Role of Honey in Topical and Systemic Bacterial Infections

Abstract

Background:

The development of bacterial resistance to antibiotics has made it more difficult and expensive to treat infections. Honey is getting worldwide attention as a topical therapeutic agent for wound infections and potential future candidate for systemic infections.

Objectives:

The purpose of this review was to summarise different antibacterial bio-active compounds in honey, their synergistic interaction and their clinical implications in topical and systemic infections. In addition, contemporary testing methods for evaluating peroxide and non-peroxide antibacterial activity of honey were also critically appraised.

Design:

MEDLINE, EMBASE, Cochrane Library, Pub Med, reference lists and databases were used to review the literature.

Results:

Honey contains several unique antibacterial components. These components are believed to act on diverse bacterial targets, are broad spectrum, operate synergistically, prevent biofilm formation, and decrease production of virulence factors. Moreover, honey has the ability to block bacterial communication (quorum sensing), and therefore, it is unlikely that bacteria develop resistance against honey. Bacterial resistance against honey has not been documented so far. Unlike conventional antibiotics, honey only targets pathogenic bacteria without disturbing the growth of normal gastrointestinal flora when taken orally. It also contains prebiotics, probiotics, and zinc and enhances the growth of beneficial gut flora. The presence of such plethora of antibacterial properties in one product makes it a promising candidate not only in wound infections but also in systemic and particularly for gastrointestinal infections. Agar diffusion assay, being used for evaluating antibacterial activity of honey, is not the most appropriate and sensitive assay as it only detects non-peroxide activity when present at a higher level. Therefore, there is a need to develop more sensitive techniques that may be capable of detecting and evaluating different important components in honey as well as their synergistic interaction.

Conclusions:

Keeping in view the current guidelines for treatment of diarrhea, honey is considered one of the potential candidates for treatment of diarrhea because it contains a natural combination of probiotics, prebiotics, and zinc. Therefore, it would be worthwhile if such a combination is tested in RCTs for treatment of diarrhea.

Introduction

Honey has been largely used as food as well as therapeutic agent throughout the history, across a broad and diverse array of communities.¹ The antimicrobial properties of honey along with activation of immune system and healing process are one of the main reasons for its worldwide popularity.^2,3 However, despite its long history as medicine, honey was not recognized as a therapeutic agent by modern medicine until recent past, probably due to incomplete understanding of its mechanism and spectrum of antibacterial activity.⁴

A number of studies in the last two decades have looked into identification, mechanism of action, and synergistic nature of its bioactive compounds.^4

–7 Thereby, honey has recently become part of conventional medicine for wound care.^8
–10 However, currently only a limited number of honey brands (Manuka, Medihoney) are available for treatment of wound infections.^11,12 This recognition is due to the high nonperoxide antibacterial activity, identified specifically in Manuka honey.¹³ It has been standardized according to phenol equivalence and labeled as Unique Manuka Factor (UMF).¹³

Subsequent studies reveal that the nonperoxide activity of Manuka honey is mainly because of plant-derived bioactive compound, methylglyoxal.¹⁴ However, there is a small difference (<5%) between antibacterial activity of UMF honeys and other honeys as observed by minimum inhibitory concentration (MIC) assay.¹⁵ The significance of these differences in a clinical setting is also not clear. Furthermore, bacterial resistance was not induced against both UMF and non-UMF honey.⁴ These reports raise the question, whether the UMF rating system is a real index of overall antibacterial activity of honey and whether it is actually or always the best available honey.

A number of studies have revealed that honey also contain probiotics, prebiotics, and zinc along with multiple antibacterial substances.^16

–20 The presence of such valuable substances in honey has significant clinical implications regarding treatment of diarrhea, since the current treatment guidelines for diarrhea discourage the use of antibiotics and instead recommend the use of probiotics, prebiotics, and zinc along with rehydration therapy.^21

–24 This further expands the role of honey beyond topical application to systemic use, particularly for gastrointestinal disorders. In this review, implications of the above findings are discussed in topical and systemic clinical infections, along with recent advancements in understating of the multiple antibacterial compounds and their synergistic interaction that play their part in therapeutic effects of honey.

Antibacterial Components in Honey

The antimicrobial activity of honey is mainly derived from hydrogen peroxide generated by glucose oxidase (bee origin), its acidity (pH between 3.2 and 4.5), osmotic effect of its high sugar content, and a variety of nonperoxide factors (plant origin).^2,25 The water activity (aw) of “super-saturated” sugar solution in honey is around 0.6, while most bacteria required 0.94 and above. This level is well below the threshold needed for bacterial growth.²⁶ The osmotic pressure of high sugar content in honey draws water from bacterial cells and makes them dehydrated and deprives them from the most essential requirement of life.²⁷

The acidity of honey also contributes in preventing the growth of bacteria. Low pH of honey is due to the presence of several different organic acids. These are formed in honey from conversion of glucose and water into the gluconic acids and hydrogen peroxide by bee-generated glucose oxidase enzyme.²⁸ However, there is tremendous variation in the content and concentration of these components in different types of honey.¹³ Therefore, honey from different sources is found to be unique in its composition, aroma, color, taste, and level of antimicrobial activity. For the purpose of simplification and understanding different types of honey, the contents can be classified into hydrogen peroxide and nonhydrogen peroxide antibacterial components.

Hydrogen Peroxide

Hydrogen peroxide is generally considered to be the main contributor for antibacterial activity of honey, and is present in most of them in variable concentrations.^29,30 However, the quantity of H₂O₂ in honey is about 400–4000 times fewer than needed for bacteriolysis.³¹ Glucose oxidase is found to be in an inactive state in undiluted honey.²⁵ On dilution, this enzyme converts water and sugar into hydrogen peroxide.² This makes undiluted honey an ideal therapeutic agent for wound care, as exudate from the wound dilutes it, thereby enhancing its antibacterial activity. The dilution at which honey produces its highest hydrogen peroxide activity is between 40% and 60%.³² Unlike H₂O₂-induced cytotoxicity in isolation, honey is cytocompatible and has no tissue detrimental effects due to the production of optimal levels of H₂O₂ when applied on wounds.³³

The concentrations of hydrogen peroxide present in several disinfectants are between 3% and 30% (0.8–8 mol/L) in comparison with some Canadian honeys (0.002 mol/L).³⁴ It has been shown recently that hydrogen peroxide activity is augmented by other unknown polyphenols present in honey.³⁵ More recently, a synergistic interaction between H₂O₂, polyphenols, and transition metals was identified in honey, which is responsible for phenolic auto-oxidation and release of radical species and thus causing bacterial DNA degradation. The DNA degrading potential of the tested honeys was closely linked to the redox capacity of polyphenols and total phenolic content.³⁶ The polyphenols possess higher oxygen radical quenching ability and are effective antioxidants.³⁷

The polyphenols generate OH from H₂O₂ via Fenton reaction in the presence Fe(II) or Cu(I)⁶, and interestingly, honey contains all the needed substrates for the generation of Fenton activity.³⁸

The antimicrobial impact of OH is stronger compared to H₂O₂ because the former cannot be neutralized by any enzyme.⁶ Conversely, H₂O₂ is less active and can be destroyed be antioxidants.³⁸ Higher amounts of hydrogen peroxide and polyphenols are present in Canadian buckwheat honey.⁶ Considering the importance of OH, it could be another indicator for evaluation of antibacterial activity of honeys before using them as therapeutic agent for infected wounds and burns.⁶ However, presently, the nonperoxide antibacterial activity of Manuka honey is considered more important, which has been standardized according to phenol equivalence and designated as UMF by agar well diffusion assay.^13,39

The agar well diffusion assay is widely used for evaluating antibacterial activity of honey against bacterial pathogens^13,40
–42; however, the assay has a number of limitations. These include lack of sensitivity, and large-sized plant-derived bioactive compounds present in honey may not be able to diffuse at all or diffuse very slowly and thus missed by this technique.⁴³ For instance, polymyxin, a well-known large antibiotic poorly diffuses in the diffusion test, and therefore, more sensitive assays such as the broth dilution assay or agar dilution assay are used for its testing.⁴⁴

As the diffusion of honey is a slow process and the honey sample is further diluted by diffusion process into the agar, bacteria can grow on the outer area before the inhibitory substance reaches them.⁴⁵ Moreover, nonpolar substances may not readily diffuse through water-based agar.⁴⁶ A study revealed that there is lack of clear relationship between zone size obtained through agar diffusion assay and MIC evaluation in dilution methods.⁴¹ These reports highlight that agar diffusion assay may not be the most appropriate method for assessing antibacterial activity of honey.⁴¹ Therefore, the results obtained through agar diffusion assay are not truly representative of overall antibacterial activity of any honey.

Reproducibility of UMF rating system has been facing some criticism as well because of insensitivity of agar diffusion assay.⁴⁷ Moreover, the UMF rating system may not in essence be a real index of the overall or synergistic antibacterial activity of honey, since it only measures the partial or nonperoxide antibacterial activity, ignoring the synergistic interaction of H₂O₂ and OH radicals with other factors in honey. Comparison between clinical effectiveness of Manuka honey and high hydrogen peroxide-containing honey, such as ulmo, buckwheat, jarrah, beri, garanda, and black seed honey, to treat wound infections is not evaluated yet and therefore is an important area for future research.^{29,40,42,48,49} A list of medicinal honey products for management of wounds is shown in Table 1.

Table 1.

List of Medicinal Honey Products for Wound Management Showing Their Laboratory and Clinical Evidences

Type of honey	Products available	Laboratory evidence	Clinical evidence
Manuka honey	Medihoney dressings (tulle, HCS, apinate), gel, cream	Cooper et al.¹²¹; George and Cutting¹²³	Gethin and Cowman¹²²; Biglari et al.¹²⁴
L-Mesitran honey	L-Mesitran^® wound dressings (tulle, border, hydro), net, ointments	Boekema et al.⁵⁰	Thomas et al.¹²⁵
Surgihoney	Surgihoney RO^™ wound gel	Dryden et al.¹²⁶	Dryden et al.¹²⁷
Revamil honey	Revamil dressing, gel, balm	Kwakman et al.¹²⁸	Kwakman et al.¹²⁹
Beri honey	Beri honey dressing, cream	Hussain et al.⁹⁷	Imran et al.¹³⁰
Tualang honey	Aquacel-tualang honey dressing	Nasir et al.¹³¹	Nawfar et al.¹³²

HCS, hydrogel colloidal sheet.

It has been shown that Manuka honey contains an active ingredient, methylglyoxal (MGO), which is responsible for the nonperoxide antibacterial activity.¹⁴ Based on this research, Manuka honey is also marketed with precise labeling of its MGO concentration. However, MGO is not the sole antibacterial agent rather represents only half of the nonperoxide activity of Manuka honey, as an unidentified synergism exists between MGO and other plant-derived nonperoxide factors.³⁹

Therefore, there is need of more sensitive and appropriate assays that take care of both peroxide and nonperoxide factors and their synergistic interaction. In this context, time-kill assay can be performed in which different dilutions of honey are mixed with bacteria and surviving bacteria are followed in time (hours) by means of CFU, allowing comparison of different honey sources or products.⁴¹ Alternatively, in vitro human wound models can also be used successfully to study the effect of topical treatments, including honey. This model allows monitoring any cytotoxic effects and re-epithelialization of wound induced by topical applications besides evaluating their antibacterial potential.⁵⁰

Nonperoxide Antibacterial Components

Phenolic compounds, derived from plant nectar, are considered important components of nonperoxide antibacterial potential of honey. A number of phenolic compounds have been recognized in honey.^51,52 Such compounds are methylglyoxal, glycoproteins, fatty diacid glycoside derivatives, leptosin, lysozyme, pinocembrin, 1,4-dihydroxybenzene, flavonoids, and so on.^{14,53

–58} The activity of each of these components individually is too low to have clinically relevant effects, however, their combined activity contributes significantly to the antimicrobial activity.⁵⁸ Unlike hydrogen peroxide, these components retain their antibacterial activity on heating or catalase treatment. However, their presence and concentrations are markedly variable, depending on floral source and other factors.⁵⁹

As mentioned earlier, MGO is recognized as one of the bioactive compounds in Manuka honey, previously designated as UMF.¹⁴ MGO is capable of inhibiting the growth of pathogenic bacteria at 0.3 mmol/L concentration and bactericidal at 0.6 mmol/L in culture medium.⁶⁰ Mavric et al. demonstrated that the minimum concentration needed for inhibition of bacterial growth is 1.1 mmol/L for both Escherichia coli and Staphylococcus aureus by an agar well diffusion assay.¹⁴ The protective effect of MGO is also observed in rat gastric mucosa pretreated with 80% ethanol, 25% NaCl, and 0.2% NaoH. The effect is probably mediated through increase in mucous production and scavenging of free radical.⁶¹ MGO exerts its antibacterial effect by forming glutathione adducts in the bacterial cytoplasm and reacts with thiol group of proteins, inhibiting enzymatic activity and subsequently rendering protein nonfunctional.⁶⁰

Considering the antibacterial properties of MGO, it can be a potential antibiotic in future. However, developing MGO as antibiotic has certain limitations. Since MGO is a small, simple molecule, it may induce bacterial resistance in the same manner as other antibacterial agents.⁶² However, antibiotic based on combination of synergistic compounds could slow or prevent bacterial resistance.⁶³ Recently, researchers identified a number of constituents in medicinal plant goldenseal (Hydrastis canadensis) that interact synergistically to enable H. canadensis extracts to fight bacteria by using “synergy directed fractionation assay.”⁶⁴ This assay can also be utilized to identify more synergistic compounds in honey and their synergistic interaction.

Lately, bee defensin-1 was identified in Revamil honey.²⁸ It is a cationic antibacterial peptide and is an essential constituent of bee defense system. It was detected in honeybee hemolymph head, royal jelly, and thoracic glands.⁵⁸ The peptide has effective antibacterial activity against S. aureus and Bacillus subtilis.⁶⁵ The H₂O₂ and bee defensin-1 were considered to be main compounds involved in antimicrobial activity of Revamil honey.²⁸ Brudzynski et al. have shown that glycoprotein is one of the important active molecules in buckwheat honey that have a broad-spectrum antibacterial activity against multidrug-resistant pathogenic bacteria.⁶⁶ The glycoproteins may also serve as a potential candidate for developing a novel antibacterial drug.

Mechanisms of Action

Molecular and cellular studies have revealed that honey exhibits a unique multifaceted antibacterial activity against pathogenic bacteria.^4,28 It has been revealed recently that buckwheat honey and ampicillin induced identical morphologic changes to the cell wall of E. coli.⁶⁷ The antibacterial activity of honey is not limited to bactericidal effect rather it disrupts quorum sensing, biofilm formation, and expression of virulence factors.²⁶ It is observed that there are differences in the pattern of gene expression in E. coli microarrays following exposure to Manuka honey in comparison to antibiotics. Both types of honey, that is, peroxide honey and nonperoxide honey, are effective in preventing bacterial resistance.⁴

Honey showed multifactorial bactericidal activity when its individual bactericidal factors were selectively neutralized. This approach unraveled that MGO, bee defensin-1, and H₂O₂ have distinct mechanisms as potent antibacterial factors in Revamil honey.²⁸ The approach can also be utilized to screen novel bactericidal factors in other types of honey. It has been found by transmission electron microscopy that the growth of honey-exposed bacterial cells was unable to proceed normally and arrested at the point of cell division with completely formed septa without sorting out.⁶⁸ Autolysins (murein hydrolases) were responsible for this effect.⁶⁹ Persistence of the septa and failure to complete the cell cycle are considered to be due to lack of peptidoglycan to cleave.⁷⁰ In addition, a recent study revealed that on exposure to Manuka honey, universal stress protein A was not expressed fully.⁶⁹

Multiple cellular effects were observed in E. coli structure via transcriptome analysis on exposure to Manuka honey.⁴ Recently, a proteomic study indicated that Manuka honey caused differential expression of 12 cellular proteins in S. aureus.⁷¹ Manuka honey has shown to bring on extensive blebbing of Pseudomonas aeruginosa cell wall, eventually resulting in cell lysis.⁷² Recently, Jenkins et al. demonstrated that genes implicated in the virulence, quorum-sensing, tricarboxylic acid cycle, and cell division show decreased expression. Marked reductions of virulence genes and downregulation of global regulators were also observed.⁷³ These studies reveal that honey has a unique and multidimensional mode of action.

Research has shown that honey has the ability to prevent the development of biofilm produced by strains of Proteus mirabilis, Enterobacter cloacae, Staphylococcus epidermidis, and S. aureus.^5,74,75 The ability of S. enteritidis to attach on intestinal epithelial was inhibited by honey.⁷⁶ The result shows that honey can prevent the attachment of pathogenic bacteria on host cells. More recently, a decrease in the expression of streptococcal fibronectin binding surface adhesions involved in biofilm growth, commonly associated with chronic infection, is observed following honey treatment.⁷⁷

Bacterial resistance against honey has never been observed and reported so far, thus making it a promising antibacterial agent for pan-resistant and multiresistant infection. A study has revealed that P. aeruginosa and S. aureus were unable to generate resistance against honey, whereas they developed resistance to antibiotics readily under the same conditions.⁴ However, recently it has been shown for the first time that bacterial isolates from biofilm developed resistance against Manuka honey.⁷⁸ The bacteria are highly interactive and via quorum sensing can generate mutations under stressful conditions and eventually become antibiotic resistant, form biofilm, and produce a number of virulence factors.⁷⁹ Therefore, disruption of bacterial communication is an important strategy to slow or prevent bacterial resistance.

Honey has shown to inhibit quorum sensing in Chromobacterium violaceum by inhibiting the production of acyl-homoserine lactones.⁸⁰ Most of the previous studies have shown that a higher concentration of honey is required to disrupt quorum sensing and biofilm.^77,80,81 However, a recent study revealed that the concentration of honey as low as 0.5% could reduce biofilm formation and the expression of quorum-sensing genes and virulence genes in E. coli O157:H7.⁸² The quorum-sensing inhibitors are a good choice for developing such antibiotics, which could avoid generation of bacterial resistance.⁸⁰

Use of Honey in Topical Infections

Honey has been used in wound care and burns for millennia. In more recent times, the Russian and the German armies used honey for wounds in the First World War and this remained popular till the discovery of antibiotics in 1940.⁸ On account of increasing problem of antimicrobial resistance to antibiotics and on the basis of recent studies, honey is being integrated into modern medicine. There are several studies which reflect that a variety of beneficial effects of honey in wound healing have originated from multiple bioactive compounds.^83,84 These effects encompass a wide range of benefits such as broad spectrum in nature, lack of bacterial resistance, promoting debridement, and reduction in inflammation and malodor.^85,86 A number of clinical trials have been conducted to check the efficacy of honey both in acute and chronic wounds.^87,88 For example, there is ample literature with evidence-based conclusions that honey impregnated dressings are more effective than conventional treatment in superficial and partial-thickness burns.^89,90

A recent review summarizes sixteen controlled randomized trials of honey in wound management published since 2006. The review elaborates the expanding role of honey in treatment of different types of wounds.⁹¹ More recently, Jull et al. in their review have shown that honey dressings are more effective in moderate burns compared to some contemporary dressings; however, there is lack of evidence to give guidance in other types of wounds.⁹²

It has been observed that some clinical trials have problems related to methodology and quality; therefore, it is difficult to devise conclusive guidelines. Sufficiently large and well-designed randomized clinical trials (RCTs) are needed to provide appropriate levels of evidence of clinical efficacy of honey in a variety of wounds. It is important to identify new honey with a high therapeutic value for wound infection because presently a limited range of approved honey dressings are available and they are quite expensive and not easily available everywhere.⁹³ Therefore, more research is required to identify new sources of honey from different countries so that patients can be benefited with cheap, easily accessible, and locally produced products. Moreover, there is little knowledge regarding difference in clinical efficacy of medically graded honey and honey with high level of hydrogen peroxide activity. Therefore, it would be worthwhile to check the efficacy in a well-designed RCT.

Use of Honey in Systemic Infections

Although honey has been recognized and registered as medicine for topical infections, however, its role in systemic infections is still unknown. There are a number of in vitro studies that show the effectiveness of honey against multidrug-resistant bacteria causing systemic infections such as typhoid fever, diarrhea, and tuberculosis.^94

–97 Hannan et al. reported that growth of twenty-four multidrug-resistant typhoidal salmonellae isolated from blood of typhoid patients were completely inhibited by black seed honey at a concentration of 9.0% (v/v).⁹⁴ Similarly, another report revealed that Manuka honey had an inhibitory effect on Helicobacter pylori at 5.0% (v/v).⁹⁸

However, the application of in vitro findings of honey research to systemic infections is not a straightforward phenomenon, rather another area where more research is required. In vitro MIC assay, widely used to evaluate the efficacy of antibiotics and honey against bacterial pathogens, is considered gold standard in microbiology, but the assay inherited serious limitations when translated to clinical practice. For the in vitro MIC assay, the level of honey concentrations remains constant throughout the course of procedure, but this situation is not the same in vivo for various reasons. Eye drops containing honey or antibiotic, when used in infected eye, tend to dilute with tears and wash away after few minutes; therefore, MIC assay is not useful to evaluate the effect of antimicrobial agents for the treatment of such cases.⁹⁹

Similarly, MIC of antibiotic against H. pylori was not representative of the in vivo study because the assay did not evaluate the viability of bacteria in three hours.¹⁰⁰ Furthermore, the bioactive compounds present in honey may be diluted significantly by body fluids and eventually total concentrations fall under the MIC level. On the contrary, they may be excreted from the body via urine before they actually come in contact with target bacteria.¹⁰¹ Hence, the effectiveness of honey in the treatment of systemic infections may not be as good as indicated from MIC assays.

Therefore, to overcome this limitation, pharmacokinetic and pharmacodynamic studies are recommended to evaluate the effectiveness of drug. However, in pharmacokinetics, known substances are monitored and evaluating the complex substances of unknown composition, such as honey, is not easily possible.¹⁰² In these circumstances, pharmacodynamic models seem to be preferable because they predict the eradication of bacteria either by a single compound such as antibiotic or a complex substance such as honey.¹⁰³

Another important issue is how to achieve honey concentration at MICs higher than equivalent to be bactericidal in systemic infection? It is not possible by oral route because honey is diluted with saliva, gastric secretions, and plasma many folds before it actually comes into contact with target bacteria. Furthermore, the catalase present in plasma and body fluids would probably neutralize H₂O₂ in honey, thereby neutralizing peroxide antibacterial activity.

The nonperoxide antibacterial activity, which resists catalase treatment, would be more important in systemic infections. Therefore, those forms of honey containing a higher level of nonperoxide activity such as Manuka honey might be more useful in systemic bacterial infections. One study has shown that a clinically effective concentration of honey (>MIC) may be achieved in systemic infection by intravenous route and this is demonstrated in sheep.¹⁰⁴ However, by this route only sterile honey with optimal dilution compatible to plasma may be used. There may be some risk of allergic reactions associated with this route.

The use of natural product in its crude form as drug is getting worldwide attention because the bioactive compounds present in complex, heterogeneous polymolecular products such as honey interact synergistically with each other and produce a much higher impact on host or bacterial cell in comparison with influence induced by sum of the parts.¹⁰⁵ However, it may be important to know that bioactive compounds present in natural product may undergo substantial metabolism after being ingested by human.¹⁰⁶

Al Somal et al. suggested that inhibitory concentration of Manuka for H. pylori can be achieved in the gastrointestinal tract by oral intake and proposed a clinical trial to evaluate the role of Manuka honey for treating H. pylori infection.⁹⁸ Such clinical trial is still awaited. However, McGovern et al. conducted a small study comprising 12 volunteers with H. pylori infection, confirmed by ¹⁴C urea breath test. One group was treated with omeprazole and other with omeprazole and Manuka honey for two weeks. The authors concluded that Manuka honey was not effective at eradicating H. pylori infection, however, it improved the symptoms of dyspepsia.¹⁰⁷

The ineffectiveness of Manuka honey could be due to degradation of hydrogen peroxide by catalase and methylglyoxal by digestive enzymes present in the gastrointestinal tract. It has been shown that methylglyoxal was readily inactivated by digestive process of intestine and therefore ineffective for systemic infections.¹⁰⁸ The stability and bioavailability of hydrogen peroxide and active ingredient such as methylglyoxal can be improved if they are coupled with cyclodextrins.^109,110 The cyclodextrins consist of glucopyranose units and readily form stable inclusion complexes with several compounds.¹¹⁰ Therefore, it is suggested that RCT may be undertaken with honey blended with cyclodextrins.

Role of Honey in Gastrointestinal Illnesses

Studies have shown the effectiveness of honey in treating gastrointestinal disorders.⁸⁷ A clinical trial shows that 5% honey solution controls bacterial diarrhea in a shorter time than routine medical management.¹¹¹ Honey is also found to be effective in treating dyspepsia and peptic ulcer, caused by H. pylori.¹¹² Manuka honey, in a clinical trial, is found to be effective in treating periodontal disease and gingivitis.¹¹³ Recently, it is revealed that intrarectal administration of honey is effective in treating colitis.¹¹⁴

Honey on one hand inhibits more than sixty different pathogenic bacterial species and on the other hand enhances the growth of beneficial gastrointestinal tract flora.^115,116 Recently, Olofsson and Vásquez have discovered a unique lactic acid bacterial microbiota in honey bee stomach, which is also present in large quantities in fresh honey.²⁰ A number of prebiotics have also been found in honey, which support the growth of useful bacteria such as bifidobacteria and lactobacilli.¹¹⁷ Furthermore, honey also contains a number of minerals, including zinc.¹¹⁸

The presence of probiotics, prebiotics, and zinc in honey has significant clinical implications as far as treatment of diarrhea is concerned. The current treatment guidelines of diarrhea discourage antibiotic use in children presenting with acute gastroenteritis (AGE).²¹ Instead, probiotics are recommended for the treatment of AGE, as they can decrease the duration of diarrhea without adverse effects.²² More recently, it has been revealed that fecal microbiota transplant and use of zinc supplementation are also useful in infectious diarrhea.²³ Moreover, the role of prebiotics in the management of diarrhea is also becoming evident because the ingested prebiotic stimulates the growth of beneficial bacteria.²⁴

Recently, it has been shown that a combination of probiotics and prebiotics (synbiotic mixture) is more useful in the treatment of diarrhea.¹¹⁹ Keeping in view the current guidelines for treatment of diarrhea, it is realized that there is a need for a combination therapy consisting of probiotics, prebiotics, and zinc. At the same time, the medical community also desperately requires an effective, safe, and selective drug, which does not allow bacteria to generate resistance and does not harm the beneficial gut flora. Honey in this context is a potential therapeutic agent for treatment of diarrhea as it contains all these properties.^18,20,58,120 To provide appropriate level of evidence of clinical efficacy of honey in treating diarrhea, large and well-designed RCTs are required. Honey intended to be used in RCT must be screened for the presence of probiotics, prebiotics, and zinc, so that the most appropriate honey may be selected.

Conclusions and Future Trends

The antibacterial effect of honey cannot be solely attributed to a single compound, rather it is due to a complex combination of compounds. These compounds work together and create a synergistic antibacterial activity. Further studies are needed to explore the nature and interactions of these synergistic compounds. This will allow developing specific therapeutic agents with an optimal combination of synergistic antibacterial compounds for treating pan- or multidrug-resistant bacterial infections.

Present categorization of honey, nonperoxide and peroxide, is required to be revised because each type of honey may contain variable amounts of plant-derived nonperoxide factors. Agar diffusion assay, being used for evaluating antibacterial activity of honey, is not the most appropriate and sensitive assay as it only detects nonperoxide activity when present at a higher level. Therefore, there is a need to develop more sensitive techniques that may be capable of detecting and evaluating different important components in honey as well as their synergistic interaction. The difference in clinical applications of hydrogen peroxide and nonperoxide honey is required to be addressed in in vivo studies.

Footnotes

Acknowledgments

This work was supported by the Deanship of Scientific Research (DSR), King Abdulaziz University, Jeddah, under grant no. (828-52-D1436). The author, therefore, gratefully acknowledges the DSR technical and financial support. He is also grateful to Dr. Shahid Shamim for language editing of the article.

Author Disclosure Statement

No competing financial interests exist.

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