The importance of honey in the diets of human foragers throughout history has been well documented. Honey, as well as residual bee larvae in wild honey, may have been an important source of energy, fat, and protein for early humans (reviewed in (23)). It has been suggested that routine consumption of honey, an energy-dense and easily digestible food source, to supplement meat and plant foods, may have played an important role in shifting the diet from a low-calorie to an energy-rich, calorie-dense diet to support increasing brain activity during the evolution of larger hominin brains (23–25). The reduction of molar size, indicating the consumption of foods requiring less mechanical breakdown, along with the documented use of Oldowan tools (50,000–10,000 BCE) that may have been used for honey collecting as denoted in rock art also support this idea (23).

Honey has a long history as a treatment for gastrointestinal conditions. Circa 25 AD, Roman physicians prescribed different types of honey as a cure for both diarrhea and constipation, and Islamic holy scripts dating back to the 8th century show the prophet Muhammad recommending the use of honey for diarrhea (26, 27). In various books and records from eastern Europe and Arab countries, the use of honey in the prevention and treatment of peptic ulcers, gastritis, and gastroenteritis is often reported (28).

Many modern studies into the digestive health benefits of honey have shown that ingesting honey shortens the duration of bacterial diarrhea in children (29) and in critically ill tube-fed patients who were also reported to be less likely to suffer from organ failure on honey treatment (30). Honey also improved the recovery of patients with viral gastroenteritis (31). Other studies suggest that honey has a protective effect on the stomach (32). The consumption of relatively large amounts of honey (50–100 g) can also have a mild laxative effect, due to insufficient absorption of the fructose in honey (27).

Honey is a naturally sweet substance produced by honey bees (Apis mellifera) from the nectar of flowers or from plant secretions. The composition of honey is complex with over 200 components, many of which are dependent on the floral source (28). The nectar collected by bees to make honey affects the flavor, color, and medicinal properties of different honeys (21). Honey is composed mostly of sugar (up to 80%) with the monosaccharides fructose and glucose making up the majority (∼70%), and di-, tri-, oligo-, and polysaccharides composing the remainder. Other components of honey include a water content of between 15 and 20%, proteins, organic acids (such as gluconic acid), minerals, plant phytochemicals, and vitamins (25, 33).

Honey has numerous nutritional and therapeutic benefits including antimicrobial, antioxidant, anti-inflammatory, and wound healing activities. Of these, the most extensively studied through in vitro and in vivo experiments and human trials has been antimicrobial activity (19, 22, 27, 34–37). The continued medicinal use of honey as a therapeutic agent can be attributed to its broad-spectrum antimicrobial properties, which have proven effective against many pathogenic organisms, including multi-drug resistant strains. The antimicrobial activity of honey is multi-factorial and is derived from osmolarity, acidity, the production of hydrogen peroxide, and the presence of non-peroxide factors (36). There have been no documented cases of microbial resistance to the inhibitory effects of honey and honey resistance cannot be induced (38–40). This is likely because honey has multiple mechanisms of antimicrobial action (41).

Relevant to the gut, honey inhibits undesirable microbes such as Listeria monocytogenes in milk, as well as Clostridium perfringens and Eubacterium aerofaciens (42). Additionally, honey also inhibits many enteropathogenic organisms, such as Salmonella species (multi-drug resistant strains); Shigella species; enteropathogenic E. coli (including multi-drug resistant strains), Enterobacter species, Yersinia enterocolitica, Campylobacter species, and Clostridium difficile (37, 43–49). Apart from its direct antibacterial activity, honey has been shown to prevent the attachment of Salmonella species to mucosal epithelial cells in vitro, thereby preventing the establishment of infection (50).

The antioxidant effect of honey is largely attributed to its phenolic compounds which, when ingested by an individual, can provide protection in the bloodstream and within cells (51). As with antimicrobial activity, the antioxidant capacity of honey is highly variable and dependent on floral sources. Generally, darker-colored honeys show higher levels of antioxidant activity than their lighter counterparts, as color is also determined by phenolic content. The phenolic content of honey has also been linked to its anti-inflammatory effects, and honey has been reported to downregulate pro-inflammatory cytokines, upregulate anti-inflammatory cytokines (52), and interrupt inflammation mediators (53, 54). Thus, the anti-inflammatory and antioxidant effects of honey are closely linked. The anti-inflammatory, antioxidant, antimicrobial, and wound healing properties of some honeys have been used extensively in the treatment of wounds, burns, and ulcers (20, 55–57); however less is known about their systemic effects when ingested.

The gut microbiome is recognized as playing a significant role in human health. Its composition varies significantly between individuals and within the same individual over time, influenced by factors such as age, sex, ethnicity, geographic location, medication usage, stress, gastrointestinal infections, smoking status, and diet (13, 58–61). Studies have implicated the gut microbiome in brain health and cognitive function, nervous system development and maturation, and the immune system and response, as well as asthma and allergies, cardiovascular health, and obesity (13, 14, 58, 59, 61–66). Consequently, there have been concentrated research efforts to identify a core ‘healthy’ human microbiome (58, 59, 67, 68).

Much of the earlier research was focused on profiling the microbiota of the gut to identify bacterial species and groups associated with beneficial outcomes—that is, probiotic species. Certain types of probiotic gut bacteria, such as bifidobacteria and lactobacilli, have been noted to lessen the severity of symptoms of rotavirus- and antibiotic-associated diarrhea in infants (69), aid in the breakdown of lactose in individuals with lactose intolerance, help with bile deconjugation, promote beneficial organic acid production, and compete with gastroenteritis-causing bacteria to prevent infection (70, 71). In contrast, an ‘unhealthy’ gut microbiome is linked to a reduction of beneficial bacteria, overgrowth of certain fungal species, increase in putrefactive bacteria, and increase in opportunistic pathogens (58). Although the association of specific commensal microbial types in health and disease is recognized, it is not always clear whether the microbes are the cause or effect (72, 73).

However, it is now more commonly accepted that a ‘healthy’ gut microbiome is one that performs desired metabolic functions and has a symbiotic relationship with its host, rather than only specific bacterial populations in greater or lesser numbers (58, 59, 74, 75). Molecular studies confirm that many genes encode for similar microbial functions across different bacterial species, including those associated with degradation and digestion of complex sugars, production of SCFA, energy production, and the synthesis of vitamins (59, 74, 76). A predominance of beneficial microbes, microbial activities, and resultant metabolites, acts to maintain a healthy gut barrier, facilitate immune homeostasis, and host metabolic health. Reductions in beneficial microbial activity in the gut, along with increased intestinal permeability, can increase interactions between microbial antigen and the immune system, triggering inflammatory processes both in the gut and systemically, and contribute to, or drive, poor host health (77). However, the ability to manipulate the gut microbiome using targeted nutritional approaches, which can reduce the severity of disease or improve health outcomes, is a key goal in translating an understanding of the gut microbiome into a therapeutic benefit (5, 73, 78).

Diet plays a significant role in the functioning and composition of the gut microbiome (14, 79). The impact of diet on the gut microbiome has been shown as early as infancy, where the composition and diversity of the microbiota of breast-fed and formula-fed infants differed significantly (80). Studies have shown that the gut microbiome may co-evolve with diet. A study comparing the diet and gut microbiota of children from Europe and a rural African village showed that the African microbiome had a depletion of Firmicutes and was enriched with Acinetobacteria, Bacteroidetes, and a specific abundance of Xylanibacter and Prevotella that could improve the ability to extract calories from the indigestible plant polysaccharides that contributed to the diet of the African children (10). Long-term dietary patterns, particularly protein and animal fat as compared to carbohydrate/fiber intake, are linked to the assemblage of the gut microbial community and associated with population-wide patterns such as the relative abundance of Bacteroides and Prevotella (81). While the adult microbial community is relatively stable over time and linked to long-term diet (82, 83), it is possible to alter both the compositional makeup and function of the gut microbiota through short-term dietary alteration (84, 85).

Prebiotic foods, such as non-digestible carbohydrates, do not get absorbed in the upper gut and reach the colon intact where they are readily available for use as a selective substrate by gut microbiota. This results in selective stimulation of beneficial microbial populations and functions in the gut (16, 86). Dietary prebiotics have been linked to health-promoting effects including immunostimulation, improved digestion and absorption, vitamin synthesis, reduced cholesterol, reduced gas distension, regulation of opportunistic and invading pathogen growth, improved mineral (especially calcium) absorption, modulation of lipid metabolism via fermentation products, anti-inflammatory activity, and decreased risk of cancer and cardiovascular disease (11, 14, 87–95). The importance of bacterial functions related to carbohydrate metabolism in the colon is well established (4, 96). Indigestible complex carbohydrates, oligosaccharides, polysaccharides, and peptides are major drivers of gut microbial composition and activity (97). As such, there is a great interest in identifying sources of these carbohydrates for use as prebiotics.

Although honey is predominantly made up of simple sugars (monosaccharides) that are rapidly absorbed in the small intestine, there are also di-, tri-, and oligosaccharides that are present in smaller quantities (98, 99). These oligosaccharides and low-weight polysaccharides in honey are likely to resist degradation by host enzymes and are capable of reaching the lower gut to exert prebiotic effects (100). Many studies suggest a prebiotic effect of various kinds of honeys of different floral varieties (Table 1). The proposed prebiotic effects of honey, and honey oligosaccharides, are summarized in Figure 1.

There is significant evidence of the prebiotic potential of honey from in vitro studies that assess the effect of honey on the growth of probiotic bacteria (100–107) and in probiotic food products, such as milk or yogurt, supplemented with honey (108–111). Numerous studies show that honey supports and promotes the growth of probiotic Bifidobacterium and Lactobacillus species, including B. longum, B. adolescentis, B. breve, B. bifidum, and B. infantis, Lactobacillus. acidophilus, Lactobacillus plantarum, Lactobacillus reuteri, and Lactobacillus rhamnosus (103–107, 113). The growth-promoting effect of honey on bifidobacteria and lactobacilli is usually comparable to that of oligosaccharide prebiotics, including fructooligosaccharide (FOS), galactooligosaccharide (GOS), or inulin, where these prebiotics are included as controls (42, 104, 105, 110, 112, 113). Other studies have shown that honey not only promotes the growth of probiotic cultures but has a positive effect on the metabolism of bacterial strains from the human gut (95).

As oligosaccharide composition can affect prebiotic activity, it is not surprising that different honeys can have different prebiotic properties (114). Honey can contain source-specific oligosaccharides (99)for example, native New Zealand honeys showed high levels of isomaltose and melezitose (114, 115), while raffinose was reported in Italian honey (116); and also different concentrations of commonly occurring oligosaccharides (107) influencing their prebiotic potential.

Oligosaccharides isolated from honeydew had a positive impact on the growth of fecal bacteria, specifically by promoting the populations of the beneficial bifidobacteria and lactobacilli, and by reducing the numbers of the potentially harmful Bacteroides and clostridia (100), quantified by the prebiotic index that scores the ratio of potentially beneficial vs. harmful bacteria relative to the overall changes (117). The prebiotic index for the honey-derived oligosaccharides was similar to that of the commercial prebiotic, FOS. Similarly, three Malaysian Tualang honeys that had been pre-treated to remove simple sugars supported enhanced growth of the probiotic Bifidobacterium longum (118).

Numerous in vivo studies using animal models show that honey acts as a prebiotic, specifically by promoting the populations of probiotic bacteria, including Bifidobacterium spp. and Lactobacillus spp., (104, 106, 107, 119), and alleviating symptoms of constipation and ulcerative colitis (107, 119). The prebiotic effect of honey has also been reported in shrimp, where honey promoted the growth of known probiotics Microbavterium spp., Lactobacillus spp., and Neptumonas spp. (120). Shrimp receiving the honey prebiotic also had a higher abundance of gut microbes than the control or shrimp receiving either a probiotic or synbiotic. Another study investigating the prebiotic effect of honey on pacific white shrimp with Vibrio parahaemolyticus infection showed that those that were fed honey during the infection phase had a reduced pathogen load and higher survival rate compared to the control (no treatment) group (121).

The anti-inflammatory effect of honey can also contribute to its overall prebiotic potential, as many conditions in the gut (regardless of infection state) involve inflammation of the bowels. Various studies on the anti-inflammatory properties of honey, spanning both the gut and wound environment, suggest that honey promotes the upregulation of anti-inflammatory cytokines and downregulation of pro-inflammatory cytokines (38, 52, 53, 122, 123). In rats with acetic acid-induced gastric ulcers, a significant increase in the presence of pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)1-β, and IL-6 was noted. Following administration of manuka honey treatment, cytokine levels significantly decreased, the ulcers healed faster, and oxidative damage caused by acetic acid was reversed compared to the control group (122). Similarly, rats with dextran sodium sulfate-induced ulcerative colitis had a significant reduction in IL-1β and IL-6 in serum and TNF-α in colonic tissue samples after administration of Egyptian honey (124). The mechanisms suggested for inflammation reduction by honey include inhibition of reactive oxygen species, inhibition of leukocyte infiltration, inhibition of cyclooxygenase-1 and 2 (COX-1 and COX-2), and inducible nitric oxide synthase expression (53, 123). The main components in honey responsible for the anti-inflammatory and related antioxidant effects are the polyphenols, and polyphenols found in honey have been shown to alter the gut microbiome in rats with ulcerative colitis, showing both a reduction in inflammation and suppression of the populations of the potentially harmful organisms (54).

To date, there has been one human clinical study investigating the effect of daily honey consumption – specifically looking at the safety of eating manuka honey with high antibacterial activity compared to multi-floral honey (125). No significant changes in the numbers of five major bacterial groups in the gut were found, however, measuring prebiotic activity was not a primary aim of the study and the authors noted that any effects may have been masked due to interactions with other dietary components, the dose of honey used, as well as honey and storage conditions.