Uric acid drives intestinal barrier dysfunction through TSPO-mediated NLRP3 inflammasome activation

Lv, Qiulan; Xu, Dian; Ma, Jinfeng; Wang, Yan; Yang, Xiaomin; Zhao, Peng; Ma, Liang; Li, Zhiyuan; Yang, Wan; Liu, Xiu; Yang, Guanpin; Xing, Shichao

doi:10.1007/s00011-020-01409-y

Cited by 26 publications

(15 citation statements)

References 44 publications

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“…Recently, alterations in the intestine associated with HUA has received more attention. , HUA is consistently characterized by increased intestinal permeability, resulting from the impairment of mucosal mechanical barrier integrity . The intestinal barrier that is composed of an epithelium and junctional complex also works as a dynamic interface, having the key function in the maintenance of intestinal homeostasis .…”

Section: Discussionmentioning

confidence: 99%

“…15,58 HUA is consistently characterized by increased intestinal permeability, resulting from the impairment of mucosal mechanical barrier integrity. 70 The intestinal barrier that is composed of an epithelium and junctional complex also works as a dynamic interface, having the key function in the maintenance of intestinal homeostasis. 71 Our results showed severe intestinal histopathological injuries including incomplete villi structure in HUA mice, but after folic acid intervention, the damaged intestinal mucosal barrier was remarkably alleviated, with the regular epithelial monolayer columnar cell arrangement and improved intestinal leakage symptoms.…”

Section: ■ Discussionmentioning

confidence: 99%

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Folic Acid Protects against Hyperuricemia in C57BL/6J Mice via Ameliorating Gut–Kidney Axis Dysfunction

Wang

Zhang

Zheng

et al. 2022

J. Agric. Food Chem.

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Emerging lines of research evidence point to a vital role of gut–kidney axis in the development of hyperuricemia (HUA), which has been identified as an increasing burden worldwide due to the high prevalence. The involved crosstalk which links the metabolic and immune-related pathways is mainly responsible for maintaining the axial homeostasis of uric acid (UA) metabolism. Nowadays, the urate-lowering drugs only aim to treat acute gouty arthritis as a result of their controversial clinical application in HUA. In this study, we established the HUA model of C57BL/6J mice to evaluate the effectiveness of folic acid on UA metabolism and further explored the underlying mechanisms. Folic acid attenuated the kidney tissue injury and excretion dysfunction, as well as the typical fibrosis in HUA mice. Molecular docking results also revealed the structure–activity relationship of the folic acid metabolic unit and the UA transporters GLUT9 and URAT1, implying the potential interaction. Also, folic acid alleviated HUA-induced Th17/Treg imbalance and intestinal tissue damage and inhibited the active state of the TLR4/NF-κB signaling pathway, which is closely associated with the circulating LPS level caused by the impaired intestinal permeability. Furthermore, the changes of intestinal microecology induced by HUA were restored by folic acid, including the alteration in the structure and species composition of the gut microbiome community, and metabolite short-chain fatty acids. Collectively, this study revealed that folic acid intervention exerted improving effects on HUA by ameliorating gut–kidney axis dysfunction.

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Section: Discussionmentioning

confidence: 99%

Section: ■ Discussionmentioning

confidence: 99%

Folic Acid Protects against Hyperuricemia in C57BL/6J Mice via Ameliorating Gut–Kidney Axis Dysfunction

Wang

Zhang

Zheng

et al. 2022

J. Agric. Food Chem.

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“…Studies have shown that high uric acid level could disrupt intestinal barrier and intervene the balance of gut microbiota. 44,45 Approximately 1/3 of uric acid is metabolized by the intestine, with purine metabolizing enzymes, intestinal flora, and uric acid transporters being the most relevant factors in the process. 46,47 Intestinal pathogens like E. coli could promote the breakdown of purines into uric acid, while probiotics like Lactobacillus and Bifidobacterium could reduce uric acid level.…”

Section: Discussionmentioning

confidence: 99%

Fusobacterium nucleatum aggravates ulcerative colitis through promoting gut microbiota dysbiosis and dysmetabolism

Lin

Zhu

Jiao

et al. 2022

Journal of Periodontology

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Background The correlation between periodontitis and ulcerative colitis (UC) has drawn widespread attention recently. Fusobacterium nucleatum (F. nucleatum) as a periodontal pathogen also has reservoirs in gut and may play a role in intestinal diseases. However, its role in the pathogenesis of UC is unclear. Methods Mice were orally given dextran sulphate sodium (DSS) solution and F. nucleatum to construct experimental models. The survival rate, weight, and disease activity index (DAI) of mice were monitored. Alveolar bone loss, abundance of F. nucleatum in colon, colon length, histopathological assessment, and inflammatory cytokines were detected. Apoptosis of intestinal epithelial cells (IECs) were evaluated by TUNEL assay and pro‐apoptotic gene Bax. The epithelial barrier function was assessed by tight junction proteins. By 16S rRNA gene sequencing and LC‐MS‐based methods, the composition of the intestinal microbiota and metabolites in mice were analyzed. Results F. nucleatum facilitated alveolar bone loss and colonized only in infected colon tissue. Mice fed with DSS showed destruction of gut structure, increased expressions of interleukin one‐beta (IL‐1β) and tumor necrosis factor alpha (TNF‐α), decreased expression of IL‐10, higher apoptosis of IECs, microbiota dysbiosis and bile acid dysmetabolism compared to healthy ones. F. nucleatum further aggravated intestinal inflammation and epithelial barrier damage. Probiotics such as Bifidobacterium and Faecalibacterium decreased, opportunistic pathogens Escherichia‐Shigella increased and the differential microorganisms highly associated with inflammatory parameters and metabolites. Meanwhile, level of uric acid involving in the purine metabolism significantly elevated compared to UC mice. Conclusions F. nucleatum promotes gut inflammation, epithelial barrier dysfunction, microbiota dysbiosis and dysmetabolism to aggravate UC.

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“…In addition, our previous studies revealed that the analgesic effect of KM is inhibited by another TSPO ligand, PK11195, in a CCI induced neuropathic pain model ( Jin et al, 2018a ). A recently research find that uric acid drives intestinal barrier dysfunction through TSPO-mediated NLRP3 inflammasome ( Lv et al, 2020 ). Therefore, further investigation is needed to elucidate whether KM modulates the ROS/NF-κB/NLRP3 signaling pathway via a mechanism dependent on TSPO.…”

Section: Discussionmentioning

confidence: 99%

Koumine Suppresses IL-1β Secretion and Attenuates Inflammation Associated With Blocking ROS/NF-κB/NLRP3 Axis in Macrophages

Luo

Xiong

et al. 2021

Front. Pharmacol.

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Koumine (KM), one of the primary constituents of Gelsemium elegans, has been used for the treatment of inflammatory diseases such as rheumatoid arthritis, but whether KM impacts the activation of the NOD-like receptor protein 3 (NLRP3) inflammasome remains unknown. This study aimed to explore the inhibitory effect of KM on NLRP3 inflammasome activation and the underlying mechanisms both in vitro using macrophages stimulated with LPS plus ATP, nigericin or monosodium urate (MSU) crystals and in vivo using an MSU-induced peritonitis model. We found that KM dose-dependently inhibited IL-1β secretion in macrophages after NLRP3 inflammasome activators stimulation. Furthermore, KM treatment efficiently attenuated the infiltration of neutrophils and suppressed IL-1β production in mice with MSU-induced peritonitis. These results indicated that KM inhibited NLRP3 inflammasome activation, and consistent with this finding, KM effectively inhibited caspase-1 activation, mature IL-1β secretion, NLRP3 formation and pro-IL-1β expression in LPS-primed macrophages treated with ATP, nigericin or MSU. The mechanistic study showed that, KM exerted a potent inhibitory effect on the NLRP3 priming step, which decreased the phosphorylation of IκBα and p65, the nuclear localization of p65, and the secretion of TNF-α and IL-6. Moreover, the assembly of NLRP3 was also interrupted by KM. KM blocked apoptosis-associated speck-like protein containing a CARD (ASC) speck formation and its oligomerization and hampered the NLRP3-ASC interaction. This suppression was attributed to the ability of KM to inhibit the production of reactive oxygen species (ROS). In support of this finding, the inhibitory effect of KM on ROS production was completely counteracted by H2O2, an ROS promoter. Our results provide the first indication that KM exerts an inhibitory effect on NLRP3 inflammasome activation associated with blocking the ROS/NF-κB/NLRP3 signal axis. KM might have potential clinical application in the treatment of NLRP3 inflammasome-related diseases.

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Uric acid drives intestinal barrier dysfunction through TSPO-mediated NLRP3 inflammasome activation

Cited by 26 publications

References 44 publications

Folic Acid Protects against Hyperuricemia in C57BL/6J Mice via Ameliorating Gut–Kidney Axis Dysfunction

Folic Acid Protects against Hyperuricemia in C57BL/6J Mice via Ameliorating Gut–Kidney Axis Dysfunction

Fusobacterium nucleatum aggravates ulcerative colitis through promoting gut microbiota dysbiosis and dysmetabolism

Koumine Suppresses IL-1β Secretion and Attenuates Inflammation Associated With Blocking ROS/NF-κB/NLRP3 Axis in Macrophages

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