Mechanisms Underlying SCFAs Protective Effect on Blood–Brain Barrier: Comparison
View Latest Version
Please note this is a comparison between Version 2 by Sirius Huang and Version 1 by Rimma Parnova.

Impairment of the blood–brain barrier (BBB) integrity is implicated in the numerous neurological disorders associated with neuroinflammation, neurodegeneration and aging. Short-chain fatty acids (SCFAs), mainly acetate, butyrate and propionate, produced by anaerobic bacterial fermentation of the dietary fiber in the intestine, have a key role in the communication between the gastrointestinal tract and nervous system and are critically important for the preservation of the BBB integrity under different pathological conditions.

  • short-chain fatty acids
  • blood–brain barrier
  • gut microbiota
  • tight junction proteins
  • histone deacetylase
  • receptors
  • nuclear factor kappa B
  • nuclear erythroid 2-related factor 2

1. Introduction

BBB injury associated with neurodegenerative and neuroinflammatory disorders is driven mainly by oxidative stress and inflammation induced by numerous inflammatory mediators that act both from the capillary lumen and the brain parenchyma. As in other barrier tissues, the mechanisms of the protective effect of SCFAs on BBB integrity are generally based on their antioxidant and anti-inflammatory actions mediated by inhibition of NF-κB and activation of Nrf2, a redox-sensitive transcription factor, important in counteracting the NF-κB-driven inflammatory response. Both nuclear factors compete for the same binding site in the nucleus and reciprocally influence each other’s expression and activity through a variety of mechanisms (for reviews, see [1][2]).

2. SCFAs/HDAC/NF-κB

Numerous data provide evidence that inhibition of NF-κB transcriptional activity plays a central role in the anti-inflammatory effects of SCFAs, mainly butyrate, in various cellular types [3][4][5][6][7] (Figure 21). Excessive ROS production is a common trigger for the downstream pathways that mediate BBB leakage, rearrangement of the cytoskeleton and suppression of TJ proteins expression [8][9][10]. Oxidative stress triggers nuclear translocation of NF-κB/p65, that promotes the transcription of a great diversity of pro-inflammatory genes, such as cytokines, chemokines, adhesion molecules, COX2 and iNOS enzymes, which affect all NVU components and disrupt the BBB integrity by numerous mechanisms, including suppression of the assembly and expression of TJ proteins [11][12][13]. Inhibition of NF-κB activity restores the low permeability and upregulates the expression of TJPs, as was shown in different barrier tissues including the BBB [14][15][16][17]. Overexpression of the NF-κB/p65 alone repressed claudin 5 promoter activity in mouse brain endothelial cells [12]. SB was shown to inhibit NF-κB/p65 nuclear translocation alleviating inflammatory stimuli-induced damage of the barrier integrity in intestinal [17][18][19], bovine ruminal [20] and mammary [21] epithelia. Inhibition of NF-κB activation under propionate was observed in the brain microvascular cell line hCMEC/D3 [22].
Cells 12 00657 g002 550
Figure 21. Mechanisms of SCFA effects on a brain endothelial cell (Part 1). Pathological stimuli activate NF-κB-mediated expression of multiple genes, including MMP-9 and NLRP3, and cause the degradation of TJ proteins. Activation of Nrf2 counteracts the NF-κB-driven inflammatory response. SCFAs suppress NF-κB and promote Nrf2 activation, leading to the recovery of TJPs. SCFAs can act after entry via transporters (MTC1, FAT/CD36) or via binding to receptors (e.g., GPR41). SCFAs inhibit HDAC, which results in an increase in histone acetylation, facilitating expression of genes, including Nrf2, that contribute to BBB integrity, and increase NF-κB acetylation, inhibiting its transcriptional activity. Under pathological stimuli, MLCK phosphorylates MLC2 to form actin stress fibers resulting in the endocytosis of transmembrane TJPs and loss of BBB integrity. SCFAs may promote the reassembly of TJs via suppression of the MLCK/MLC2 pathway. Dotted lines—putative signaling pathways. Blue lines—positive effects; red lines—negative effects. Symbols on the scheme—see in the list of abbreviations.
The underlying mechanisms of the SCFAs effect on inhibition of NF-κB are poorly understood. NF-κB activity is known to be modulated by its post-translational acetylation that depends on the balance between the HDACs and the histone acetyltransferase activities [23][24]. Inhibition of HDACs can cause hyperacetylation of NF-κB/p65 leading to modulation of p65 binding to IκB and downregulation of NF-κB transcriptional activity [25]. Such a mechanism of NF-κB signaling interruption and subsequent protection of the BBB has been demonstrated in a rat model of cerebral ischemia upon administration of valproate [26], a broad HDAC inhibitor, or RGFP966, an HDAC3-specific inhibitor [27], suggesting that SCFAs, being HDAC inhibitors, can suppress NF-κB by the same mechanism (Figure 21). In the human colon adenocarcinoma cell line, Colo320DM, butyrate, propionate and acetate dose-dependently inhibited NF-κB reporter activity with the same rank of potency as HDAC inhibition (butyrate > propionate > acetate) [7].

3. SCFAs/GPR43/β-Arrestin-2/NF-κB

The GPR43 receptor engages a signaling pathway mediated by β-arrestin-2 which directly interacts with IκB, the NF-κB inhibitor, and blocks IκB phosphorylation/degradation, thereby suppressing NF-κB downstream signaling [28][29]. GPR43/β-arrestin-2-mediated suppression of NF-κB signaling pathway has been shown to be a mechanism of the anti-inflammatory effect of SCFAs in macrophages [4] and microglia [3]. The expression of GPR43 in brain microvessels has not yet been confirmed, so this mechanism may be rather important for the indirect effect of SCFAs on the BBB through the activation of GPR43 in microglia (see below).

4. SCFAs/NF-κB/NLRP3 Inflammasome

Activation of NF-κB induces NOD-, LRR- and the pyrin domain-containing protein 3 (NLRP3) inflammasome that causes the amplification of the inflammatory response, mainly by induction of IL-1β and caspase-1 expression [30]. The NLRP3 inflammasome has been identified as a mediator of BBB disruption in sepsis-associated encephalopathy [31]. In brain microvessel epithelial cells treated with LPS, downregulation of NF-κB-mediated NLRP3 activation was shown to restore TJ protein expression and cell monolayer permeability [31]. SCFA-induced suppression of the NLRP3 inflammasome, resulting in the restoration of the barrier function and TJ protein expression, has been shown in the intestinal epithelium [19][32][33].

5. SCFAs/NF-κB/MMP-9

NF-κB activation leads to upregulation of MMP-9, a member of the zinc-dependent endopeptidase family [15][26][34]. In brain tissues, MMP-9 is a critically important contributor to BBB damage (Figure 21). Under the action of pro-inflammatory cytokines, MMP-9 can be activated and secreted by recruited neutrophils [35], pericytes, microglia, and brain microvascular endothelial cells resulting in the proteolytic damage of the extracellular matrix components, degradation of the basement membrane and TJ proteins [15][16]. Both in vivo and in vitro data indicate that down-regulation of MMP-9 expression or activity in endothelial cells restores BBB disruption and elevates TJ protein expression [15][16][36][37]. In brain microvascular endothelial cells, IL-1β-induced MMP-9 expression occurs via complex signaling pathways including ROS-triggered c-Src-mediated transactivation of the EGF receptor and subsequent upregulation of MAP-kinases (e.g., ERK1/2, p38, and JNK1/2), resulting in turn in activation of NF-κB and MMP-9 expression [38].
Downregulation of the NF-κB/MMP-9 signaling pathway by SCFAs was demonstrated in a rat focal cerebral ischemic model [26]. I.p.-injected butyrate significantly reduced nuclear translocation of NF-κB, strongly inhibited MMP-9 protein expression and activity followed by the restoration of protein levels of claudin-5 and ZO-1 in cortex and striatum [26]. The inhibition of the NF-κB/MMP-9 pathway by butyrate was also observed in other cell types, such as IL-1β-inflamed chondrocytes [39].

6. SCFA/Keap-1/Nrf2 Signaling Pathway

SCFA-induced suppression of excessive ROS production and oxidative stress observed in endothelial and other cell types is realized via numerous mechanisms, affecting both ROS producing and expression/activity of ROS eliminating enzymes [40][41][42][43][44]. Ubiquitous defense networks against oxidative stress and inflammation involve the Keap-1 (Kelch-like ECH-associated protein)/Nrf2/ARE (antioxidant response element) signaling pathway, which promotes the expression of multiple antioxidant genes containing ARE in their promoter region (for reviews, see [1][2][45]). In different cell types, the anti-oxidative effect of SCFAs depends on activation of the Nrf2 defense pathway [40][43][44][45][46][47]. In microglia and mammary epithelial cells, butyrate-induced Nrf2 activation and oxidative stress inhibition are mediated by GPR109A [40][46].
Although Nrf2 activation is regulated at multiple levels via various signaling pathways, the excessive ROS production is a well-known Nrf2 activator and trigger for transcription of Nrf2-target antioxidant genes [48]. In the BBB, Nrf2 augments oxidative stress and preserves integrity by increasing TJ and AJ protein expression under different pathological conditions [49][50][51][52][53] (Figure 21). Silencing Nrf2 in hCMEC/D3 cells abrogated the expression of claudin-5 and VE-cadherin leading to an increase in permeability of the monolayers and to the decline of TEER [53]. Pharmacological activation of Nrf2 signaling post-brain injury significantly restored the loss of TJ proteins and prevented BBB disruption [49].
Nrf2-mediated attenuation of BBB disruption in rats following subarachnoid hemorrhage was observed after administration of mitoquinone (MitoQ) [54], a mitochondria-targeted antioxidant that exerts protective effects in many diseases associated with oxidative stress [55]. Although mitochondrial ROS can inactivate Keap1, promoting nuclear translocation of Nrf2 [56], a mitochondrial ROS scavenger also inhibits Nrf2 degradation and subsequently upregulates the antioxidant genes, thus protecting barrier integrity, as was demonstrated in various barrier-forming cells [54][57][58][59]. The precise mechanisms of the MitoQ effect on Nrf2 activity are still poorly understood.
SCFAs, being HDAC inhibitors, can activate Nrf2 via alterations of histone acetylation state [60][61]. Such a mechanism of the SCFA anti-oxidative effect has been convincingly demonstrated in different cells [46][60][62]. In high glucose-treated aortic endothelial cells, SB inhibited HDAC activity and increased the occupancy of the transcription factor aryl hydrocarbon receptor and transcriptional adaptor P300 on the Nrf2 gene promoter, elevating Nrf2 mRNA/protein expression and alleviating oxidative stress and inflammation [60]. The interaction between SB-induced HDAC inhibition and Nrf2-associated anti-oxidative capacity has also been studied in bovine mammary epithelial cells subjected to H2O2-driven oxidative stress. SB promoted Nrf2 nuclear accumulation and H3K9/14 acetylation through the AMPK signaling pathway. Chromatin immunoprecipitation assays detected that SB enhanced acetylation of histones associated with anti-oxidative genes such as Nrf2, HO-1, GCLC, GCLM, SOD1 and NQO1, leading to the increase in their transcription and oxidative stress alleviation [46]. The contribution of HDAC to Nrf2 activity was also found to be important in the restoration of the BBB integrity. In a mouse model of T2DM, HDAC3 inhibition by its specific inhibitor RGFP966 upregulated miR-200a, thereby reducing the Keap1–Nrf2 interaction and promoting Nrf2 activation, which in turn significantly ameliorated the BBB permeability and TJ protein downregulation associated with T2DM [62]. These data indicate that epigenetic modification of Nrf2 and downstream genes may be a potential mechanism of SCFA action in the restoration of the BBB integrity under oxidative stress.
The involvement of both NF-κB- and Nrf2-driven pathways in the effect of propionate at physiological concentration (1 μM) was shown in the hCMEC/D3 cell line, a human BBB in vitro model [22]. Transcriptomic analysis revealed two particular clusters of pathways regulated by propionate treatment: those involved in the non-specific inflammatory response to microbial products, including NF-κB and Toll-like receptor signaling pathways and those involved in the response to oxidative stress [22]. Propionate restrained TLR4 activation by inhibiting the expression of the accessory protein CD14 mRNA following the reduction in protein abundance on the cell surface, thereby disrupting TLR4 signaling. In addition, exposure of hCMEC/D3 cells to propionate resulted in the upregulation of a number of antioxidant genes observed in transcriptomic analysis, and these changes occur downstream of the transcription factor Nrf2. Propionate induced translocation of Nrf2 into the nucleus and diminished the level of intracellular ROS in parallel with the alleviation of the LPS-evoked marked disruption in the intracellular localization of occludin, claudin-5 and ZO-1 [22]. These data indicate that the protective effect of propionate on BBB integrity is based on the involvement of anti-inflammatory and anti-oxidative defense mechanisms.

7. SCFAs/HDAC/FoxO1/Claudin-5

HDACs are known to be activators of FoxO1, a transcription factor involved in the negative regulation of the expression of claudin-5, the most important sealing component of the TJs. Loss of HDAC activity prevents the nuclear accumulation of FoxO1, resulting in suppression of FoxO1 activity and removal of transcriptional repression of claudin-5. Pharmacological inhibition of HDAC1 activity by entinostat, a class I HDAC inhibitor, rescued claudin-5 expression in the BBB [63]. Such a mechanism can mediate SCFAs-induced enhancement of claudin-5 expression in the BBB.

8. SCFAs / HDAC / PPAR γ

Inhibition of HDAC3 may promote acetylation of peroxisome proliferator-activated receptor γ (PPARγ) thereby increasing its transcriptional activity independently of ligand [64][65] (Figure 32). In models of cerebral ischemia, both in vitro and in vivo, PPARs have been shown to contribute to the protection of the integrity of the BBB, which is partially attributed to modulating TJ protein expression [66][67][68]. In human brain microvascular endothelial cells subjected to oxygen-glucose deprivation in the presence of a specific HDAC3 inhibitor and a PPARγ antagonist, it was shown that HDAC3 inhibitor-induced reduction in increased endothelial permeability is at least partly mediated by promotion of PPARγ DNA binding activity [66]. The effect of SCFAs (a mixture of acetate, propionate and butyrate in 3:1:1 ratio) on the prevention of high-fructose diet-induced intestinal epithelial barrier impairment in mice was mimicked by a selective PPARγ agonist [69].
Cells 12 00657 g003 550
Figure 32. Mechanisms of SCFA effects on a brain endothelial cell (Part 2). Inhibition of HDAC by SCFAs leads to hyperacetylation of PPARγ and its translocation into the nucleus potentiating transcription of TJPs. Activation of the Wnt signaling pathway promotes translocation of β-catenin into the nucleus and upregulation of transcription of ZO-1, occludin and claudin-5. The crosstalk between SCFA signaling and the canonical Wnt/β-catenin pathway could be presumed. SCFAs can interact with microglia by binding to G-protein receptors or by inhibiting HDAC, suppressing their activation. Dotted lines—putative signaling pathways. Symbols on the scheme—see in the list of abbreviations.

9. SCFAs/Myosin Light Chain Kinase

BBB “opening” depends on the endothelial actin–myosin cytoskeleton which regulates junction assembly and function. Non-muscle myosin II binds to actin, which is linked via adapter proteins to TJ proteins providing a driving power for their rearrangement. Phosphorylation of the myosin light chain (MLC) by MLCK results in the contraction of the TJPs-associated actin filaments, leading to the relocalization of the TJ proteins and intercellular barrier opening [70][71] (Figure 21). Pharmacological inhibition of MLCK prevented an increase in BBB permeability induced by pathological stimuli, as was demonstrated both in vivo [72][73] and in vitro [73]. MLCK deficiency attenuates endothelial barrier dysfunction [74]. Using primary brain microvessel endothelial cells isolated from mice null for MLCK, Beard and coauthors found that MLCK mediates IL-1β-induced claudin 5 repression and barrier dysfunction acting in a manner that promotes the nuclear translocation of β-catenin, resulting in the repression of Cldn5 gene expression [75]. Thus, myosin light chain kinase (MLCK) is now considered a crucial regulator of endothelial permeability and a potential therapeutic target in the treatment of tissue barrier dysfunction.
A link between SCFAs and MLCK was studied in the intestinal epithelium. In Caco-2 cell monolayers, SB had no effect on the expression level of several components of the TJ complex, but promoted the reassembly of TJ proteins through AMPK-dependent suppression of MLCK activity and subsequent decrease in the phosphorylation of MLC2 [76]. Data obtained on fish intestine subjected to infection showed that SB dietary supplementation maintained the intestinal epithelium integrity decreasing the level of MLCK mRNA in the intestine [47] indicating that the protective effect of SB is at least partly mediated by MLCK inhibition.
Given the critical importance of an MLCK-dependent mechanism in BBB function and dysregulation, the study of the potential involvement of SCFAs, mainly butyrate, in MLCK regulation in the BBB is a promising direction.

10. SCFAs/Wnt/β-Catenin

Both canonical and non-canonical Wnt pathways are involved in the regulation of BBB integrity (Figure 32). The canonical Wnt/β-catenin signaling is critically required for the formation of BBB-specific barrier properties in endothelial cells during brain angiogenesis [77] and is essential for the maintenance of the BBB integrity in the mature brain via transcriptional regulation of the expression of TJ proteins [78]. In the canonical Wnt signaling pathway, Wnt inhibits the degradation of β-catenin through its binding to Frizzled receptors, promoting its translocation into the nucleus and upregulation of genes critical for the maintenance of the BBB, such as claudin-1 and -3 [78][79]. The noncanonical β-catenin-independent Wnt pathways, which include Wnt/calcium and Wnt/planar cell polarity (PCP) pathways, contribute to the regulation of TJ complex stability and endothelial cell polarity in the BBB [80].
Despite the critical importance of the Wnt signaling pathway for the integrity of the BBB, researchers found only one work linking the protective effect of SCFAs in the BBB with its activation [81]. In aged mice subjected to anesthesia/surgery, SB or Lactobacillus bacteria mixture improved postoperative cognitive function, reduced BBB permeability and increased the expression of occludin, claudin-5 and ZO-1. β-Catenin protein expression in the hippocampus was significantly enhanced under both treatments, suggesting crosstalk between SCFA signaling and the canonical Wnt/β-catenin pathway [81].

References

  1. Ahmed, S.M.U.; Luo, L.; Namani, A.; Wang, X.J.; Tang, X. Nrf2 signaling pathway: Pivotal roles in inflammation. Biochim. Biophys. Acta Mol. Basis Dis. 2017, 1863, 585–597.
  2. Bellezza, I.; Giambanco, I.; Minelli, A.; Donato, R. Nrf2-Keap1 signaling in oxidative and reductive stress. Biochim. Biophys. Acta (BBA) Mol. Cell Res. 2018, 1865, 721–733.
  3. Liao, H.; Li, H.; Bao, H.; Jiang, L.; Du, J.; Guo, Y.; Si, Y. Short Chain Fatty Acids Protect the Cognitive Function of Sepsis Associated Encephalopathy Mice via GPR43. Front. Neurol. 2022, 13, 909439.
  4. Luo, Q.-J.; Sun, M.-X.; Guo, Y.-W.; Tan, S.-W.; Wu, X.-Y.; Abassa, K.-K.; Lin, L.; Liu, H.-L.; Jiang, J.; Wei, X.-Q. Sodium butyrate protects against lipopolysaccharide-induced liver injury partially via the GPR43/β-arrestin-2/NF-κB network. Gastroenterol. Rep. 2020, 9, 154–165.
  5. Zapolska-Downar, D.; Siennicka, A.; Kaczmarczyk, M.; Kołodziej, B.; Naruszewicz, M. Butyrate inhibits cytokine-induced VCAM-1 and ICAM-1 expression in cultured endothelial cells: The role of NF-κB and PPARα. J. Nutr. Biochem. 2004, 15, 220–228.
  6. Segain, J.P.; de la Blétière, D.R.; Bourreille, A.; Leray, V.; Gervois, N.; Rosales, C.; Ferrier, L.; Bonnet, C.; Blottière, H.M.; Galmiche, J.P. Butyrate inhibits inflammatory responses through NFkappa B inhibition: Implications for Crohn’s disease. Gut 2000, 47, 397–403.
  7. Tedelind, S.; Westberg, F.; Kjerrulf, M.; Vidal, A. Anti-inflammatory properties of the short-chain fatty acids acetate and propionate: A study with relevance to inflammatory bowel disease. World J. Gastroenterol. 2007, 13, 2826–2832.
  8. Pun, P.B.L.; Lu, J.; Moochhala, S. Involvement of ROS in BBB dysfunction. Free Radic. Res. 2009, 43, 348–364.
  9. Haorah, J.; Ramirez, S.H.; Schall, K.; Smith, D.; Pandya, R.; Persidsky, Y. Oxidative stress activates protein tyrosine kinase and matrix metalloproteinases leading to blood-brain barrier dysfunction. J. Neurochem. 2006, 101, 566–576.
  10. Schreibelt, G.; Kooij, G.; Reijerkerk, A.; van Doorn, R.; Gringhuis, S.I.; van de Pol, S.; Weksler, B.B.; Romero, I.A.; Couraud, P.; Piontek, J.; et al. Reactive oxygen species alter brain endothelial tight junction dynamics via RhoA, PI3 kinase, and PKB signaling. FASEB J. 2007, 21, 3666–3676.
  11. Liu, J.; Jin, Y.; Ye, Y.; Tang, Y.; Dai, S.; Li, M.; Zhao, G.; Hong, G.; Lu, Z.-Q. The Neuroprotective Effect of Short Chain Fatty Acids against Sepsis-Associated Encephalopathy in Mice. Front. Immunol. 2021, 12, 626894.
  12. Aslam, M.; Ahmad, N.; Srivastava, R.; Hemmer, B. TNF-alpha induced NFκB signaling and p65 (RelA) overexpression repress Cldn5 promoter in mouse brain endothelial cells. Cytokine 2012, 57, 269–275.
  13. Blecharz-Lang, K.G.; Wagner, J.; Fries, A.; Nieminen-Kelhä, M.; Rösner, J.; Schneider, U.C.; Vajkoczy, P. Interleukin 6-Mediated Endothelial Barrier Disturbances Can Be Attenuated by Blockade of the IL6 Receptor Expressed in Brain Microvascular Endothelial Cells. Transl. Stroke Res. 2018, 9, 631–642.
  14. Yang, T.; Datsomor, O.; Jiang, M.; Ma, X.; Zhao, G.; Zhan, K. Protective Roles of Sodium Butyrate in Lipopolysaccharide-Induced Bovine Ruminal Epithelial Cells by Activating G Protein-Coupled Receptors 41. Front. Nutr. 2022, 9, 842634.
  15. Qin, W.; Li, J.; Zhu, R.; Gao, S.; Fan, J.; Xia, M.; Zhao, R.C.; Zhang, J. Melatonin protects blood-brain barrier integrity and permeability by inhibiting matrix metalloproteinase-9 via the NOTCH3/NF-κB pathway. Aging 2019, 11, 11391–11415.
  16. Zhu, H.; Dai, R.; Zhou, Y.; Fu, H.; Meng, Q. TLR2 Ligand Pam3CSK4 Regulates MMP-2/9 Expression by MAPK/NF-κB Signaling Pathways in Primary Brain Microvascular Endothelial Cells. Neurochem. Res. 2018, 43, 1897–1904.
  17. Chen, G.; Ran, X.; Li, B.; Li, Y.; He, D.; Huang, B.; Fu, S.; Liu, J.; Wang, W. Sodium Butyrate Inhibits Inflammation and Maintains Epithelium Barrier Integrity in a TNBS-induced Inflammatory Bowel Disease Mice Model. EBioMedicine 2018, 30, 317–325.
  18. Fu, J.; Li, G.; Wu, X.; Zang, B. Sodium Butyrate Ameliorates Intestinal Injury and Improves Survival in a Rat Model of Cecal Ligation and Puncture-Induced Sepsis. Inflammation 2019, 42, 1276–1286.
  19. Yue, X.; Wen, S.; Long-Kun, D.; Man, Y.; Chang, S.; Min, Z.; Shuang-Yu, L.; Xin, Q.; Jie, M.; Liang, W. Three important short-chain fatty acids (SCFAs) attenuate the inflammatory response induced by 5-FU and maintain the integrity of intestinal mucosal tight junction. BMC Immunol. 2022, 23, 19.
  20. Yang, Y.; Rosenberg, G.A. Blood-brain barrier breakdown in acute and chronic cerebrovascular disease. Stroke 2011, 42, 3323–3328.
  21. Sun, X.; Luo, S.; Jiang, C.; Tang, Y.; Cao, Z.; Jia, H.; Xu, Q.; Zhao, C.; Loor, J.J.; Xu, C. Sodium butyrate reduces bovine mammary epithelial cell inflammatory responses induced by exogenous lipopolysaccharide, by inactivating NF-κB signaling. J. Dairy Sci. 2020, 103, 8388–8397.
  22. Hoyles, L.; Snelling, T.; Umlai, U.-K.; Nicholson, J.K.; Carding, S.R.; Glen, R.C.; McArthur, S. Microbiome–host systems interactions: Protective effects of propionate upon the blood–brain barrier. Microbiome 2018, 6, 55.
  23. Seidel, C.; Schnekenburger, M.; Dicato, M.; Diederich, M. Histone deacetylase modulators provided by Mother Nature. Genes Nutr. 2012, 7, 357–367.
  24. Chen, L.-F.; Fischle, W.; Verdin, E.; Greene, W.C. Duration of nuclear NF-kappaB action regulated by reversible acetylation. Science 2001, 293, 1653–1657.
  25. Chen, S.; Ye, J.; Chen, X.; Shi, J.; Wu, W.; Lin, W.; Lin, W.; Li, Y.; Fu, H.; Li, S. Valproic acid attenuates traumatic spinal cord injury-induced inflammation via STAT1 and NF-κB pathway dependent of HDAC3. J. Neuroinflamm. 2018, 15, 150.
  26. Wang, Z.; Leng, Y.; Tsai, L.-K.; Leeds, P.; Chuang, D.-M. Valproic acid attenuates blood-brain barrier disruption in a rat model of transient focal cerebral ischemia: The roles of HDAC and MMP-9 inhibition. J. Cereb. Blood Flow Metab. 2011, 31, 52–57.
  27. Lu, H.; Ashiqueali, R.; Lin, C.I.; Walchale, A.; Clendaniel, V.; Matheson, R.; Fisher, M.; Lo, E.H.; Selim, M.; Shehadah, A. Histone Deacetylase 3 Inhibition Decreases Cerebral Edema and Protects the Blood–Brain Barrier after Stroke. Mol. Neurobiol. 2022, 60, 235–246.
  28. Lee, S.U.; In, H.J.; Kwon, M.S.; Park, B.-O.; Jo, M.; Kim, M.-O.; Cho, S.; Lee, S.; Lee, H.-J.; Kwak, Y.S.; et al. β-Arrestin 2 mediates G protein-coupled receptor 43 signals to nuclear factor-κB. Biol. Pharm. Bull. 2013, 36, 1754–1759.
  29. Gao, H.; Sun, Y.; Wu, Y.; Luan, B.; Wang, Y.; Qu, B.; Pei, G. Identification of β-arrestin2 as a G protein-coupled receptor-stimulated regulator of NF-κB pathways. Mol. Cell 2004, 14, 303–317.
  30. Bai, B.; Yang, Y.; Wang, Q.; Li, M.; Tian, C.; Liu, Y.; Aung, L.H.H.; Li, P.-F.; Yu, T.; Chu, X.-M. NLRP3 inflammasome in endothelial dysfunction. Cell Death Dis. 2020, 11, 776.
  31. Chen, S.; Tang, C.; Ding, H.; Wang, Z.; Liu, X.; Chai, Y.; Jiang, W.; Han, Y.; Zeng, H. Maf1 Ameliorates Sepsis-Associated Encephalopathy by Suppressing the NF-kB/NLRP3 Inflammasome Signaling Pathway. Front. Immunol. 2020, 11, 594071.
  32. Li, X.; Wang, C.; Zhu, J.; Lin, Q.; Yu, M.; Wen, J.; Feng, J.; Hu, C. Sodium Butyrate Ameliorates Oxidative Stress-Induced Intestinal Epithelium Barrier Injury and Mitochondrial Damage through AMPK-Mitophagy Pathway. Oxidative Med. Cell. Longev. 2022, 2022, 3745135.
  33. Feng, Y.; Wang, Y.; Wang, P.; Huang, Y.; Wang, F. Short-Chain Fatty Acids Manifest Stimulative and Protective Effects on Intestinal Barrier Function through the Inhibition of NLRP3 Inflammasome and Autophagy. Cell. Physiol. Biochem. 2018, 49, 190–205.
  34. Yang, C.; Hawkins, K.E.; Doré, S.; Candelario-Jalil, E. Neuroinflammatory mechanisms of blood-brain barrier damage in ischemic stroke. Am. J. Physiol. Cell Physiol. 2019, 316, C135–C153.
  35. Turner, R.J.; Sharp, F.R. Implications of MMP9 for Blood Brain Barrier Disruption and Hemorrhagic Transformation Following Ischemic Stroke. Front. Cell. Neurosci. 2016, 10, 56.
  36. Yang, Y.; Estrada, E.Y.; Thompson, J.F.; Liu, W.; Rosenberg, G.A. Matrix Matrix metalloproteinase-mediated disruption of tight junction proteins in cerebral vessels is reversed by synthetic matrix metalloproteinase inhibitor in focal ischemia in rat. J. Cereb. Blood Flow Metab. 2007, 27, 697–709.
  37. Li, X.-F.; Zhang, X.-J.; Zhang, C.; Wang, L.-N.; Li, Y.-R.; Zhang, Y.; He, T.-T.; Zhu, X.-Y.; Cui, L.-L.; Gao, B.-L. Ulinastatin protects brain against cerebral ischemia/reperfusion injury through inhibiting MMP-9 and alleviating loss of ZO-1 and occludin proteins in mice. Exp. Neurol. 2018, 302, 68–74.
  38. Tsai, M.-M.; Chen, J.-L.; Lee, T.-H.; Liu, H.; Shanmugam, V.; Hsieh, H.-L. Brain Protective Effect of Resveratrol via Ameliorating Interleukin-1β-Induced MMP-9-Mediated Disruption of ZO-1 Arranged Integrity. Biomedicines 2022, 10, 1270.
  39. Pirozzi, C.; Francisco, V.; Di Guida, F.; Gómez, R.; Lago, F.; Pino, J.; Meli, R.; Gualillo, O. Butyrate Modulates Inflammation in Chondrocytes via GPR43 Receptor. Cell. Physiol. Biochem. 2018, 51, 228–243.
  40. Zhang, H.; Xu, J.; Wu, Q.; Fang, H.; Shao, X.; Ouyang, X.; He, Z.; Deng, Y.; Chen, C. Gut Microbiota Mediates the Susceptibility of Mice to Sepsis-Associated Encephalopathy by Butyric Acid. J. Inflamm. Res. 2022, ume 15, 2103–2119.
  41. Aguilar, E.C.; dos Santos, L.C.; Leonel, A.J.; de Oliveira, J.S.; Santos, E.A.; Navia-Pelaez, J.M.; da Silva, J.F.; Mendes, B.P.; Capettini, L.S.; Teixeira, L.G.; et al. Oral butyrate reduces oxidative stress in atherosclerotic lesion sites by a mechanism involving NADPH oxidase down-regulation in endothelial cells. J. Nutr. Biochem. 2016, 34, 99–105.
  42. Tian, Q.; Leung, F.P.; Chen, F.M.; Tian, X.Y.; Chen, Z.; Tse, G.; Ma, S.; Wong, W.T. Butyrate protects endothelial function through PPARδ/miR-181b signaling. Pharmacol. Res. 2021, 169, 105681.
  43. Li, D.; Bai, X.; Jiang, Y.; Cheng, Y. Butyrate alleviates PTZ-induced mitochondrial dysfunction, oxidative stress and neuron apoptosis in mice via Keap1/Nrf2/HO-1 pathway. Brain Res. Bull. 2021, 168, 25–35.
  44. Kim, S.Y.; Chae, C.W.; Lee, H.J.; Jung, Y.H.; Choi, G.E.; Kim, J.S.; Lim, J.R.; Lee, J.E.; Cho, J.H.; Park, H.; et al. Sodium butyrate inhibits high cholesterol-induced neuronal amyloidogenesis by modulating NRF2 stabilization-mediated ROS levels: Involvement of NOX2 and SOD1. Cell Death Dis. 2020, 11, 469.
  45. González-Bosch, C.; Boorman, E.; Zunszain, P.A.; Mann, G.E. Short-chain fatty acids as modulators of redox signaling in health and disease. Redox Biol. 2021, 47, 102165.
  46. Guo, W.; Liu, J.; Sun, J.; Gong, Q.; Ma, H.; Kan, X.; Cao, Y.; Wang, J.; Fu, S. Butyrate alleviates oxidative stress by regulating NRF2 nuclear accumulation and H3K9/14 acetylation via GPR109A in bovine mammary epithelial cells and mammary glands. Free. Radic. Biol. Med. 2020, 152, 728–742.
  47. Wu, P.; Tian, L.; Zhou, X.-Q.; Jiang, W.-D.; Liu, Y.; Jiang, J.; Xie, F.; Kuang, S.-Y.; Tang, L.; Tang, W.-N.; et al. Sodium butyrate enhanced physical barrier function referring to Nrf2, JNK and MLCK signaling pathways in the intestine of young grass carp (Ctenopharyngodon idella). Fish Shellfish Immunol. 2018, 73, 121–132.
  48. Tebay, L.E.; Robertson, H.; Durant, S.T.; Vitale, S.R.; Penning, T.M.; Dinkova-Kostova, A.T.; Hayes, J.D. Mechanisms of activation of the transcription factor Nrf2 by redox stressors, nutrient cues, and energy status and the pathways through which it attenuates degenerative disease. Free Radic. Biol. Med. 2015, 88, 108–146.
  49. Zhao, J.; Moore, A.N.; Redell, J.B.; Dash, P.K. Enhancing expression of Nrf2-driven genes protects the blood brain barrier after brain injury. J. Neurosci. 2007, 27, 10240–10248.
  50. Alfieri, A.; Srivastava, S.; Siow, R.C.; Cash, D.; Modo, M.; Duchen, M.R.; Fraser, P.A.; Williams, S.C.; Mann, G.E. Sulforaphane preconditioning of the Nrf2/HO-1 defense pathway protects the cerebral vasculature against blood–brain barrier disruption and neurological deficits in stroke. Free. Radic. Biol. Med. 2013, 65, 1012–1022.
  51. Prasad, S.; Sajja, R.K.; Kaisar, M.A.; Park, J.H.; Villalba, H.; Liles, T.; Abbruscato, T.; Cucullo, L. Role of Nrf2 and protective effects of Metformin against tobacco smoke-induced cerebrovascular toxicity. Redox Biol. 2017, 12, 58–69.
  52. Zolotoff, C.; Voirin, A.-C.; Puech, C.; Roche, F.; Perek, N. Intermittent Hypoxia and Its Impact on Nrf2/HIF-1α Expression and ABC Transporters: An in Vitro Human Blood-Brain Barrier Model Study. Cell. Physiol. Biochem. 2020, 54, 1231–1248.
  53. Sajja, R.K.; Green, K.N.; Cucullo, L. Altered Nrf2 signaling mediates hypoglycemia-induced blood-brain barrier endothelial dysfunction In Vitro. PLoS ONE 2015, 10, e0122358.
  54. Zhang, T.; Xu, S.; Wu, P.; Zhou, K.; Wu, L.; Xie, Z.; Xu, W.; Luo, X.; Li, P.; Ocak, U.; et al. Mitoquinone attenuates blood-brain barrier disruption through Nrf2/PHB2/OPA1 pathway after subarachnoid hemorrhage in rats. Exp. Neurol. 2019, 317, 1–9.
  55. Fock, E.M.; Parnova, R.G. Protective Effect of Mitochondria-Targeted Antioxidants against Inflammatory Response to Lipopolysaccharide Challenge: A Review. Pharmaceutics 2021, 13, 144.
  56. Wang, P.; Geng, J.; Gao, J.; Zhao, H.; Li, J.; Shi, Y.; Yang, B.; Xiao, C.; Linghu, Y.; Sun, X.; et al. Macrophage achieves self-protection against oxidative stress-induced ageing through the Mst-Nrf2 axis. Nat. Commun. 2019, 10, 755.
  57. Cen, M.; Ouyang, W.; Zhang, W.; Yang, L.; Lin, X.; Dai, M.; Hu, H.; Tang, H.; Liu, H.; Xia, J.; et al. MitoQ protects against hyperpermeability of endothelium barrier in acute lung injury via a Nrf2-dependent mechanism. Redox Biol. 2021, 41, 101936.
  58. Zhang, S.; Zhou, Q.; Li, Y.; Zhang, Y.; Wu, Y. MitoQ Modulates Lipopolysaccharide-Induced Intestinal Barrier Dysfunction via Regulating Nrf2 Signaling. Mediat. Inflamm. 2020, 2020, 3276148.
  59. Hou, L.; Zhang, J.; Liu, Y.; Fang, H.; Liao, L.; Wang, Z.; Yuan, J.; Wang, X.; Sun, J.; Tang, B.; et al. MitoQ alleviates LPS-mediated acute lung injury through regulating Nrf2/Drp1 pathway. Free. Radic. Biol. Med. 2021, 165, 219–228.
  60. Wu, J.; Jiang, Z.; Zhang, H.; Liang, W.; Huang, W.; Zhang, H.; Li, Y.; Wang, Z.; Wang, J.; Jia, Y.; et al. Sodium butyrate attenuates diabetes-induced aortic endothelial dysfunction via P300-mediated transcriptional activation of Nrf2. Free. Radic. Biol. Med. 2018, 124, 454–465.
  61. Dong, W.; Jia, Y.; Liu, X.; Zhang, H.; Li, T.; Huang, W.; Chen, X.; Wang, F.; Sun, W.; Wu, H. Sodium butyrate activates NRF2 to ameliorate diabetic nephropathy possibly via inhibition of HDAC. J. Endocrinol. 2017, 232, 71–83.
  62. Zhao, Q.; Zhang, F.; Yu, Z.; Guo, S.; Liu, N.; Jiang, Y.; Lo, E.H.; Xu, Y.; Wang, X. HDAC3 inhibition prevents blood-brain barrier permeability through Nrf2 activation in type 2 diabetes male mice. J. Neuroinflamm. 2019, 16, 103.
  63. Li, J.; Zheng, M.; Shimoni, O.; Banks, W.A.; Bush, A.I.; Gamble, J.R.; Shi, B. Development of Novel Therapeutics Targeting the Blood–Brain Barrier: From Barrier to Carrier. Adv. Sci. 2021, 8, e2101090.
  64. Brunmeir, R.; Xu, F. Functional Regulation of PPARs through Post-Translational Modifications. Int. J. Mol. Sci. 2018, 19, 1738.
  65. Jiang, X.; Ye, X.; Guo, W.; Lu, H.; Gao, Z. Inhibition of HDAC3 promotes ligand-independent PPARγ activation by protein acetylation. J. Mol. Endocrinol. 2014, 53, 191–200.
  66. Zhao, Q.; Yu, Z.; Zhang, F.; Huang, L.; Xing, C.; Liu, N.; Xu, Y.; Wang, X. HDAC3 inhibition prevents oxygen glucose deprivation/reoxygenation-induced transendothelial permeability by elevating PPAR γ activity in vitro. J. Neurochem. 2019, 149, 298–310.
  67. Mysiorek, C.; Culot, M.; Dehouck, L.; Derudas, B.; Staels, B.; Bordet, R.; Cecchelli, R.; Fenart, L.; Berezowski, V. Peroxisome Peroxisome-proliferator-activated receptor-α activation protects brain capillary endothelial cells from oxygen-glucose deprivation-induced hyperpermeability in the blood-brain barrier. Curr. Neurovasc. Res. 2009, 6, 181–193.
  68. Hind, W.H.; England, T.J.; O’Sullivan, S.E. Cannabidiol protects an in vitro model of the blood-brain barrier from oxygen-glucose deprivation via PPARγ and 5-HT1A receptors. Br. J. Pharmacol. 2015, 173, 815–825.
  69. Li, J.M.; Yu, R.; Zhang, L.P.; Wen, S.Y.; Wang, S.J.; Zhang, X.Y.; Xu, Q.; Kong, L.D. Dietary fructose-induced gut dysbiosis promotes mouse hippocampal neuroinflammation: A benefit of short-chain fatty acids. Microbiome 2019, 7, 98.
  70. Hicks, K.; O’Neil, R.G.; Dubinsky, W.S.; Brown, R.C. TRPC-mediated actin-myosin contraction is critical for BBB disruption following hypoxic stress. Am. J. Physiol. Physiol. 2010, 298, C1583–C1593.
  71. Cunningham, K.E.; Turner, J.R. Myosin light chain kinase: Pulling the strings of epithelial tight junction function. Ann. N. Y. Acad. Sci. 2012, 1258, 34–42.
  72. Huppert, J.; Closhen, D.; Croxford, A.; White, R.; Kulig, P.; Pietrowski, E.; Bechmann, I.; Becher, B.; Luhmann, H.J.; Waisman, A.; et al. Cellular mechanisms of IL-17-induced blood-brain barrier disruption. FASEB J. 2010, 24, 1023–1034.
  73. Kuhlmann, C.R.; Tamaki, R.; Gamerdinger, M.; Lessmann, V.; Behl, C.; Kempski, O.S.; Luhmann, H.J. Inhibition of the myosin light chain kinase prevents hypoxia-induced blood-brain barrier disruption. J. Neurochem. 2007, 102, 501–507.
  74. Sun, C.; Wu, M.H.; Yuan, S.Y. Nonmuscle myosin light-chain kinase deficiency attenuates atherosclerosis in apolipoprotein E-deficient mice via reduced endothelial barrier dysfunction and monocyte migration. Circulation 2011, 124, 48–57.
  75. Beard, R.S., Jr.; Haines, R.J.; Wu, K.Y.; Reynolds, J.J.; Davis, S.M.; Elliott, J.E.; Malinin, N.L.; Chatterjee, V.; Cha, B.J.; Wu, M.H.; et al. Non-muscle Mlck is required for β-catenin- and FoxO1-dependent downregulation of Cldn5 in IL-1β-mediated barrier dysfunction in brain endothelial cells. J. Cell Sci. 2014, 127, 1840–1853.
  76. Miao, W.; Wu, X.; Wang, K.; Wang, W.; Wang, Y.; Li, Z.; Liu, J.; Li, L.; Peng, L. Sodium Butyrate Promotes Reassembly of Tight Junctions in Caco-2 Monolayers Involving Inhibition of MLCK/MLC2 Pathway and Phosphorylation of PKCβ2. Int. J. Mol. Sci. 2016, 17, 1696.
  77. Daneman, R.; Agalliu, D.; Zhou, L.; Kuhnert, F.; Kuo, C.J.; Barres, B.A. Wnt/β-catenin signaling is required for CNS, but not non-CNS, angiogenesis. Proc. Natl. Acad. Sci. USA 2009, 106, 641–646.
  78. Tran, K.A.; Zhang, X.; Predescu, D.; Huang, X.; Machado, R.; Göthert, J.; Malik, A.B.; Valyi-Nagy, T.; Zhao, Y.-Y. Endothelial β-Catenin Signaling Is Required for Maintaining Adult Blood–Brain Barrier Integrity and Central Nervous System Homeostasis. Circulation 2016, 133, 177–186.
  79. Liebner, S.; Corada, M.; Bangsow, T.; Babbage, J.; Taddei, A.; Czupalla, C.J.; Reis, M.; Felici, A.; Wolburg, H.; Fruttiger, M.; et al. Wnt/β-catenin signaling controls development of the blood–brain barrier. J. Cell Biol. 2008, 183, 409–417.
  80. Artus, C.; Glacial, F.; Ganeshamoorthy, K.; Ziegler, N.; Godet, M.; Guilbert, T.; Liebner, S.; Couraud, P.-O. The Wnt/planar cell polarity signaling pathway contributes to the integrity of tight junctions in brain endothelial cells. J. Cereb. Blood Flow Metab. 2014, 34, 433–440.
  81. Wen, J.; Ding, Y.; Wang, L.; Xiao, Y. Gut microbiome improves postoperative cognitive function by decreasing permeability of the blood-brain barrier in aged mice. Brain Res. Bull. 2020, 164, 249–256.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)
Video Production Service
Feedback