RU2843379C1 - Composition for preventing and treating dysbiosis - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to use of composition containing 0.05–5.1 wt. % of olive product, 0.1–10 wt. % of betaine and 1–20 wt. % of xylitol, for treating and/or preventing dysbiosis, wherein said olive product is olive oil and/or olive fruit extract. Group of inventions also relates to the use of said composition for preventing pathology, which contributes to dysbiosis or which complicates dysbiosis, for oral hygiene, nasal cavity, vagina or skin of the human body, as well as to maintain natural hydration of mucous membrane or skin of human body.

EFFECT: group of inventions provides preventing or treating dysbiosis.

18 cl, 3 dwg, 27 tbl, 9 ex

Description

FIELD OF INVENTION

The present invention relates to the field of the microbiome and its relationship to health and disease. In particular, it relates to a composition for use in the prevention and treatment of dysbiosis.

PRIOR ART

Microbiome and microbiota are sometimes used as analogous terms. Microbiota refers to the collection of microorganisms, including bacteria, fungi, archaea, viruses and parasites, that live in or on our body, while microbiome is a broader term that refers to the entire habitat, including not only the microorganisms, but also their genes and metabolites, and their ecosystem. This invisible to the eye 3D (three-dimensional) architectural structure is based on the extracellular matrix, which serves as a physicochemical framework for biofilms and, in the opinion of the present inventors, is key to the onset of dysbiosis and health restoration (eubiosis). This framework not only has chemical properties, but it also physically contributes to the shape of this universe, providing protection from environmental aggression (among others, changes in humidity, pH shifts, temperature fluctuations, antiseptics, antibacterials, stress). Ideally, it should also contain what is necessary for cell life, i.e. water, nutrients, and limit the penetration of harmful agents.

Biofilms are considered as specific microbiota and its ecosystem that live in different parts of the body, attached to a specific surface, organized three-dimensionally. Examples of biofilms are oral, dental, skin and vaginal biofilm.

The microbiota is gradually established in or on our body at birth, depending on the birth canal (vaginal or cesarean), the mother's microbiome, diet, geography, habits, psychology and lifestyle. It gives the host its individuality by stabilizing the bidirectional communication between the host and the microbiota and vice versa. Lifestyle, stress, education, personality, age, geography, climate are known to change the microbiota and its ecosystem, and at the same time, the microbiota can change the ecosystem and then, ultimately, the individual. Drugs, tobacco and alcohol, stress, wounds, mouth breathing, sleep apnea, eating disorders and other systemic diseases such as cancer and diabetes, among others, negatively affect the mucosal microbiome of the body in different places such as the mouth, lung, intestine, vagina and skin, giving place to an emerging portfolio of newly recognized and emerging dysbiosis of varying severity.

The mucosa is a membrane lining the cavities and channels of the body that lead to the outside, mainly the respiratory, digestive and genitourinary tracts. These include, among others, the mouth, nose, eyelids, cerebellum, lungs, stomach, intestines, ureters, urethra, vagina and connections between different sites. The mucosa of the body lines all ducts and tracts and has common histological characteristics and secretes mucus, which acts as a barrier and adapts to different sites (papillae, microvilli, etc.). The skin also shows common histological characteristics throughout the body and also has a barrier function with some adaptive features depending on the location (hair, sweat glands, etc.). The mucosa and skin represent the largest habitat of the microbiome and are the most sensitive to imbalance or dysbiosis of the microbiome that connects different sites.

The link between dysbiosis and overall health has been described by several studies, giving rise to different schools of thought advocating connections between different microbiomes, giving rise to what is now known as the oral-gut axis, oral-liver axis, oral-lung axis, oral-gut-lung axis, oral-brain axis, oral-cardiovascular axis, gut-lung axis, gut-skin axis, oral-diarthrosis axis, oral-thoracic axis (Lira-Junior & Boström, 2018) and the oral-cutaneous axis described again here (see below).

Regarding the oral-pulmonary axis, dysbiosis in periodontitis as a source of inflammatory mediators has been associated with exacerbation of pulmonary disease (Paju & Scannapieco, 2007). The increasing evidence on the role of the pulmonary microbiome and its impact on the progression and severity of pulmonary diseases in different groups such as pneumonia, cold, influenza, cystic fibrosis, pulmonary fibrosis, chronic obstructive pulmonary disease (COPD) were examined.

Evidence of the gut-cutaneous axis through inflammatory skin diseases associated with gut microbiome imbalance has so far translated into recognition of the potential benefit of probiotics to improve skin conditions via the gut microbiome (Atarashi, Wataru, & Chengwei, 2017). Recently, transplantation efforts have emerged in an attempt to replicate this sub-universe from healthy individuals (donors) to diseased subjects (recipients). Similarly, some practitioners have advocated transplantation of skin microbiota from healthy subjects to alleviate the symptoms and clinical course of atopic dermatitis in place of antibiotics against the pathogen S. aureus. Unfortunately, microbiome transplantation-based therapies require further development, are proving to be an expensive approach, and have so far had little practical application remaining in the hospital environment and appear to be far from becoming routine practice.

To date, attempts to correct the dysbiosis-damaging microbiome by displacement or transplantation (probiotic science) or elimination (antibiotic therapy) have shown uncertain safety and efficacy issues. Therefore, there is still a need for improved therapies to prevent and treat dysbiosis.

PURPOSE OF THE INVENTION

The first aspect of the present invention relates to a composition comprising an olive product, betaine and xylitol for use in the prevention and/or treatment of dysbiosis, wherein said olive product is olive oil and/or olive fruit extract.

The second aspect of the present invention relates to the use of a composition containing an olive product, betaine and xylitol for the production of a medicament for the prevention and/or treatment of dysbiosis, wherein said olive product is olive oil and/or olive fruit extract.

A third aspect of the present invention relates to a method for treating dysbiosis in a subject in need thereof, comprising administering a therapeutically effective amount of a composition comprising an olive product, betaine and xylitol, wherein said olive product is olive oil and/or olive fruit extract.

The fourth aspect of the present invention relates to a method for preventing dysbiosis in a subject, which comprises administering to said subject a prophylactically effective amount of a composition comprising an olive product, betaine and xylitol, wherein said olive product is olive oil and/or olive fruit extract.

The fifth aspect of the invention relates to the use of a composition containing an olive product, betaine and xylitol for oral, nasal, vaginal and/or skin hygiene and for use in maintaining the natural hydration of the mucous membrane and/or skin of the human body, where said olive product is olive oil and/or olive fruit extract.

Other objects, characteristics, advantages and aspects of the present application will become apparent to those skilled in the art from the following description and the appended claims.

BRIEF DESCRIPTION OF GRAPHIC MATERIALS

Fig. 1. Schematic drawing of the structure of the skin and mucous membrane (oral mucosa), emphasizing the similarities and parallelism between the skin and mucous membrane.

Fig. 2. Model of the dynamics of the microbiome of eubiosis and dysbiosis. This ecosystem is part of the microbiome self-repair cycle to promote symbiosis (health) and prevent dysbiosis (disease), but is also a participant in the vicious circle of the microbiome maintaining dysbiosis.

Fig. 3. Dynamics of the microbiome using the composition of the invention. The composition of the invention enhances the resistance of this ecosystem, stimulating a healthy environment, microbiota balance and eubiosis.

DETAILED DESCRIPTION OF THE INVENTION

The singular forms as used herein include their corresponding plural forms, unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. For ease of understanding and clarity of the meaning of specific terms in the context of the present invention, the following definitions and their specific and preferred embodiments are provided, applicable to all embodiments of the various aspects of the present invention:

The term "microbiome" as used here refers to the microbes that live in and on the human body and their genetic content, both persistently and transiently, including eukaryotes, archaea, bacteria, and viruses (including bacterial viruses (i.e., phages)). "Genetic content" includes genomic DNA, RNA such as ribosomal RNA, the epigenome, plasmids, and all other types of genetic information. A healthy microbiome provides many benefits to the host, including resistance to colonization by a wide range of pathogens, the biosynthesis and uptake of essential nutrients, and immunostimulation that maintains healthy epithelium and appropriately controlled systemic immunity. The microbiome can be characterized in healthy individuals and in those with disease. In healthy individuals, the microbiome is defined as normal.

Dysbiosis, as the opposite of eubiosis, occurs as a result of a loss of balance in the microbiome, either due to a shift in the microbiota or a change in the microbiome ecosystem.

"Dysbiosis" refers to a condition of the microbiome of any region of the body, including mucosal surfaces and skin, in which the normal diversity or function of the ecological network is disrupted. Thus, in a specific embodiment, dysbiosis is mucosal dysbiosis, cutaneous dysbiosis, or a combination of both. Any disruption from the preferred (e.g., ideal, normal) state of the microbiota may be considered dysbiosis, even if such dysbiosis does not result in detectable impairment of health. A given dysbiotic state may be unhealthy, it may be unhealthy only under certain conditions, or it may prevent a subject from becoming healthier. At the same time, dysbiosis may be a cause or consequence of disease, and may contribute to and/or exacerbate disease. Dysbiosis may be due to a decrease in diversity, an overgrowth of one or more pathogens or pathobionts, symbiotic organisms that can cause disease only when certain genetic or environmental conditions are present in the host, or a shift to an ecological network that no longer provides a beneficial function to the host and therefore no longer promotes health. Dysbiosis may be induced by disease (diabetes, cancer, infections, obesity, depression), treatment (e.g., overuse) of an agent (e.g., an antibiotic, e.g., an antibiotic that reduces commensal flora), or other environmental factors (pH changes, inflammation, diet, drugs).

In situations of “dysbiosis” or disrupted symbiosis, microbiome functions may be lost or impaired, leading to increased susceptibility to pathogens, altered metabolic profiles, or the induction of proinflammatory signals that may lead to local or systemic inflammation or autoimmunity.

In a specific embodiment according to any of the aspects of the present invention, the dysbiosis is selected from mucosal dysbiosis, skin dysbiosis or a combination thereof. In another specific embodiment according to any of the aspects of the present invention, the dysbiosis is selected from oral dysbiosis, pulmonary dysbiosis, skin dysbiosis and/or vaginal dysbiosis.

"Oral dysbiosis" refers to dysbiosis that affects part or all of the oral mucosa and/or the teeth of the subject.

"Skin dysbiosis" refers to dysbiosis that affects part or all of the subject's skin.

"Vaginal dysbiosis" refers to vaginosis.

"Pulmonary dysbiosis" refers to dysbiosis that affects all or part of the mucosa in the lung and/or its surrounding area (e.g. trachea).

The term "prevent" or "warning" means the prevention, delay and/or reduction of the severity of a disease and/or signs and/or symptoms associated with a disease.

The term "prophylactically effective amount" refers to an amount that, when delivered, prevents, delays, and/or reduces the severity of a disease and/or signs and/or symptoms associated with that disease.

The term "treatment" refers to the alleviation or elimination of a disease and/or signs and/or symptoms associated with the disease.

"Therapeutically effective amount" refers to an amount that is effective in reducing or eliminating a disease and/or signs and/or symptoms associated with that disease.

In particular, in the present invention, the disease is a dysbiosis or a pathology that is promoted by dysbiosis or complicated by dysbiosis.

The Human Oral Microbiome Database (HOMD) has described oral taxa and phyla, strains, reaching almost six hundred and twenty taxa, of which 65% have been cultured to date, while only 1% have been cultured from other sites in the body. Firmicutes , Bacteroidetes , Proteobacteria , Actinobacteria , Spirochetes and Fusobacteria account for 95%. In the skin, the four dominant phyla are Actinobacteria , Proteobacteria , Firmicutes and Bacteroidetes . Both the skin and the oral cavity show diverse topographic populations associated with different microenvironments. In the mouth, the palatal and lingual aspect of the teeth provide different phyla in relation to the sublingual or buccal or lingual area, showing parallelism with the lipid environments of the upper parts of the body in relation to phyla with greater diversity in the skin of the flexures and the lower part of the body. Both the skin and the mouth have high topographical diversity dictated by the environment as mentioned above, with high temporal variability within an individual but rather stability over the lifespan per individual. Abundance, which has been the focus of many researchers over the years, is now considered only as a relative marker of disease, as all individuals will exhibit Staphylococcus , Propionibacterium , and Corynebacterium when it comes to the skin, and Streptococcus mutans and Porphyromonas gingivalis when it comes to the mouth. The present study supports that the pressure of the habitual Firmicutes types of either the skin ( Streptococcus epidermidis ) or the mouth ( Streptococcus mutans ) allows penetration through the skin by another member of the Firmicutes type Staphylococci , taking advantage of the inflammatory conditions. In the mouth, the shift imposed by anticaries agents that reduce the population of Streptococcus mutans will result in a decrease in acid metabolites from these bacteria and will increase the pH that will be exploited by non-saccharolytic bacteria that prefer a higher pH and a lower oxygen gradient, meaning an increase in the levels of anaerobic subgingival gram-negative bacteria that lead to periodontitis. Periodontitis is commonly associated with Staphylococci invasion of the skin of patients with oral lichen planus (OLP), a common chronic autoimmune mucocutaneous disease described as the second most common oral mucosal disorder after oral ulceration. Twenty to thirty-five percent of patients with OLP also have lesions on the skin, scalp, and/or vagina.

The most common oral microbiota are Streptococcus , Lactobacillus , and Prevotella . An analysis of respiratory bacteria from patients with aspiration-risk pneumonia showed that oral streptococci were the most common type of bacteria found in both the bronchi and the lung.

In balanced, non-inflammatory healthy conditions, both the skin and mucosa exhibit barrier-like properties in that the microbiome and human cells reside in distinct compartments throughout one of the two tissues. The symbiotic dual host-microbe interaction requires microscopic separation between the microbiota and host epithelial cells. When the skin or mucosa is disrupted, such as in wounds or inflammatory conditions, mechanisms result in altered communication between the host and microbiome, leading not only to a variety of inflammatory dysbiotic diseases but also, ultimately, to oncogenesis. Research in the oral cavity is now consistent with the finding that oral dysbiosis and dysbiotic biofilm underlie common, widespread diseases such as dental caries and periodontitis. In our view, teeth have their own microbiome that protects them from problems as long as symbiosis occurs. At the same time, the teeth themselves, when healthy, constitute a barrier to the jawbones from the moment they penetrate the oral mucosa during eruption. When a tooth is eventually lost, the mucosa takes its place and closes the gap, as the barrier function is essential for human survival. As mentioned above, for the skin and mucosa, both the tooth and its microbiome are in different compartments, physicochemically attached to each other, and the integrity of both compartments is essential for health and barrier function. When the microbiome is damaged, such as by separation and loss, disruption or disappearance of the integrity of both compartments, a new dysbiotic relationship between the host and the microbiome leads to a non-symbiotic inflammatory state (periodontitis dysbiosis) and/or increased tooth permeability (hypersensitivity, demineralization and loss of tooth structure). When this microbiome is lost, disrupted or damaged, the tooth barrier is lost. Hypersensitivity, demineralization, caries and tooth wear occur, either physical, chemical or a combination of these (bruxism, attrition, dentin loss, abrasion). The disrupted microbiome barrier ceases to act as a lipophilic shield and the tooth begins to dissolve in an acidic or highly acidic environment. Every mouth is different. The mineral content of teeth and the thickness of enamel also vary between individuals. Other variables such as salivation and salivary mineral saturation combine to explain why some teeth will resist better than others, termed the critical pH (Dawes, 2003). In vitro conditions ignored living microbes and their ecosystem, which may indeed be the major reservoir of minerals, water, peptides and their own metabolism that arrest and prevent the dissolution of human teeth. This theory is supported by the fact that without plaque, even salivary stimulation will not stimulate mineral deposition. According to the present authors, a dysbiotic microbiome makes efforts to remineralize teeth through saliva stimulation or through the supply of minerals or remineralizing agents, which some authors are beginning to explore (Lussi & Carvalho, The future of fluorides, 2015), futile. With physical abrasion and wear of teeth, the habitat is altered as previously hidden dentin emerges, providing altered support for the microbiome.

The greater the tooth wear and loss of tooth structure, the greater the challenge to the oral microbiota, which finds flatter and more altered tooth surfaces to attach to. In advanced cases of tooth wear, the interdental areas follow the disappearance of all biting surfaces in the loss of specific microbiota habitats. Ultimately, mastication deteriorates with a shift to softer foods, with further tooth loss and deeper oral dysbiosis - an example of the vicious cycle of dysbiosis described by the present authors.

Control of any form of dental plaque or dental biofilm by biocidal disinfectants, chemical or physical treatments has not been shown to be effective in eradicating periodontal conditions such as gingivitis or periodontitis and caries, which underlie premature tooth loss. The increasing number of patients treated with dental implants has given rise to a new condition called peri-implantitis. Implants, lacking a thick mucosal barrier placed in areas of non-keratinized gingiva, demonstrate the potential for a specific peri-implantitis dysbiosis that can neither be prevented nor treated with antibiotics. Patients wearing dentures or restorative materials and the rapidly growing group of patients receiving orthodontic treatment may also suffer from oral dysbiosis as a result of an unbalanced microbiome as a consequence of the altered habitat imposed by artificial materials.

Like the oral cavity, the skin is home to a vast microbiome with specific microbiota for different skin types and areas. The skin exhibits a high rate of cell shedding and renewal, similar to the mucous membrane. Depending on the degree of sebum or water secretion, we can find 3 different skin types:

- oily areas include the scalp, forehead, back, posterior ear fold and underarm fold;

- moist areas include the armpit, inguinal fold, gluteal fold, foot, popliteal fossa and the fossa anterior to the elbow joint;

- dry areas include the forearms, buttocks and various parts of the hand.

Inflammation and ulceration of varying degrees are the most common signs of skin disease. When the skin loses its healthy state, it manifests itself with a weakened barrier function with cracking and redness.

Among the daily challenges to the skin, alcohols and detergents from soaps and creams can disrupt the integrity of the epidermal barrier by, among other mechanisms, removing lipids, which facilitates colonization by several harmful bacteria ( Staphylococcus aureus ). This occurs in atopic dermatitis, where during outbreaks of dermatitis, bacterial colonization triggers a shift to low-diversity species incompatible with healthy skin. A similar situation applies to psoriasis.

There is a link between some medical conditions, such as chronic inflammatory conditions and cancer, and both the mucosal and cutaneous microbiomes. In chronic inflammatory conditions like type II diabetes, not only are the oral and cutaneous microbiomes involved in the etiopathogenesis and course of this complex metabolic condition, but diabetes alters the environment of the oral, cutaneous, and intestinal microbiomes, with increasing evidence establishing diabetic dysbiosis. Oral dysbiosis in diabetes is associated with a higher risk of dental caries, higher prevalence and severity of periodontitis, whereas cutaneous dysbiosis in diabetes is associated with foot ulceration, decreased skin elasticity, decreased sebaceous gland activity, and lower lipid levels.

In addition, skin and oral microbiomes have been linked to oncogenic changes leading to melanoma and oral cancer. At the other end of the scale, cancer dysbiosis occurs as a result of living with cancer. This cancer dysbiosis is associated with a group of signs and symptoms with low severity but high negative impact on quality of life. Oral dysbiosis in cancer occurs or is characterized by, among others, one, more, or all of the following: mouth pain, dysgeusia (change in taste), high frequency of chipping, high frequency of caries, angular labial inflammation (cracks in the corners of the lips), mouth pain, and even decreased ability to eat and have interest in food - an unexpected similarity. Skin dysbiosis in cancer occurs or is characterized, among other things, by one, several or all of the following: inflamed skin areas, altered sense of touch, high rate of crack formation, inflammatory phenomena, pain and functional impairments related to the skin of distal parts of the body, mainly the arms and legs, but also the skin of the back, legs and trunk.

The oral mucosa, like many mucous membranes in the body, is in many ways analogous to the skin. The oral mucosa is composed of two distinct layers: the stratified squamous epithelium and the lamina propria. In some areas of the oral cavity, the oral mucosa is attached to the underlying structures by a component of loose connective tissue, the submucosa. These three layers are analogous to the epidermal, dermal, and hypodermal layers of the skin (see Fig. 1). In fact, pathologies such as lichen planus and pemphigus vulgaris affect both the skin and the oral mucosa. Thus, in the present invention, they represent embodiments of both oral dysbiosis and skin dysbiosis.

Pulmonary dysbiosis follows a disruption of the lung microbiome, which loses homeostasis and initiates dysbiosis. The most common initiators of pulmonary dysbiosis are environmental changes such as, among others, dehydration, dehydration through oxygen therapy, temperature changes, pH changes, tobacco smoking, smoking tobacco substitutes (vaping), lifestyle habits, alcohol, diet, pollution, radiation, oxygen gradient, medications, diseases such as cancer, infections and diabetes, obesity and aging. Interestingly, a decrease in the diversity and specificity of the microbiome across different microenvironments within the body is found in the elderly population, explaining the increased frailty with aging associated with the loss of species diversity.

Pulmonary dysbiosis may also occur as a consequence of bacteria, viruses, or fungi penetrating the mucosa and encountering a microbiota with reduced diversity. Whether microbiome changes are a cause or consequence of the development of pneumonia, for example, or simply coincide with or are associated with the disease state, remains controversial. However, in the view of the present inventors, the vicious circle of the microbiome and the maintenance of dysbiosis in disease and disease in dysbiosis is described as a dynamic model of microbiome eubiosis, and dysbiosis in the present invention explains why lung health is the result of a complex interaction between the host and the microbiome.

Taking into account all of the above, in a specific embodiment of any aspect of the present invention, "oral dysbiosis" includes, but is not limited to, halitosis dysbiosis, dental caries dysbiosis, periodontal dysbiosis, aphthous dysbiosis, peri-implantitis dysbiosis, lichen planus dysbiosis, pemphigus vulgaris dysbiosis, sleep apnea dysbiosis, stress dysbiosis, tooth wear dysbiosis, diabetic oral dysbiosis, cancer oral dysbiosis, and combinations thereof. Preferably, the oral dysbiosis is selected from dental caries dysbiosis, dental wear dysbiosis, periodontal dysbiosis, aphthous dysbiosis, peri-implantitis dysbiosis, sleep apnea dysbiosis, diabetic oral dysbiosis, cancer oral dysbiosis, and combinations thereof.

Similarly, in a specific embodiment of any aspect of the present invention, "skin dysbiosis" includes, but is not limited to, dysbiosis in atopic dermatitis, dysbiosis in acne vulgaris, dysbiosis in psoriatic dysbiosis, dysbiosis in xeroderma, dysbiosis in skin allergies, dysbiosis in radiation dermatitis, dysbiosis in sun dermatitis, dysbiosis in contact dermatitis, dysbiosis in seborrheic dermatitis, dysbiosis of the scalp (dandruff, alopecia), dysbiosis with unpleasant body odor (armpits, feet), dysbiosis in premature aging of the skin, dysbiosis in lichen planus, dysbiosis in pemphigus vulgaris, and combinations thereof. Preferably, the skin dysbiosis is selected from dysbiosis in atopic dermatitis, dysbiosis in acne vulgaris, psoriatic dysbiosis, dysbiosis in xeroderma, dysbiosis with unpleasant body odor, dysbiosis in premature aging of the skin, dysbiosis of the scalp, and combinations thereof.

In a specific embodiment of any aspect of the present invention, "pulmonary dysbiosis" includes, but is not limited to, chronic pulmonary dysbiosis, dysbiosis in chronic obstructive pulmonary disease (COPD), dysbiosis in cystic fibrosis, dysbiosis in asthma, dysbiosis in tracheitis, dysbiosis in bronchitis, dysbiosis in respiratory infections.

In a specific embodiment, the respiratory infection is a lower respiratory tract infection caused by bacterial colonization (e.g. Streptococcus ), viral colonization (e.g. influenza, parainfluenza, coronavirus, SARS-CoV-2 coronavirus, respiratory syncytial virus) or fungal colonization (e.g. candida, pneumocystis). More specifically, said respiratory infection is selected from the group consisting of cold, pneumonia, influenza and SARS-CoV-2 coronavirus disease (Covid-19). Thus, in a specific embodiment according to the present invention, the pulmonary dysbiosis is cold dysbiosis, pneumonia dysbiosis, influenza dysbiosis or SARS-CoV-2 coronavirus dysbiosis.

In a specific embodiment of the present invention, oral dysbiosis is assessed by clinical parameters (signs and symptoms) such as: bleeding gums when brushing between teeth, tooth sensitivity, presence of inflamed gums or inflamed papillae, malodor associated with dysbiosis, tooth discoloration, tooth wear (erosion, tooth abrasion, bruxism) and/or caries, mucosal sloughing, mucosal dehydration, ulceration, aphthous ulcers, pain, dysgeusia (altered taste or lack of taste sensation), lack of elasticity, peri-implantitis. Similarly, skin dysbiosis is assessed by clinical parameters such as: dry skin, itching, redness, scaling, ulceration, pain, bleeding, lack of elasticity, lack of tactile sensitivity (altered or absent tactile sensitivity), vesicles or blisters after sun exposure.

In another specific embodiment of the present invention, pulmonary dysbiosis is assessed by clinical parameters such as sputum, rhinorrhea, congestion, conjunctivitis, headache, myalgia, aches and pains, cough, dryness, sore throat, wheezing, hoarse voice, dysgeusia-ageusia, anosmia, decreased oxygenation, chest pain or pressure, rapid breathing, difficulty breathing, and/or fever.

The Covid-19 complex represents an unknown entity both in its origin and its treatment. However, increasing evidence on the role of an altered microbiome in the course of the disease offers a new perspective for both prevention and treatment. The observed reduction in bacterial diversity in Covid-19 patients compared to healthy subjects, along with the fact that most patients with moderate Covid-19 have a parallel and simultaneous restoration of the upper respiratory tract and gut microbiomes, supports the theory that coronavirus-associated dysbiosis has an impact beyond the lung. Furthermore, the reduced diversity in most microbiome environments in older individuals, which is inherent to aging, could ultimately explain the rapid severe progression of Covid-19 and the high mortality rate. In the view of the present inventors, coronavirus dysbiosis involves a disturbance of the microbiome that penetrates through the pulmonary mucosa to other mucosa, such as the gastrointestinal mucosa, but also to the skin, which is a specific example of the mouth-lung-gut-skin axis. In fact, the symptoms and signs associated with coronavirus dysbiosis appear in the mouth, lungs and upper respiratory tract, digestive system and skin, and the list of symptoms and signs is constantly updated. In any case, in the present invention, Covid-19 dysbiosis is considered a particular variant of pulmonary dysbiosis, since it was originally described as a respiratory infection.

Paying attention to the above order, the signs and symptoms of coronavirus dysbiosis are the signs and symptoms in the mouth: dry mucous membrane (dry mouth), taste change or lack of taste (dysgeusia or ageusia), vesiculobullous lesions, aphthosis-like lesions, loss or lack of smell (anosmia). In the upper respiratory tract and lung - dry mucous membrane of the respiratory tract (dry cough), change in voice, sore throat, difficulty breathing and rapid breathing. In the intestine - diarrhea, on the skin - skin rash, change in color of the fingers and toes.

In a first aspect, the present invention relates to a composition comprising an olive product, betaine and xylitol (hereinafter referred to as the composition of the invention), for use in the prevention and/or treatment of dysbiosis. In light of Example 7, it also relates to a composition of the invention for use as an adjuvant in the prevention and/or treatment of dysbiosis.

Compositions containing an olive product, such as olive oil, betaine and xylitol, are already known in the prior art, see, for example, EP 2 119 477 A1 and WO 2019/025366 A1, but for other, unrelated uses. In particular, the composition according to EP 2 119 477 can be used to treat xerostomia. Nothing in the prior art suggests that proper function of the salivary glands would prevent the occurrence of dysbiosis, nor that patients without xerostomia would not have a risk of developing dysbiosis. Sufficient saliva production is no guarantee of eubiosis, otherwise caries, periodontitis and other dysbiosis of the oral cavity would be prevented by a normal saliva flow. In fact, nothing has been written about a preventive effect of saliva flow in the most predominant dysbiosis of the oral cavity, which is periodontitis, and, conversely, patients with xerostomia do not show a higher risk of periodontitis. Similarly, patients suffering from eating disorders or from disorders associated with gastroesophageal reflux, experience a compensatory excess of saliva and still suffer from an easily recognizable oral dysbiosis associated with tooth wear, consisting of a breakdown of the dental biofilm first on the lingual surface of the teeth, then on the biting surfaces (chewing surface) and finally on the buccal surfaces. The teeth are eventually stripped of all lipophilic content, weakening the barrier effect that this dental biofilm should perform and destroying the teeth, which cannot be saved by oral protectors of any kind.

The composition according to WO 2019/025366 A1 can be used for the treatment of oncology treatment-induced orogastric intestinal mucositis (OTIOM), a life-threatening condition in cancer patients undergoing treatment with either chemotherapy or radiotherapy. This OTIOM differs from oral and cutaneous dysbiosis in that it is self-limiting, it does not affect either the skin or the teeth, and it is not associated with the microbiome or a pathogen of any origin. It is an acute disorder of the orogastric intestinal mucosa, which is one of the most feared complications of cancer therapy and which is not treated with antibiotics, probiotics or prebiotics. In fact, probiotics are absolutely contraindicated during OTIOM due to the high risk of sepsis.

Interestingly, as shown in the Examples, the composition of the present invention comprising an olive product, betaine and xylitol has a new medical application, as it is useful for the prevention and/or treatment of dysbiosis. Surprisingly, compositions comprising an olive product, betaine and xylitol show an unexpected synergistic effect relative to compositions containing only one of the said ingredients or a combination of an olive product and betaine (see Examples 1, 3, 4 and 8). In addition, various Examples demonstrate the usefulness of the composition of the invention for the treatment and/or prevention of both mucosal dysbiosis and skin dysbiosis.

Particular and preferred embodiments of dysbiosis are those described above and applicable to all aspects of the present invention.

In a specific embodiment according to the first aspect of the invention, the olive product is selected from olive oil, olive fruit extract and mixtures thereof. The olive fruit extract may be a liquid olive fruit extract (also known as a liquid olive fruit extract), a dry olive fruit extract (also known as a dry powder olive fruit extract) or a mixture thereof. Preferably, the olive fruit extract is a liquid olive fruit extract and a dry olive fruit extract.

Extracts of olive fruits are known to those skilled in the art and are commercially available. Likewise, methods of extraction from olive fruits are well known. Examples of said methods are disclosed in WO 2008142178 A1 and ES 2051238 A1. In a particular embodiment, the olive fruit extract is a hydroxytyrosol-rich olive fruit extract. More particularly, the olive fruit extract comprises at least 20% (w/w) hydroxytyrosol. Examples of these extracts are available from Nutexa Inc and Natac, among others. Preferably, the olive product is olive oil, more preferably the olive oil is selected from the group consisting of unrefined extra virgin olive oil, virgin olive oil and a combination thereof, and even more preferably the olive oil is unrefined extra virgin olive oil (EVOO), which is known in the Examples to have outstanding effects in the treatment and prevention of dysbiosis.

Betaine can be used in any of its forms, either in the form of aqueous solutions or powder. In a specific embodiment according to any of the previous embodiments, betaine is selected from the group consisting of trimethylglycine (TMG), cocamidopropyl betaine, dimethylamine betaine, alkyl (C ₁₂ -C ₁₈ ) amidobetaines, alkyl (C ₈ -C ₁₈ ) betaines, amidobetaines, alkylamidobetaines, sulfohydroxybetaines and combinations thereof, preferably betaine is trimethylglycine, which, as shown in the Examples, has outstanding effects in the treatment and prevention of dysbiosis. More specifically, trimethylglycine is selected from preparations for the mucous membrane and skin.

Olive oil is used in the food industry as a preservative due to its antibacterial, antifungal, antiviral properties. It has been reported to be a pungent-tasting irritant and even to have a barrier-disrupting effect on the integrity of the stratum corneum via increased transepidermal water loss (TEWL) after topical application to the skin of subjects with and without atopic dermatitis. Olive oil on the skin has been claimed to cause contact dermatitis and has anti-inflammatory benefits, but also irritant side effects with barrier disruption consequences. Betaines, commonly used in mouthwashes for their antiseptic activity, carry a risk of disrupting the healthy biofilm balance when used for 2 weeks.

Xylitol is a well-known anti-tumor ingredient that is increasingly being introduced to consumers. Xylitol has documented activity against Streptococcus, especially when used alone as a remineralizing agent. However, a recent study using state-of-the-art computer science using rRNA gene sequencing examined the effects of xylitol on the composition of the oral microbiota, showing no evidence of either xylitol or sorbitol on previously documented caries-associated or caries-protective species after use. This adds a new element to the debate about the dental benefits of xylitol. Interestingly, when included in oral hygiene formulations, accompanied by other minerals and salts with remineralizing potential, xylitol was found to have a proven reduction in the anti-plaque effect. Despite the possible beneficial effects of xylitol in humans (highly toxic in animals) when taken orally at high percentages or over a long period of time, the digestive changes that follow (flatulence, diarrhea) may be a marker of an undesirable imbalance in the intestinal microbiome, which returns to homeostasis when the intake is stopped (Storey, Lee & Bornet, 2007). In skin dysbiosis and/or vaginal dysbiosis (vaginosis), high concentrations of xylitol are also undesirable, since it could shift taxonomic groups such as Bacilli ( Lactobacilli ) and Streptococci and Staphylococci . Surprisingly, the composition of the present invention does not show any of these harmful effects. In fact, the composition of the present invention preserves hydrophilic bacteria and lipophilic bacteria without demonstrating the antimicrobial properties of olive oil, betaine and xylitol when used alone. The composition of the present invention has proven effective in preventing dysbiosis on the mucous membrane and skin when applied topically by forming a 3D (three-dimensional) structure that helps maintain one's own microbiota when dangers arise.

The composition of the present invention provides a three-dimensional amphipathic framework that also includes water from the atmosphere, hydrating the microbiome ecosystem and, at the same time, hydrating the skin and mucous membrane of a person, ultimately providing protection from external aggressive influences (among others, dehydration, pH shifts, temperature fluctuations, antiseptics, detergents, radiation), limiting the penetration of harmful agents and preserving what is necessary for cell life, i.e. water and nutrients.

The microbiome ecosystem is enhanced by the composition of the invention, as it is improved for better attachment of the resident microbiota by the hydrophobicity of olive oil, the moisture retention of betaine and the moisturizing effect of xylitol, which captures moisture from the atmosphere, a more stable humectant than a simple solution in water or a two-phase solution. In fact, an olive oil emulsion in the absence of betaine and xylitol is not able to provide a moisturizing effect desirable both on the skin and on the mucous membrane.

The idea of epithelial homeostasis explains that there is a continuous replacement of cells with the shedding of more superficial cells with the positive effect of limiting microbial colonization and the negative effect of partly losing the resident microbiota. However, these living microbes need to establish their own ecosystem.

The researchers set out to identify the good bacteria that underlie the healthy state and, conversely, the populations that underlie the disease. Unfortunately, this simplification turned out to be incorrect, as the same types of bacteria are found in patients and controls, but in different proportions. It has not yet been possible to conclude that the microbiota shift is the underlying cause of the disease itself. It is assumed that the relationship is more associative than causal, while the latter is more prevalent in infectious conditions. In other words, a certain disease microbiota appears to be more associated with than caused by the condition.

In nature, ecological changes begin in a habitat and then either adaptation or extinction of certain species occurs. Attempting to maintain a stable microbiome by acting through the microbiota has had conflicting results so far. The present inventors view the ecosystem as the first recipient of damage. This in turn is responsible for the shift in the microbiota, which itself is the cause of environmental changes. This is represented by what the present inventors define as the eubiosis and dysbiosis microbiome dynamics model (Figure 2).

Human evolution has led to primary symbiosis or eubiosis, with health representing normality. However, when dysbiosis occurs, the non-symbiotic microbial population, along with the altered ecosystem, perpetuates a vicious cycle similar to obesity or depression, both of which are now understood to be related to the dysbiotic microbiome and to the disappointing failure of both diet and psychotherapy.

Our body is exposed to daily aggressors such as stress, pollution, hyperconnectivity, WiFi, chemicals, antiseptics, antibiotics, drugs, detergents, radiation, oxidative stress, infectious agents, fast food, oral and skin hygiene, shampoos, feminine hygiene, wounds, eating disorders, mouth breathing, sleep apnea, systemic and chronic conditions that have an impact on our microbiome.

Certain individuals lack the necessary internal and external conditions to correct the microbiome and, therefore, develop disease. Once the microbiota has shifted, a health promoter is needed to restore a healthy bacterial population, which can act directly on the microbiota or indirectly on the environment. Surprisingly, the composition of the present invention was able to restore and stimulate a healthy microbiota and its ecosystem by enhancing support for the ecosystem of a healthy environment. The approach of the present inventors is aimed at improving the environmental and ecosystem conditions that are favorable for the maintenance and restoration of a healthy microbiota, whatever the location. This composition improves the resident microbiota compartment, since it has not been possible to identify microbes - one or more - with a causal relationship with most of the conditions and diseases investigated to date. Improvement of the human microbiome through the ecosystem compartment is less site-specific, as shown in the Examples. This mechanism is schematically represented in Fig. 3.

In a specific embodiment according to any of the previous embodiments, the composition does not contain any other vegetable oil, more specifically, it does not contain parsley oil. Likewise, the use of inferior oils, such as palm oil, is avoided. However, the composition may contain essential oils, so in a specific embodiment, the composition does not contain any other vegetable oil except essential oils.

In a particular embodiment according to any of the previous embodiments, the composition comprises 0.05%-5.1% by weight of an olive product, preferably 0.05%-4.1%, and more preferably 0.05%-2.6% of an olive product. Preferably, when the olive product comprises or is an olive fruit extract, then the composition comprises 0.05%-0.1% of an olive fruit extract, and when the olive product comprises or is olive oil, then the composition comprises 0.1%-5%, more preferably 0.1%-4%, and even more preferably 0.2%-2.5% of olive oil.

In another specific embodiment according to any of the previous embodiments, the composition comprises 0.1%-10% by weight of betaine, preferably 1.0%-6%, and more preferably 1.20%-5%.

In another specific embodiment according to any of the previous embodiments, the composition comprises xylitol, preferably 1%-20% by weight of xylitol, more preferably 1%-15%. Advantageously in lower concentrations (e.g. 20% or less), xylitol acts as a humectant and freshener, helping to improve the prevention and treatment of dysbiosis.

All percentages given in the present invention are given on a weight-to-weight basis of the total composition (w/w), unless otherwise stated.

As shown in the Examples, compositions containing amounts of olive product, betaine and xylitol within the ranges defined above are very effective in treating and preventing dysbiosis. In another preferred embodiment, the composition of the invention contains olive product, betaine and xylitol in amounts defined in any of the preparations described in these Examples.

In a specific embodiment according to any of the previous embodiments, the present composition comprises an antioxidant and/or vitamins. Preferably, the antioxidant is a natural antioxidant, more preferably an antioxidant from Olea europeae. Preferably, the antioxidant is selected from the group of hydroxytyrosol, tyrosol, oleuropein and mixtures thereof. Interestingly, hydroxytyrosol, tyrosol, oleuropein potentiate the anti-inflammatory and antioxidant activities of olive oil and are apparently able to stabilize the present composition (i.e. reducing or even eliminating the need for additional preservatives, which will make the preparation better tolerated by subjects). Thus, in a preferred embodiment, the present composition comprises hydroxytyrosol and/or tyrosol and/or oleuropein, preferably it comprises hydroxytyrosol, tyrosol and oleuropein.

According to the desired form/preparation, the composition comprises all necessary components to provide the desired organoleptic and rheological form. Thus, in a specific embodiment according to any of the previous embodiments, the composition further comprises one or more components selected from the group consisting of remineralizing agents, viscosity control agents, humectants, preservatives, colorants, pH adjusting agents (buffer), sweeteners, emulsifiers, proteolytic enzymes, bleaches, probiotics, abrasives, essential oils, healing agents, flavors, animal or vegetable gelatins, a rheological agent, a solvent, excipients and combinations thereof.

These additional components of the composition according to the invention are generally known to a person skilled in the art, and non-limiting examples of said compounds are given below. In a specific embodiment according to any of the previous embodiments, these compounds are selected from the following examples. The remineralizing agent can be selected from fluoride anions, phosphate anions, calcium cations, potassium cations and mixtures thereof. The rheological agent can be selected from the group consisting of acacia, tragacanth gum, xanthan gum, carboxymethylcellulose, polymers of the carbopopol type, pectins, mucins and mixtures thereof. The humectant can be selected from the group consisting of glycerol, propylene glycol, sorbitol and mixtures thereof, preferably glycerol. The preservatives may be selected from the group consisting of sodium benzoate, potassium sorbate, benzoic acid, diazolidinyl urea, imidazolinyl urea, sodium methylparaben, sodium propylparaben and mixtures thereof. The sweetener may be selected from the group consisting of maltitol, isomaltitol, mannitol, lactitol, sodium saccharin, acesulfame potassium, aspartame, cyclamate, thaumatin, sucralose, Stevia rebaudiana, neohesperidin DC and mixtures thereof. The emulsifier may be selected from the group consisting of polyethylene glycol (PEG) 40, hydrogenated castor oil, lecithin and mixtures thereof.

Recent studies have confirmed the link between the use of biocides in general-use toothpastes and many serious direct side effects in distant parts of the body. A multicenter university animal study showed that triclosan, widely used in oral care products, was detected in the blood when applied in the mouth and was directly associated with several pathological conditions, such as colitis, inflammatory bowel disease, and the most common form of cancer, colon cancer, among others (Yang, Wang, & Romano, 2018). The authors of this study acknowledge the translational issues between animals and humans, but caution health authorities and professionals, as they describe that the results obtained in this study were observed after low-level exposure to triclosan, and people widely use it for oral hygiene three times a day for long periods of time.

Antifungal agents, even though they have proven effective in treating dandruff, are not able to stop the recolonization of yeast after several weeks. However, the composition of the present invention is able to enhance the microbial balance by providing the necessary conditions for the microhabitat of the scalp, which will help stop the predominant colonization of pathogenic microbes, like yeasts of the genus Malassezia.

Thus, in a specific embodiment according to any of the previous embodiments, the composition according to the invention does not contain any additional active principle (for example, antibiotics, antifungals). In particular, it does not contain triclosan.

The composition of the invention provides ideal physicochemical conditions (pH, barrier integrity and nutrients) that help maintain and restore a healthy balanced microbiota on the skin and mucous membrane. Each ecological niche has its own conditions, defined, among others, by pH (Table 1). Depending on the location of the body, the pH will be adjusted to comply with the characteristics within the body. The pH will be adjusted by buffers. Thus, in a specific embodiment, the composition of the invention comprises a buffer. Any buffer known in the art can be used in the composition of the invention. In particular, this buffer can be selected from the group consisting of lactic acid, lactates, citric acid, citrates, malic acid and their salts, sodium hydroxide, potassium phosphates, sodium phosphates, potassium pyrophosphate, sodium pyrophosphates and mixtures thereof.

Table 1

Region pH Vagina 3.8-4.5 Skin of the palmar side of the hand 4.7 Hairy part of the head 4.80 Forehead 4.80 Lips 6.61 Language 6.65 Buccal side of the mouth 6.68 Sky 7.23 Lung 6.6

It has been unexpectedly found that the composition of the present invention retains its beneficial effects, no matter what the pH required for different areas of the skin and/or mucous membrane.

A person skilled in the art can prepare the composition of the invention in any suitable form that provides easy application for preventing and/or treating dysbiosis. In a specific embodiment according to any of the previous embodiments, this composition is prepared in the form of a face and/or body moisturizer, a deodorant cream, a restorative barrier cream, a body gel, a shampoo, a hair conditioner, a hair lotion, a skin ampoule, a tonic, a capsule, a tablet, a spray, a gel, a lubricating gel, a topical gel for the vulva, a nasal inhaler, a nasal spray, an aerosol solution, an aerosol spray, aerosol capsules, a toothpaste, a mouthwash, a chewing gum, a chewable tablet, resorbable capsules, resorbable lozenges, palatal plates, candies, impregnated tampons for the mouth, impregnated gauze for the mouth, a lipstick, a balm.

In a preferred embodiment, the gel is formed by the use of gelling agents such as agar, alginate, carrageenan, guar gum, pectates, gum tragacanth, carbomers, polymers and silicon dioxide.

Dry extract of olive fruit is preferred for the preparation of lozenges or pastilles, while olive oil, preferably EVOO, and liquid or dry extract of the fruit are the preferred source of olive product for preparations in the form of gels, toothpastes, mouthwashes, shampoos, conditioners, hair lotions, creams, masks, lipsticks, sprays, serums, deodorants, capsules, ovules, shower gels. Treatment of aphthous dysbiosis of the oral cavity has a preferred embodiment in the form of a gel with EVOO as a source of olive product and with hydroxytyrosol due to its powerful antioxidant action with the taste of olive fruit (without pungent tastes). Patients with recurrent aphthous ulcers (RAU) benefit from preventive hygiene using the same approach in the form of toothpaste, which can also have a remineralizing agent, natural non-irritating tastes, vitamins and the necessary for a pleasant hygiene. Patients with inflammatory bowel disease (IBD), Crohn's disease or gluten intolerance also suffer from aphthous dysbiosis and are candidates for the same measures. For oral dysbiosis associated with stress and dental wear and for oral dysbiosis in sleep apnea, as well as for oral dysbiosis associated with eating disorders or gastric reflux, the gel is ideally prepared for topical application to the oral tissues several times a day after oral hygiene and, in particular, before bedtime and upon awakening.

The administration of the composition according to the invention for the prevention or treatment of pulmonary dysbiosis can be carried out by any known route of administration. Non-limiting examples are liquid forms for a nasal inhaler, nasal spray, nasal aerosol, nasal gel, oropharyngeal syrup and oropharyngeal gel, and solid forms in the form of capsules with an aerosol. The composition according to the invention can be included in products for the care and hygiene of various areas of the skin and mucous membrane.

"Care" refers to the restoration, improvement or protection of the microbiota of the mucous membrane and skin, necessary whenever a danger puts the natural and healthy microbiome at risk (i.e. hygiene using caustic soda or alcohol products, detergents, etc.).

"Hygiene" refers to the act by which we eliminate excess naturally produced debris and other substances that are susceptible to causing disruption to the natural and healthy microbiome.

Different formulations and carriers and/or excipients should be used depending on the area of the body in which the composition is to be applied. The person skilled in the art knows how to adapt each composition to each area of the body depending on, among other things, the pH of the tissue and other specific physicochemical properties of the tissue.

For example, some areas of the skin are more oily, moist, or dry than others.

Care and hygiene products should be adapted to this property.

In the same sense, different products should be adapted to different mucous membranes, since the mucous membrane in the mouth or the mucous membrane in the vagina are very different from each other. In a specific embodiment, when including detergents for hygiene, the composition of the invention continues to deliver beneficial effects for the ecosystem and restore eubiosis, as seen in the examples. In forms including whitening ingredients, either for teeth or for the skin, the composition of the invention also carries out beneficial activity in relation to the microbiome, reducing possible irritating, peeling effects or effects of sensitivity to whitening agents.

The human microbiota adapts to different habitats with some peculiarities. According to the Human Microbiome Project, there are different microbial communities between 10 different specific sites within the gastrointestinal tract, such as the buccal region, gums, and hard palate (group 1), and saliva, tongue, tonsils, and pharynx (group 2) (Segata, Kinder Haake, & Mannon, 2012). This topographic variation is surprisingly higher than between individuals. Similarly, the skin has oily sites (scalp, back, forearms) and moist locations with site-specific microbiota that, like the oral mucosa, also show temporal variations but remain largely stable over long periods. Topographic and temporal characteristics and richness or abundance are currently being investigated. Similarities were found in the fact that lipophilic bacteria in the oral cavity are found mainly on the hard palate, the lingual side of the teeth, the keratinized gingiva and the buccal mucosa. As the authors of the present invention see, these bacteria not only show greater resistance to digestive acids and to the passage of the food bolus, but they also generate fatty acids by metabolizing triglycerides, which bathe the rest of the oral cavity in a lipid mantle that serves as protection, lubrication and helps to preserve the lipid component of the oral biofilm. In the same way, the authors of the present invention propose a positive enhancement of this natural lipophilic protection using the present composition.

Whether high (oral mucosa) or low (scalp, back or vagina) diversity, this biofilm seems to perform valuable functions such as immune defense, nutrition, metabolism, even growth and personalization while behaving in a symbiotic (healthy) manner. It remains unclear when and why it shifts to a dysbiotic state (disease) through an as yet undiscovered trigger, whether it is a key pathogen or a major environmental challenge such as stress or, more shockingly, hygiene as previously claimed.

The microbiota is in constant flux and renewal, and at the same time, it demonstrates resistance to change. Identifying the core microbiome of a specific anatomical site or the key pathogen of a specific dysbiosis remains a formidable challenge, despite the advent of next-generation sequencing, which offers less bias than previous culture-based technologies. This is the case for periodontitis, an oral dysbiosis that is the most prevalent disease in the world population. Over the years, periodontists have evolved from the belief that gram-negative bacteria were responsible for periodontitis to the acceptance that gram-positive and gram-negative bacteria underlie the shift from initial gingivitis to advanced periodontitis with the emergence of not true pathogens but associative bacteria adapted to oxygen deprivation (anaerobic) and hemophilic (the "red complex"bacteria; Treponema denticola , Tannerella forsythia , and Porphyromonas gingivalis ) benefiting from what was originally thought to be secondary inflammation. To complicate matters further, the question of whether P. gingivalis , widely recognized as a major pathogen in periodontitis, triggers an inflammatory response by shifting the normal commensal microbiota, which is then called dysbiotic, or whether even under low abundance conditions this pathogen has a deleterious symbiotic behavior with dormant, so-called fastidious microbes that have only recently been identified, is ignored. This is the case for Filifactor alocis , which appears to be involved in major oral dysbiosis, as it is rarely detected in healthy individuals. Surprisingly, F. alocis is a Gram-positive, non-saccharolytic anaerobic bacterium that inhabits perigingival areas with a low oxygen gradient and is able to live on short-chain fatty acids, which when metabolized release ammonia and increase the pH to the neutral range. This in turn excludes gram-positive oxygen-dependent bacteria with acid metabolism like Streptococcus mutans . This is the reason why patients exhibit periodontal sensitivity rather than caries risk, and vice versa. It is not yet known whether the ability of F. alocis to successfully grow in highly oxidative conditions leads to further environmental changes associated with oxidative stress, potentially predisposing to other dysbiosis like OLP or oncogenic changes.

In an unbalanced situation of dysbiosis, the altered microbiota interacts with the human body in an atmosphere of modified environment (temperature, pH, humidity and oxygen conditions), which tends to maintain microbial shift.

Not only are the microbes replaced, but the ecosystem is altered at the same time, and this double shift is clinically manifested through negative conditions such as inflammation, barrier breakdown, bleeding, scaling, irritation, dehydration and sometimes infection of the body or, ultimately, oncogenic changes.

The role of the human microbiome in the diseases mentioned herein, such as skin dysbiosis and oral dysbiosis, is currently being established through research, but has been suspected previously, since many of these negative conditions of unknown origin have been improved by the use of antibiotics (AB). Unfortunately, resistance to AB and side effects are common drawbacks. As shown in these Examples, the composition of the invention is able to reverse these negative conditions and improve health by strengthening the ecosystem, ultimately achieving eubiosis. Thus, in a specific embodiment of the invention according to any of the previous embodiments, the composition does not contain antibiotics. In another specific embodiment according to any of the previous embodiments, said composition contains an olive product, betaine and xylitol as the only active ingredients.

Attempts to improve health through the microbiome have been mainly carried out by trying to modify the microbiota, usually by adding supposedly beneficial microbes, so-called probiotics, with conflicting results. In any case, the present invention is compatible with pre- and probiotics. Thus, in a specific embodiment according to any of the previous embodiments, the composition further comprises prebiotics and/or probiotics. In a preferred embodiment, the composition is a lozenge that contains dry olive fruit extract, betaine, xylitol and probiotics, more preferably it also contains the necessary ingredients for preparing it in dry form.

The composition of the present invention contains a lipid-lipophilic fraction (olive product), which attaches to tissues for a longer time, preventing evaporation, and a hydrophilic fraction (betaine and xylitol), which attracts moisture within this framework to ensure interaction of the microbiota with the host and its ecosystem. The microbiome ecosystem is strengthened by this composition, since it is improved due to better attachment of the resident microbiota.

As demonstrated in these Examples, the composition of the present invention has unprecedented beneficial properties that not only counteract the negative effects of topically applied olive oil or betaine, but also enhance the unexpected benefits to the oral and skin microbiome when directly applied to the skin and mucosa.

The skin and mucous membrane provide an effective barrier against pathogens and water loss. Disruption of the skin and mucous membrane barrier results in inflammatory redness, which means vasodilation and increased blood flow. The use of the composition according to the invention has shown a reduction in inflammation and, at the same time, regeneration of damaged tissue. It is important to emphasize that other inflammation inhibitors are not able to regenerate tissue, which makes this composition unique, since this property has not been obtained in humans using any other composition (Van Dyke, 2017) (see, for example, Example 4).

Selection of bacteria occurs as a consequence of altered skin or mucous membrane. Inflammation of the gums increases the levels of collagen peptides, plasma proteins and hemoglobin, which leads to the selection of specific bacteria that differ in the consumption of essential amino acids and hemin as nutrients.

The composition of the invention reduces permeability and regenerates tissues, avoiding the release of nutrients that stimulate dysbiosis (collagen peptides, plasma proteins and hemoglobin), thus obtaining a natural and healthy balance of bacteria that inhabit this tissue. At the same time, avoiding the release of these molecules helps maintain the natural healthy color of any of the mucous membranes, teeth and skin.

In the present invention, the composition enhances, rather than eliminates, adequate oral and skin biofilm by stimulating a balanced and diverse microbiota and maintaining and restoring the body's own microbiome while sparing the underlying tissues.

In addition, the discovery of a composition according to the invention that treats and prevents oral dysbiosis and skin dysbiosis and enhances oral and skin homeostasis maintains an adequate environment for the oral and skin microbiome without exerting any pressure on commensal microbes that can trigger and spread a dysbiotic surge.

The composition of the present invention has a lipid-lipophilic fraction (olive product), which attaches to tissues for a longer time, preventing evaporation, and a hydrophilic fraction (betaine and xylitol), which attracts moisture within this framework to ensure interaction of the microbiota with the host and with its ecosystem. The microbiome ecosystem is strengthened by this composition, since it is improved for better attachment of the resident microbiota.

To the knowledge of the inventors, nothing in the state of the art suggests the existence of an oral-skin axis. Gingivitis is common in patients suffering from acne vulgaris. In acne, the skin is burning, and patients also experience bleeding and swelling of the gums, sometimes to the point of breaking the skin. Both conditions commonly occur in adolescents, but also in children, and are not uncommon in adults. Both conditions are associated with a Western diet, stress, and are among the common reasons for visiting specialists. The severity varies from open or closed comedones (blackheads and whiteheads) to overtly inflammatory lesions (pustules, even cysts) in acne and gingivitis to bleeding and ulceration (ulcerative necrotic lesions). The current trend is to regard acne vulgaris as a skin dysbiosis with colonization of Propionibacterium acnes as an associative agent, facilitated by changing skin environmental conditions. Gram-positive bacteria are also found in gingivitis. However, no pathogen has been identified to date, but similar to acne, there is an increased host response that disrupts the barrier and allows colonization. As shown in the Examples, improvement in gingival health is associated with resolution of acne, consistent with this newly described oral-skin axis.

Finally, nothing in the state of the art has linked tooth wear to oral dysbiosis, however, taking into account the present invention, the imbalance in mineral metabolism underlying the loss of mineral substance in erosive damage can be prevented by restoring a suitable barrier function of the oral microbiota when in a state of equilibrium. As shown in the Examples and explained in the preceding arguments, a balanced microbiota in a favorable ecosystem counteracts acid challenges and there is an indirect reduction in tooth hypersensitivity after application of the composition of the present invention. The use of the composition of the invention, in particular in the form of toothpaste and mouth rinse, prevents dysbiosis and restores homeostasis. If dysbiosis is present, all these conditions benefit from topical application of said composition, ideally in the form of a gel or spray to restore eubiosis at the early onset of dysbiosis.

The gut-skin axis is currently the focus of university research to explain and describe the link between the gut microbiome and skin health, the hitherto illusory connection between these seemingly unrelated areas of the body, and the potential for translating gut microbiome improvement and skin therapies (Salem, Ramser, Isham, & Ghannoum, 2018) (Lee, Byun, & Kim, 2019) (Vaughn, Notay, Clark, & Sivamani, 2017) (Szántó, Dózsa, & Antal, 2019).

To the best of our knowledge, the state of the art has not disclosed anything about the oral microbiome and the systemic effect that occurs in the form of oral dysfunction during sleep, called sleep apnea or obstructive sleep apnea (OSA), and is considered by the present inventors as dysbiosis. Sleep apnea ranges from snoring to true breathing interruptions in severe forms, which negatively affect the quality of sleep with frequent awakenings and poor rest during the night. Patients experience daytime irritability, lack of concentration, daytime sleepiness, depression and anxiety, along with cardiovascular risk, and physicians refer patients to oral surgeons and dentists for invasive or non-invasive (removable mouth splints) jaw advancement therapy as an alternative to continuous mechanical positive airway pressure sleep, known as CPAP. Nothing has been written about the role of the oral microbiome in OSA, nor about the origins of the problem, nor about its consequences. The present study suggests that dysbiosis in sleep apnea begins in an altered environment, similar to what occurs in mouth breathers. Intense and persistent changes in mucosal moisture conditions impair the structural architecture of the mucosa, but also the microbiome compartment with a failing pathway critical for airflow in OSA. Hydration by sipping water upon awakening is only a short-term solution and causes nocturnal polyuria. OSA comes with repeated interruption of sleep, poor night rest and daytime consequences in the social, psychological and health aspects of the individual. As mentioned above, a connection in the form of an oral-brain axis has been described and this could indeed be another example of such a connection. Patients using the composition of the invention in the form of a spray applied before going to bed and upon awakening during the night show a significant improvement in the signs and symptoms associated with dysbiosis in sleep apnea, such as quality of night rest, irritability during the day, episodes of awakening at night, episodes of sipping water throughout the night. Patients with CPAP using this composition had better compliance with the treatment regimen and regimen compared to a water spray.

Finally, as explained above, the composition according to the invention serves to prevent and/or treat dysbiosis. Advantageously, as shown in Example 5, it also serves to prevent pathologies that are promoted by dysbiosis or that are complicated by dysbiosis. Furthermore, it can serve to treat, in particular as an adjunctive treatment of said pathologies. Said pathologies can be aggravated by dysbiosis, since dysbiosis increases the number of episodes of said pathologies, or since dysbiosis aggravates the signs and/or symptoms of said pathologies. These signs and/or symptoms can be aggravated by dysbiosis in terms of variety, intensity and/or duration. Thus, the first aspect of the invention also relates to a composition according to the invention, as described in any of the above-mentioned embodiments, for use in the prevention and/or adjunctive treatment of a pathology that is promoted by dysbiosis or that is complicated by dysbiosis.

Recent studies are consistent in implicating scalp microbiome imbalances as a major contributing factor to conditions such as dandruff or seborrheic dermatitis. There is a link between some medical conditions and both the mucosal and cutaneous microbiome, such as chronic inflammatory conditions and cancer. In fact, the skin and oral microbiome have been linked to oncogenic changes leading to skin cancers (e.g. melanoma) and oral carcinoma.

In the lung, similar to what happens in any dysbiosis, the loss of beneficial commensal bacteria implies a reduced defense against opportunistic pathogens like bacteria, fungi, and viruses that, if colonized, will maintain dysbiosis. In addition, at the same time, pulmonary dysbiosis, if present, can exacerbate otherwise normal conditions and diseases of various origins. The human lung has evolved to prevent the entry of airborne particles and pathogens, with the normality being eubiosis and the health enjoyed by young adults and other age groups, provided that dysbiosis is absent. This is true for the younger population exposed to coronavirus, who experience asymptomatic or mild cold-like symptoms as part of the dysbiosis associated with the common cold, and who return to homeostasis within 24 hours. It is the younger group that generally benefits from eubiosis when confronted with the Covid-19 coronavirus, in most cases not suffering from severe disease and experiencing a moderate or even asymptomatic course that does not progress to true coronavirus disease, whereas in the presence of dysbiosis, which occurs in the older group, the penetration of the coronavirus will cause a significantly more severe form (eg, more severe breathing difficulties, often requiring hospitalization and the use of oxygen and / or ventilation) as a result of the aggravation caused by dysbiosis. Coronaviruses are a large family of viruses that are known to cause disease ranging from the common cold to more severe diseases such as Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS).

Oral, skin, and vaginal hygiene disrupt and even destroy biofilms, degrading microbiome compartments. A neglected population of more than 300 different facultative anaerobic bacteria (including Streptococcus salivarius , S. mitis , S. aureus , S. epidermidis , and Corynebacterium ) resides in the crypts of the dorsum of the tongue and have the unique ability to reduce dietary nitrate to nitrite, the body’s natural vasodilator and promoter of gastric defense. Surprisingly, the role of the oral microbiome in blood pressure, platelet function, and bone marrow physiology, as well as in cerebral blood flow and peripheral arterial disease, is undeniable, but, astonishingly, all these beneficial effects are abolished by the use of an antibacterial mouth rinse. Radically, in healthy subjects with a poor green leafy diet using an antibacterial mouth rinse, a significant increase in systolic and diastolic blood pressure, apparently associated with a decrease in plasma nitrite, was not echoed in a mandatory study that still needs to be conducted to prove whether chronic use of an antibacterial mouth rinse leads to an increase in blood pressure and therefore to a higher risk of cardiovascular disease. In addition, dysbiosis in periodontitis and cardiovascular disease often occurs in the patient who may use antibacterial agents in the oral cavity (Hezel & Weitzberg, 2015).

Thus, among others, the pathology promoted or complicated by dysbiosis may be selected from the group consisting of dandruff, seborrheic dermatitis, chronic inflammatory pathologies, skin cancer (e.g. melanoma), oral carcinoma and respiratory infections. The latter may be bacterial infections (e.g. streptococcus), viral infections (e.g. influenza, parainfluenza, coronavirus, SARS-CoV-2 coronavirus, respiratory syncytial virus) or fungal infections (e.g. candida, pneumocystis).

In a preferred embodiment, the pathology promoted by dysbiosis or complicated by dysbiosis is a respiratory infection. More preferably, the respiratory infection is a cold, Covid-19 or pneumonia. As shown in Example 5, the use of the composition according to the invention unexpectedly prevents colds, since it reduces the number of cold episodes.

The second aspect of the present invention relates to the use of a composition comprising an olive product, betaine and xylitol for the preparation of a medicament for the prevention and/or treatment of dysbiosis, wherein the olive product is olive oil and/or olive fruit extract. Similarly, it relates to the use of a composition comprising an olive product, betaine and xylitol for the preparation of a medicament for the prevention of a pathology promoted by dysbiosis or complicated by dysbiosis, or for the preparation of an adjuvant for the treatment of a pathology promoted by dysbiosis or complicated by dysbiosis.

The third aspect of the present invention relates to a method for treating dysbiosis or a pathology promoted by dysbiosis or complicated by dysbiosis in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a composition comprising an olive product, betaine and xylitol, wherein said olive product is olive oil and/or olive fruit extract.

The fourth aspect of the present invention relates to a method for preventing dysbiosis in a subject, which comprises administering to said subject a prophylactically effective amount of a composition comprising an olive product, betaine and xylitol, wherein the olive product is olive oil and/or olive fruit extract. Similarly, it relates to a method for preventing in a subject a pathology promoted or complicated by dysbiosis, comprising administering to said subject a prophylactically effective amount of a composition comprising an olive product, betaine and xylitol, wherein the olive product is olive oil and/or olive fruit extract.

Finally, recent publications have proclaimed that oral hygiene is the first and main cause of dysbiosis of the oral microbiome (Sudhakara, Gupta, & Bhardwaj, 2018). The same has been claimed by skin researchers in relation to skin hygiene and skin dysbiosis using a decrease in biodiversity as a marker of loss of skin health and demonstrating the effect of synthetic ingredients in daily cosmetics (Wallen-Russell, 2019). Thus, the fifth aspect of the present invention relates to the use of a composition as defined in any of the embodiments of the first aspect of the present invention for the hygiene of the oral cavity, nasal cavity, vagina and/or skin of the human body and to a composition as defined in any of the embodiments of the first aspect of the present invention for use in the hygiene of the oral cavity, nasal cavity, vagina and/or skin of the human body, and/or for use in maintaining the natural hydration of the mucosa or skin of the human body. Likewise, it also relates to a method for hygiene of the oral cavity, nasal cavity, vagina and/or skin of the human body, comprising administering a composition as defined in any of the embodiments of the first aspect of the present invention. Likewise, the subject of the present invention is also the use of a composition as defined in any of the embodiments of the first aspect of the present invention for maintaining the natural hydration of the mucous membrane and/or skin of the human body, and a composition as defined in any of the embodiments of the first aspect of the present invention for use in maintaining the natural hydration of the mucous membrane and/or skin of the human body. Likewise, the subject of the present invention is also a method for maintaining the natural hydration of the mucous membrane and/or skin of the human body, comprising administering a composition as defined in any of the embodiments of the first aspect of the present invention. Preferably, the administration is local. Preferably, the mucous membrane is the mucous membrane of the oral cavity.

The specific and preferred embodiments of the composition of the invention, dysbiosis and pathology promoted by dysbiosis or complicated by dysbiosis, described for the first aspect of the present invention are applicable to the second, third, fourth and fifth aspects of the present invention.

In a particular embodiment of the present invention, according to any of the embodiments of all aspects of the present invention, the protocol for administering the composition of the invention is the protocol described in the Examples below.

LIST OF REFERENCES

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Sudhakara, P., Gupta, A., & Bhardwaj, A. (2018). Oral dysbiotic communities and their implications in systemic diseases. Dent. J, 6(16). doi:10.3390/dj6020010

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EXAMPLES

Specific embodiments of the present invention are described in detail below, which serve to illustrate the present invention without limiting its scope.

EXAMPLE 1 - periodontal dysbiosis

In the mouth, periodontal disease is a late result of oral dysbiosis, often preceded by inflammation and other changes that, because of their high frequency, were considered normal. The authors of this invention cite symptoms such as bleeding gums, bad breath, tooth sensitivity, and others.

In the following study, signs and symptoms of dysbiosis were investigated in a population of outpatients with a history of periodontal dysbiosis. Subjects were ranked for the intensity of complaints on a scale of 0 to 10 at baseline and after 15 days using the prescribed composition.

Several compositions prepared in the form of toothpaste (Table 2) were applied three times daily as part of the usual routine hygiene by brushing the teeth with a toothbrush for 2 minutes, followed by rinsing with water. No other oral hygiene measures were performed during this study, except for interdental cleaning.

Table 2 shows the qualitative and quantitative composition of each composition (comp.).

Dysbiosis was analyzed by assessing the following signs/symptoms:

1. Inflammation of the gums, papillae (G, PI).

2. Redness or soaking (R, B).

3. Bleeding during cleaning (BB).

4. Bleeding during interdental cleaning (BIB).

5. Sensitivity (S).

6. The presence of an unpleasant odor on exhalation detected by a third party (H).

7. Teeth Discoloration (TD).

Table 2

Comp. 1.a
(% mass) Comp. 1.b
(% mass) Comp. 1.c
(% mass) Comp. 1.d
(% mass) Olive oil 0,5000 0,5000 0,0000 0,0000 TMG 4,0000 4,0000 0,0000 0,0000 Xylitol 10,0000 0,0000 10,0000 0,0000 Humidifier 39,7714 49,7714 45,0000 54,2714 Solvent 19,9000 19,9000 19,1564 19,9000 Abrasive agent 18,0000 18,0000 18,0000 18,0000 Source of minerals 3,1000 3,1000 3,5200 3,1000 Dye 1,0036 1,0036 1,0036 1,0036 Surfactant 1,0000 1,0000 1,0000 1,0000 Enzyme 1,0000 1,0000 1,0000 1,0000 Flavoring agent 1,1000 1,1000 1,1000 1,1000 Sweetener 0,1250 0,1250 0,1200 0,1250 Preservative 0,5000 0,5000 0,1000 0,5000 100,0000 100,0000 100,0000 100,0000

The results in the form of average intensity of inflammation of the gums, papillae (G, PI), redness or soaking (R, B), bleeding during brushing (BB), bleeding during interdental brushing (BIB), sensitivity (S), presence of bad breath (H), tooth discoloration (TD) with scores from 0 to 10 from 5 patients of each group at the beginning of the study (t equals 0) and after 15 days (t equals 15) are shown in Table 3.

Table 3

Average intensity of complaints Comp. 1.a Comp. 1.b Comp. 1.c Comp. 1.d t=0 t=15 t=0 t=15 t=0 t=15 t=0 t=15 G, PI 6.8 1.8 5.4 4.2 6.4 6.2 5.0 5.0 R, B 7.2 2,2 6.2 4.4 7.2 6.8 6.8 6.6 BB 7.8 1.6 6.4 4.8 7.4 6.8 6.6 6.6 BIB 7.8 2.0 7.4 5.2 8.4 7.6 6.8 6.8 S 5.4 2.0 6.2 5.6 6.2 5.8 6.6 7.0 H 7.2 2.4 5.2 4.4 7.2 6.6 7.6 7.2 TD 7.0 2.4 7.0 5.8 6.8 6.6 8.0 7.6

The results in terms of changes in complaint intensity assessed for each composition between t = 0 and t = 15 days are shown in Table 4.

Table 4

Change after 15 days Comp. 1.a Comp. 1.b Comp. 1.c Comp. 1.d Intensity P Intensity P Intensity p Intensity P G, PI -5 <0.01 -1,2 0.2 -0.2 0.82 0 1 R, B -5 <0.01 -1.8 0.04 -0.4 0.47 -0.2 0.83 BB -6.2 <0.01 -1.6 0.05 -0.6 0.32 0 1 BIB -5.8 <0.01 -2.2 0.03 -0.8 0.30 0 1 S -3.4 <0.01 -0.6 0.58 -0.4 0.77 0.4 0.57 H -4.8 <0.01 -0.8 0.29 -0.6 0.72 -0.4 0.69 TD -4.6 <0.01 -1,2 0.02 -0.2 0.76 -0.4 0.70

When all signs/symptoms were considered together, the mean reduction in complaints was 4.97 for composition 1.a, 1.34 for composition 1.b, 0.46 for composition 1.c, and 0.09 for composition 1.d.

Thus, when comparing the reduction in complaints of signs and symptoms associated with oral dysbiosis obtained for each composition after 15 days of use, a statistically significant effect is demonstrated with the composition of the invention containing olive oil, betaine and xylitol. Surprisingly, an unexpected synergistic effect is obtained for the composition of the invention (1.a) compared to the other compositions (1.b-1.d).

Improvement of signs or symptoms means restoration of a balanced microbiome and thus a shift from dysbiosis to eubiosis. Thus, the composition of the invention is capable of treating dysbiosis and converting dysbiosis to eubiosis.

In addition, to measure the association of the detectable presence of the periodontal pathogen Porphyromonas gingivalis , patients in groups 1.a and 1.d were asked to continue using the assigned toothpaste for an additional 15 days. At the end of this period, periodontal probing was performed with a commercially available assay for the detection of P. gingivalis following the manufacturer's instructions (PerioPOC ^® by Genspeed Biotech).

The patients were also asked to answer again the same questions as before (intensity of gingival inflammation, papillae, redness or soaking, bleeding on brushing, bleeding on interdental brushing, sensitivity, presence of halitosis, tooth discoloration) in order to detect any possible relapse of dysbiosis and as an assessment of the maintenance of eubiosis. The results of the screening for P. gingivalis are presented in Table 5.

Table 5

Percentage of patients with detectable P. gingivalis in group 1.a Percentage of patients with detectable P. gingivalis in group 1.d 25% 75%

With regard to the symptoms and signs of dysbiosis, no reversion from eubiosis to dysbiosis was observed in this group using the composition of the invention, whereas no symptoms improved in the control group.

It was found that the result of continued use of the composition according to the invention in periodontal dysbiosis of the oral cavity is effective in treating dysbiosis and maintaining eubiosis, whereas in the control group the state of dysbiosis retained symptoms, despite the possible benefit of brushing teeth.

EXAMPLE 2 - dysbiosis in atopic dermatitis

To evaluate the ability of the composition of the invention to improve signs and/or symptoms associated with skin dysbiosis, the composition of the invention was applied to the skin of seven patients aged 6 to 14 years diagnosed with atopic dermatitis. Signs and symptoms were assessed by the patients before (t equals day 0) and 15 days after application of the product. The subjects marked a vertical line through a 100 mm horizontal line to indicate the intensity of complaints (visible analog scale (VAS)).

The composition, prepared as a hydrating gel (Table 6), was applied three times daily as a routine hydration regimen by gentle manual distribution. No other hydrating or cosmetic cream was applied during this study.

Signs/symptoms to look for:

1. Feeling of dry skin.

2. Itching.

3. Redness.

4. Peeling.

Table 6

Comp. 2 (% mass) Olive oil 0.50 TMG 4.00 Xylitol 10.00 Olive Fruit Liquid Extract 0.10 Others: Solvent (47.70%), Humectant (34.50%), Mineral Source (1.00%), Surfactant (1.00%), Gelling Agent (0.60%), Preservative (0.50%), Vitamin (0.10%) 85.40

The results in the form of the average intensity of complaints of 7 patients at the beginning of the study (t equals 0) and after 15 days (t equals 15) are shown in Table 7, and the % change is shown in Table 8.

Table 7

Average Complaint Intensity (VAS) t=0 t=15 days Dryness 60,00 25.71 Itching 65.71 42.86 Redness 40,00 24.29 Peeling 50,00 34.29

Table 8

% change after 15 days P Dryness -57.14 p<0.01 Itching -34.78 p<0.1 Redness -39.29 p=0.1 Peeling -31.43 p<0.1

As can be seen from Table 8, all the analyzed signs and symptoms were significantly improved after 15 days when using the hydrating gel with the composition of the invention. All the analyzed signs and symptoms are directly or indirectly related to the skin microbiome. A reduction in signs or symptoms means the restoration of a balanced microbiome and thus a shift from dysbiosis to eubiosis in the skin. Thus, the composition of the invention is able to treat skin dysbiosis and transform dysbiosis to eubiosis.

EXAMPLE 3 - dysbiosis in xeroderma

In the skin, flaking, dryness and other signs of skin dysbiosis, due to its high rate of occurrence, were understood as normal. The authors of this invention refer, among others, to symptoms such as dryness, itching, redness, flaking and irritability.

In the following study, signs and symptoms were examined in a population of subjects with a history of dysbiosis in xeroderma. Subjects were labeled with a value on a scale of 0 to 10, where they gave their subjective score at baseline and after 15 days using the assigned composition.

Several compositions prepared as a hydrating gel (Table 9) were applied twice daily after showering and before bedtime.

Signs/symptoms to look for:

1. Dry skin sensation (DS).

2. Itching (I).

3. Redness (R).

4. Peeling (DQ).

5. Irritability (IR).

6. Cracked skin (CS).

7. Sense of calm (SS).

8. Increased elasticity (E).

9. Hydration (H).

Table 9

Comp. 3.a
(% mass) Comp. 3.b
(% mass) Comp. 3.c
(% mass) Comp. 3.d
(% mass) Comp. 3.e
(% mass) Olive oil 0.50 0,00 0.50 0,00 0,00 TMG 4.00 4.00 0,00 0,00 0,00 Xylitol 10.00 0,00 0,00 10.00 0,00 Olive Fruit Liquid Extract 0.10 0,00 0.10 0,00 0,00 Solvent 47.70 58.30 61.70 52.30 62.30 Humidifier 34.50 34.50 34.50 34.50 34.50 Source of minerals 1.00 1.00 1.00 1.00 1.00 Surfactant 1.00 1.00 1.00 1.00 1.00 Gelling agent 0.60 0.60 0.60 0.60 0.60 Preservative 0.50 0.50 0.50 0.50 0.50 Vitamin 0.10 0.10 0.10 0.10 0.10 100,00 100,00 100,00 100,00 100,00

The results in terms of the mean intensity of the above signs/symptoms of each group at the beginning of this study (t equals 0) and after 15 days (t equals 15) are shown in Table 10.

Table 10

Comp. 3.a Comp. 3.b Comp. 3.c Comp. 3.d Comp. 3.e t=0 t=15 t=0 t=15 t=0 t=15 t=0 t=15 t=0 t=15 D.S. 8.0 2.0 7.2 6.6 7.2 5.0 7.4 5.0 7.8 7.6 I 6.6 1,2 6.8 6.8 6.4 4.8 6.8 5.6 7.4 7.6 R 6.4 2.0 6.6 6.4 6.4 6.0 6.4 5.4 6.8 7.2 DQ 7.0 1.0 6.6 6.6 6.4 5.0 7.0 5.6 7.0 6.6 IR 7.0 2,2 6.6 7.0 6.6 5.6 7.2 6.4 7.2 7.2 CS 8.4 0.4 6.8 7.2 7.4 5.2 6.8 5.0 7.6 7.0 SS 1.6 9.2 3.0 3.2 2.4 4.4 2.6 4.0 1.8 2,2 E 2,2 8.6 3.0 3.4 2.8 4.4 2.6 4.6 2,2 1.6 H 1.0 9.6 2.0 2.8 2.6 5.0 2.4 4.6 1.6 2.0

The decrease in intensity (int., in table) of complaints assessed for each composition and the increase in beneficial effects for each composition are shown in Table 11.

Table 11

Change after 15 days Comp. 3.a Comp. 3.b Comp. 3.c Comp. 3.d Comp.3.e Int. p Int. p Int. p Int. p Int. p D.S. -6 <0.01 -0.6 0.51 -2.2 0.01 -2.4 0.03 -0.2 0.83 I -5.4 <0.01 0 1 -1.6 0.03 1,2 0.04 0.2 0.74 R -4.4 <0.01 -0.2 0.81 -0.4 0.61 -1 0.16 0.4 0.38 DQ -6 <0.01 0 1 -1.4 0.01 -1.4 0.05 -0.4 0.61 IR -4.8 <0.01 0.4 0.53 -1 0.25 -0.8 0.26 0 1.00 CS -8 <0.01 0.4 0.77 -2.2 <0.01 -1.8 0.04 -0.6 0.54 SS 7.6 <0.01 0.2 0.82 2 0.01 1.4 0.05 0.4 0.47 E 6.4 <0.01 0.4 0.69 1.6 0.01 2 <0.01 -0.6 0.22 H 8.6 <0.01 0.8 0.46 2.4 <0.01 2,2 <0.01 0.4 0.46

Finally, the mean reduction in all complaints and the mean increase in all beneficial effects after 15 days of gel use are presented for all groups in Table 12.

Table 12

Comp. 3.a Comp. 3.b Comp. 3.c Comp. 3.d Comp. 3.e Average decrease in complaints 5.77 0,00 1.47 1.43 0.10 Average increase in benefit 7.53 0.47 2.00 1.90 0.07

Conclusion

Complaints, including signs and symptoms of skin dysbiosis, are significantly reduced by using the composition of the invention containing the olive product, betaine and xylitol for 15 days. The beneficial effects are enhanced to a significantly greater extent after using the gel containing the olive product, betaine and xylitol for 15 days. When comparing the reduction in complaints and the increase in beneficial effects obtained with each composition after 15 days of use, a synergistic beneficial effect with the composition of the invention can be observed.

EXAMPLE 4 - aphthous dysbiosis of the oral cavity

Oral aphthous dysbiosis was evaluated in a group of patients with symptoms such as pain and ulcers associated with oral aphthous dysbiosis. Pain and healing of aphthae or ulcers were measured and compared between 4 groups using different compositions (Table 13).

These products were prepared in the form of a gel and applied before each main meal and before going to bed until the aphthae were remitted. If pain persisted throughout the day, additional application was also allowed.

Table 13

Comp. 4.a
(% mass) Comp. 4.b
(% mass) Comp. 4.c
(% mass) Comp. 4.d
(% mass) Olive oil 0.50 0.50 0,00 0,00 TMG 4.00 4.00 0,00 0,00 Xylitol 10.00 0,00 10.00 0,00 Olive Fruit Liquid Extract 0.10 0.10 0,00 0,00 Solvents 46.70 56.70 51.30 61.30 Humidifier 34.50 34.50 34.50 34.50 Buffering agent 1.50 1.50 1.50 1.50 Source of minerals 1.00 1.00 1.00 1.00 Surfactant 1.00 1.00 1.00 1.00 Preservative 0.50 0.50 0.50 0.50 Gelling agent 0.10 0.10 0.10 0.10 Vitamin 0.10 0.10 0.10 0.10 100,00 100,00 100,00 100,00

Sixteen patients were included in this study and randomly divided into four groups. Three parameters were recorded:

1. Time for remission.

2. Pain when performing oral hygiene.

3. Pain when talking.

The results in terms of the average number of days required for remission of the aphthae for the 4 groups are shown in Table 14. As can be seen from this table, the patients using the composition containing olive oil, betaine and xylitol had an average time of ulcer/aphthae healing of 2.25 days compared to 3.25 days for the group using the composition with olive oil and betaine, 5 days for the group using the composition with xylitol. The control group had to wait on average more than 7 days for ulcer healing. These data correlate with the measurement of the average pain intensity during oral hygiene and talking, measured at the beginning of the study (t = 0) and after 24 hours (t = 24) of using these products, and presented for the 4 groups in Table 15.

Table 14

Comp. 4.a Comp. 4.b Comp. 4.c Comp. 4.d Time of remission 2.25 3.25 5.00 7.67

Table 15

Comp. 4.a Comp. 4.b Comp. 4.c Comp. 4.d t=0 t=24 t=0 t=24 t=0 t=24 t=0 t=24 Pain during oral hygiene 7.5 1.5 7.0 4.7 6.0 5.7 7.5 7.0 Pain when talking 7.5 1.5 7.7 5.3 7.0 4.7 9.0 8.0

The composition of the invention has a synergistic effect in oral dysbiosis, such as aphthous oral dysbiosis, with statistically significant improvement in ulcer healing and pain control compared to other compositions.

Traditional control of aphthous dysbiosis is carried out by local analgesics and disinfectants. Preparations with hyaluronic acid and/or aloe vera provide barrier protection against ulcers, but are combined with antiseptics in high concentrations, such as alcohol. The composition of the invention could restore the barrier function of the mucosa in the absence of antiseptics with immediate pain relief.

The pain stopped immediately with the possibility of brushing teeth and talking, when measured 24 hours after application. The composition of the invention immediately relieved the pain, showing a positive sum effect, statistically significant with immediate pain relief when compared with the composition of the olive and betaine product, and even greater when compared with the composition with only xylitol as the active ingredient (Table 16).

Table 16

Comp. 4.a Comp. 4.b Comp. 4.c Comp. 4.d Difference (different) P Misc. p Misc. p Misc. p Pain during hygiene 6 <0.01 2 0.13 0.5 0.6 0.49 0.7 Pain when speaking 6 <0.01 2,3 0.06 1.5 0.4 0.46 1.7

EXAMPLE 5 - cold

The lung mucosa, like any other mucosa in a state of eubiosis and benefiting from the homeostasis of the microbiome, benefits from the moisturizing effect of the microbiome, as well as from the protective barrier effect of the microbiome against the penetration of harmful agents, experiencing the comfort of hydration, the absence of pain and the absence of cough, while, on the contrary, the feeling of dehydration, the presence of dry cough and symptoms of cold attacks have been associated with the presence of dysbiosis and a shift in the microbiome with an increased risk of infections or worsening of infections. Age is an initiator of dysbiosis, as the microbiome loses specificity, making older patients more susceptible to infections.

A group of patients analyzed the preventive effect of the composition of the invention, measuring the subjective feeling of hydration of the mucosa and the number of respiratory episodes (colds) when using the composition of the invention. Nineteen cloistered nuns with an average age of 77 years counted the number of cold episodes developed during the study period, when using a topical gel applied through the nose, mouth and throat, with the composition of the invention (Table 17), and compared it with the number of episodes developed in the previous year. They also answered the question: "Now you feel that your mucosa is more hydrated, yes or no" (Table 18).

Table 17

Comp. 5 (% mass) Olive oil 1.11 TMG 4.00 Xylitol 10.00 Others: Solvent (46.19%), Humectant (34.50%), Buffer (1.50%), Mineral Source (1.00%), Surfactant (1.00%), Preservative (0.50%), Gelling Agent (0.10%), Vitamin (0.10%) 85.40

Table 18

Yes No Patients' responses to the question: "Do you now feel that your mucous membrane is more hydrated?" 16 3

Table 19 shows the number of cold episodes developed by the 19 nuns during the study compared with the previous year.

Table 19

Episodes of colds in the previous year Episodes of colds during this study % reduction P 32 20 37.5 0.037

As shown in Table 19, the difference in the number of episodes is statistically significant.

The results of this study demonstrate that the use of the composition of the present invention can significantly prevent dysbiosis and help reduce the incidence of colds.

EXAMPLE 6 - dysbiosis in COPD (chronic obstructive pulmonary disease)

The following study investigated the development of altered or absent taste sensation (dysgeusia or ageusia) in a group of 8 patients diagnosed with chronic obstructive pulmonary disease (COPD), a common pulmonary dysbiosis. The patients were divided into 2 groups, and each group was treated with 2 different tablets: a tablet comprising a composition of the invention containing olive fruit dry extract, betaine and xylitol, and a commercially available lozenge with xylitol (Tables 20a and 20b).

Table 20a

Comp. (%) Dry extract of olive fruits 0,100 TMG 1,250 Xylitol 25,000 Others: fragrance (2.400%), humectant (68.000%), flow enhancer (2.925%), antistatic agent (0.300%), vitamin (0.025%) 73,650

Table 20b

Commercially available xylitol lozenge (data obtained from manufacturer's website) Sweeteners (xylitol (87%), aspartame), flavoring, fully hydrogenated cottonseed oil

Subjects answered the question: “Do you taste food?” before taking the tablets and after 5 days of taking them.

The results in the form of an answer to this question at the beginning (t equals 0) and after 5 days (t equals 5) of resorption of 3 tablets per day are given in Table 21.

Table 21

t=0 t=5 Answer to the question: "Do you taste food?" Yes No Yes No Composition according to the invention 4 4 Composition available for sale 4 4

Patients with dysgeusia or ageusia, a common symptom of mucosal dysbiosis and in particular pulmonary dysbiosis, typically suck on candies and/or lozenges to mask the taste change or to improve taste. These tablets are usually flavored and sweet. In this study, commercially available tablets with a high concentration of xylitol did not help in restoring food taste after 5 days. In contrast, tablets with the composition of the invention had an unexpectedly positive result in restoring taste associated with dysbiosis in COPD.

EXAMPLE 7 - Dysbiosis in OLP

Oral lichen planus (OLP) is a dysbiosis that may affect either the skin or the oral cavity, or both. It is treated with corticosteroids. Oral hygiene during the course of the disease is painful, and the progression of periodontitis in patients with OLP is difficult to treat and severe. Eating and hygiene may deteriorate during OLP outbreaks.

This study analyzed whether the composition of the invention could improve the efficacy of corticoids when used in the treatment of OLP.

Twenty patients with OLP were included in this study.

Two groups of 10 patients each were divided as follows:

Group 1 - patients who were treated with corticosteroids and special hygiene measures using the composition of the invention in the form of a toothpaste (Composition 7.a in Table 22).

Group 2 - patients who were treated with corticosteroids and hygiene measures without the composition of the invention (Composition 7.b in Table 22).

Table 22

Comp. 7.a (% wt.) Comp. 7.b (% wt.) TMG 4,0000 0,0000 Olive oil 0,5000 0,0000 Olive Fruit Liquid Extract 0,0500 0,0000 Xylitol 11,0000 0,0000 Humidifier 67,6150 83,1650 Abrasive agent 5,0000 5,0000 Source of minerals 8,0500 8,0500 Surfactant 0,8500 0,8500 Enzyme 1,0000 1,0000 Flavoring agent 1,1000 1,1000 Sweetener 0.085 0.085 Preservative 0,5000 0,5000 Gelling agent 0,2000 0,2000 Vitamin 0,0500 0,0500 100,0000 100,0000

The treatment lasted for 30 days and a graded scale of 1 to 10 was obtained for pain at the beginning of the study (T0), after 15 days of treatment (T15) and after 30 days of treatment (T30). The results are shown in Table 23.

Table 23

T0 T15 T30 Corticoids + composition 7.a 6.47 3.2 2.14 Corticoids + composition 7.b 6.45 4.84 4.26

As shown in Table 23, treatment combining corticosteroids with a toothpaste comprising the composition of the invention improves the effectiveness of the corticosteroids after 15 and 30 days of treatment, as patients treated with the composition of the invention reported less pain.

EXAMPLE 8 - halitosis dysbiosis

Halitosis dysbiosis occurs due to a shift in the oral microbiome towards anaerobic bacteria such as Porphyromonas gingivalis , Treponema denticola and Tannrella forsythia among others. The shift in microbiome comes with an inflammatory environment and volatile sulfur compounds (VSC) as a consequence of protein breakdown. Some known VSC are hydrogen sulfide, methyl mercaptan and dimethyl sulfide. It has been reported that the level of VSC present in patients with periodontal dysbiosis is 8 times greater than that in patients without periodontal dysbiosis. However, halitosis dysbiosis is also found in dietary restriction and is associated with other oral dysbiosis.

This study examines the effects of different formulations on halitosis dysbiosis after 4 weeks of use.

Materials and method

Twenty patients diagnosed with halitosis dysbiosis were divided into 4 groups. Each group used one of the four compositions (Table 24) in the form of a mouth spray and used them 3 times a day by spraying twice into the oral cavity.

Table 24

COMPOSITION Comp. 8.a
(% mass) Comp. 8.b
(% mass) Comp. 8.c
(% mass) Comp. 8.d
(% mass) Olive oil 2,2574 2,2574 0,0000 0,0000 TMG 2,0000 2,0000 0,0000 0,0000 Xylitol 20,0000 0,0000 20,0000 0,0000 Humidifier 2,0000 2,0000 2,0000 2,0000 Buffering agent 2,1000 2,1000 2,1000 2,1000 Surfactant 10,0000 10,0000 10,0000 10,0000 Flavoring agent 2,3200 2,3200 2,3200 2,3200 Sweetener 1,5100 1,5100 1,5100 1,5100 Preservative 0,4000 0,4000 0,4000 0,4000 Solvent 57,4126 77,4126 61,6700 81,6700 100,0000 100,0000 100,0000 100,0000

Method

VSC was measured in the mouth using a device that measures the amount of sulfur compound.

Interpretation of VSC results

Normal values (absence of halitosis dysbiosis): from 0 to 100 ^ppm .

Mild halitosis dysbiosis: from 101 to 150 ^ppm .

Severe halitosis dysbiosis: from 151 to 300 ^ppm .

Very strong halitosis dysbiosis: more than 300 million ^-1 .

Number of subjects and measurement

Twenty patients were included in this study. The initial baseline VSC scores were measured, and four groups of patients were formed according to the distribution of scores, without allowing statistical differences between these groups. All patients were instructed to use the prescribed products for 4 weeks. The final scores were measured at the end of the study, and comparisons were made between the groups. Two measurements were made, one after the other, and the average of these two measurements was calculated.

Results

The mean VSC level ( ^ppm ) for each group at the beginning and end of this study is shown in Table 25.

Table 25

Comp. 8.a Comp. 8.b Comp. 8.c Comp. 8.d Original 212 195.4 209 188.4 Finite 89.8 165.4 170 198.4 p <0.001* 0.095 <0.218 <0.71

(*) statistically significant.

For composition 8.a (122.2 ^ppm ), composition 8.b (30 ^ppm ) and composition 8.c (39 ^ppm ), a decrease in VSC levels was observed after 4 weeks of application of the analyzed compositions, whereas for composition 8.d (10 ^ppm ), a slight increase was observed.

Conclusions

The composition according to the invention (comp. 8.a) containing xylitol, olive oil and betaine demonstrates a beneficial effect in relation to halitosis dysbiosis. Unexpectedly, a synergistic improvement was obtained with the composition according to the invention compared to compositions 8.b and 8.c, which lack xylitol and olive oil, respectively.

EXAMPLE 9 - Dysbiosis in Sleep Apnea and Tooth Wear

As disclosed in the description of the present invention, the microbiome protects teeth from challenges in symbiotic conditions. In stress, oral dysbiosis due to tooth wear and sleep apnea, as well as oral dysbiosis associated with eating disorders or gastric reflux, disruption or alteration of the microbiome leads to hypersensitivity and demineralization of teeth. When the microbiome is changed or disrupted, hypersensitivity, demineralization, caries and/or tooth wear (e.g., due to bruxism, erosion, abfraction, abrasion) occur, and teeth begin to dissolve in an acidic or extremely acidic environment, with hypersensitivity being the first symptom of these dysbioses.

Materials and method

Eight patients diagnosed with sleep apnea dysbiosis and demonstrating tooth wear and hypersensitivity were recruited and divided into two groups.

The first group was treated with a traditional commercially available antihypersensitivity mouthwash and gel containing a fluoride source (sodium fluoride) and potassium nitrate. The contents of these ingredients are known, but the remaining quantitative composition is not known and is therefore not shown in Table 26.

The second group was treated with the composition of the invention, used in a mouth rinse and in a gel. The compositions for both groups, shown in Table 26, were composition 9.a - a mouth rinse with the composition of the invention, composition 9.b - a gel with the composition of the invention, composition 9.c - a commercially available mouth rinse and composition 9.d - a commercially available gel.

Patients used the mouth rinse 3 times daily for two minutes after brushing their teeth, and applied the gel topically to the oral cavity after rinsing in the morning and before going to bed.

For both groups, treatment lasted 15 days.

Table 26

Comp. 9.a
(% mass) Comp. 9.b
(% mass) Comp. 9.c
(% mass) Comp. 9.d
(% mass) Olive oil 2,000 1,110 TMG 2,000 4,000 Xylitol 1,000 10,000 Olive Fruit Liquid Extract 0,100 Potassium nitrate 10,000 5,000 Sodium fluoride 0.220 0.320 Humidifier 7,000 34,500 Buffering agent 0.855 1,500 Surfactant 12,000 1,000 Flavoring agent 0.405 Sweetener 0.025 Preservative 0,700 0,500 Solvent 73,282 46,090 Vitamin 0,300 0,100 Source of minerals 0.183 1,000 Healing remedy 0,200 Dye 0,050 Gelling agent 0,100

Method

Self-reported responses to the following questions were recorded:

- Can you drink cold water?

- Can you eat a piece of fruit from the refrigerator?

- Do you feel sensitivity when brushing your teeth?

- Do you feel that your mouth is not dehydrated?

- Do you grind your teeth at night?

Results

The responses to these questions for both groups before and after 15 days of treatment are shown in Table 27, which shows the number of subjects who said “Yes” or “No”.

Table 27

Comp. 9.a and 9.b Comp. 9.c and 9.d To After To After Yes No Yes No Yes No Yes No Can you drink cold water? 0 4 4 0 0 4 1 3 Can you eat a piece of fruit from the refrigerator? 0 4 4 0 0 4 2 2 Do you experience sensitivity when brushing your teeth? 4 0 0 4 4 0 3 1 Do you feel like your mouth is dehydrated? 0 4 4 0 0 4 0 4 Do you grind your teeth at night? 4 0 0 4 4 0 3 1

Conclusions

While the group using the composition of the invention had a 100% improvement in symptom outcome, the groups using commercially available products had no improvement (hydration) or only had 25 to 50% improvement (remainder of symptoms).

Claims (22)

1. Use of a composition containing 0.05%-5.1% by weight of an olive product, 0.1%-10% by weight of betaine and 1%-20% by weight of xylitol for the treatment and/or prevention of dysbiosis, wherein said olive product is olive oil and/or olive fruit extract. 2. The use according to paragraph 1, wherein the dysbiosis is dysbiosis of the mucous membrane or dysbiosis of the skin. 3. The use according to claim 2, wherein the dysbiosis of the mucous membrane is dysbiosis of the oral cavity, preferably said dysbiosis of the oral cavity is selected from the group consisting of halitosis dysbiosis, dysbiosis in caries, periodontal dysbiosis, aphthous dysbiosis, dysbiosis in peri-implantitis, dysbiosis in lichen planus, dysbiosis in pemphigus vulgaris, dysbiosis in sleep apnea, stress dysbiosis, dysbiosis in tooth wear, dysbiosis of the oral cavity in diabetes, dysbiosis of the oral cavity in cancer and combinations thereof. 4. The use according to claim 2, wherein the dysbiosis is a skin dysbiosis, preferably said skin dysbiosis is selected from the group consisting of dysbiosis in atopic dermatitis, dysbiosis in acne vulgaris, psoriatic dysbiosis, dysbiosis in xeroderma, dysbiosis in skin allergies, dysbiosis in radiation dermatitis, dysbiosis in solar dermatitis, dysbiosis in contact dermatitis, dysbiosis in seborrheic dermatitis, dysbiosis of the scalp, dysbiosis with unpleasant body odor, dysbiosis in premature aging of the skin, dysbiosis in lichen planus, dysbiosis in pemphigus vulgaris and combinations thereof. 5. Use according to item 2, wherein the dysbiosis of the mucous membrane is vaginal dysbiosis. 6. The use according to claim 2, wherein the dysbiosis of the mucous membrane is pulmonary dysbiosis, preferably said pulmonary dysbiosis is selected from the group consisting of chronic pulmonary dysbiosis, dysbiosis in chronic obstructive pulmonary disease, dysbiosis in cystic fibrosis, dysbiosis in asthma, dysbiosis in tracheitis, dysbiosis in bronchitis, dysbiosis in respiratory infections. 7. Use of a composition containing 0.05%-5.1% by weight of an olive product, 0.1%-10% by weight of betaine and 1%-20% by weight of xylitol, for preventing a pathology that is promoted by dysbiosis or complicated by dysbiosis, selected from the group consisting of dandruff, seborrheic dermatitis, chronic inflammatory pathologies, skin cancer, oral carcinoma and respiratory infections, wherein said olive product is olive oil and/or olive fruit extract. 8. Use of a composition containing 0.05%-5.1% by weight of an olive product, 0.1%-10% by weight of betaine and 1%-20% by weight of xylitol for treating a pathology promoted by dysbiosis or complicated by dysbiosis, as an adjuvant, wherein said pathology promoted by dysbiosis or complicated by dysbiosis is selected from the group consisting of dandruff, seborrheic dermatitis, chronic inflammatory pathologies, skin cancer, oral carcinoma and respiratory infections, wherein said olive product is olive oil and/or olive fruit extract. 9. Use of a composition according to claim 7 or 8, wherein said respiratory infection is selected from the group consisting of the common cold, Covid-19 and pneumonia. 10. Use of a composition containing 0.05%-5.1% by weight of an olive product, 0.1%-10% by weight of betaine and 1%-20% by weight of xylitol for hygiene of the oral cavity, nasal cavity, vagina or skin of the human body, wherein said olive product is olive oil and/or olive fruit extract. 11. Use of a composition containing 0.05%-5.1% by weight of an olive product, 0.1%-10% by weight of betaine and 1%-20% by weight of xylitol, for maintaining natural hydration of the mucous membrane or skin of the human body, wherein said olive product is olive oil and/or olive fruit extract. 12. The use according to any one of claims 1-11, wherein the olive fruit extract is a dry olive fruit extract and/or a liquid olive fruit extract. 13. The use according to any one of claims 1 to 12, wherein the olive fruit extract comprises at least 20% w/w hydroxytyrosol; and/or wherein the olive oil is unrefined extra virgin olive oil, virgin olive oil or a combination thereof, preferably said olive oil is unrefined extra virgin olive oil; and/or wherein the betaine is selected from the group consisting of trimethylglycine, cocamidopropyl betaine, dimethylamine betaine, alkyl( _C12 - _C18 )amidobetaines, alkyl( _C8 - _C18 )betaines, amidobetaines, alkylamidobetaines, sulfohydroxybetaines and combinations thereof, preferably said betaine is trimethylglycine. 14. The use according to any one of claims 1-13, wherein said composition comprises 0.05%-0.1% by weight of olive fruit extract and/or 0.1%-5% by weight of olive oil; and/or 1.0%-6% wt. betaine; and/or 1%-15% wt. xylitol. 15. The use according to any one of claims 1-14, wherein said composition additionally contains an antioxidant, preferably selected from the group consisting of hydroxytyrosol, tyrosol, oleuropein and mixtures thereof, and/or vitamins. 16. Use according to any one of claims 1 to 15, wherein said composition is made in the form of a face and/or body moisturizer, a deodorant cream, a barrier regeneration cream, a body gel, a shampoo, a hair conditioner, a hair lotion, a skin ampoule, a tonic, a capsule, a tablet, a spray, a gel, a lubricating gel, a topical gel for the vulva, a toothpaste, a mouthwash, a chewing gum, a chewable tablet, resorbable capsules, resorbable lozenges, palatal plates, candies, soaked mouth swabs, soaked mouth gauze, a lipstick, a balm, a nasal inhaler, a nasal spray, a nasal aerosol, a nasal gel, an oropharyngeal syrup, an oropharyngeal gel or aerosol capsules. 17. Use according to any one of claims 1-16, wherein said composition additionally contains prebiotics and/or probiotics. 18. The use according to any one of claims 1-17, wherein said composition comprises an olive product, betaine and xylitol as the only active ingredients.