Folic acid intervention changes liver Foxp3 methylation and ameliorates the damage caused by Th17/Treg imbalance after long-term alcohol exposure

Guo, Peiyu; Zuo, Yuwei; Wang, Yanhui; Zhao, Hui; Lan, Tongtong; Xue, Meilan; Zhang, Zhihong; Liang, Hui

doi:10.1039/d1fo04267j

Cited by 14 publications

(15 citation statements)

References 54 publications

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“…Alcohol consumption is typically accompanied with folic acid deficiency ( 28 ). Our previous study has demonstrated that folic acid supplementation may relieve ethanol-induced Th17/Treg disbalance by altering Foxp3 promoter methylation patterns, which suggest that folic acid may be a feasible preventive strategy for ALD ( 29 ). In this study, in the FA group, histopathological liver changes induced by alcohol were improved, and liver index and the levels of serum ALT, AST, and TG were significantly lower than those in the MOD group.…”

Section: Discussionmentioning

confidence: 99%

Folic acid ameliorates alcohol-induced liver injury via gut–liver axis homeostasis

et al. 2022

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The gut–liver axis (GLA) plays an important role in the development of alcohol-induced liver injury. Alcohol consumption is typically associated with folic acid deficiency. However, no clear evidence has confirmed the effect of folic acid supplementation on alcohol-induced liver injury via GLA homeostasis. In this study, male C57BL/6J mice were given 56% (v/v) ethanol and 5.0 mg/kg folic acid daily by gavage for 10 weeks to investigate potential protective mechanisms of folic acid in alcohol-induced liver injury via GLA homeostasis. Histopathological and biochemical analyses showed that folic acid improved lipid deposition and inflammation in the liver caused by alcohol consumption and decreased the level of ALT, AST, TG, and LPS in serum. Folic acid inhibited the expression of the TLR4 signaling pathway and its downstream inflammatory mediators in the liver and upregulated the expression of ZO-1, claudin 1, and occludin in the intestine. But compared with the CON group, folic acid did not completely eliminate alcohol-induced intestine and liver injury. Furthermore, folic acid regulated alcohol-induced alterations in gut microbiota. In alcohol-exposed mice, the relative abundance of Bacteroidota was significantly increased, and the relative abundance of unclassified_Lachnospiraceae was significantly decreased. Folic acid supplementation significantly increased the relative abundance of Verrucomicrobia, Lachnospiraceae_NK4A136_group and Akkermansia, and decreased the relative abundance of Proteobacteria. The results of Spearman’s correlation analysis showed that serum parameters and hepatic inflammatory cytokines were significantly correlated with several bacteria, mainly including Bacteroidota, Firmicutes, and unclassified_Lachnospiraceae. In conclusion, folic acid could ameliorate alcohol-induced liver injury in mice via GLA homeostasis to some extent, providing a new idea and method for prevention of alcohol-induced liver injury.

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Section: Discussionmentioning

confidence: 99%

Folic acid ameliorates alcohol-induced liver injury via gut–liver axis homeostasis

et al. 2022

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“…After gently washing twice with PBS (pH7.4) on an ice plate, the single-cell suspension of samples was prepared by PBS (pH7.4) with a concentration of 1 × 10 6 cells/mL. Th17 and Treg were detected as described in our previous procedure . Finally, lymphocytes were detected by the application of a BD FACSAriaIII flow cytometer (BD, USA).…”

Section: Methodsmentioning

confidence: 99%

“…Th17 and Treg were detected as described in our previous procedure. 43 Finally, lymphocytes were detected by the application of a BD FACSAriaIII flow cytometer (BD, USA). Data analysis was performed by FlowJo software (BD, USA).…”

Section: ■ Materials and Methodsmentioning

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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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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“…56,57 FA is a free radical scavenger with a crucial role in this modulation by exerting antioxidant activity essential for nucleotide synthesis, redox state maintenance, and methylation reactions. 14,28,29 Additionally, the influence of FA on the homocysteine (Hcy) levels is notable. Elevated Hcy, a cytotoxic sulfur-containing amino acid, exacerbates oxidative stress 34,58 and is linked to increased dopaminergic neuron depletion in MPTP models.…”

Section: ■ Discussionmentioning

confidence: 99%

Folic Acid Rescues Dopaminergic Neurons in MPTP-Induced Mice by Inhibiting the NLRP3 Inflammasome and Ameliorating Mitochondrial Impairment

Jia,

Li,

Wang

et al. 2024

J. Agric. Food Chem.

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Parkinson's disease (PD) is marked by the degeneration of dopaminergic neurons of the substantia nigra (SN), with neuroinflammation and mitochondrial dysfunction being key contributors. The neuroprotective potential of folic acid (FA) in the dopaminergic system of PD was assessed in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model. MPTP (20 mg/kg of body weight) was administered to C57BL/6J mice to simulate PD symptoms followed by FA treatment (5 mg/kg of body weight). Behavioral tests, pole, rotarod, and open-field tests, evaluated motor function, while immunohistochemistry, ELISA, RT-qPCR, and Western blotting quantified neuroinflammation, oxidative stress markers, and mitochondrial function. FA supplementation considerably improved motor performance, reduced homocysteine levels and mitigated oxidative damage in the SN. The FA-attenuated activation of the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome lessened glial cell activity and reduced neuroinflammation. At the molecular level, FA reduced DNA damage, downregulated phosphorylated p53, and induced the expression of peroxisome proliferator-activated receptor α coactivator 1α (PGC-1α), enhancing mitochondrial function. Therefore, FA exerts neuroprotection in MPTP-induced PD by inhibiting neuroinflammation via NLRP3 inflammasome suppression and promoting mitochondrial integrity through the p53-PGC-1α pathway. Notable limitations of our study include its reliance on a single animal model and the incompletely elucidated mechanisms underlying the impact of FA on mitochondrial dynamics. Future investigations will explore the clinical utility of FA and its molecular mechanisms, further advancing it as a potential therapeutic for managing and delaying the progression of PD.

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Folic acid intervention changes liver Foxp3 methylation and ameliorates the damage caused by Th17/Treg imbalance after long-term alcohol exposure

Abstract: Folic acid, as a key source of methyl donor in DNA methylation, has been proved to play a beneficial role in inflammation modulation, usually impaired in alcoholic liver disease (ALD)....

Cited by 14 publications

References 54 publications

Folic acid ameliorates alcohol-induced liver injury via gut–liver axis homeostasis

Folic acid ameliorates alcohol-induced liver injury via gut–liver axis homeostasis

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

Folic Acid Rescues Dopaminergic Neurons in MPTP-Induced Mice by Inhibiting the NLRP3 Inflammasome and Ameliorating Mitochondrial Impairment

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