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Niacin ameliorates ulcerative colitis via prostaglandin D2‐mediated D prostanoid receptor 1 activation

Abstract

Niacin, as an antidyslipidemic drug, elicits a strong flushing response by release of prostaglandin (PG) D2. However, whether niacin is beneficial for inflammatory bowel disease (IBD) remains unclear. Here, we observed niacin administration‐enhanced PGD2 production in colon tissues in dextran sulfate sodium (DSS)‐challenged mice, and protected mice against DSS or 2,4,6‐trinitrobenzene sulfonic acid (TNBS)‐induced colitis in D prostanoid receptor 1 (DP1)‐dependent manner. Specific ablation of DP1 receptor in vascular endothelial cells, colonic epithelium, and myeloid cells augmented DSS/TNBS‐induced colitis in mice through increasing vascular permeability, promoting apoptosis of epithelial cells, and stimulating pro‐inflammatory cytokine secretion of macrophages, respectively. Niacin treatment improved vascular permeability, reduced apoptotic epithelial cells, promoted epithelial cell update, and suppressed pro‐inflammatory gene expression of macrophages. Moreover, treatment with niacin‐containing retention enema effectively promoted UC clinical remission and mucosal healing in patients with moderately active disease. Therefore, niacin displayed multiple beneficial effects on DSS/TNBS‐induced colitis in mice by activation of PGD2/DP1 axis. The potential efficacy of niacin in management of IBD warrants further investigation.

Keywords: DP1 receptor, niacin, prostaglandin, retention enema, ulcerative colitis

Subject Categories: Digestive System, Immunology

Introduction

Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) characterized by recurrent episodes of active disease, which commonly affects the colon, the rectum, or both simultaneously. Histologically, it displays chronic inflammatory alterations limited to the mucosa and submucosa with cryptitis and crypt abscesses (Danese & Fiocchi, 2011). Despite UC‐related mortality being low, its morbidity remains high and 10–20% of affected individuals undergo colectomy. Although the UC etiology is largely unknown, accumulated evidence supports an interaction between genetic predisposition and microbial/environmental factors that trigger pro‐colitogenic perturbations of the host–commensal relationship and an aberrant mucosal immune response (Khor et al, 2011). Genome‐wide association studies (GWAS) have identified 47 genetic susceptibility loci for UC, 28 of which are shared between Crohn's disease (CD) and UC (Franke et al, 2010; Anderson et al, 2011). Indeed, these risk loci implicated in IBD are involved in different key signal pathways which are essential for intestinal homeostasis, such as epithelial restitution, barrier function, innate and adaptive immune regulation, microbial defense, cellular stress, and metabolism (Khor et al, 2011). Moreover, vascular injury including dilated vessels and increased vascular permeability also contributes to the inflammatory disorder of colonic mucosa in UC patients (Deng et al, 2013).

Niacin (nicotinic acid) is also known as vitamin B3 and serves as a precursor for coenzymes such as nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP), which are essential for living cells. Niacin has been used for more than five decades to treat dyslipidemia, because it reduces low‐density lipoprotein cholesterol (LDLc), very low‐density lipoprotein cholesterol (VLDLc), and triglycerides (TGs), and elevates high‐density lipoprotein cholesterol (HDLc) (Song & FitzGerald, 2013). The orphan G‐protein‐coupled receptor GPR109A, also known as hydroxycarboxylic acid 2 (HCA2) in mice, and as HM74A in humans, can be activated by niacin (Wise et al, 2003). The beneficial effect of niacin on free fatty acid and TGs is mediated by GPR109A suppression of lipolysis; however, the effects on HDLc and LDLc are not mediated by the GPR109A receptor (Bodor & Offermanns, 2008). GPR109A expression is markedly upregulated in macrophages upon inflammatory stimulation (Feingold et al, 2014). Moreover, emerging evidence demonstrated that niacin displays multiple anti‐inflammatory properties through GPR109A receptor activation (Holzhauser et al, 2011; Digby et al, 2012; Godin et al, 2012; Zandi‐Nejad et al, 2013; Zhou et al, 2014). Thus, the potential therapeutic efficacy of niacin on patients with UC warrants further clinical investigation.

One unpleasant side effect caused by niacin is cutaneous flushing. Niacin stimulates prostaglandin D2 (PGD2) release in both mice and humans (Hanson et al, 2010; Song & FitzGerald, 2013), which plays a central role in the niacin‐induced flushing. Low‐dose aspirin could depress niacin‐evoked PGD2 release and reduce the associated flushing (Cefali et al, 2007; Song & FitzGerald, 2013). PGD2 promotes the niacin‐evoked flushing through its specific D prostanoid receptor 1 (DP1). Blockade of DP1 receptor completely inhibits niacin‐induced vasodilation in mice and humans without affecting its effects on lipid metabolism (Cheng et al, 2006; Paolini et al, 2008; Maccubbin et al, 2009). In addition, PGD2 mediates active resolution of inflammation through DP1 receptor (Rajakariar et al, 2007; Kong et al, 2016). Interestingly, marked elevation of PGD2 production was observed in inflamed colon tissues from both UC patients and experimental colitis murine models (Ajuebor et al, 2000; Vong et al, 2010), which is associated with long‐term remission in humans (Vong et al, 2010). Yet, it remains to be determined whether niacin‐mediated protection against UC depends on PGD2 production.

In this study, we investigated the therapeutic effect of niacin on colitis both in mice and in patients with moderately active UC. We found that niacin shows anti‐inflammatory and anti‐apoptotic properties through downregulation of colonic inflammatory cytokine levels, suppression of vascular permeability, and inhibition of colonic epithelium apoptosis by activation of DP1 receptor in macrophages, endothelial cells, and colonic epithelium. Furthermore, treatment with retention enema containing niacin effectively promoted clinical remission and mucosal healing in patients with moderately active UC.

Results

Niacin boosts PGD2 generation in mice

To explore whether niacin protects against inflammatory bowel diseases (IBDs) through releasing PGD2, we first examined niacin‐induced PGD2 production in colon tissues and urinary secretion of PGD2 metabolites‐ 11,15‐Dioxo‐9α‐hydroxy‐2,3,4,5‐tetranorprostan‐1,20‐dioic acid (tetranor PGDM) from DSS‐induced colitis mouse model by using mass spectrometry analysis. Indeed, PGD2 production in homogenized colons and urinary tetranor PGDM was markedly elevated by niacin administration in DSS‐challenged mice in a dose‐dependent manner (Fig 1A and B). In addition, niacin treatment induced PGF2α product in colon tissues (Fig EV1A) and increased urinary metabolites of PGE2, PGI2, and PGF2α (Fig EV1B) in DSS‐challenged mice, indicating niacin may upregulate PG biosynthesis pathway. Accordingly, we observed niacin treatment upregulated cytosolic phospholipase A2 (cPLA2), COX‐2, and hematopoietic PGD synthase (hPGDS) in peritoneal macrophages (Fig 1C–E). However, niacin had no markedly influence on specialized pro‐resolving mediators (SPMs) in colon tissues from DSS‐challenged mice, such as lipoxin (LX) A4, resolvin (Rv) E1 (Fig EV1C).


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