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Abstract

Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, is characterized by chronic nonspecific intestinal inflammation. Despite considerable efforts, IBD remains a heavy burden on society and human health, with increasing morbidity. Posttranslational modification, especially histone acetylation, is a key process in controlling DNA transcriptional activity. Histone deacetylases (HDACs) play a vital role in the mechanism of IBD pathogenesis through histone and nonhistone protein deacetylation. Herein, we present a summary of different categories of HDACs as well as HDAC inhibitors (HDACis) and analyze the role of HDAC inhibition in alleviating IBD along with its mechanism, as well as clinical potential of HDACis in IBD treatment.

Keywords

HDAC inhibitors (HDACis)histone deacetylases (HDACs)inflammatory bowel disease (IBD)T cell function

Introduction

Inflammatory bowel disease (IBD) is a general term for a group of diseases characterized by chronic nonspecific intestinal inflammation, mainly ulcerative colitis (UC) and Crohn's disease (CD). Lesions in UC are usually confined to the colonic mucosa, with a common expansion pattern from the rectum to the proximal colon, and persistent superficial inflammation is frequently accompanied by ulcers.¹ CD can affect the whole digestive tract from the oral cavity to the anus, with lesions distributed in a segmental and jumping pattern. The terminal ileum and ileocecal junction are the most common sites of CD occurrence. In addition to common manifestations, such as abdominal pain, diarrhea, and hematochezia in UC, CD can also lead to perianal lesions, intestinal stenosis, fistulas, etc.²

Epidemiology studies have shown that the incidence and prevalence of IBD have increased rapidly worldwide in recent years, especially in newly industrialized areas such as Asia.³ In China, from 1990 to 2019, the female age-standardized prevalence rate increased from 20.7 cases per 100,000 persons (95% uncertainty interval (UI) 17.2–24.5) to 44.2 cases per 100,000 persons (95% UI 37.7–51.4), with an annual rate of change of 1.14% (95% CI 1.05–1.26); the male age-standardized prevalence rate increased from 25.1 cases (95% UI 20.9–30.2) to 50.0 cases (95% UI 42.5–58.5) per 100,000 population, with an annual rate of change of 0.99% (95% CI 0.90–1.09).⁴ As a chronic and incurable disease, IBD impedes both the physical and psychological health of patients, and it is speculated that the direct medical costs attributable to IBD patients are three times greater than those associated with patients without IBD and are even increasing these years, placing a heavy burden on both families and the society as a whole.⁵

To date, the pathogenesis and etiology of IBD are still not clear and are believed to be related to multiple factors, including genetics, immunity, the environment and gut microorganisms, etc.⁶ Despite many choices of medications, such as aminosalicylates, corticosteroids, and immunosuppressants,⁷ a portion of patients still suffer from unsatisfactory therapeutic effects, disease relapse and withdrawal of medication due to side effects (including infections, anemia, headaches, lymphopenia, and cardiovascular events).⁸ Surgery is ultimately inevitable among patients who are not responsive to medication, and for CD, the recurrence rate even after surgery approaches 100%, often at the anastomosis.⁹ In summary, IBD places a heavy burden on healthcare services, and new effective medications with minimal side effects are urgently needed.

In recent years, experts in IBD drug development have focused on a new promising field, epigenetics, a new regulatory mechanism of diseases.¹⁰ Epigenetics refers to the control of gene expression by altering chromatin, not the DNA sequence.¹¹ In eukaryotic cells, nucleosomes are the basic subunits of chromatin, and their core particles are formed by genomic DNA superhelices wrapped around histone octamers.^12–14 Histones, as the main components of chromatin, can be divided into five types, H2A, H2B, H3, H4, and H1, which promote gene transcription when DNA and histones are loosely attached.¹⁵ The N- and C-termini of core histones mediate the high-level folding of chromatin, and the different amino acids in their tails (such as lysine, arginine, serine, and threonine) can be targeted for posttranslational modification (PTM), which regulates DNA binding to transcription factors and RNA polymerase II and then causes transcription to cease because of compact chromatin.¹⁶

PTMs of histones include methylation, acetylation, phosphorylation, ubiquitination, malonylation, propionylation, butyrylation, crotonylation, and lactylation.^17–20 PTMs can participate in IBD pathogenesis by modulating immune cells, cytokine secretion, the intestinal flora, etc.^21–23 Among all PTMs, histone acetylation is the most common.^24–26 Histone acetylation is regulated by histone deacetylase (HDAC) and histone acetylase (HAT): HATs catalyze the translocation of acetyl groups to lysine residues, which loosens chromatin for transcription, whereas HDACs deacetylate histones, resulting in stronger attachment to DNA, compressed chromatin, and reduced transcriptional activity.²⁷ Evidence has indicated that histone acetylation is promoted, and HDAC inhibitor (HDACi) administration relieves disease severity in IBD.²⁸ Therefore, in this review, we will systematically review the effects and mechanisms of HDACs in IBD and discuss the potential clinical application and future prospects of HDACis in IBD treatment. The summarized frame of current review is shown in Figure 1.

Figure 1.

Summary of the mechanisms by which HDACis and HDAC deficiency inhibit IBD. HDAC deficiency and HDACis inhibit IBD through regulating T cell, B cell, macrophage, epithelial cell, and other cells function, respectively.

Histone deacetylases

On the basis of their structure, there are 18 different isoforms of HDACs that belong to four different classes^29–31: class I Rpd3-like proteins (HDAC1, HDAC2, HDAC3, and HDAC8); class II Hda1-like proteins (HDAC4, HDAC5, HDAC6, HDAC7, HDAC9, and HDAC10); class III Sir2-like proteins (SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, and SIRT7); and class IV proteins (HDAC11). Class I, II, and IV HDACs share similar structures and require zinc for catalysis, whereas class III HDACs require NAD as a cofactor for enzymatic activity.³²

Class I HDACs are highly homologous to the yeast HDAC Rpd3 and consist of a highly conserved deacetylation structural domain; they are expressed mainly in the nucleus and have strong deacetylation activity toward histones.³³ Among class I HDACs, HDAC1 is the most extensively studied and plays an important regulatory roles in angiogenesis, redox homeostasis and inflammatory signaling,³⁴ especially in regulating the Fas promoter region of activated T cells and mediating immune homeostasis. T cell dysfunction is linked to various autoimmune diseases, including IBD, rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus.^35,36 Dual HDAC1/HDAC2 loss has been reported to reduce the colonic inflammatory response.³⁷

HDAC inhibitors

HDACis have strong anti-inflammatory effects, and the application of HDACis in IBD has attracted increased attention in recent years. On the basis of their chemical structure, HDACis are categorized into seven types: short-chain fatty acids (SCFAs) (valproic acid/VPA, sodium butyrate, etc.), hydroxamic acids (trichostain-A/TSA, vorinostat/SAHA, givinostat/ITF2357, etc.), benzamides (entinostat/MS-275, chidamide, etc.), cyclic peptides (depsipeptide and apicidin), mercaptoketones (KD5170), sirtuin inhibitors (nicotinamide, sirtinol, EX527, etc.), and others (citarinostat, etc.).^38,39 To date, the U.S. Food and Drug Administration (FDA) has approved five HDACis for the treatment of different diseases: vorinostat for cutaneous T cell lymphoma (CTCL); romidepsin for peripheral T cell lymphoma (PTCL) and CTCL; belinostat for PTCL; panobinostat for multiple myelomas (although withdrawn by the FDA in 2022); and givinostat for Duchenne muscular dystrophy.^39–44 A variety of HDACis, such as VPA or SAHA,^45,46 givinostat,⁴⁷ the statin hydroxamate,⁴⁸ and MS-275,⁴⁹ have also shown potential therapeutic effects in IBD.^36,50,51 The role and mechanisms of action of HDACis in IBD will be discussed in depth.

Regulatory mechanism of HDACs in IBD

HDACs regulate T cell function

Multiple types of primary immune cells, including T cells,^52,53 B cells,⁵⁴ macrophages,⁵⁵ and neutrophils,^56,57 are generally acknowledged to be involved in IBD pathogenesis and serve as therapeutic targets. Among them, T cells have been shown to be the most important component mediating the regulation of histone acetylation in IBD (Table 1).

Table 1.

Summary of the mechanisms by which HDACs regulate different cells in IBD.

Cells	HDACi/HDAC	Affecting protein/transcription factor/biological processes	Pathological/histological effects	References
Treg	ITF2357	Enhance Foxp3⁺ colonic Tregs polarization through the IL-6/STAT3/IL-17 pathway	Ameliorate experimental colitis	Glauben et al.⁶⁰
Treg	Tubacin	Promote the suppressive activity of Foxp3⁺ colonic Tregs through the inhibition of HSP90	Relieve DSS-induced colitis in mice	de Zoeten et al.⁶¹
Treg	HDAC9 knockout	Increase Treg function and HSP70 levels	Prevent colitis in mice	de Zoeten et al.⁶²
Treg	TSA	Increase production of Foxp3⁺ Treg cells and promote Foxp3 acetylation	Diminish disease severity in DSS-induced colitis	Tao et al.⁶³
Th17	Butyrate	Reduce Th17 differentiation	Ameliorate colitis in an animal model	Zhang et al.⁷⁰
Th17	Butyrate	Maintain the Th17/Treg balance to block the IL-6/STAT3/IL17 pathway and promote Foxp3 expression	Ameliorate colorectal colitis	Zhou et al.⁷¹
Treg, T17/Treg	β-HB	Promote Treg differentiation, decrease the Th17/Treg ratio, and increase Foxp3 expression by promoting histone H3 acetylation	Ameliorate colitis in mice	Hao et al.⁷²
Th17	RGFP109	Inhibit Th17 cell differentiation and compromise IL-17A secretion	Alleviate colon inflammation	Gu et al.⁷³
Naïve T cells, Tregs	Butyrate	Enhance acetylation of Foxp3 in naïve T cells and induce the differentiation of Treg cells	Ameliorate T-cell-dependent experimental colitis	Furusawa et al.⁷⁴
CD4⁺ and CD8⁺ T cells	Butyrate	Induce the apoptosis of CD4⁺ and CD8⁺ T cells to eliminate the source of inflammation	Suppress colonic inflammation	Zimmerman et al.⁷⁵
CD4⁺ T cells	Butyrate	Induce IL-22 production through increasing the H3K9 acetylation in HRE on IL-22 promoter	Inhibit colitis	Yang et al.⁷⁶
iTreg	Butyrate	Enhances CPT1-dependent iTreg cell differentiation and fatty acid oxidation	Alleviate colitis in mice	Hao et al.⁷⁷
B10 cells	Butyrate	Activate p38 MAPK and increase the abundance of B10 cells	Inhibit inflammation in DSS-induced colitis	Zou et al.⁸⁰
CD19⁺ B cells	BML-281	Suppress the infiltration of CD19⁺ B cells into the colonic lamina propria	Attenuate inflammation in DSS-treated mice	Do et al.⁸¹
M1 macrohpages	H3K9Ac induced by lactic acid	Inhibit the NLRP3 inflammasome and NLRP3-mediated macrophage activation and M1 polarization	Alleviate the inflammatory response in UC	Sun et al.⁹⁵
Macrophages	ESM-HDAC528	Attenuate colon monocyte to macrophages differentiation and peritoneal macrophage activity in DSS-induced colitis	Achieve therapeutic benefit in a T cell transfer colitis model	Elfiky et al.⁹⁶
BMDM and colonic LP macrophages	Butyrate	Downregulate LPS-induced proinflammatory mediators by increasing levels of H3K9Ac	Regulate intestinal macrophage function	Chang et al.⁹⁷
THP-1	Butyrate	Inhibit the translocation of NF-κB p65 from the cytoplasm to the nucleus	Inhibit TNBS-induced colitis	Segain et al.⁹⁸
RAW264.7	Butyrate	Inhibit DNA binding by NF-κB and the degradation/phosphorylation of IκBα	Improve histological scores in colitis models	Lee et al.⁹⁹
RAW264.7	NMJ-2	Inhibit phospho-NF-κB	Show anti-colitis effects in both colitis models and anti-inflammatory effect	Joshi et al.¹⁰⁰
RAW264.7	CKD-506	Inhibit NF-κB signaling	Ameliorate acute and chronic murine colitis	Lee et al.¹⁰¹
RAW264.7	H3K9Ac induced by L. casei LH23	Inhibit macrophages (CD11b⁺F4/80⁺) and inflammatory cytokines secretion through suppressing JNK/p38 pathway	Ameliorate DSS-induced colitis	Liu et al.¹⁰²
Peritoneal macrophages	HDAC2 recruited by Tet2	Specifically inhibit IL-6 transcription	Inhibit DSS-induced colitis	Zhang et al.¹⁰³
Macrophages	HDAC3 knockout in macrophages	Regulate GBP5-NLRP3 axis	Inhibit disease severity and the inflammatory response in colitis	Che et al.¹⁰⁴
Macrophages	butyrate	Induce ferroportin and facilitate iron export	Ameliorate colitis	Xiao et al.¹⁰⁷
CMT93 and T84	Givinostat and vorinostat	Increase intestinal epithelial regeneration through the secretion of TGF-β1	Inhibit intestinal inflammation	Friedrich et al.¹¹¹
MSIE	Class I HDAC inhibition by propionate	Stimulate cell migration, epithelial renewal and repair in a STAT3- and GPR43-dependent manner	Reduce ulceration in DSS-induced colitis	Bilotta et al.¹¹²
HCEC	SAHA	Increase EBI3 expression and IL-35 formation	Inhibit DSS-induced colitis	Wetzel et al.¹¹³
NCI-H716 and HCT15	Butyrate	Increase the expression of MFG-E8	Attenuate intestinal inflammation in DSS-induced colitis	Mishiro et al.¹¹⁴
Epithelial cells	MS-275	Target VDR and increase the acetylation of VDR	Alleviate colitis in DSS-exposed mice	Li et al.⁴⁹
Epithelial cells	HDAC1- and HDAC2-deficiency	Inhibit JAK-STAT signaling pathway	Present restored intestinal homeostasis	Gonneaud et al.¹¹⁵
Epithelial cells	HDAC activation by SP	Promote CYR61 expression	Reduce colonic mucosal damage in colonocytes in DSS-induced colitis	Koon et al.¹¹⁶
IPEC-J2	H3K9Ac by caprylic acid and nonanoic acid	Activate pBD-1 and pBD-2	Enhance intestinal epithelial barrier function	Wang et al.¹¹⁷
Neutrophils	Butyrate	Inhibit neutrophil-associated immune responses and NETs formation	Alleviate mouse colitis	Li et al.¹¹⁸
Neutrophils	HDAC9 inhibition by FBA	Block neutrophil recruitment	Reduce inflammatory intestinal damage in DSS-induced colitis	Simeoli et al.¹¹⁹
Fibroblasts	VPA	Inhibit TGF-β-induced profibrotic metabolites and suppress collagen-I	Inhibit intestinal fibrosis	Lewis et al.¹²⁰
Colonic muscularis externa	HDAC3 upregulation by NO	Restrict NFκB	Inhibit ICAM-1 expression in TNBS-induced colitis model	Li et al.¹²¹
Colon tissues	SPA3074	Upregulate SOCS1 expression and strengthen the epithelial barrier	Alleviate inflammation in DSS-induced colitis	Yoon et al.¹²²

BMDM, bone marrow-derived macrophages; CPT1, carnitine palmitoyltransferase 1; DSS, dextran sulfate sodium; FBA, N-(1-carbamoyl-2-phenylethyl) butyramide; HCEC, human colon epithelial cells; HDAC, histone deacetylase; HDACi, HDAC inhibitor; IBD, inflammatory bowel disease; iTreg, inducible regulatory T; LP, lamina propria; LPS, lipopolysaccharide; MSIE, mouse small intestinal epithelial cells; NET, neutrophil extracellular trap; NO, nitric oxide; SP, substance P; TGF-β, transforming growth factor beta; TNBS, 2,4,6-trinitrobenzene sulfonic acid; Treg, regulatory T cell; TSA, Trichostain-A; UC, ulcerative colitis; VDR, vitamin D receptor; VPA, valproic acid.

Colonic regulatory T cells (Tregs) are characterized by the expression of transcription factor Foxp3 and are critical for maintaining intestinal homeostasis as well as limiting intestinal inflammation.^58,59 The HDACi ITF2357 enhances Foxp3⁺ colonic Tregs polarization in the lamina propria (LP) through the IL-6/STAT3/IL-17 pathway, ameliorating experimental colitis.⁶⁰ The HDAC6-specific inhibitor tubacin has been shown to promote the suppressive activity of Foxp3⁺ colonic Tregs through the inhibition of heat shock protein 90 (HSP90), relieving dextran sulfate sodium (DSS)-induced colitis in mice.⁶¹ HDAC9 knockout has been shown to increase Treg function and HSP70 levels and prevent colitis in mice.⁶² In addition, HDACi TSA intervention has been shown to increase the number of Foxp3⁺ Treg cells and promote Foxp3 acetylation, diminishing disease severity in DSS-induced colitis.⁶³

In addition to Tregs, Th17 cells also participate in the pathogenesis of IBD and act as effector cells of HDACs during colitis.^64–67 The intestinal mucosal immune microenvironment is regulated via cytokines, such as IL-26, IL-17, and IL-21.^68,69 Butyrate has been shown to inhibit HDAC3 to reduce Th17 differentiation and ameliorate colitis in an animal model.⁷⁰ Butyrate has also been shown to maintain the Th17/Treg balance by inhibiting HDAC1 to block the IL-6/STAT3/IL17 pathway and promote Foxp3 expression, ultimately ameliorating colorectal colitis.⁷¹ β-hydroxybuty rate (β-HB) has been shown to promote Treg differentiation, decrease the colonic Th17/Treg ratio, and increase Foxp3 expression by increasing histone H3 acetylation, ameliorating colitis in mice.⁷² RGFP109, a selective inhibitor of HDAC1 and 3, has been shown to alleviate colon inflammation through the inhibition of Th17 cell differentiation from human peripheral blood mononuclear cells (PBMCs) and compromising IL-17A secretion.⁷³

Other mechanisms by which HDACs regulate T cells, such as naïve T cells, CD4⁺ and CD8⁺ T cells, and inducible regulatory T (iTreg) cells, also exist, as discussed below. Butyrate treatment enhances histone H3 acetylation in the conserved noncoding sequence regions and the promoter of the Foxp3 locus in naïve T cells, and induces the differentiation of Treg cells, ameliorating T-cell-dependent experimental colitis.⁷⁴ Butyrate suppresses colonic inflammation through a double-hit mechanism: inducing the apoptosis of CD4⁺ and CD8⁺ T cells to eliminate the source of inflammation and suppressing IFN-γ-induced STAT1 activation and inflammation.⁷⁵ Furthermore, butyrate can also induce IL-22 production in CD4⁺ T cells and innate lymphoid cells through increasing the H3K9 acetylation of the hypoxia response element on the IL-22 promoter, thus inhibiting colitis.⁷⁶ Butyrate also enhances carnitine palmitoyltransferase 1-dependent fatty acid oxidation and iTreg cells differentiation, alleviating DSS-induced colitis in mice.⁷⁷

HDACs regulate B cell function

Recent reports have focused on the important role of B lymphocytes in maintaining gastrointestinal homeostasis^78,79 through HDAC inhibition (Table 1). B10 cells are regulatory B cells capable of producing IL-10 to maintain immune homeostasis, and a butyrate-induced increase in B10 cells has been observed in mice with DSS-induced colitis. The adoptive transfer of B cells pretreated with butyrate inhibits inflammation in DSS-induced colitis; mechanistically, transcriptomic analysis revealed that the activation of p38 MAPK by butyrate in an HDAC inhibitory activity-dependent manner is critical for increasing the abundance of B10 cells.⁸⁰ Moreover, the administration of a potent HDAC6 inhibitor, BML-281, has been shown to attenuate inflammation by suppressing the infiltration of CD19⁺ B cells into the colonic LP in DSS-treated mice, suggesting that targeting HDAC6 is an anti-inflammatory strategy against IBD progression.⁸¹

HDACs regulate macrophage function

Macrophages are involved in both the initiation and progression of IBD through multiple mechanisms, including polarization,^82–85 immunoregulation,⁸⁶ ferroptosis,⁸⁷ and pyroptosis,^88,89 etc. Evidence has shown that histone deacetylation mediates the mechanism of which macrophage regulates in colitis (Table 1).

When stimulated by different internal environments or cytokines, M0 macrophages polarize into several phenotypes (including proinflammatory M1 macrophages and anti-inflammatory M2 macrophages), and the balance between M1 and M2 macrophages plays a critical role in intestinal homeostasis during IBD pathogenesis.^90–94 HDAC inhibition has been reported to alleviate IBD through regulating macrophage polarization: histone 3 lysine 9 (H3K9) acetylation (H3K9Ac) induced by lactic acid has been shown to inhibit the NLRP3 inflammasome and NLRP3-mediated macrophage activation and M1 polarization, alleviating the inflammatory response in UC⁹⁵; and esterase-sensitive motif (ESM)-tagged HDACi ESM-HDAC528 has been shown to attenuate colon monocyte to macrophage differentiation and peritoneal macrophage activity in DSS-induced colitis, and achieve therapeutic benefit in a T cell transfer colitis model.⁹⁶

Macrophages mediate immunoregulation not only through the production of proinflammatory and anti-inflammatory cytokines, toxic mediators, chemokines, and macrophage extracellular traps but also via the modulation of epithelial cell proliferation and fibrosis in the intestine as well as its accessory tissues and the mediation of HDACs during these processes, especially the NF-κB signaling pathway.⁸⁶ Butyrate downregulates lipopolysaccharide (LPS)-induced proinflammatory mediators at the transcription level in bone marrow-derived macrophages and colonic LP macrophages, including nitric oxide, IL-12 and IL-6, by increasing levels of H3K9Ac.⁹⁷ In addition, butyrate has been shown to inhibit the LPS-induced translocation of NF-κB p65 from the cytoplasm to the nucleus in THP-1 monocytes and in PBMCs, and NF-κB p65 has also been shown to be inhibited by butyrate in 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis.⁹⁸ DNA binding by NF-κB has been shown to be inhibited, as has the degradation/phosphorylation of IκBα, in LPS-stimulated murine RAW264.7 cells (a macrophage cell line) by butyrate; histological scores in colitis models have also been shown to be improved after the administration of butyrate.⁹⁹ A cinnamyl sulfonamide hydroxamate derivative possessing nonselective HDAC inhibition ability, NMJ-2, has shown anti-colitis effects in both acetic acid and 2,4-dinitrochlorobenzene (DNCB)-induced colitis models and anti-inflammatory effects through the inhibition of phospho-NF-κB in LPS-induced RAW264.7 cells.¹⁰⁰ NF-κB signaling in macrophages and intestinal epithelial cells has been shown to be inhibited by CKD-506, a novel HDAC6 inhibitor, and to ameliorate acute and chronic murine colitis.¹⁰¹

Other mechanisms are also involved in HDAC inhibition and macrophage-mediated immunoregulation in IBD. First, the restoration of H3K9Ac by Lactobacillus casei (L. casei) LH23 has been shown to ameliorate DSS-induced colitis by inhibiting macrophages (CD11b⁺F4/80⁺) as well as the secretion of inflammatory cytokines through suppressing JNK/p38 signal pathways and inducing an increase in CD3⁺CD4⁺CD25⁺ Tregs.¹⁰² Second, ten eleven translocation (Tet) 2 has been shown to recruit HDAC2 and specifically inhibit IL-6 transcription through histone deacetylation in innate myeloid cells (including peritoneal macrophages and dendritic cells), and Tet2-deficient mice has been shown to be more susceptible to colitis.¹⁰³ Third, HDAC3 knockout in macrophages has been shown to inhibit disease severity and the inflammatory response in colitis by regulating the guanylate-binding protein 5 (GBP5)-NLRP3 axis.¹⁰⁴

Ferroptosis is a distinct form of iron-dependent nonapoptotic regulated cell death associated with IBD pathogenesis and interestingly, ferroptosis also participates in HDAC-mediated regulation of macrophages in IBD in a cell-specific way.^87,105,106 Butyrate has also been shown to induce ferroportin expression in macrophages by decreasing the enrichment of HDACs around the Slc40a1 promoter, facilitating iron export and thus ameliorating colitis.¹⁰⁷

HDACs regulate epithelial cell function

Various types of epithelial cells, including Paneth, M, columnar, tuft and goblet cells, collaborate to maintain intestinal barrier integrity and play indispensable roles in regulating interactions between the immune system, the intestinal contents and other components.^108,109 Recent studies have indicated that epithelial cell dysfunction is strongly associated with IBD pathogenesis¹¹⁰ and mediates the regulation of histone deacetylation in IBD (Table 1).

Multiple HDACis have been shown to play a protective role in the intestinal epithelium of individuals with colitis: givinostat and vorinostat have been shown to increase intestinal epithelial regeneration through the secretion of transforming growth factor beta 1 (TGF-β1) in murine (CMT93) and human (T84) colonic epithelial cell lines, and givinostat has also been shown to improve epithelial wound healing and barrier recovery in DSS-stressed mice¹¹¹; propionate, a type of SCFA, has been shown to stimulate cell migration, epithelial renewal and repair upon class I HDAC inhibition, in a STAT3- and GPR43-dependent manner in mouse small intestinal epithelial cells, and propionate has also been shown to reduce ulceration in DSS-induced colitis¹¹²; SAHA treatment has been shown to increase Epstein-Barr virus-induced gene 3 (EBI3) expression and anti-inflammatory cytokine IL-35 formation under inflammatory conditions in human colon epithelial cells, and inhibit DSS-induced colitis in wild-type but not in EBI3-deficient mice¹¹³; and butyrate acid has been reported to increase the acetylation of H3K9 around the promoter of milk fat globule-epidermal growth factor 8 (MFG-E8) and the expression of MFG-E8 in colon epithelial cells (NCI-H716 and HCT15) and attenuate intestinal inflammation in DSS-induced colitis.¹¹⁴

Our previous study demonstrated that the level of histone H3 acetylation was decreased in epithelial cells in UC patients and that the HDACi MS-275 targeted the vitamin D receptor (VDR) and increase the acetylation of VDR in epithelial cells to reduce inflammation and apoptosis, and restore intestinal barrier function, thereby alleviating colitis in DSS-exposed mice.⁴⁹

Genetic manipulation of or chemical intervention to disrupt HDACs or histone acetylation has also been shown to produce similar results: intestinal epithelial cell-specific HDAC1- and HDAC2-deficient mice have been shown to present restored intestinal homeostasis via the inhibition of the JAK-STAT signaling pathway¹¹⁵; substance P (SP) has been shown to promote the cysteine-rich angiogenic inducer 61 (CYR61) expression through increased HDAC activity, and colonic mucosal damage has been shown to be reduced in colonocytes in DSS-induced mice¹¹⁶; and the facilitation of the acetylation of H3K9 at the promoters of porcine β-defensins 1 (pBD-1) and pBD-2 by medium chain fatty acids (caprylic acid and nonanoic acid) has been shown to significantly activate pBD-1 and pBD-2 and enhance intestinal epithelial barrier function in porcine jejunal epithelial cell line IPEC-J2.¹¹⁷

HDACs regulate other factors

In addition to the abovementioned effects on effector cells, HDAC inhibition has also been shown to alleviate IBD through neutrophils, fibroblasts, colonic muscularis externae tissues, colon tissues (Table 1), etc.

Butyrate has been shown to significantly alleviate mouse colitis via the inhibition of neutrophil-associated immune responses and neutrophil extracellular traps formation.¹¹⁸ A butyrate-releasing derivative, N-(1-carbamoyl-2-phenylethyl) butyramide (FBA), has been reported to inhibit HDAC9, restore H3 histone acetylation, block neutrophils recruitment, and lead to inflammatory remission in colitis.¹¹⁹ For fibroblasts in CD, the hypoacetylation of H3K27 has been observed during stricture formation in CD, and VPA has been shown to inhibit TGF-β-induced profibrotic metabolites in primary CD fibroblasts, and suppress collagen-I in intestinal fibroblasts through increasing histone acetylation.¹²⁰ Nitric oxide (NO) release by S-nitrosoglutathione (GSNO) has been shown to increase the transcription of HDAC3 and suppress H4K12 acetylation at the ICAM-1 promoter to restrict NFκB in the colonic muscularis externae tissues of naïve adult rats, inhibiting ICAM-1 expression in TNBS-induced colitis model.¹²¹ Furthermore, the novel HDAC8 inhibitor SPA3074 has been shown to upregulate suppressor of cytokine signaling 1 (SOCS1) expression in colon tissues, thus strengthening the epithelial barrier and alleviating inflammation in DSS-induced colitis.¹²²

Conclusion

In the past decade, the landscape of IBD treatment has undergone substantial transformation, largely due to advances in immunomodulatory drug development and the emergence of other novel therapies. However, many more effective and tolerable therapies are needed. Already existed HDACis and new therapy targeting diverse HDACs, as summarized above (Tables 2 and 3), have shown great potential in IBD treatment.

Table 2.

Summary of the mechanisms by which HDACis regulate IBD in different cells and tissues.

HDACis	Target	Mechanisms in different cells and tissues	References
Givinostat (ITF2357)	pan-HDAC	T cells: Enhance Foxp3⁺ colonic Tregs polarization through the IL-6/STAT3/IL-17 pathway	Glauben et al.⁶⁰
Tubacin	HDAC6	Epithelial cells: Increase intestinal epithelial regeneration through TGF-β1 secretion and improve epithelial wound healing and barrier recovery	Friedrich et al.¹¹¹
Trichostain-A	pan-HDAC	T cells: Promote the suppressive activity of Foxp3⁺ colonic Tregs through the inhibition of HSP90	de Zoeten et al.⁶¹
Butyrate	Class I, II HDAC	T cells: Increase production of Foxp3⁺ Treg cells and promote Foxp3 acetylation	Tao et al.⁶³
		T cells: Reduce Th17 differentiation	Zhang et al.⁷⁰
		T cells: Maintain the Th17/Treg balance to block the IL-6/STAT3/IL17 pathway and promote Foxp3 expression	Zhou et al.⁷¹
		T cells: Enhance acetylation of Foxp3 in naïve T cells and induce the differentiation of Treg cells	Furusawa et al.⁷⁴
		T cells: Induce apoptosis of CD4⁺ and CD8⁺ T cells	Zimmerman et al.⁷⁵
		T cells: Induce IL-22 production in CD4⁺ T cells and innate lymphoid cells	Yang et al.⁷⁶
		T cells: Increase iTreg cell differentiation	Hao et al.⁷⁷
		B cells: Activate p38 MAPK to increase the abundance of B10 cells	Zou et al.⁸⁰
		Macrophages: Downregulate LPS-induced proinflammatory mediators in BMDM and colonic LP macrophages	Chang et al.⁹⁷
		Macrophages: Inhibit LPS-induced translocation of NF-κB p65 from the cytoplasm to the nucleus in THP-1 monocytes and PBMCs	Segain et al.⁹⁸
		Macrophages: Inhibit DNA binding by NF-κB and the degradation/phosphorylation of IκBα in LPS-stimulated RAW264.7	Lee et al.⁹⁹
		Macrophages: Induce ferroportin expression by decreasing the enrichment of HDACs around the Slc40a1 promoter and facilitate iron export	Xiao et al.¹⁰⁷
		Epithelial cells: Increase the acetylation of H3K9 around the promoter of MFG-E8 and expression of MFG-E8	Mishiro et al.¹¹⁴
		Neutrophils: Inhibit neutrophil-associated immune responses and NETs formation	Li et al.¹¹⁸
β-HB	Class I HDAC	T cells: Promote Treg differentiation, decrease Th17/Treg ratio and increase Foxp3 expression	Hao et al.⁷²
RGFP109	HDAC1, 3	T cells: Inhibit Th17 cell differentiation and compromise IL-17A secretion	Gu et al.⁷³
BML-281	HDAC6	B cells: Suppress the infiltration of CD19⁺ B cells	Do et al.⁸¹
ESM-HDAC528	pan-HDAC	Macrophages: Attenuate colon monocyte to macrophages differentiation and peritoneal macrophage activity	Elfiky et al.⁹⁶
NMJ-2	pan-HDAC	Macrophages: Inhibit phospho-NF-κB in LPS-induced RAW264.7 cells	Joshi et al.¹⁰⁰
CKD-506	HDAC6	Macrophages and intestinal epithelial cells: Inhibit NF-κB	Lee et al.¹⁰¹
Vorinostat (SAHA)	pan-HDAC	Epithelial cells: Increase intestinal epithelial regeneration through the secretion of TGF-β1	Friedrich et al.¹¹¹
Vorinostat (SAHA)	pan-HDAC	Epithelial cells: Increase EBI3 expression and IL-35 formation under inflammatory conditions	Wetzel et al.¹¹³
Entinostat (MS-275)	Class I HDAC	Epithelial cells: Target VDR to reduce inflammation and apoptosis, and restore intestinal barrier function	Li et al.⁴⁹
Valproic acid	Class I, IIa HDAC	Fibroblasts: Inhibit TGF-β-induced profibrotic metabolites and suppress collagen-I	Lewis et al.¹²⁰
SPA3074	HDAC8	Colon tissues: Upregulate SOCS1 expression and strengthen the epithelial barrier	Yoon et al.¹²²

BMDM, bone marrow-derived macrophages; HDAC, histone deacetylase; LP, lamina propria; LPS, lipopolysaccharide; NET, neutrophil extracellular trap; PBMC, peripheral blood mononuclear cell; SOCS1, suppressor of cytokine signaling 1; Tregs, regulatory T cells; VDR, vitamin D receptor.

Table 3.

Summary of the mechanisms by which HDACs and histone acetylation regulate IBD in different cells and tissues.

HDACs	Mechanisms in different cells and tissues	References
HDAC9	T cells: HDAC9 knockout increases Treg function and HSP70	de Zoeten et al.⁶²
	Neutrophils: FBA inhibits HDAC9 to block neutrophils recruitment	Simeoli et al.¹¹⁹
HDAC2	Macrophages: Tet2 recruits HDAC2 to inhibit IL-6 transcription	Zhang et al.¹⁰³
HDAC3	Macrophages: HDAC3 knockout regulates the GBP5-NLRP3 axis	Che et al.¹⁰⁴
	Colonic muscularis externae tissues: NO release by GSNO increases HDAC3 to restrict NFκB	Li et al.¹²¹
Class I HDAC	Epithelial cells: propionate inhibits class I HDAC to stimulate cell migration, epithelial renewal and repair in a STAT3- and GPR43-dependent manner	Bilotta et al.¹¹²
HDAC1 and 2	Epithelial cells: HDAC1 and 2 deficiency restore intestinal homeostasis via the inhibition of the JAK-STAT signaling pathway	Gonneaud et al.¹¹⁵
HDAC	Epithelial cells: HDAC activation by SP promotes CYR61 expression	Koon et al.¹¹⁶
H3K9Ac	Macrophages: H3K9Ac induced by lactic acid inhibits the NLRP3 inflammasome and macrophage activation and M1 polarization	Sun et al.⁹⁵
	Macrophages and Tregs: The restoration of H3K9Ac by L.casei LH23 inhibits macrophages and inflammatory cytokines through suppressing JNK/p38, and induce an increase in CD3⁺CD4⁺CD25⁺ Tregs	Liu et al.¹⁰²
	Epithelial cells: Caprylic acid and nonanoic acid induce H3K9Ac to activate pBD-1 and pBD-2, and enhance intestinal epithelial barrier function	Wang et al.¹¹⁷

GBP5, guanylate-binding protein 5; GSNO, S-nitrosoglutathione; HDAC, histone deacetylase; IBD, inflammatory bowel disease; NO, nitric oxide.

To date, the FDA has approved five HDACis for use for the treatment of other diseases but not for IBD because of their relatively narrow therapeutic window, short half-life, and adverse events.⁵⁰ In a phase I study, panobinostat has been combined with a proteasome, carfilzomib, to treat relapsed/refractory multiple myeloma patients. It was found that the maximum tolerated regime is panobinostat 20 mg with carfilzomib 36 mg/m², and adverse events include thrombocytopenia, fatigue, and nausea/vomiting.¹²³ In a phase I/Ib trial, vorinostat has been combined with pembrolizumab, an inhibitor of the programmed cell death protein 1, in the treatment of advanced/metastatic non-small cell lung cancer. No patients showed dose-limiting toxicities but only fatigue and nausea/vomiting as adverse events. The recommended dose is vorinostat 400 mg with perbrolizumab 200 mg in this phase I study.¹²⁴ In another phase Ia study, bisthianostat, has been found to be well tolerated in multiple myeloma patients with no grade 3/4 nonhematological adverse events.¹²⁵ In previous clinical trials, HDACis are overall safe and the incorporation of HDACis into the therapeutic arsenal for IBD still needs to be explored further, with the aim of increasing patient longevity and improving quality of life.

Future prospects

It is very meaningful and significant for clinical treatment to explore more about the molecular mechanism of HDACs in IBD pathogenesis, including the correlation between HDACs and immunity, connection between HDACs and intestinal microbiota, etc. Furthermore, the ongoing challenge of searching for newer and more effective HDACis with minimal toxicity for IBD underscores the need for further continuous research. What is more, exploring novel therapeutic combinations are urgently needed for IBD treatment optimization, such as combinations of one or two HDACis with other classic treatment for IBD. As research progresses, we anticipate that the targeted application of HDACis will be integrated into the treatment paradigm for IBD, increasing the effectiveness and safety of treatment options for IBD patients.

Footnotes

Appendix

Acknowledgements

None.

Declarations

ORCID iDs

Chunxiao Li

Shaobo Gu

Yi Chen

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Histone deacetylase in inflammatory bowel disease: novel insights

Abstract

Keywords

Introduction

Histone deacetylases

HDAC inhibitors

Regulatory mechanism of HDACs in IBD

HDACs regulate T cell function

HDACs regulate B cell function

HDACs regulate macrophage function

HDACs regulate epithelial cell function

HDACs regulate other factors

Conclusion

Future prospects

Footnotes

Appendix

Acknowledgements

Declarations

ORCID iDs

References