Potassium Acetate Blocks Clostridium difficile Toxin A-Induced Microtubule Disassembly by Directly Inhibiting Histone Deacetylase 6, Thereby Ameliorating Inflammatory Responses in the Gut

Abstract

Clostridium difficile toxin A is known to cause deacetylation of tubulin proteins, which blocks microtubule formation and triggers barrier dysfunction in the gut. Based on our previous finding that the Clostridium difficile toxin A-dependent activation of histone deacetylase 6 (HDAC-6) is responsible for tubulin deacetylation and subsequent microtubule disassembly, we herein examined the possible effect of potassium acetate (PA; whose acetyl group prevents the binding of tubulin to HDAC-6) as a competitive/false substrate. Our results revealed that PA inhibited toxin A-induced deacetylation of tubulin and recovered toxin A-induced microtubule disassembly. In addition, PA treatment significantly decreased the production of IL-6 (a marker of inflamed tissue) in the toxin A-induced mouse enteritis model. An in vitro HDAC assay revealed that PA directly inhibited HDAC-6-mediated tubulin deacetylation, indicating that PA acted as a false substrate for HDAC-6. These results collectively indicate that PA treatment inhibits HDAC-6, thereby reducing the cytotoxicity and inflammatory responses caused by C. difficile toxin A.

Targeted inhibition of histone deacetylase 6 in inflammatory diseases

“…LTB2 also exerts a significant protective effect in dextran sulfate sodium‐induced colitis, and LTB2 treatment was associated with diminished rectal bleeding and diarrhea, and longer colon lengths in mice . Furthermore, potassium acetate, which serves as a decoy substrate for HDAC6, reduces cytotoxicity and inflammation in a toxin A‐induced mouse enteritis model . These results highlight the potential clinical role of HDAC6 inhibition in prevention and treatment of colonic inflammation and IBD in humans.…”

“…68 Furthermore, potassium acetate, which serves as a decoy substrate for HDAC6, reduces cytotoxicity and inflammation in a toxin A-induced mouse enteritis model. 69 These results highlight the potential clinical role of HDAC6 inhibition in prevention and treatment of colonic inflammation and IBD in humans.…”

Intraperitoneal Injection of Acetate Protects Mice Against Lipopolysaccharide (LPS)‑Induced Acute Lung Injury Through Its Anti-Inflammatory and Anti-Oxidative Ability

“…Zhang et al [42] discovered that HDAC inhibitor could be beneficial during sepsis-induced ALI. Similarly, the interaction between acetate and HDAC6 has provided new therapeutic strategies for clostridium difficile infection [43]. In contrast, acetate increases the susceptibility of human CD4 + T cells to human immunodeficiency virus (HIV)-1 infection [44].…”

SKLB-23bb, A HDAC6-Selective Inhibitor, Exhibits Superior and Broad-Spectrum Antitumor Activity via Additionally Targeting Microtubules

“…Altered tubulin acetylation status could influence cell behaviors, such as cytoskeleton organization, intracellular cargo transporting, and cell migration (41)(42)(43)(44)). Whether HDAC6 could impact the basic tubulin assembly process via modulation of acetylation of the a-tubulin subunit is still unclear (45,46). Thus, it would be essential to clarify whether SKLB-23bb directly targets tubulin or if its impact on the microtubule system was caused indirectly by the agent's inhibition of HDAC6.…”