Honey as a Natural Nutraceutical: Its Combinational Therapeutic Strategies Applicable to Blood Infections-Septicemia, HIV, SARS-CoV-2, Malaria

The paper frames antimicrobial resistance (AMR) as a major global health threat, citing millions of annual deaths and rising resistant infections in the US, UK, and Western Europe. It argues for renewed investigation into natural and synthetic agents with antimicrobial activity, highlighting honey—particularly manuka honey—as a promising nutraceutical due to its diverse bioactive constituents and historical and modern medicinal use. Honey’s composition varies with geography and bee species but generally comprises about 80% sugars and 20% water, plus vitamins, minerals, flavonoids, proteins, amino acids, peptides, enzymes, and phenolic acids. Manuka honey from Leptospermum scoparium is emphasized for its antioxidant, anticancer, and antimicrobial properties, with historical use in wound care and increasing contemporary study as an antibiotic-adjunct or delivery agent.

The review summarizes bioactivities of honey across geographies and floral sources. Phenolic profiles identified in Western Australian and Hungarian honeys show shared and unique compounds (e.g., syringic acid, taxifolin, gallic acid, caffeic acid), supporting antioxidant capacity and potential for fingerprinting honey origins. Organic acids, though <0.5% of honey, contribute to bioactivity and quality markers; gluconic acid often comprises 64.6–99.8% of total organic acids. Antioxidant actions may involve synergistic chelation of metals by organic acids with phenolics. Manuka honey demonstrates antiproliferative effects on cancer cell lines and non-peroxide antimicrobial activity linked to methylglyoxal (MGO), which can evade bacterial efflux and act on both Gram-positive and Gram-negative bacteria. Assays of total antioxidant capacity in graded UMF manuka honeys confirm bioactivity but show assay- and condition-dependent variation. Ethyl acetate extracts of manuka honey can enrich phenolics (~30×) and antioxidant capacity (~100×) relative to unfractionated honey, yet whole honey showed stronger antibacterial activity, suggesting that phenolic content and antibacterial effects may be partly independent and matrix-dependent. Additional literature documents anti-biofilm effects, immune stimulation (e.g., TLR4 activation by a 5.8-kDa component), and applications in wound healing and post-surgical recovery.

This is a narrative review synthesizing findings from in vitro, in vivo animal models, and limited clinical studies on honey’s bioactivities and combinational therapeutic potential for blood and systemic infections. Key methodologies of cited studies include: (1) Sepsis models: LPS-induced endotoxemia in rats treated with chrysin (50–100 mg/kg) derived from honey-associated flavonoids, with serum cytokines, liver enzymes, and oxidative stress markers measured; mouse sepsis models pretreated with 30% solutions of Arbutus, Chestnut, Fir, or manuka honey, assessing serum TNFα/IL-6, hepatic iNOS/TNFα expression, CYP1A1/CYP2B10 modulation, and bacterial burden in organs. (2) Antibacterial assays: Agar well diffusion, dye-reduction assays, MIC/MBC determinations for undiluted African honey against S. aureus and E. coli. (3) HIV: A randomized controlled study in asymptomatic patients not on ART received Tualang honey 20 g once, twice, or thrice daily for 6 months, with CD4 counts, viral load, and quality-of-life outcomes monitored. (4) SARS-CoV-2: In vitro macrophage models (RAW264.7) examining stingless bee honey effects on proinflammatory mediators (TNFα, IL-6, NOx, MCP-1, IL-12p70, IFNγ, IL-10) and mechanistic hypotheses (pathway modulation including NF-κB, PI3K/Akt, MAPK; quercetin-mediated lysosomal H+-ATPase inhibition). (5) Malaria: Plasmodium berghei-infected mouse models treated with stingless bee honey, Citrus aurantifolia extracts, alone or combined, compared to artemisinin-based chemotherapy (DHP), with parasitemia suppression measured. Additionally, multiple antioxidant capacity assays (FRAP, ABTS) and chemical analyses (LC-MS/MS for organic acids) were part of the reviewed literature.

- AMR burden: 1.27 million deaths directly attributable to AMR globally in 2019, with nearly 5 million associated; US sees ~2.8 million resistant infections and ~35,000 deaths annually; UK resistant infections increased 2.2% from 2020 to 2021; Western Europe had ~51,000 deaths in 2019. - Honey composition: Approximately 80% sugars, 20% water, plus diverse bioactives (vitamins, minerals, phenolics, enzymes, peptides). Organic acids are minor constituents, with gluconic acid representing 64.6–99.8% of total organic acids. - Antioxidant and phenolic profiles: Western Australian and Hungarian honeys share key phenolics (e.g., syringic acid, taxifolin). Organic acids (citric, malic, gluconic) can synergize with phenolics to enhance antioxidant activity. - Antimicrobial activity: MGO correlates with manuka honey’s non-peroxide antibacterial effect and can impact MDR Pseudomonas aeruginosa by evading efflux pumps; activity spans Gram+ and Gram− bacteria. - Antioxidant assays: Manuka honeys of varying UMF exhibit confirmed antioxidant capacity with assay-dependent variability. Manuka honey extracts showed ~30× total phenolics and ~100× antioxidant capacity vs. whole honey, yet whole honey produced larger antibacterial inhibition zones and stronger microtiter inhibition, indicating matrix effects. - Sepsis models: Chrysin (50–100 mg/kg) in LPS-induced rat sepsis reduced IL-1β, IL-10, TNF-α, IL-6, AST, ALT, and malondialdehyde; increased SOD, catalase, and glutathione peroxidase; mitigated tissue injury. Greek honeys (Arbutus, Chestnut, Fir) reduced serum TNFα and hepatic TNFα/iNOS expression similar to manuka; reversed LPS suppression of hepatic CYP1A1 and CYP2B10; reduced bacterial loads in liver and lungs depending on honey type. - Antibacterial metrics: Undiluted African honey yielded inhibition zones of 10–15 mm (E. coli) and 14–15 mm (S. aureus); MIC 7.8125–15.625 mg/mL; MBC 125–500 mg/mL, demonstrating bacteriostatic and bactericidal potential. - HIV adjunct: In asymptomatic patients (not on ART), 20 g Tualang honey once to thrice daily over 6 months improved CD4 counts and quality of life, with indications of reduced viral load; amino acids like tryptophan/phenylalanine may contribute to psychological benefits. - SARS-CoV-2: Stingless bee honey reduced TNFα by ~23% and IL-6 by ~43.9% in vitro, and markedly inhibited interferons (~88.8%); proposed to modulate TNF, NF-κB, PI3K/Akt, MAPK, immune signaling, and lysosomal entry processes (e.g., quercetin inhibiting lysosomal H+-ATPase). Gelam honey reduced PGE2 and thromboxane B2, increased NO end-products, potentially aiding oxygen diffusion and vasodilation. - Malaria: Stingless bee honey and Citrus aurantifolia extracts suppressed Plasmodium berghei parasitemia, with stingless bee honey showing greater suppression; flavonoids and other phytochemicals may synergize with artemisinin therapy.

The review supports honey’s potential as a natural nutraceutical with combinational therapeutic strategies against bloodstream and systemic infections. Mechanistically, honey’s antimicrobial actions involve MGO-mediated bacteriostasis/bactericidal effects, anti-biofilm activity, membrane depolarization, efflux pump disruption, and quorum sensing inhibition. Its anti-inflammatory and antioxidant properties mitigate cytokine storms and oxidative stress, relevant to sepsis and COVID-19 pathophysiology. In sepsis models, honey-derived flavonoids (e.g., chrysin) and whole honeys downregulated proinflammatory mediators, improved antioxidant enzyme profiles, modulated hepatic detoxification enzymes, and reduced bacterial translocation. For HIV, adjunct Tualang honey intake correlated with improved CD4 counts and quality of life, indicating immunomodulatory support in untreated patients. Regarding COVID-19, stingless bee honey’s attenuation of key cytokines and pathway modulation provides a rationale for reducing pulmonary inflammation and coagulopathy. In malaria, stingless bee honey showed antiparasitic activity and potential synergy with artemisinin-based therapies. Collectively, these findings address the overarching goal of identifying natural, multi-target agents that can complement existing antimicrobials and mitigate AMR-related burdens.

Honey contains diverse bioactive molecules conferring antioxidant, antimicrobial, anti-inflammatory, immune-modulatory, and wound-healing properties. Evidence from in vitro, animal models, and preliminary clinical studies suggests honey and its constituents can complement therapies for sepsis, HIV, COVID-19, and malaria, improving inflammatory profiles, immune parameters, and antimicrobial efficacy. The paper advocates for honey’s inclusion as a nutraceutical and for its fortification applications in foods. Future research should prioritize: rigorous standardization of honey types and bioactive markers; well-designed randomized clinical trials for systemic indications; mechanistic studies on synergy with conventional antimicrobials (including artemisinin and antibiotics); evaluation of dosage forms and processing impacts; and exploration of selective effects on pathogenic versus commensal microbiota.

Key limitations include: (1) High variability in honey composition by floral source, geography, season, and bee species, complicating reproducibility and standardization; (2) Processing methods (e.g., heat, filtration, pasteurization) can degrade heat-sensitive enzymes, phenolics, and peptides, altering bioactivity; (3) Clinical use in patients with diabetes or those requiring glycemic control is challenging due to high sugar content; (4) Potential publication bias favoring positive results may overestimate efficacy; (5) Limited number of robust randomized clinical trials for systemic infections; (6) Translational gaps between in vitro/animal findings and human outcomes; (7) Unclear dosing regimens and long-term safety profiles for different honey types and extracts.