Several biological activities of pomegranate have been widely described in the literature, but the anti-inflammatory effect in the gastrointestinal tract has not been reviewed till now. The aim of the present paper is to summarize the evidence for or against the efficacy of pomegranate for coping with inflammatory conditions of the gastro-intestinal tract. The paper has been organized in three parts: (1) the first one is devoted to the modifications of pomegranate active compounds in the gastro-intestinal tract; (2) the second one considering the literature regarding the anti-inflammatory effect of pomegranate at gastric level; (3) the third part considers the anti-inflammatory effect of pomegranate in the gut.
PG is used in the traditional medicine of different Asian cultures for the treatment of a variety of ailments. In India, Tunisia, and Guatemala, dried PG peels are decocted and employed both internally and externally as astringents and germicides and used for treating aphthae and diarrhoea. In Ayurvedic medicine the plant, described under its Sanskrit name “dadima” (fruit), is considered as a “blood purifier” and used to cure parasitic infections (for a review, see [
The biological activity of PG has been widely investigated, including
The gastrointestinal tract represents an important barrier between the human hosts and microbial populations. One potential consequence of host-microbial interactions is the development of mucosal inflammation, which can lead to gastritis and ulcer.
Gastritis is defined as inflammation of the gastric mucosa. There are several etiological types of gastritis, differing for clinical manifestations and pathological features. Gastritis can be caused by endogenous and exogenous factors, including acid, pepsin, stress, and noxious agents such as alcohol, nonsteroidal anti-inflammatory drug (NSAIDs),
Inflammatory bowel diseases (IBDs), among which Crohn’s disease (CD) and ulcerative colitis (UC), are the most common inflammatory-related diseases in the gut; IBDs occur in response to genetic or environmental factors and are characterized by the uncontrolled response of the intestinal immune system against the normal enteric microflora, leading to abdominal pain and chronic diarrhoea. All components of the gut, including the epithelial barrier, the mucosal immune system, and stromal/supportive cells, participate in the intestinal immune response. Immune and nonimmune cells, that is, epithelial, endothelial, mesenchymal, and nerve cells, exchange regulatory signals via the production of mediators (cytokines, growth factors, adhesion molecules, etc.), which facilitate and amplify cell interactions and inflammation [
Epithelial cells, in response to a proinflammatory stimulus, that is, TNF
Anti-inflammatory properties of PG and its major components have been widely described in the literature (for a review, see [
Although some papers describe the beneficial effects of this fruit against gastro-intestinal inflammation, surprisingly this has not been reviewed till now.
The aim of the present paper is to summarize the evidence for or against the efficacy of PG for addressing inflammatory conditions of the gastro-intestinal tract.
The paper will be divided in three parts: (1) the first one will be devoted to the modifications of PG active compounds in the gastro-intestinal tract, with particular attention to the intestinal metabolites; (2) the second one considers the literature regarding the anti-inflammatory effect of PG and individual compounds at gastric level; (3) the third part considers the anti-inflammatory effect of PG and individual compounds in the gut, taking into account also the main metabolites which are formed by microbial biotransformation after PG consumption.
PG has been shown to contain more than 100 different phytochemicals, and a substantial part of them contributes to the antioxidant activity elicited by the extracts [
Ellagitannins (ETs) and anthocyanins (ANs) represent the most abundant polyphenols in PG juice. ETs constitute a complex class of polyphenols characterized by one or more hexahydroxydiphenoyl (HHDP) moieties esterified to a sugar, usually glucose. ETs content in PG juice is around 1500–1900 mg/L [
ETs are quite stable under the physiological conditions of the stomach. The acid conditions (HCl, pH 1.8–2.0) and the gastric enzymes do not hydrolyse the native ETs to ellagic acid, and no degradation of ETs has been observed. The stomach seems to be a location for the absorption of free EA, but ETs are not absorbed [
In addition to ETs, PG fruit is an important source of ANs as well; these include the 3-glucosides and 3,5-diglucosides of delphinidin, cyanidin, and pelargonidin [
The pH of the stomach (1-2) ensures that ANs are maintained as the flavylium cation, which is the most stable form of ANs. The stability of ANs under the gastric conditions has been confirmed by
There are no clinical studies in the literature investigating the beneficial effect of PG in the stomach. The anti-inflammatory activity of PG at gastric level has been evaluated mainly by
A small number of studies report that PG is able to treat
Indeed, further studies with PG extracts alone and combined with drugs commonly used for
Some biochemical parameters, such as superoxide dismutase (SOD), catalase, tissue lipid peroxidation, and glutathione peroxidase (GSH-PX), were reduced in animals treated with acetylsalicylic acid and returned at the basal levels in animals that received the fruit rind methanolic extract [
Gharzouli et al. demonstrated that aqueous extract of PG peel (AEP) shows a gastroprotective effect in rats with ethanol-induced gastric lesions [
Among the pure compounds, Beserra et al. demonstrated that the oral pretreatment with EA (3, 10, and 30 mg/kg) significantly reduced gastric injury by 59, 79, and 70%, respectively, whereas the inhibitory effect by ranitidine (50 mg/kg) was −83% [
Nonprotein sulfhydryls (NP-SH) are antioxidant compounds involved in the maintenance of gastric integrity. They control the cascade of inflammatory cytokines and promote detoxification and excretion of ROS produced mainly by noxious agents and stress. Pretreatment with EA (3 and 10 mg/kg) significantly increased the NP-SH content in rats thus suggesting a protective role of EA against ethanol-induced gastritis [
TNF-
NO is considered to be one of the most important defensive endogenous agents in the gastric mucosa. Pretreatment with inhibitors of NO synthase such as L-NAME has been demonstrated to worsen the ethanol-induced ulcer. Rats pretreated with L-NAME increased the severity of the gastric lesions induced by ethanol, whereas treatments with L-arginine, in the absence or in the presence of EA, significantly attenuated the deleterious effect of L-NAME (−22% and −19.6%, resp.). When EA was coadministrated with L-arginine, the gastroprotective effect was found 2-fold higher (−39%) with respect to EA alone [
PG hydroalcoholic extract (methanol 70%) from powdered rind showed a significant UI reduction in rats treated with 400 mg/kg acetylsalicylic acid. The inhibitory effect showed by PG extract, at 250 and 500 mg/kg, was −22.4% and −74.2%, respectively, whereas ranitidine (50 mg/kg) showed 44.7% inhibition [
Prostaglandins produced by COX-1, mainly PGI2 and PGE2, are essential for gastric mucosa protection. The ulcerogenic effect of NSAIDs seems to be related to the inhibition of endogenous prostaglandin synthesis, although it has also been established that indomethacin modifies other protective mechanisms of the gastric mucosa, including gastric secretion and the permeability of the gastric mucosal barrier [
Hydroalcoholic (methanol : water 80 : 20) extract from powdered flowers of PG (980 mg/kg) showed significant prevention of gastric lesions in indomethacin-treated rats, higher inhibition of ulceration (83.9%), and reduced gastric acid secretion in comparison with omeprazole 20 mg/kg (69.5%). Although pure compounds were not tested during this study, the authors suggest that the anti-ulcerogenic activity of the extract may be due to the presence of saponins, tannins, and flavonoids [
The treatment with EA (3, 10, and 30 mg/kg) significantly decreased UI by 82, 74, and 77%, respectively, whereas the inhibitory effect, after treatment with cimetidine (100 mg/kg), was 88% [
The same study investigated the effect of EA on indomethacin-induced cytokines release in the gastric mucosa. Indomethacin administration increased the release of several cytokines, including TNF-
In acetic acid ulcer model the plasma levels of TNF
PG hydroalcoholic extracts (ethanol 50%) from peel (100 mg/kg), rind (500 mg/kg), and seed (500 mg/kg) significantly decreased the mucosal injury at the 6th day of treatment, showing the antiulcer effect [
Reduction of hemorrhagic lesions following gastric ischemia/reperfusion significantly started at 3 mg/mL of EA. The increased levels of lipid peroxidation induced by ischemia/reperfusion was significantly inhibited when animals were pretreated with either EA (6 mg/mL) or SOD (15000 unit/kg/hr), the inhibition being 78.3% and 82.6%, respectively [
In another study, topical application of NH4OH (60 mM) produced a persistent reduction of gastric potential difference in the stomach made ischemic by bleeding and resulted in hemorragic damage 1 hr later. The development of gastric lesions induced by NH4OH plus ischemia was dose-dependently inhibited by preexposure of the mucosa to EA (1–6 mg/mL), and a significant effect was observed at concentrations above 3 mg/mL [
Anti-inflammatory properties of PG and its major components have been widely described in the literature (for a review, see [
Both urolithins C and D as well as urolithin A demonstrated a high antioxidant activity
There are two main standardized methods to produce an experimental animal model of IBD: (i) oral administration of dextran sulphate sodium (DSS) in drinking water; (ii) intracolonic administration of trinitrobenzene sulfonic acid (TNBS). The use of DSS method mimics the development of UC, while symptoms manifested after TNBS treatment present the clinical and morphological features of CD.
In a rat model of DSS-induced UC, oral administration of EA using colonic delivering microsphere (containing 1–10 mg/kg of EA) significantly reduced the severity of colonic lesions and the shortness of colonic length. This activity could be accounted by the antioxidative action of EA, as demonstrated by the decreased myeloperoxidase (MPO) activity and lipid peroxidation in the colonic mucosa of animals treated with EA microspheres [
In a rat model of UC induced by 2,4-dinitrochlorobenzene (DNCB) and acetic acid, intragastric administration of an aqueous extract from PG peel (200–800 mg/kg) relieved diarrheic and ulcerative symptoms, decreasing MPO activity, lipid peroxidation, IL-1
In another study, the PG peel extract (PPE) demonstrated also to downregulate the expression of inflammatory genes (COX-2, IL-6, and IL-1
Pomegranate seed oil (PSO) is predominantly composed of triglycerides containing unsaturated fatty acids, as conjugated linolenic acids, oleic acid, linolenic acid, palmitic acid, and stearic acid. The major conjugated linolenic acid in PSO (representing 60 to 80% of total fatty acids) is punicic acid (PuA). Increasing evidence suggested that fatty acids with conjugated double bonds, such as PuA, exert beneficial effects in inflammation and some types of cancer [
Few
Unfortunately, no clinical studies coping with the anti-inflammatory activity of PG at the gastric level have been found, thus suggesting that the effect of the extracts and individual compounds in this area need to be elucidated. In particular, it is necessary to draw clinical trials considering the effects of PG extracts in patients with
Different preparations of PG, including extracts from peels, flowers, and seeds, in addition to the juice, show a significant anti-inflammatory activity in the gut. From all the studies taken into consideration in the present paper, some conclusions can be drawn. First of all, the pure compounds occurring in PG fruits seem to act through different pathways. Oil derived from PG seeds and its major component PuA could inhibit the expression of proinflammatory cytokines (such as IL-6, IL-8, IL-23, IL-12, and TNF-
The fellowship of E. Colombo is partially funded by FSE, Regione Lombardia. The authors thank Ms. Elda Desiderio Pinto for excellent administrative management.