Butyrate potentiates Enterococcus faecalis lipoteichoic acid-induced inflammasome activation via histone deacetylase inhibition

Abstract

Enterococcus faecalis, a Gram-positive opportunistic pathogen having lipoteichoic acid (LTA) as a major virulence factor, is closely associated with refractory apical periodontitis. Short-chain fatty acids (SCFAs) are found in the apical lesion and may affect inflammatory responses induced by E. faecalis. In the current study, we investigated inflammasome activation by E. faecalis LTA (Ef.LTA) and SCFAs in THP-1 cells. Among SCFAs, butyrate in combination with Ef.LTA markedly enhanced caspase-1 activation and IL-1β secretion whereas these were not induced by Ef.LTA or butyrate alone. Notably, LTAs from Streptococcus gordonii, Staphylococcus aureus, and Bacillus subtilis also showed these effects. Activation of TLR2/GPCR, K+ efflux, and NF-κB were necessary for the IL-1β secretion induced by Ef.LTA/butyrate. The inflammasome complex comprising NLRP3, ASC, and caspase-1 was activated by Ef.LTA/butyrate. In addition, caspase-4 inhibitor diminished IL-1β cleavage and release, indicating that non-canonical activation of the inflammasome is also involved. Ef.LTA/butyrate induced Gasdermin D cleavage, but not the release of the pyroptosis marker, lactate dehydrogenase. This indicated that Ef.LTA/butyrate induces IL-1β production without cell death. Trichostatin A, a histone deacetylase (HDAC) inhibitor, enhanced Ef.LTA/butyrate-induced IL-1β production, indicating that HDAC is engaged in the inflammasome activation. Furthermore, Ef.LTA and butyrate synergistically induced the pulp necrosis that accompanies IL-1β expression in the rat apical periodontitis model. Taken all these results together, Ef.LTA in the presence of butyrate is suggested to facilitate both canonical- and non-canonical inflammasome activation in macrophages via HDAC inhibition. This potentially contributes to dental inflammatory diseases such as apical periodontitis, particularly associated with Gram-positive bacterial infection.

Repeated ( S )-ketamine administration ameliorates the spatial working memory impairment in mice with chronic pain: role of the gut microbiota–brain axis

“…Since butyric acid is a histone deacetylase (HDAC) inhibitor, 39 we measured HDAC1–3, HDAC6, and HDAC8 expression in the hippocampus by western blotting. Hippocampal HDAC2 expression was significantly higher in the CCI + saline group than in the sham + saline group, and this effect was reversed by ( S )-ketamine administration ( Figure 4G ).…”

Lipoteichoic acids influence cell shape and bacterial division of Streptococcus suis serotype 2, but play a limited role in the pathogenesis of the infection

“…LTA has long been compared to the LPS of Gram-negative bacteria [ 18 ], which is a component recognized by immune cells and participates in the initiation of the inflammatory response. Although this hypothesis is still proposed in recent publications [ 67 , 68 ], other studies have challenged this role for the LTA [ 21 , 60 ] and it is now accepted that lipoproteins (and not LTA) are the main activators of the innate immune system [ 7 , 20 , 21 , 69 ]. To further study the role of LTA in inflammation caused by S. suis , activation of DCs by the mutant lacking LTA was compared to the wild-type strain.…”

Advances in gut microbiome in metabonomics perspective: based on bibliometrics methods and visualization analysis

“…However, butyrate could stimulate enteroendocrine cells(EEC) to release neuropeptide and neurotransmitter like serotonin in role of controlling immune cells like Treg cell in anti-inflammation, else, and regulating nervi vagus to adjust permeability of intestinal barrier and blood-brain barrier(BBB) for better regulation of interaction among gut microbiome, metabolism, and human body( Stilling et al., 2016 ). Furthermore, butyrate is a key to reduce inflammation, improve macrophage development and restrain the excessive growth of intestinal epithelium by inhibting histone deacetylase(HDAC) ( Salvi and Cowles, 2021 ; Liu et al., 2023 ; Park et al., 2023 ). Butyrate is supported to influence the growth of glioblastoma acrossing BBB ( Lyu et al., 2022 ).…”