Gastro-esophageal reflux disease (GERD) is among the most common chronic diseases in the Western world, affecting up to 30% of the general population in Europe and the US. It is a condition which develops when the acidic contents of the stomach flow backwards into the esophagus and cause what’s known as heartburn. While most patients respond well to the standard therapy of proton pump inhibitors which block acid-secreting cells in the stomach, we are still trying to understand the molecular reasons why 30-40% of reflux patients do not respond adequately to acid-suppressant therapy. Not only does GERD have a significant negative impact on health-related quality of life, but the over-subscription of ineffective drugs causes a significant economic burden on healthcare.

Heartburn is the most noticeable and troublesome symptom of GERD. From what we currently understand about the pathophysiology of the disease, we know that the reflux of acid evokes different types of pain, but the basic mechanisms and pathways by which this pain is generated is incompletely understood. The junction between the esophagus and stomach is structurally and functionally designed in a way to ensure that any acid secreted in the gastrointestinal tract flows towards the stomach, and not up onto the lining of the esophagus. This function is served by the muscle structure sitting at this junction, called the lower esophageal sphincter (LES), which ensures that the ingested food following a meal does not reflux. However, there are several factors which can make the LES’s job more difficult. One of the most obvious factors includes the excessive consumption of food, particularly during the later hours of the day. There is convincing evidence that 90% of reflux episodes occur post-prandially, due to minor elevations of intragastric pressure which causes the LES to relax and therefore allow the reflux of acid. In more advanced cases of reflux disease, acid pockets form at the gastroesophageal junction where unbuffered acid collects into a reservoir. When the LES fails in this setting, there is reflux of a higher volume of acid.

Focusing on the microscopic structure of the esophagus and stomach, we can see a minute yet essential difference between the linings of these two gastrointestinal organs. The esophagus has a stratified squamous epithelial lining, which acts as a tight protective barrier against food but is readily damaged when exposed to a chemical environment. On the other hand, the stomach is lined by tall columnar epithelium, which is designed to withstand very low pH and high levels of proteolytic activity. Our gastrointestinal tract (and the human body in its entirety) is perfectly designed to carry out the specific role of transporting food from the oral cavity from the esophagus to the stomach, where it is digested for our nourishment. It is oftentimes our greediness and overindulgence which disrupt the perfect order of our anatomy at a molecular level, resulting in the macroscopic changes we see at endoscopy and the symptomatic discomfort we feel from the painful circumstances of reflux. 

The stomach is our center of nourishment. Given that every food particle has the purpose of nourishing the cells of our body, why do we so commonly make the mistake of eating excessively, nocturnally, and quickly? Fatty foods influence the relaxation of the lower esophageal sphincter, along with alcohol, coffee, and acidic drinks. Large meals and rapid food intake distend the stomach, increase intragastric pressure and facilitating the reflux of acid from the stomach. Given these, it is plain to see that, in most cases, simple lifestyle changes can prevent the development of such chronic and discomforting diseases. The following verse in the Holy Qur’an offers a short but very effective prescription: “Eat and drink, but do not be wasteful” (7:31).

The philosopher and physician Ibn Sina (Avicenna) summarized the science of medicine as follows: “Eat little when you eat, and after eating do not eat again for a certain period of time; health lies in digestion. There is nothing heavier for the body to tolerate than putting food after food in the stomach.” Frugality in eating is also echoed in the teachings of Prophet Muhammad, peace be upon him, who famously said “There is no vessel which the son of Adam can fill more evil than his stomach, for it is sufficient for him to take a few mouthfuls in order to straighten his back; but if he must, then fill one-third with food, one-third with drink, and one-third with air” (Tirmidhi).

The lifestyle factors that are strongly associated with GERD are obesity and smoking. In the 30-40% of GERD patients who do not respond to acid-suppressant therapy, simple lifestyle changes such as cutting out acidic drinks and eating more slowly, and not after 7 pm have been effective alternative treatments. While our understanding of molecular pain mechanisms of the esophagus need further improvement, the simple act of making minor changes in our eating habits can ensure that the anatomy and function of our gastrointestinal tract remains optimal.

Hay and Su had been hungry for almost a week. Spring was in full bloom, and birds were chirping. Living in a cave was safer and warmer than outside, especially during the long winters. However, the food stock they had was almost finished. As the sun rose higher, the hunter-gatherer couple left their cave to find some food and hunt some animals to cook with the fire they had recently invented. As they searched for some fruit in the forest, they heard wood cracking and then a sudden loud growl from the bushes. The grizzly bear started to chase them, and they ran away quickly. They successfully ran back to their safe cave; however, during the chase, a tree branch scratched and wounded Su’s shoulder and she was severely bleeding. Hay first applied some ash to the wound to stop the bleeding; then he went out to the cliff, a smoking branch in his hand. He tied his rope ladder to a tree and climbed down the cliff. Once he reached the bee’s nest, he gently waved his smoky branch to numb the honeybees and collected their honey, pouring it into a carved stone. Then he rushed back to the cave, covered Su’s open wound with honey, and fed her the leftovers. The wound was closed within a couple of days without any significant inflammation, infection, or scar. Then Su and Hay carved their adventure into the wall of their cave, which is located in today’s Valencia, Spain, and was recently discovered by anthropologists – a mere 8000 years later.

Honey is a viscous, supersaturated sugar solution derived from nectar and honeydew. It’s gathered from flowers and modified by the honeybee, Apis mellifera. Honey is composed of more than 200 components, which are mostly carbohydrates (76%) and water (20%), as well as many other substances, such as amino acids, vitamins, minerals, organic acids, polyphenols, and enzymes. From ancient times, due to its high biological activity potential, honey has been used in wound care, infection control, and treatment of abdominal pains and skin and eye diseases. Thus, it was frequently mentioned in the early pharmacopeia of the Sumerians, Babylonians, Egyptians, Greeks, Romans, Indians, Chinese, Turks, Arabs, and other civilizations.

For the last two decades, scientists and healthcare professionals have studied the potential uses and benefits of honey. Cell assays, animal studies, and clinical trials have provided evidence for the use of medical grade honey in the control and treatment of wounds, cancer, diabetes, and asthma, as well as cardiovascular, neurological, and gastrointestinal diseases.

Medical grade honeys possess high bioactivity potential, which differs depending on the floral source, geographical origin, and harvest time. Worldwide, the most common honey types used for medical purposes are Manuka, Tualang, Gelam, Ulmo, Castanea (chestnut), Rhododendron (Azalea), Quercus (Oak), Acacia, Thyme, and Jungle.

Honey in wound treatment

A wound is, broadly, the destruction of the integrity of tissue, which may also include neighboring areas. This destruction can be either penetrating or non-penetrating, and induced by accidents, surgeries, or violence (Martinotti et al). Depending on the healing time, wounds are classified as acute or chronic. Generally acute wounds heal in a short and predicted amount of time without major complications. The chronic wounds take much longer to heal and present different complications such as infection, contamination of the wound bed, or ischemia, the limited supply of blood that carries oxygen and nutrients to the wounded tissue. The chronic wounds are also known as ulcers and can be grouped as pressure (bed sores), diabetic, venous, and arterial ulcers, which mostly result from chronic medical illnesses such as diabetes, atherosclerosis, thrombosis, paralysis, etc. (woundcarecenters.org). The process of wound healing is generally divided into four overlapping stages: homeostasis (seconds to minutes), inflammation (3-5 days), proliferation (4-14 days), and remodeling (8 days to 1 year) (Miguel 2017).

Different clinical trials and in vitro studies have reported the broad-spectrum antimicrobial properties of honey (Israili 2014). Moreover, honey provides hygroscopic, immunostimulatory, anti-inflammatory, and anti-oxidant properties, which are necessary for the healing of both infected and ischemic chronic wounds. Therefore, medical grade honey promotes the immune response, treats microbial infections, prevents cross-contamination, promotes autolytic debridement, balances inflammatory activity, stimulates growth of wounded tissue to hasten healing, and promotes the healing process in chronic wounds (Miguel 2017).

In a recent Cochrane review, which is considered as the highest standard in evidence-based clinical resources, Jull AB et. al. reviewed the evidence about the healing effects when applying honey on different kinds of wounds (Jull 2015). They analyzed 26 different clinical studies involving 3011 people with acute (e.g. burns, lacerations) and/or chronic (e.g. venous ulcers) wounds. Honey was compared with many alternative wound dressings and topical treatments in the included studies. They concluded that there is high quality evidence that honey heals partial thickness burns around 4 to 5 days more quickly than conventional dressings. There is also reasonable evidence that honey is more effective than antiseptic gauze for healing infected wounds (Jull 2015).

As a particular example, Yusoff KM and his colleagues treated 102 patients with untreatable chronic wounds with honey as a last resort. Most of these wounds were infected with pathogenic bacteria of 14 different strains, and two of them were antibiotic-resistant bacteria, which could not be treated using conventional antibiotics. Of the 102 patients, 100% of them were successfully cured with topical application of honey within 4 to 7 weeks of daily treatment. Moreover, limbs of the diabetic wound patients were saved from amputation after their ulcers were healed (Figure 1). 

Meanwhile, studies on different animal models provided evidence that honey accelerates wound healing in animals. Fifteen of the 16 controlled trials in five different animal models (mice, rats, rabbits, pigs, and buffalo calves) found that honey-treated incisional and excisional wounds, and that standard burns healed faster than control wounds (Jull 2015). 

Consequently, existing evidence from animal studies and clinical trials strongly suggests that medical grade honey has the potential to treat various types of wounds without causing any serious side effects.

Honey in cancer

Cancer is uncontrolled cell growth within a certain tissue or throughout the body due to mutations in the genome. As one of the major causes of death worldwide, more than 8.8 million deaths were reported in relation to cancer in 2015 (WHO). Meanwhile, cancer is not a disease occurring in one cell type only; there are more than 100 cancer types identified to date (cancer.gov). Both the genetic and environmental factors contribute to the development of cancer in different cells. There are three major steps when cancer attacks the body: initiation, proliferation, and progression. The normal cell transforms into a cancer cell due to an irreversible mutation within its genome; then it starts to replicate in an uncontrollable manner and forms a tumor mass; finally, these mutated cells invade the bloodstream and metastasize to different tissues within the body. Despite extensive research projects devoted to diagnosing and treating cancer, it remains as one of the least treatable diseases.

Conventional treatments for cancer are surgery, chemotherapy, radiotherapy, immunotherapy, and cellular therapy. Meanwhile, natural products with high anticancer potential are also being considered for research and treatment as complementary and integrative medicine (CIM) agents. Due to limitations of conventional methods, such as affordability and side effects, and promising evidence-based results of various CIM approaches, physicians and patients are getting more interested in CIM applications for the treatment of various cancer types.

Among the CIM agents, medical grade honey is one of the most promising natural products for treatment of some cancers due to its high bioactivity potential. Scientists studied the capacity of honey to both prevent tumor development and inhibit progression. Most of these studies were performed in vitro, using cell cultures in the lab. When tested on several types of human cancer cell lines (breast, prostate, liver, endometrial, cervical, lung, skin, kidney, bladder, oral squamous cell carcinoma, and osteosarcoma), honeys from diverse floral sources demonstrated potential anticancer activity (Ahmed S 2018, Erejuwa 2014). Moreover, several studies showed that different cancers, in animal models, were successfully treated with honey (Ahmed S 2018). It has been shown that honey provides antiproliferative, antitumor, antimetastatic, and anticancer effects via diverse mechanisms, including cell cycle arrest, the activation of mitochondrial pathways, induction of apoptosis, modulation of oxidative stress, amelioration of inflammation, modulation of insulin signaling, and inhibition of angiogenesis in cancer cells. It has also been shown that honey is highly and selectively cytotoxic against tumor or cancer cells while it is non-cytotoxic to normal cells. It can inhibit cancer development by modulating or interfering with the molecular processes or events of initiation, proliferation, and progression (Erejuwa 2014). In the PubMed, the largest database of biomedical research articles, there are almost 400 research papers and review articles published about the use of honey in cancer treatment. Moreover, there are more than 15 active clinical trials using honey for treatment of cancer and side effects of chemotherapy (Clinicaltrials.gov). Consequently, medical grade honey can be considered as a potential and promising anticancer agent which warrants further research—both in experimental and clinical studies.

Besides wound healing and cancer, honey is being actively studied for treatment of diabetes, neurological, cardiovascular, and metabolic disorders, as well as eye diseases.

REFERENCES

1. Jull AB, Cullum N, Dumville JC, Westby MJ, Deshpande S, Walker N. Honey as a topical treatment for wounds. Cochrane Database Syst Rev. 2015; 3:CD005083.
2. Martinotti S.; Ranzato, E. Honey’s healing history. In Cellular and Molecular Mechanisms of Honey Wound Healing; Nova Publishers Inc.: Hauppauge, NY, USA, 2014
3. Ahmed S, Sulaiman SA, Baig AA, Ibrahim M, Liaqat S, Fatima S, Jabeen S, Shamim N, Othman NH. Honey as a Potential Natural Antioxidant Medicine: An Insight into Its Molecular Mechanisms of Action. Oxid Med Cell Longev. 2018 Jan 18. doi: 10.1155/2018/8367846.
4. Israili ZH. “Antimicrobial properties of honey,” American Journal of Therapeutics, vol. 21, no. 4, pp. 304–323, 2014.
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10. World Health Organization (WHO). http://www.who.int/cancer/en/ – accessed 6/17/2018
11. National Cancer Institute (NCI) https://www.cancer.gov/about-cancer/understanding/what-is-cancer#types – accessed 6/17/2018
12. Erejuwa OO, Suleiman SA, Ab Wahab MS. Effects of Honey and Its Mechanisms of Action on the Development and Progression of Cancer. Molecules 2014, 19(2), 2497-2522; https://doi.org/10.3390/molecules19022497
13. Ahmed S and Othman NH. Honey as a Potential Natural Anticancer Agent: Review of Its Mechanisms. Evidence-Based Complementary and Alternative Medicine Volume 2013. http://dx.doi.org/10.1155/2013/829070
14. https://clinicaltrials.gov – accessed on 6/18/2018

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