. Abd El-Fattah ◽

Galal Yahya ◽

Naglaa A. Gobba ◽

Abdalkareem Omar Maghmomeh ◽

...

Keyword(s):

Ulcerative Colitis ◽

Nlrp3 Inflammasome ◽

Sodium Sulfate ◽

High Fat Diet ◽

Intestinal Inflammation ◽

Dextran Sodium Sulfate ◽

Ldl Oxidation ◽

Ros Generation ◽

Inflammasome Activation ◽

High Fat

Inflammasome targeting and controlling dysbiosis are promising therapeutic approaches to control ulcerative colitis. This report is the first to investigate the mechanisms underlying the coloprotective effects of rosuvastatin and Lactobacillus and their combined therapy on dextran sodium sulfate (DSS)-induced colitis in high-fat diet (HFD)-fed rats. Our results demonstrate the aggravation of intestinal inflammation as a consequence of an HFD following DSS administration. An association between dyslipidemia, LDL oxidation, CD36 expression, ROS generation, thioredoxin-interacting protein (TXNIP) upregulation, and NLRP3 inflammasome activation was demonstrated by DSS exposure in HFD-fed rats. We demonstrated that rosuvastatin/Lactobacillus significantly suppressed the DSS/HFD-induced increase in colon weight/length ratio, DAI, MDI, and myeloperoxidase, as well as corrected dysbiosis and improved histological characteristics. Additionally, caspase-1 activity and IL-1β-driven pyroptotic activity was significantly reduced. Rosuvastatin/Lactobacillus showed prominent anti-inflammatory effects as revealed by the IL-10/IL-12 ratio and the levels of TNF-α and IL-6. These latter effects may be attributed to the inhibition of phosphorylation-induced activation of NF-κB and a concomitant reduction in the expression of NLRP3, pro-IL-1β, and pro-IL-18. Furthermore, rosuvastatin/Lactobacillus reduced Ox-LDL-induced TXNIP and attenuated the inflammatory response by inhibiting NLRP3 inflammasome assembly. To conclude, rosuvastatin/Lactobacillus offers a safe and effective strategy for the management of ulcerative colitis.

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787 A High Fat Diet Containing Coconut Oil Prevents the Onset of Chronic Intestinal Inflammation in Experimental Crohn's Disease

Gastroenterology ◽

10.1016/s0016-5085(14)60475-3 ◽

2014 ◽

Vol 146 (5) ◽

pp. S-134

Author(s):

Ashley Trotter ◽

Alexander Rodriguez-Palacios ◽

Lindsey Kaydo ◽

Davide Pietropaoli ◽

Wei Xin ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

High Fat Diet ◽

Intestinal Inflammation ◽

Coconut Oil ◽

High Fat ◽

Chronic Intestinal Inflammation

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Intestinal Microbiota Mediates High-Fructose and High-Fat Diets to Induce Chronic Intestinal Inflammation

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2021.654074 ◽

2021 ◽

Vol 11 ◽

Author(s):

Rong Tan ◽

Huiwei Dong ◽

Zhengshan Chen ◽

Min Jin ◽

Jing Yin ◽

...

Keyword(s):

Intestinal Microbiota ◽

High Fat Diet ◽

Intestinal Inflammation ◽

Control Group ◽

High Fat ◽

Microbial Composition ◽

High Fructose ◽

High Fat Diets ◽

Fat Diets ◽

Chronic Intestinal Inflammation

An unhealthy diet has been linked to increased incidence of chronic diseases. To investigate the relationship between diet and intestinal inflammation, mice in two experimental groups were fed on a high-fat diet or high-fructose diet, respectively. The result showed that the defecation volume of the experimental groups was significantly reduced compared with that of the control group, and the levels of pro-inflammatory cytokines (interleukin (IL)-1β and IL-6) and IgG in serum were increased significantly. In addition, inflammatory cell infiltration was observed in intestinal tissue, indicating that a high-fructose or high-fat diet can lead to constipation and inflammation. Further analysis showed that the microbial composition of the experimental groups changed significantly, including a decrease of the Bacteroidetes/Firmicutes ratio and increased levels of Bacteroides, Akkermansia, Lactobacillus, and Ruminococcus, which might be associated with inflammation. The results of pro-inflammatory metabolites analysis showed that the levels of arachidonic acid, stearic acid, and indoxylsulfuric acid were significantly increased in the experimental groups, which were related significantly to Bacteroides, Enterococcus, and Akkermansia. Meanwhile, the content of 5-hydroxytryptamine (5-HT) was significantly decreased, which might cause constipation by reducing intestinal peristalsis. Moreover, transplantation of fecal bacteria from inflammatory mice caused constipation and inflammation in normal mice, which could be relieved by feeding a normal diet. The results of the present study indicated that changes in intestinal microbiota and microbial metabolites may underlie chronic intestinal inflammation and constipation caused by high-fructose and high-fat diets.

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