Bioflavonoids, also known as vitamin P due to their effect on vascular permeability,1 are a group of compounds that are found throughout many plants, fruits, vegetables, and leaves. Bioflavonoids belong to the polyphenol group of plant compounds2 which are an extensive group of phytochemicals produced by plants in response to stress as a plant defence mechanism.3 To date over 8,000 different polyphenols have been identified.3 Though polyphenols differ in chemical structure, all share the same structural feature of an aromatic ring and at least one hydroxyl group.3 (See Figure 1)
Vitamin C and bioflavonoids – the perfect pair
First discovered by accident while trying to isolate vitamin C, Hungarian biochemist Albert Szent-Györgyi observed that the medicinal benefits of vitamin C were enhanced when used in combination with bioflavonoids rather than using vitamin C alone.4
Bioflavonoids are often found in combination in supplements rather than in isolation, mimicking how they are found in nature and are used frequently due to their ability to modify a range of health conditions.5
Bioflavonoids and immunity
Bioflavonoids may assist with modulating immunity via a range of functions including regulation of T-lymphocytes6 as well as suppression of pro-inflammatory transcription factors such as NF-kB.7
QUERCETIN
Quercetin (3,3′,4′,5,7-pentahydroxyflavone) is the most studied bioflavonoid and is found in a range of food sources including apples, berries, Brassica vegetables, capers, grapes, onion skins, shallots, as well as several herbal medicines including Sambucus canadensis, Ginkgo biloba and Hypericum perforatum.7 Quercetin exerts antioxidant, antihistamine, and anti-inflammatory properties.8
Quercetin as an anti-allergic
Quercetin regulates T helper 1 and 2 (Th1/Th2) and T regulatory and T helper 17 (Treg/Th17) ratios, modulating the immune system and reducing inflammation.6,9
In a randomised controlled trial involving 66 individuals with seasonal allergies, 200 mg/day of quercetin consumed for 4 weeks was shown to significantly reduce eye itching, sneezing, nasal discharge, and sleep disturbance when compared to placebo10 making it a compelling choice when treating seasonal allergies.
Quercetin as an anti-viral
Quercetin has also been studied in various models of viral infection including Orthomyxoviridae (influenza family) and Coronaviridae (SARS-CoV-2).11 As an anti-viral, quercetin works via multiple mechanisms including the inhibition of polymerases and proteases, the suppression of DNA gyrase, reverse transcriptase, and the binding of viral capsid proteins preventing virus entry into cells.11
COVID-19
Meta-analysis examining quercetin as an adjuvant therapy for individuals with COVID-19 observed a reduced length of hospitalisation and reduced risk of ICU admission in patients receiving the adjuvant treatment.12 A 2021 study examining the use of quercetin in those with COVID-19 observed that individuals who received quercetin in addition to standard care, tested negative to SARS-CoV-2 earlier, demonstrating their ability to clear the virus quicker. Furthermore, those taking quercetin were able to reduce the severity of symptoms quicker when compared to individuals who received standard care only.13 Interestingly, despite the known anti-inflammatory effects of quercetin, some studies showed no effect on C-reactive protein (CRP) levels.14
Absorption
Quercetin has low solubility in water with approximately 93% of orally administered quercetin lost in the gut as a result.15 Bioavailability can be increased with the co-ingestion of lipids.16 Quercetin combined with sunflower phospholipids has been shown to increase absorption up to 20-fold.13 Simultaneous ingestion of quercetin with vitamin C, folate, and additional flavonoids also improves bioavailability.17
Cautions
Oral intake of quercetin in humans appears to be well tolerated with doses up to 1,000 mg/day not associated with major side effects over a duration of 12 weeks. High doses may cause mild stomach discomfort and nausea if quercetin is taken on an empty stomach. This may be ameliorated by consuming food first.
HESPERIDIN
Hesperidin is a flavone glycoside found in high concentrations within the citrus family including oranges and lemons. It possesses a variety of benefits including anti-inflammatory, antioxidant,19 and immune-modulating properties.
Hesperidin content is influenced by type, part, and maturity of the citrus fruit, with the flavedo (the coloured outer layer of the peel) and the albedo (a white soft middle layer part) containing higher amounts of hesperidin (see Figure 2).20
Hesperidin and immunity
Treatment with hesperidin of influenza-infected cells has been shown to enhance host immunity. Rodent studies have shown that treatment with hesperidin may increase NK cells activity and T helper cells in the thymus.22
Experimental data also demonstrates that hesperidin can inhibit 3-chymotrypsin-like protease 3 (3CLpro) interfering with SARS-CoV2 replication,23 as well as disrupting the binding point between the spike protein of SARS-CoV2 and angiotensin-converting enzyme 2 (ACE2) receptors.24 Hesperidin’s ability to interfere with viral entry through ACE2 receptors as well as reduce the release of pro-inflammatory mediators protecting against virus-induced cytotoxic damage has led to it being suggested as a possible prophylactic agent against COVID-19.25 Despite this, a human clinical trial examining 1 gram of hesperidin over 2 weeks in individuals during the third wave of COVID-19 failed to observe statistically significant benefits when compared to placebo.23 This may be because it was used in isolation, rather than synergistically with vitamin C and bioflavonoids as well as due to individual variations in human gut microbial diversity.
Hesperidin is transformed into hesperetin by bacterial flora in the gut intestine.26 An individual’s gut microbiome is therefore also a factor that may influence an individual’s response to hesperidin.
RUTIN
Rutin is a polyphenolic flavonoid found in buckwheat, onions, oranges, lemons, as well as in beverages such as wine and black tea.27 Rutin is made up of one molecule of quercetin in the form of an aglycone as well as rutinosei making it structurally similar to quercetin.27
Rutin possesses immune-modulatory and anti-viral activity, with experimental research suggesting that rutin may work as an ACE2 inhibitor, making it useful for the management of COVID-19 as the SARS-CoV2 virus enters its target cells via ACE2.28
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