Flaxseed (Linum usitatissimum), Chamomile (Matricariae flos) and Marshmallow (Althaea officinalis) Mouth Rinses in the Therapy of Oral Mucosa Diseases – A Review

ABSTRACT Background: Several pathological conditions of oral mucosa are an indication for the use of mouth rinses. Objectives: The aim of this paper is to indicate that herbal oral rinses seem to be a good choice due to their easy accessibility, low cost and simple handling. Methods: The study was based on a literature search of three electronic databases for clinical study or systematic review published until January 2023 exploring the use of selected herbal products in the treatment of oral mucosa diseases. Results: A combination of flaxseed, chamomile and marshmallow can be used to prepare an oral rinse which provides an effective coating, anti-inflammatory and antioxidant effect. It can also be recommended in many pathological conditions such as xerostomia, oral lichen planus, burning mouth syndrome and others because such herbal rinses relieve dryness, burning and pain together with moistening and lubricating effect. Conclusions: Flaxseed, chamomile and marshmallow mouth rinses help to reduce inflammation, promote healing and coating oral mucosa being a beneficial supplement to the daily oral hygiene and treatment procedures.


Introduction
The need for saliva substitutes in oral coating rinses has resulted in the use of herbal products in the treatment of oral mucosa diseases due to easy accessibility, low costs and simple handling.Mouthwashes of herbal origin may be an alternative over the chemical ones containing chlorhexidine regarded as "a gold standard" but having disadvantages like discoloration of teeth, numbness and alteration in taste perception (Deus and Ouanounou 2022).Flaxseed, chamomile and marshmallow play an important role due to their effective coating, anti-inflammatory and antioxidant properties (Albuquerque et al. 2010;Batista et al. 2014;Scheffer and König 1991).Mouth rinses of herbal origin are noteworthy and valuable as an outsized proportion of the population prefers herbal origin products (Kukreja and Dodwad 2012).Mouthwashes can be prepared by patients at home using only natural products.
The purpose of this review is to indicate the role of herbal rinses containing flaxseed, chamomile and Althaea in the treatment of oral mucosa diseases and prepare the introduction for the clinical research aiming to evaluate the effectiveness of such rinses.

Methods
This review was based on a literature search of three electronic databases: PubMed, Web of Science and Science Direct.The criteria for selection were based on exploring clinical study or systematic reviews concerning the use of selected herbal products in the treatment of oral mucosa diseases published in English until January 2023.The phrases chosen for search were flaxseed OR Althaea OR chamomile AND mouth rinse; and flaxseed OR Althaea OR chamomile AND mouth rinse AND lichen planus; and mouth rinse AND xerostomia.

Flaxseed
Linum usitatissimum -Latin name for flax (or linseed) meaning "most useful" -has accompanied the humanity for millennia and is commonly used for textiles, food, medicine and cosmetics.Flax was already common in the Neolithic times in Europe around 5000 BC.The health benefit of flaxseed is related to a high level of polyunsaturated fatty acid (PUFAs) (Kołodziejczyk, Ozimek, and Kozłowska 2012).In addition, flaxseed has an unusually high level of alpha-linoleic acid (Kołodziejczyk, Ozimek, and Kozłowska 2012).The majority of flaxseed contains 40-45% of oil and 20-25% of protein per weight (Kołodziejczyk, Ozimek, and Kozłowska 2012).Furthermore, flaxseed is also rich in the soluble dietary fiber called "flax mucilage," which consists of complex carbohydrates known as edible germ and has the potential to become an important component of low caloric emulsion used in the food and medicine industry (Kołodziejczyk, Ozimek, and Kozłowska 2012).Other bioactive phytochemicals in flaxseed are lignans -secoisolariciresinol diglucoside (SDG) and cyclolinopeptides (CLA), sterols and phenols -playing an important role in the structural stability of cell membranes and cell metabolism (Kołodziejczyk, Ozimek, and Kozłowska 2012).Tocopherols present in oil seeds act as antioxidants together with a small amount of the cyanogenic glucosides -linamarin, linustatin and neolinustatin (Kołodziejczyk, Ozimek, and Kozłowska 2012) (Table 1 and Figure 1).
Linseed belonging to the large group of plant raw materials called "mucilaginosa" with some amount of pectin swells in water to form colloidal solutions, which when administered orally do not penetrate through mucous membrane but cover it forming a thin layer.This layer protects the mucous membrane damaged or irritated by various agents: bacterial toxins, medicines like salicylates or nonsteroid anti-inflammatory agents (Kołodziejczyk, Ozimek, and Kozłowska 2012).The flaxseed oil is low in saturated fat (9%), contains moderate amounts of monounsaturated fat (18%) and is high in polyunsaturated fats (73%) (Pengilly 2005).About 16% of those polyunsaturated fats are the omega-6 as linoleic acid (LA), remaining 57% are the omega-3 family as alpha-linolenic acid (ALA) (Pengilly 2005).These essential to life fatty acids cannot be produced by the body and must be obtained from the diet (Pengilly 2005).They act as gatekeepers enabling entry for important nutrients and removal of toxins (Pengilly 2005).They are also converted to hormone-like substances known as eicosanoids affecting cell growth, cell division, platelet aggregation, inflammatory responses, hemorrhage, vasoconstriction and vasodilatation (Pengilly 2005).
Mucous substances in flaxseed constitute 3-9% of its mass and therefore plant mucilage with addition of pectins or fat oil swells in water and forms a colloidal solution.Such infusion administered orally helps to protect the irritated mucous membrane against various irritating factors, like acids, bacterial toxins and drugs.
A gastroprotective effect may also be expected after the use of defatted flax.After removing oil from the seed, the amount of mucous substances, proteins and lignans increases within the seed.Protective parameters increase -especially viscosity (Kozłowski et al. 2004).
These properties of linseed were used for the preparation of dried extract with active matter that is flaxseed mucilage named Bioflax.Animal studies have shown an increased protection of mucous membrane lesions caused by stress in the group of rats fed with Bioflax compared to a control group (Kołodziejczyk, Ozimek, and Kozłowska 2012).
Omega-3 fatty acids not only promote an anti-oxidant effect but also downregulate the production of inflammatory mediators -PGE2 and leukotrienes as well as inflammatory cytokines (Kołodziejczyk, Ozimek, and Kozłowska 2012).Seeds of flax as well as oils and preparations obtained from them find wide application in the manufacturing of pharmaceuticals, cosmetic agents and herbal medical products.Protective, laxative or emollient properties of linseed are recommended in the treatment of some diseases of alimentary tract (Kołodziejczyk, Ozimek, and Kozłowska 2012).In medicine, its properties are indicated in constipation, irritable bowel syndrome, gastritis and enteritis, cardio-vascular diseases treatment in relation to blood lipid metabolism, reducing cholesterol levels and preventing abnormal clot formation (Craig 1999).

Chamomile
Chamomile is one of the oldest medical plants.It is represented by two species: German chamomile (Matricaria chamomilla) and Roman chamomile (Chamaemelum nobile), which both are members of daisy family (Asteraceae).Chamomile is known to contain a variety of active flavonoids as well as its volatile oil.It contains 0.24-1.9% of volatile oil mainly composed of the terpenoids such as α-bisabolol, bisabolol oxides and its azulenes, including chamazulene or azulenesse, farnesene and spiro-ether quiterpene lactones, glycosides, matricine, hydroxycoumarins, coumarins and acetylene esters (Srivastava, Shankar, and Gupta 2010).These components provide the anti-inflammatory, antispasmodic and antibacterial activity of the chamomile (Albuquerque et al. 2010).
Chamomile is known for its antioxidant, antimicrobial, anti-inflammatory and angiogenesis activity (Miraj and Alesaeidi 2016).Such properties induce wound healing properties with the formation of inhibitory zone with reposition on collagen fibers but without the presence of necrosis (Motealleh et al. 2014).Luteolin and apigenin have the highest capacity in the development of new blood vessels (Guimarães et al. 2016).
Antimicrobial and anti-inflammatory properties of chamomile are especially beneficial when chamomile is used as a mouth rinse (Batista et al. 2014).Those properties are shown to be similar to those of chlorhexidine 0.12% (Batista et al. 2014).The anti-inflammatory effect is related to apigenin (Miraj and Alesaeidi 2016), while the antibacterial effect is caused by main essential oil components, including coumarin, flavonoids, phenolic acids and fatty acids (Móricz et al. 2013).

Althaea radix and leaf
Althaea (marshmallow) may be used in the form of leaves, peeled root or dried root (Li Thomas 2000).It possesses healing properties due to its compounds such as minerals, flavonoids, acidic polysaccharides, polyphenols, coumarin, pectin, starch and tannins (Bieloszabska and Czucha 1966;Evans 1996;Gudej 1990;Hänsel et al. 1992;Madaus, Blaschek, and Franz 1987).Therefore, it is recommended in dry cough, irritation of mucous membrane within oral cavity, stomach and esophagus due to its coating, soothing, antiseptic and anti-inflammatory properties (Beaune and Balea 1966;Bone 1993;Hänsel et al. 1992;Müller-Limmroth and Fröhlich 1980;Scheffer and König 1991;Sweetman 2002;Weiss and Fintelmann 1991).Applying Althaea officinalis's root extract leads to creating a protective film that induces a faster regeneration of lesioned mucosa (Bonaterra et al. 2022).Its anti-inflammatory and immunomodulating effect is caused by phagocytes activation and oxygen free radicals and leukotrienes release from leucocytes (Scheffer and König 1991).There are also some data describing its hypoglycemic activity (Tomoda et al. 1987).

Recommendation for flaxseed, chamomile and Althaea rinse use for patients suffering from oral mucosa diseases
Nowadays there is a wide variety of ready-made, off the shelf oral coating rinses and a wide range of oral diseases with indications for the use of moisturizing, relieving, coating drugs as a complementary treatment.
Flaxseed, chamomile basket and Althaea root used as a mixture in ratio 1:1:1 boiled for 15 min have been recommended in the Oral Mucosa Department at [institution blinded for reviewers] for 20 years and the effects are noteworthy (Knychalska-Karwan 1998).

Lichen planus
Another disease of oral mucosa appearing with increasing frequency and need for coating and pain relief is lichen planus.This common chronic, inflammatory condition can affect mucous membranes and skin.In about 20% of this condition, it can affect oral mucosa (Alrashdan, Cirillo, and McCullough 2016).The etiology of oral lichen planus is unknown, and its clinical course suggests that it may encompass differences in respective pathogenesis mechanisms.The potential triggers and contributing factors of this condition are: local and systemic inducers of cell-mediated hypersensitivity; stress; autoimmune response to epithelial antigens and microorganisms (Cheng et al. 2016).It is a disease with a typical course of relapses and remissions with predisposing factors like some drugs, systemic diseases like hypertension, diabetes mellitus (Cheng et al. 2016).The coincidence with type C hepatitis and chronic stress can also be found (Cheng et al. 2016).Different clinical variants like reticular lichen planus, erosive, atrophic or plaque-like are distinguished (Cheng et al. 2016).The typical primary lesions are papules arranged in linear form of Wickham striae appearing bilaterally, especially on the buccal mucosa and tongue (Górska 2023).
The chronicity of the disease needs the long-term use of drugs with minimizing side effects.Therefore, various studies have been conducted to find an alternative and effective treatment.The basic therapeutic algorithm of lichen planus treatment includes the use of immunosuppressive drugs like steroids or calcineurin inhibitors (tacrolimus 0,1% and pimecrolimus 1%) since it is immunologically-mediated disease (Chiang et al. 2018).If the lichen planus lesion is small and the oral symptoms are mild, topical application of steroids-dexamethasone or triamcinolone is usually sufficient to induce healing.If the lesions are large, submucosal injections of steroids may be necessary additionally to topical administration of steroids.Long-term corticosteroid therapy results in many adverse effects and the disease usually flares up again (Chiang et al. 2018).Calcineurin inhibitors are used in order to inhibit cytokines release, but they have side effects like: malignancies, nephrotoxicity, the neurotoxicity, hepatotoxicity and bacterial, viral and fungal infections resulting from immune system suppression (Safarini, Keshavamurthy, and Patel 2023).Therefore, there is the need for everyday use of oral rinse that enables calming, pain relief and moistening effect without side effects.The use of herbal medicine as an alternative therapy with antioxidant and anti-inflammatory properties seems to be promising (Ghahremanlo et al. 2019).

Burning mouth syndrome
A condition without any clear etiopathology, any clinical symptoms, accompanied by a burning sensation of tongue or other oral area is described as burning mouth syndrome (BMS) (Nosratzehi 2021).This condition could be accompanied by the feeling of numbness usually localized on the lips or other regions of oral cavity but also by the feeling of dryness.Usually, menopausal or postmenopausal women are affected.Burning pain, the dominant syndrome of this disease, is usually long-lasting or intermittent, usually bilateral and alleviated by eating or drinking (Klein et al. 2020).The medium duration of BMS is 3-4 years.The diagnosis of BMS can be made after ruling out the conditions like anemia, diabetes, xerostomia, hypothyroidism, allergies, autoimmune diseases, drugs side effects, fungal infection, galvanic reactions in oral cavity, Costen syndrome or parafunctions (Teruel and Patel 2019).Since, after eliminating the potential causes of pain, casual treatment is difficult, the therapy is usually symptomatic with accompanying coating of oral mucosa.Flaxseed, chamomile and marshmallow root mouth rinse is often prescribed for BMS thanks to its coating properties.This oral rinse is also an easily accessible, low-cost solution for the feeling of oral mucosa dryness common in BMS patients.In our clinic, it is a rinse of first choice prescribed for such patients.

Xerostomia
The use of herbal mouth rinses is of special interest in case of xerostomia as it occurs with increasing frequency.Xerostomia is the subjective sensation of dry mouth, which is often (but not always) associated with the hypofunction of the salivary glands (Tyldesley, Field, and Longman 2003).Dry mouth sensation can be caused by several factors like: drugs side effects, autoimmune systemic diseases, diabetes, hypothyroidism, head and neck radiotherapy, graft-versus-host disease (GvHD), infectious diseases (HIV/AIDS), hormonal disorders, nutrient deficiencies, local factors (nicotinism, snoring, mouth breathing), salivary gland diseases, or iatrogenic destruction of salivary gland nerves supply (Górska 2023).
The clinical manifestation of true xerostomia is frothing or stringing of saliva, dry, pale, ruptured and lusterless mucous membranes, fissures and ruptures of the lips, fetor ex ore.The patient may report problems with food ingestion, speaking, dysgeusia with predominance of bitter and salty taste and burning sensation of oral mucosa (Tanasiewicz, Hildebrandt, and Obersztyn 2016).
Human saliva is an extraordinary complex of bio-colloids which has not been completely understood so far (Sarkar, Xua, and Lee 2019).It determines proper speech, food processing and swallowing.Saliva maintains a moist oral mucosa, which helps prevent abrasion and removes food residues, microorganisms and desquamated cells.It also enables the sense of taste by dissolving tastants and distributing them to the taste buds.Saliva also plays a role in the initial stages of digestion.It protects the teeth from caries and exhibits an anti-bacterial, anti-viral, anti-fungal properties and possesses wound healing properties (Dawes et al. 2015).
Saliva is produced by the major and minor salivary glands, each of them producing different types of saliva -serous, mucous or a mixture of both.Major salivary glands like parotid, submandibular and sublingual produce the majority of saliva.They are assisted by palatal, buccal, lingual, molar glands together with glands localized in the lips and tonsils (Dodds, Johnson, and Yeh 2005).Salivary glands share in saliva production depend on stimulation.Non-stimulated saliva is produced mostly by the submandibular gland, while stimulated saliva is secreted mostly by the parotid gland (Almeida et al. 2008;Humphrey and Williamson 2001).The secretion of non-stimulate saliva is on the level of 0.1-0.3ml/min, while it reaches 7 ml/min when stimulated (Humphrey and Williamson 2001).The daily secretion of saliva on average is on the level of 1.0-1.5 L (Almeida et al. 2008).
Saliva's ability to neutralize acids and control pH depends on carbonates, phosphates and urea.Peptides, enzymes and immunoglobulins play a role in anti-infectious saliva's properties.Calcium, phosphate ions and statherin inhibit the demineralization of teeth hard tissues, they also support remineralization.Mucin lubricates the mucous membrane, which prevents from irritation; mucin also plays a role in aggregating microorganisms, which results in cleansing the oral cavity by prevention of microorganisms adhesion to the tissues (Almeida et al. 2008;Humphrey and Williamson 2001;Pytko-Polończyk et al. 2017).
Saliva is a complex, multitask substance with its composition and secretion fluctuation depending on many factors.It is essential for moistening and lubrication of oral cavity structures, for taste and smell perception, digestion, protection of oral mucosa and teeth.Flaxseed, chamomile and Althaea root rinses seem to be a good complementary therapy in saliva supplementation, minimalizing dry mouth symptoms, and even a gingivitis treatment.The advantages of herbal products are: a synergistic effect due to phytochemicals that work in combination and a low risk of side effects due to low concentrations of active ingredients (Batista et al. 2014).
The treatment of xerostomia is generally restricted to palliative measures, saliva substitutes are not very effective ones, and therefore chamomile and linseed substitutes according to some clinical research are more effective comparing to carboxymethyl cellulose conventional saliva substitutes (Morales-Bozo et al. 2017).
All of the above conditions together with limitations of mechanical oral hygiene methods have led to the development of many ready to use mouthwashes in order to obtain an antiplaque action, reduce the bacterial adhesion to the teeth surfaces, inhibit the growth and proliferation of microorganisms and protect the oral mucosa.Chlorhexidine is an excellent antimicrobial agent considered to be the most effective although presenting adverse effects when used for long period: staining tongue and teeth, bitter taste, interference in the gustatory sense (Deus and Ouanounou 2022).When taking into consideration these adverse effects of rinses with chlorhexidine, the need of oral rinses as a natural alternative is seen.

Conclusions
Oral mouth rinses with flaxseed, chamomile and marshmallow seem to be a good choice for patients with different mucous membrane problems.
As the production of human saliva for moistening and lubrication of oral cavity structures is still impossible, anti-bacterial, anti-viral, anti-fungal and stimulating wound healing functions of herbal rinses are a reasonable alternative.Such rinses possess the necessary features and are easily accessible, cheap and natural.Above all these, they have many beneficial components necessary for the human nutrition like unsaturated fatty acids, proteins and dietary fiber.

Highlights
• Herbal mouthrinse is a good choice for patients withdifferent mucous membrane problems.
• Herbal mouthrinses contain many beneficialcomponents necessary for human nutrition like unsaturated fatty acids, proteinsand dietary fiber.

Table 1 .
The nutritive composition of flaxseed.