by Dr. Miles Nichols and Aaron Mello, CNTP, MNT

Pomegranate fruit has long been held sacred by many of the world’s major religions and the pomegranate tree is said to have flourished in the Garden of Eden. The history and mythology of pomegranate would easily fill its own blog post, and not without reason: the fruit contains very high levels of powerful antioxidants, some of which are unique to the pomegranate. This antioxidant powerhouse has been shown in research to offer protection against cardiovascular disease (CVD) through its ability to neutralize free radicals and improve several markers related to CVD. In addition, pomegranate has positive effects on gut microbiota and detoxification.

In this post I will review the research on pomegranate’s health benefits, especially as they relate to cardiovascular disease. Regular consumption of pomegranate has clear cardioprotective benefits that are difficult to obtain from other foods and nutraceuticals. Because of the fruit’s extremely high levels of antioxidants, several of which are unique to the pomegranate, it’s easy to see why it has been revered for millennia. Keep reading to learn more about how to use pomegranate medicinally, both in the prevention and reversal of cardiovascular disease, as well as its applications in other areas of health such as modulation of the gut microbiota.

History of pomegranate

Before delving into the details of pomegranate’s health benefits, let’s look briefly at humanity’s lengthy history of consumption and even reverence for the pomegranate tree. Pomegranate probably originated in ancient Iran and Afghanistan. In Zoroastrianism, one of the world’s oldest monotheistic religions which was founded in ancient Iran about 3500 years ago, pomegranate was used in ritual and domestic observances (1). Many references to pomegranates can also be found in Judaism, in which pomegranate symbolized sanctity, fertility and abundance (2). In Buddhism, the pomegranate is one of the three blessed fruits and in Buddhist legend, the demoness Hariti who devoured children was cured of her evil habit when she was given pomegranate to eat by the Buddha. In China, pomegranate is widely used in ceramic art to symbolize fertility, abundance, and a blessed future (3). Pomegranate is also a symbol of resurrection, life and fertility in Christian art, and is often found in devotional statues and paintings of the Virgin and Child.

Antioxidant effects of pomegranate

Pomegranates are high in polyphenolic flavonoids, which are powerful antioxidants. The most well-known and important group of flavonoids are anthocyanins, which are water-soluble plant pigments that are responsible for the red, blue and purple colors of flowers and fruits. The primary antioxidant components of blueberries, cherries and the grapes that make red wine fall in this category. Other flavonoids are anthoxanthins, which are colorless or white to yellow and include flavanols, isoflavones, ellagic tannins and catechins. Both categories of flavonoids act as potent inhibitors of low-density lipoprotein (LDL) oxidation. They also attenuate macrophage foam cell formation and, as a result, prevent and slow the progression of atherosclerosis (4).

Superior antioxidative capacity of pomegranate

Pomegranate fruit and juice contain a higher concentration of polyphenols than other well-known antioxidant sources like green tea and fruit juices including orange, grapefruit, grape, cranberry, pear, pineapple and peach. In fact, one study found that pomegranate juice (PJ) contains three times the antioxidant levels of red wine, which is often touted as being a great source of antioxidants. This study also showed that pomegranate juice had three times the antioxidant activity of green tea (5). Another study which compared the antioxidant content of several beverages including pomegranate juice, apple juice, Concord grape juice, blueberry juice, acai juice, red wine, green tea, and others found that the antioxidant activity of PJ was at least 20% higher than any of the other beverages tested (6). It is this high concentration of antioxidants that explains why pomegranate is so effective at preventing and slowing the development of atherosclerosis.

Reduction of atherosclerosis

An important antioxidant in pomegranate is punicalagin, an ellagitannin which is believed to be primarily responsible for the very high antioxidant activity of the juice. Punicalagin has been shown to be a very potent inhibitor of LDL oxidation and atherosclerosis development in both mice and humans. There are three pathways by which pomegranate polyphenols protect LDL against oxidative damage. First, they directly reduce the ability of macrophages to oxidatively modify LDL by scavenging reactive oxygen species. Second, polyphenols accumulate in arterial macrophages, where they inhibit macrophage lipid peroxidation. Third, pomegranate polyphenols increase serum praoxonase (PON) activity, which increases hydrolysis of lipid peroxidases in oxidized lipoproteins and atherosclerotic lesions (7).

Paraoxonase 1 (PON1)

PON1 is an enzyme that protects HDL and LDL from oxidation, and its activity is increased by PJ consumption. Multiple studies on healthy subjects (8) as well as patients with carotid artery stenosis (9) and type 2 diabetes(10) found that PJ consumption was followed by an increase in serum PON1 activity. Another study on type 2 diabetic patients found similar results and also observed that consumption of PJ did not have significant negative effects on fasting blood glucose or HbA1c (10), which would be a concern in patients with metabolic syndrome and diabetes. This finding appears to support the use of PJ in diabetic patients at risk for cardiovascular disease, despite its sugar content.

Pomegranate and ox-LDL

Oxidized LDL, or ox-LDL plays a significant role in the progression of atherosclerosis. LDL which is oxidized by macrophages to create foam cells, and ultimately athersclerotic plaque is a major mechanism by which many forms of cardiovascular disease develop. Elevated serum ox-LDL is associated with accelerated atherogenesis, coronary artery disease (CAD), acute myocardial infarction and angina. High ox-LDL is also associated with metabolic syndrome, impaired glucose tolerance and insulin resistance. Reducing ox-LDL is another mechanism by which PJ appears to offer protective benefit against cardiovascular disease, as it has been demonstrated to inhibit LDL oxidation, macrophage foam cell formation and atherosclerosis. Furthermore, as I mentioned in the previous section, PON detoxifies oxidized LDL, which has a protective effect on the cardiovascular system and reduces the incidence of atherosclerosis. Because PJ upregulates the expression of the PON1 enzyme, it helps to reduce ox-LDL (11).

Intima media thickness

In addition to pomegranate’s positive effects on PON and LDL, it helps to reduce intima media thickness, which is a predictor of vascular events like stroke and myocardial infarction. This metric is used to detect the presence of atherosclerotic plaque and to track the progression of atherosclerosis. One randomized, double-blind, placebo-controlled study evaluated changes to carotid intima media thickness (CIMT) in subjects who drank 240ml of pomegranate juice per day for up to 18 months. Although no significant changes in the progression of CIMT were observed between the PJ and control group in patients at moderate risk of coronary heart disease, CIMT thickening progression was slowed in subjects with increased oxidative stress and disturbances in the triglyceride-rich lipoprotein/HDL axis (12). These results appear to support the role of PJ in reducing intima media thickness by reducing oxidative stress.

Another study on patients with carotid artery stenosis (CAS) found somewhat more impressive results. After 12 months of PJ supplementation compared to no PJ consumption, CIMT decreased 30% in the PJ group, whereas it increased by 9% in the control group. In addition, in the in the PJ group serum PON1 activity increased 83%, serum LDL basal oxidative state decreased by 90% and LDL susceptibility to copper ion-induced oxidation was reduced by 59%. Serum anti-oxLDL antibodies also decreased by 19%, and systolic blood pressure was reduced by 12%. The authors conclude that CAS patients benefit from the potent antioxidant properties of PJ polyphenols (13).

Pomegranate supports nitric oxide

Another way pomegranate supports antioxidant activity is by promoting the production of nitric oxide (NO). NO has many antioxidant and anti-inflammatory properties, including scavenging some reactive oxygen species, preventing LDL oxidation, and supporting a healthy endothelial lining in blood vessels (14). These effects help reduce the progression of atherosclerosis, and pomegranate helps to enhance the cardioprotective actions of nitric oxide. One in vitro study found that pomegranate juice dramatically increased nitric oxide production, which helps reduce LDL oxidation (15). Another cardiovascular benefit of pomegranate is its ability to protect the vascular endothelium from shear stress imparted by high blood pressure, narrowing of the arteries and disrupted blood flow (16). In addition, pomegranate even shows promise in improving endurance in cardiovascular exercise like running. This is good news for people who want to improve their athletic endurance. A double-blind, placebo-controlled study found that taking pomegranate extract 30 minutes before exercise increased the length participants were able to run on a treadmill and suggest that pomegranate may enhance blood vessel diameter and blood flow (17).

Liver and detoxification

In addition to its cardioprotective benefits, pomegranate’s antioxidant benefits are also hepatoprotective, or liver supporting. These antioxidants help prevent hepatocytes (liver cells) from oxidative damage. An in vitro (petri dish) study found that polyphenol-rich pomegranate flower extract scavenged several reactive oxygen species (ROS) including superoxide, hydrogen preoxide and hydroxyl radicals. The same study also evaluated in vivo the ability of pomegranate extract to protect against oxidative stress and hepatic injury in mice. In a ferric nitrilotriacetate (Fe-NTA) model, pretreatment with pomegranate flower extract significantly and dose dependently provided up to 60% protection against hepatic lipid peroxidation. It also preserved glutathione (GSH) levels and activities of antioxidant enzymes including catalase, glutathione peroxidase, glutathione reductase and glutathione-S-transferase. Liver enzyme markers aspartate aminotransferase (AST) and alanine aminotransferase (ALT), as well as bilirubin also improved with the use of pomegranate flower extract. The researchers conclude that the antioxidant content of pomegranate probably accounts for the hepatoprotective properties (18).

Another mouse study investigated the hepatoprotective effects of pomegranate peel extract and pomegranate seed extract in preventing liver fibrogenesis. The control mouse group with fibrosis that did not receive any treatment experienced increased levels of AST, ALT and bilirubin, and these effects were attenuated in the active pomegranate extract group. The pomegranate extract also restored superoxide dismutase (SOD) and glutathione peroxidase activities and inhibited the formation of lipid peroxidized products. Pomegranate extract also decreased levels of TGF-β1 and inhibited excessive collagen synthesis, which reduced the incidence of liver fibrosis. Similar to the previous study, the authors of this research conclude that the antioxidant activity of pomegranate accounted for its hepatoprotective qualities (19).

It’s worth noting that both of these last two studies used extracts of pomegranate flowers, peels and seeds, as opposed to the fruit (or fruit juice) itself. Because the fruit is also high in many of the same polyphenols, it may confer similar benefits, but the research on liver support did not use fruit or fruit juice.

Gastroprotective effects

I mentioned ellagic tannins earlier in this post, which are anti-inflammatory polyphenols that are also gastroprotective, or beneficial to the health of the stomach. One rat study evaluated the effects of ellagic acid on acute and chronic ulcer models and found that ellagic acid significantly prevented stomach ulceration induced by ethanol, indomethacin and acetic acid. Several gastroprotective mechanisms were observed. Ethanol-induced ulcer was alleviated due to ellagic acid increasing endogenous production of nitric oxide. In indomethacin and acetic acid induced ulcers, gastroprotection resulted from reduced levels of inflammatory cytokines like leukotriene B(4), TNF-α, interferon-γ and interleukins-4 and -6 (20). Similar to the benefits noted for other health problems, the gastroprotective effects appear primarily to stem from the antioxidant power of the polyphenols.

Pomegranate and the microbiota

As I mentioned in the introduction, pomegranate also has positive effects on the human microbiota, or gut microbes. In fact, it’s interesting to note that the majority of polyphenols are not absorbed in the small intestine (21). Somewhat amazingly, only about 5-10% of pomegranate polyphenols are absorbed in the small intestine (22). The remaining 90-95% continue on to the large intestine where they modulate the composition of the gut microbial community, primarily through the inhibition of pathogenic bacteria and stimulation of beneficial bacteria (23). In the large intestine, polyphenols and the microbiota have a reciprocal relationship. Polyphenols influence the microbiota, and the microbiota also impacts polyphenols by transforming them into metabolites that have greater biological activity than their precursor structures (24). The complex relationship between different polyphenols and the microbiota is still being illuminated. But from what we already understand, it’s clear that the health benefits of pomegranate extend far beyond those conferred by the polyphenols that are absorbed and make their way into systemic circulation.