Trichostatin A protects against intestinal injury in rats with acute liver failure

Zhang, Qian; Yang, Fan; Li, Xun; Chu, Xiaogang; Zhang, Hong; Wang, Lu-Wen; Gong, Zuojiong

doi:10.1016/j.jss.2016.05.028

Cited by 18 publications

(23 citation statements)

References 35 publications

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“…Besides, abundant experiments have also indicated that butyrate, an important member of SCFAs, can protect intestinal barrier function by up-regulating tight junction protein claudin-1 or facilitating tight junction assembly [7,8]. Furthermore, SCFAs are also well known as histone deacetylase (HDAC) inhibitors, and HDAC inhibitors such as trichostatin A can suppress inflammatory response [9,10]. Therefore, to further confirm the protective functions of SCFAs on intestinal barrier and its possible mechanisms is necessary.…”

Section: Introductionmentioning

confidence: 99%

Short-Chain Fatty Acids Manifest Stimulative and Protective Effects on Intestinal Barrier Function Through the Inhibition of NLRP3 Inflammasome and Autophagy

Feng

Wang

et al. 2018

Cell Physiol Biochem

330

200

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Background/Aims: Short-chain fatty acids (SCFAs) are the major energy resources of intestinal epithelial cells. It has been reported that SCFAs can repair the dysfunction of intestinal barrier, however, the underlying mechanisms are still not fully understood. Here, we investigated the stimulative and protective effects of SCFAs on intestinal barrier function and the possible mechanisms. Methods: To investigate the effects of SCFAs on intestinal barrier function, the Caco-2 monolayers were exposed to acetate, propionate, butyrate respectively or simultaneously without or with lipopolysaccharide (LPS). Next, Caco-2 cells were treated with trichostatin A and etomoxir to identify whether SCFAs act as HDAC inhibitors or energy substances. To activate NLRP3 inflammasome and autophagy, Caco-2 cells were treated with LPS+ATP and rapamycin respectively without or with SCFAs. The transepithelial electrical resistance (TER) and paracellular permeability were respectively detected with a Millicell-ERS voltohmmeter and fluorescein isothiocyanate-labeled dextran. Immunoblotting and immunofluorescence were applied to analyze the expression and distribution of tight junction proteins, and the activation of NLRP3 inflammasome and autophagy. Results: Acetate (0.5mM), propionate(0.01mM) and butyrate (0.01mM) alone or in combination significantly increased TER, and stimulated the formation of tight junction. SCFAs also dramatically attenuated the LPS-induced TER reduction and paracellular permeability increase, accompanying significantly alleviated morphological disruption of ZO-1 and occludin. Meanwhile, the activation of NLRP3 inflammasome and autophagy induced by LPS were significantly inhibited by SCFAs. Trichostatin A imitated the inhibiting action of SCFAs on NLRP3 inflammasome, whereas etomoxir blocked the action of SCFAs on protecting intestinal barrier and inhibiting autophagy. In addition, the activation of autophagy and NLRP3 inflammasome by rapamycin and LPS+ATP resulted in TER reduction, paracellular permeability increase and morphological disruption of both ZO-1 and occludin, which was alleviated by SCFAs. Conclusion: It is suggested that SCFAs stimulate the formation of intestinal barrier, and protect the intestinal barrier from the disruption of LPS through inhibiting NLRP3 inflammasome and autophagy. In addition, SCFAs act as energy substances to protect intestinal barrier and inhibit autophagy, but act as HDAC inhibitors to suppress NLRP3 inflammasome. Furthermore, the mutual promoting action between NLRP3 inflammasome and autophagy would destroy intestinal barrier function, which could be alleviated by SCFAs.

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Section: Introductionmentioning

confidence: 99%

Short-Chain Fatty Acids Manifest Stimulative and Protective Effects on Intestinal Barrier Function Through the Inhibition of NLRP3 Inflammasome and Autophagy

Feng

Wang

et al. 2018

Cell Physiol Biochem

330

200

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“…It results in producing pro-inflammatory cytokine and acute inflammatory response proteins which persistently aggravates hepatic insufficiency and/or failure [2]. Our previous study have indicated intestine injure plays a crucial role in the progress of ALF as well [27]. All these results support that if intestinal injury was reduced, and the liver lesion would be alleviated in ALF.…”

Section: Discussionmentioning

confidence: 86%

“…The everted sac method was used as previously described to evaluate the small intestinal mucosal barrier function [27]. First, we everted the intestine segment in ice-cold Krebs buffer (pH 7.4), gently distended by injecting 1.5 mL of Krebs, and then suspended in the organ bath which contained 500 mL Krebs with added FITC-labeled dextran 4000 (FD4, 10 mg/mL) and maintained at 37 ˚C, continuously bubbled with a gas mixture containing 95 % O 2 and 5 % CO2 for 30 min.…”

Section: Intestinal Permeabilitymentioning

confidence: 99%

Betaine ameliorates intestinal injury by targeting the LPS/TLR4/MyD88 pathway and microbial communities of intestinal tract in acute liver failure

Chen¹,

Wang²,

Jiao³

et al. 2019

Preprint

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Background: A growing body of evidence revealed that the gut microbiome has a marked impact in acute liver failure (ALF). Microbes and their products will translocate into enterocoelia and enter into circulation system from the damaged intestinal lumen. It will further aggravate liver injury by enhancing the spread of inflammation, tissue damage and sepsis. Betaine is a hepatoprotective drug which has anti-inflammatory and anti-oxidant effects. Here, we evaluated the impact of betaine on gut microbiota composition in ALF animal experiment. The potential protective effect of betaine by inhibiting Toll-like receptor 4 (TLR4) responses was explored as well.Results: Eighteen mice were randomly divided into normal, model, and betaine groups. The ALF-induced intestinal epithelial barrier disruption internal models were induced by D-galactosamine（D-Gal）and lpopolysaccharide (LPS). Betaine was administered intragastrically 1 week before exposure of D-Gal/LPS. LPS were solely applied with a rat small intestinal cell line IEC-18 to establish ALF-induced intestinal epithelial barrier disruption external model. Mice in the model group developed severe intestinal epithelial tissue injury than normal group, increased significantly in the protein levels of TLR4, MyD88, TRAF6 and TNF-a and the mRNA levels of TLR4 and MyD88, and decreased significantly in the protein and mRNA levels of (ZO)-1 and occludin. Whereas, all above indicators were improved significantly by administration of betaine than that in model. The degree of liver tissue pathological damage, liver function and serum inflammatory cytokines in betaine group were significantly reduced than that in model group. The permeability of mice intestinal epithelial and IEC-18 cell in models was improved in betaine group than models. A total of 509 Operational Taxonomic Units (OTUs) were produced from mice fecal samples according to 16s rRNA gene sequence analysis. There were 156 core microbiomes in fecal samples. There existed a total of 24 species contained 11 species at the genus level which had a significant difference between groups. The increased relative abundance of g-Enterorhabdus in the model group was detected compared with normal group. Betaine down-regulated the relative abundance of g-Enterorhabdus in model. The relative abundance of g-Bacteroides was the highest in normal group and the least in model group. The relative abundance of g-Prevotella was almost identical in normal and betaine group, and it was decreased in model group.Conclusion: Betaine effectively improved the intestinal mucosal barrier in acute liver failure. The mechanism was probably related to inhibit the LPS/TLR4/MyD88 signaling pathways, improved the intestinal mucosal barrier and then maintained the gut microbiota composition.

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“…The everted sac method was employed to evaluate the small intestinal mucosal barrier function as previously described [27].…”

Section: Intestinal Permeabilitymentioning

confidence: 99%

Betaine Inhibits Toll-like Receptor 4 Responses and Restores Intestinal Microbiota in Acute Liver Failure Mice

Chen

Wang

Jiao

et al. 2020

Preprint

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Background Previous research has revealed that the gut microbiome has a marked impact on acute liver failure (ALF). Here, we evaluated the impact of betaine on the gut microbiota composition in an ALF animal model. The potential protective effect of betaine by regulating Toll-like receptor 4 (TLR4) responses was explored as well. Methods Both mouse and cell experiments included normal, model, and betaine groups. The rat small intestinal cell line IEC-18 was used for in vitro experiments. Results Betaine ameliorated the small intestine tissue and IEC-18 cell damage in the model group by reducing the high expression of TLR4, MyD88, TRAF6 and TNF-α. Furthermore, the intestinal permeability in the model group was improved by enhancing the expression of the (ZO)-1 and occludin tight junction proteins. There were 509 operational taxonomic units (OTUs) that were identified in mouse fecal samples, including 156 core microbiome taxa. Betaine significantly improved the microbial communities, depleted the gut microbiota constituents Coriobacteriaceae, Lachnospiraceae, Enterorhabdus and Coriobacteriales and markedly enriched the taxa Bacteroidaceae, Bacteroides, Parabacteroides and Prevotella in the model group. Conclusion Betaine effectively improved intestinal injury in ALF by inhibiting the TLR4/MyD88 signaling pathway, improving the intestinal mucosal barrier and maintaining the gut microbiota composition.

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Trichostatin A protects against intestinal injury in rats with acute liver failure

Cited by 18 publications

References 35 publications

Short-Chain Fatty Acids Manifest Stimulative and Protective Effects on Intestinal Barrier Function Through the Inhibition of NLRP3 Inflammasome and Autophagy

Short-Chain Fatty Acids Manifest Stimulative and Protective Effects on Intestinal Barrier Function Through the Inhibition of NLRP3 Inflammasome and Autophagy

Betaine ameliorates intestinal injury by targeting the LPS/TLR4/MyD88 pathway and microbial communities of intestinal tract in acute liver failure

Betaine Inhibits Toll-like Receptor 4 Responses and Restores Intestinal Microbiota in Acute Liver Failure Mice

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