Compositions for the prevention and treatment of dysbiosis

Abstract

The present invention relates to a composition for use in the prevention and / or treatment of dysbiosis. It also relates to the use of said composition for the preparation of a medicament for the prevention and / or treatment of dysbiosis. Furthermore, it relates to a method of preventing and / or treating dysbiosis wherein said composition is administered to a subject in need thereof.SOLUTION: A composition for use in the treatment and / or prevention of signs and / or symptoms associated with atopic dermatitis dysbiosis, xeroderma dysbiosis or oral aphthous dysbiosis, the composition comprising an olive product, trimethylglycine and xylitol, the composition comprising between 0.05% and 4.1% by weight of the olive product; A composition, wherein the olive product is olive oil and / or olive fruit extract; for use for the treatment of dysgeusia (taste disturbance or taste loss) associated with mucosal dysbiosis and / or pulmonary dysbiosis, or for the prevention of dehydration, dry cough and / or cold associated with dysbiosis, wherein the composition comprises an olive product, trimethylglycine and xylitol, wherein the composition comprises between 0.05% and 4.1% by weight of the olive product, and wherein the olive product is olive oil and / or olive fruit extract.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to the field of the microbiome and its relationship to health and disease, particularly to compositions for use in the prevention and treatment of dysbiosis. [Background technology]

[0002] The terms microbiome and microbiota are sometimes used interchangeably. Microbiota refers to the set of microorganisms, consisting of bacteria, fungi, archaea, viruses, and parasites, living in or on our bodies, while microbiome is a broader term that refers to the entire habitat, encompassing not only microorganisms but also their genes and metabolites and their ecosystems. This invisible 3D architectural structure relies on the extracellular matrix, which serves as the physicochemical scaffolding for biofilms and, in our view, is key to the initiation of dysbiosis and the restoration of health (eubiosis). This scaffolding not only possesses chemical properties, but also physically contributes to the shape of the microcosm and provides protection from environmental insults (especially changes in humidity, pH shifts, temperature fluctuations, disinfectants, antibacterial drugs, and stress). Ideally, it should also accommodate the essentials for cellular activity, namely, water and nutrients, and limit the penetration of harmful agents.

[0003] Biofilms are understood as specific microflora and ecosystems living in different parts of the body that are attached to specific three-dimensionally structured surfaces. Examples of biofilms are oral, dental, skin, and vaginal biofilms.

[0004] The microbiota gradually colonizes in or on the body through birth, depending on the route of delivery (vaginal or cesarean section), the mother's microbiome, type of nutrition, geography, habits, psychology, and lifestyle. It bestows an individual identity on the host and establishes a two-way dialogue between the host and the microbiota, and vice versa. Lifestyle, stress, education, personality, age, geography, and climate are known to alter the microbiota and its ecosystem; at the same time, the microbiota can alter the ecosystem and 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 impact the microbiome of the body's mucous membranes in different sites, such as the mouth, lungs, intestines, vagina, and skin, giving way to an emerging portfolio of newly recognized and emerging dysbiosis of varying severity.

[0005] Mucous membranes line the body cavities and lumens that lead to the outside, primarily the respiratory, digestive, and urogenital tracts. These include, among others, the mouth, nose, eyelids, trachea, lungs, stomach, intestines, ureters, urethra, vagina, and connections between different sites. Mucous membranes line all vessels and organs of the body and share common histological features and mucus secretion, which acts as a barrier and is adapted to different sites (papillae, microvilli, etc.). Skin throughout the body also displays common histological features and also possesses barrier functions with some adaptive specializations depending on the site (hair, sweat glands, etc.). Mucous membranes and skin are the largest microbiome habitats and are the most susceptible to microbiome imbalances or dysbiosis that connect different sites.

[0006] The relationship between dysbiosis and general health has been described by several studies that have given rise to different schools of thought proposing connections between different microbiomes, giving rise to what are now known as the mouth-gut axis, mouth-liver axis, mouth-lung axis, mouth-gut-liver axis, mouth-brain axis, mouth-cardiovascular axis, gut-lung axis, gut-skin axis, mouth-joint axis, mouth-mammary axis (Lira-Junior & Bostrom, 2018), and the newly described mouth-skin axis (see below).

[0007] Regarding the oral-pulmonary axis, periodontal dysbiosis, as a source of inflammatory mediators, has been implicated in the exacerbation of lung diseases (Paju & Scannapieco, 2007). Growing evidence on the role of the lung microbiome and its impact on the progression and severity of lung diseases has been investigated in different groups, such as pneumonia, the common cold, influenza, cystic fibrosis, pulmonary fibrosis, and chronic obstructive pulmonary disease (COPD).

[0008] Evidence of a gut-skin axis linked to inflammatory skin diseases associated with gut microbiome imbalance has so far translated into the recognition of the potential benefits of probiotics for improving skin conditions via the gut microbiome (Atarashi, Wataru, & Chengwei, 2017). Transplantation procedures have recently emerged from attempts to replicate this microbiome from healthy individuals (donors) into diseased subjects (recipients). Similarly, some clinicians have advocated skin microbiota transplantation from healthy subjects to improve the symptoms and clinical course of atopic dermatitis, instead of antibiotics against the pathogen S. aureus. Unfortunately, microbiome transplantation therapy requires further development, appears to be a costly approach, and so far has few practical applications remaining in hospital settings, making it far from becoming routine practice.

[0009] To date, attempts to correct a dysbiotic harmful microbiome by means of replacement or transplantation (probiotic science) or eradication (antibiotic therapy) have demonstrated uncertain safety and efficacy issues. Thus, there remains a need for improved therapies for the prevention and treatment of dysbiosis. [Prior art documents] [Non-patent literature]

[0010] [Non-Patent Document 1] Atarashi, K., Wataru, S., & Chengwei, L. (2017). Ectopic colonization of oral bacteria in the intestine drives TH1cell induction and inflammation. Science, 358(6361), 359-365. doi:10.1126 / science.aan4526 [Non-patent document 2] Dawes, C. (2003). What is the critical pH and Why does a tooth dissolve in acid? J Can Dent Assoc, 69(11), 722-724. [Non-patent document 3] Hezel, M., & Weitzberg, E. (2015). The oral microbiome and nitric oxide homeostasis. Oral Diseases, 21(7). [Non-patent document 4] Lee, YB, Byun, EJ, & Kim, HS (2019). Potential Role of the Microbiome in Acne: A Comprehensive Review. Journal of Clinical Medicine, 987. [Non-Patent Document 5] Lira-Junior, R., & Bostrom, E. (2018). Oral-gut connection: one step closer to an integrated view of the gastrointestinal tract? Mucosa Immunology, 11(2), 316-318. doi:10.1038 / mi.2017.116 [Non-patent document 6] Lussi, A., & Carvalho, T. (2015). The future of fluorides. Caries Res, 49, 18-29. doi:10.1159 / 000380886 [Non-Patent Document 7] Paju, S., & Scannapieco, F. (2007). Oral biofims, periodontitis, and pulmonary infections. Oral Dis, 13(6), 508-512. doi:10.1111 / j.1601-0825.2007.1410a.x [Non-patent document 8] Segata, N., Kinder Haake, S., & Mannon, P. (2012). Composition of the adult digestive tract bacterial microbiome based on seven mouth surfaces, tonsils, throat and stool samples. Genome Biology, 13, R42. [Non-Patent Document 9] Sudhakara, P., Gupta, A., & Bhardwaj, A. (2018). Oral dysbiotic communities and their implications in systemic diseases. Dent. J, 6(16). doi:10.3390 / dj6020010 [Non-Patent Document 10] Szanto, M., Dozsa, A., & Antal, D. (2019). Targeting the gut-skin axis-Probiotics as new tools for skin disorder management? Experimental Dermatology, 1210-1218. [Non-Patent Document 11] Van Dyke, T. (2017). Pro-resolving Mediators in the Regulation of Periodontal Disease. Mol Aspect Med, 58, 21-36. doi:10.1016 / j.mam.2017.04.006 [Non-Patent Document 12] Vaughn, AR, Notay, M., Clark, AK, & Sivamani, RK (2017). Skin-gut axis: The relationship between intestinal bacteria and skin health. World Journal of Dermatology, 52-58. [Non-Patent Document 13] Wallen-Russell, C. (2019). The role of every-day cosmetics in altering the skin microbiome: A study using biodiversity. Cosmetics, 6(2). doi:10.3990 / cosmetics6010002 [Non-Patent Document 14] Yang, H., Wang, W., & Romano, K. (2018). A common antimicrobial additive increases colonic inflammation and colitil-associated colon tumorigenesis in mice. Sci Transl Med. doi:10.1126 / scitransmed.aan4116 Summary of the Invention [Means for solving the problem]

[0011] A 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 the olive product is olive oil and / or olive fruit extract.

[0012] A 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.

[0013] A third aspect of the present invention relates to a method of 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 the olive product is olive oil and / or olive fruit extract.

[0014] A fourth aspect of the present invention relates to a method for preventing dysbiosis in a subject, comprising administering to the 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.

[0015] A fifth aspect of the invention relates to the use of a composition comprising an olive product, betaine and xylitol for oral, nasal, vaginal and / or skin hygiene and for maintaining the natural moisturization of the mucous membranes and / or skin of the human body, wherein the olive product is olive oil and / or olive fruit extract.

[0016] Other objects, features, advantages, and aspects of the present application will become apparent to those skilled in the art from the following description and appended claims. [Brief explanation of the drawings]

[0017] [Figure 1] Schematic drawing of skin and mucosal (oral mucosa) structures highlighting the similarities and parallels between skin and mucosa. [Figure 2]Microbiome dynamics model of eubiosis and dysbiosis. The ecosystem is part of the microbiome's self-repairing cycle to promote symbiosis (health) and prevent dysbiosis (disease), but is also an actor in the microbiome's vicious cycle to perpetuate dysbiosis. [Figure 3] Microbiome Dynamics with the Compositions of the Invention The compositions of the invention enhance ecosystem resilience and promote a healthy environment and microbiota balance and eubiosis. DETAILED DESCRIPTION OF THE INVENTION

[0018] As used herein, the singular forms "a," "an," and "the" include their corresponding plural forms unless the context clearly dictates otherwise. Unless otherwise defined, 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. To facilitate understanding and clarify the meaning of certain terms in the context of the present invention, the following definitions applicable to all embodiments of the different aspects of the invention and specific and preferred embodiments thereof are provided.

[0019] As used herein, "microbiome" refers to both persistently and transiently living microorganisms in and on the human body, as well as their genetic content, and includes eukaryotes, archaea, bacteria, and viruses (including bacterial viruses (i.e., phages)). "Genetic content" includes genomic DNA, RNA, such as ribosomal RNA, epigenome, plasmids, and all other types of genetic information. A healthy microbiome provides multiple benefits to the host, including resistance to colonization against a broad spectrum of pathogens, essential nutrient biosynthesis and absorption, and immune stimulation that maintains healthy epithelium and well-controlled systemic immunity. The microbiome can be characterized in healthy individuals and those suffering from disease. In healthy individuals, the microbiome is defined as normal.

[0020] In direct contrast to eubiosis, dysbiosis occurs as a result of a loss of balance within the microbiome due to either a shift in the microbiota or an alteration in the microbiome ecology.

[0021] "Dysbiosis" refers to a state of the microbiome in any area of ​​the body, including mucous membranes and skin surfaces, in which the normal diversity or function of the ecological network is disrupted. Thus, in specific embodiments, the dysbiosis is mucosal dysbiosis, skin dysbiosis, or a combination thereof. Any disruption of the microbiome from a preferred (e.g., ideal, normal) state can be considered dysbiosis, even if such dysbiosis does not result in a detectable decrease in health. This state of dysbiosis can be unhealthy, it can be unhealthy only under certain conditions, or it can prevent a subject from becoming healthier. Dysbiosis can also be a cause or consequence of disease, contributing to and / or exacerbating the course of disease. Dysbiosis can be due to a decrease in diversity, excessive growth of one or more pathogens or pests, symbionts that can cause disease only when certain genetic or environmental conditions are present in the patient, or a shift toward an ecological network that no longer provides a beneficial function to the host and therefore no longer promotes health. Dysbiosis can be induced by disease (diabetes, cancer, infection, obesity, depression), treatment (e.g., abuse) with agents (e.g., antibiotics that reduce the resident flora), or other environmental factors (pH changes, inflammation, diet, drugs).

[0022] In situations of "dysbiosis" or interrupted symbiosis, microbiome function is lost or disrupted, which can result in increased susceptibility to pathogens, altered metabolic profiles, or the induction of pro-inflammatory signals that can lead to local or systemic inflammation or autoimmunity.

[0023] In specific embodiments according to any one of the aspects of the invention, the dysbiosis is selected from a mucosal dysbiosis, a skin dysbiosis, or a combination thereof.

[0024] In another specific embodiment according to any one of the aspects of the invention, the dysbiosis is selected from oral dysbiosis, pulmonary dysbiosis, skin dysbiosis, and / or vaginal dysbiosis.

[0025] "Oral dysbiosis" refers to a dysbiosis that affects some or all of a subject's oral mucosa and / or teeth.

[0026] "Skin dysbiosis" refers to a dysbiosis that affects some or all of the skin of a subject.

[0027] "Vaginal dysbiosis" refers to vaginosis.

[0028] "Pulmonary dysbiosis" refers to a dysbiosis that affects all or part of the mucous membranes of the lungs and / or nearby areas (e.g., the trachea).

[0029] The terms "prevent" or "prevention" mean to prevent, delay, and / or reduce the severity of a disease and / or signs and / or symptoms associated with a disease.

[0030] A "prophylactically effective amount" refers to an amount that, when delivered, prevents, delays, and / or reduces the severity of a disease and / or the signs and / or symptoms associated with the disease.

[0031] "Treatment" refers to the reduction or elimination of the disease and / or signs and / or symptoms associated with the disease.

[0032] A "therapeutically effective amount" refers to an amount that is effective to reduce or eliminate a disease and / or the signs and / or symptoms associated with the disease.

[0033] Specifically, in the present invention, the disease is a dysbiosis or a condition that is precipitated or exacerbated by a dysbiosis.

[0034] The Human Oral Microbiome Database (HOMD) describes nearly 620 oral taxa, phyla, and strains. Of these, 65% have been cultured to date, compared with barely 1% in other body sites. Firmicutes, Bacteroidetes, Proteobacteria, Actinobacteria, Spirochaetes, and Fusobacteria account for 95%. In the skin, the four dominant phyla are Actinobacteria, Proteobacteria, Firmicutes, and Bacteroidetes. Both the skin and oral cavity display diverse topographical communities associated with different microenvironments. In the mouth, the palate and lingual surfaces of the teeth harbor different phyla relative to the subgingival, buccal, or lingual surfaces, depending on the parallelism of the oily environment of the upper body compared to the higher diversity of phyla in the skin and lower body parts. Both the skin and oral cavity, as previously mentioned, have high topographical diversity determined by the environment, with high temporal variability within individuals but fairly stable over an individual's lifetime. The abundances noted by many researchers in recent years are now considered only relative markers of disease, since every individual will exhibit Staphylococcus, Propionibacterium, and Corynebacterium on the skin, and Streptococcus mutans and Porphyromonas gingivalis on the mouth. Current research supports the idea that pressuring the inhabiting Firmicutes phylum of either the skin (Streptococcus epidermidis) or the mouth (Streptococcus mutans) allows other Firmicutes from the Staphylococcus phylum to exploit inflammatory conditions and penetrate the skin. In the mouth, the shift imposed by anti-caries drugs that reduces Streptococcus mutans populations will lead to a decrease in acidic metabolites from these bacteria, enhancing the increase in pH, which will be exploited by non-saccharolytic bacteria that prefer the higher pH and lower oxygen gradient implicated by anaerobic subgingival Gram-negative bacteria leading to periodontitis.Periodontitis is commonly associated with staphylococcal infection in the skin of patients with oral lichen planus (OLP), a common chronic autoimmune mucocutaneous disease that has been reported to be the second most common oral mucosal disease after oral ulceration. 20 to 35 percent of OLP patients also have lesions on the skin, scalp, and / or vagina.

[0035] The most common oral microflora are Streptococcus, Lactobacillus, and Prevotella. Respiratory bacterial analysis of patients with pneumonia at risk for aspiration showed that oral Streptococcus was the most common bacterial phylum detected in both the bronchi and lungs.

[0036] In a balanced, non-inflammatory, healthy state, both skin and mucous membranes exhibit barrier-like properties, in the sense that the microbiome and human cells reside in distinct compartments throughout the entire length of both tissues. Minimal separation between the microbiota and host epithelial cells is required for symbiotic, dual host-microbe interactions. When the skin or mucous membranes are interrupted, as in wounds or inflammatory conditions, mechanisms lead to an altered relationship between the host and microbiome, leading not only to a world of dysbiotic inflammatory diseases but also ultimately to carcinogenesis. Today, oral research is consistent with the finding that oral dysbiosis and dysbiotic biofilms underlie common, highly prevalent diseases such as caries and periodontitis. In the present study's view, teeth possess their own microbiome, which protects them from attack, as long as it is symbiotic. At the same time, when healthy, teeth themselves are a barrier to the maxilla from the moment they penetrate the oral mucosa during eruption. Because barrier function is essential for human survival, when teeth are eventually lost, mucous membranes take over and fill the gap. As previously stated for skin and mucous membranes, teeth and their microbiomes reside in distinct compartments physicochemically attached to one another, and the integrity of both compartments is essential for health and barrier function. When the microbiome is damaged, for example, because the separation and integrity of both compartments is lost, interrupted, or eliminated, a new dysbiotic relationship between host and microbiome leads to a non-symbiotic inflammatory state (periodontitis dysbiosis) or / and increased tooth permeability (sensitivity, demineralization, and loss of tooth structure). When this microbiome is lost, interrupted, or damaged, the dental barrier is lost. Sensitivity, demineralization, caries, and tooth wear of either physical, chemical, or mixed origins (bruxism, erosion, abfraction, attrition) occur. The interrupted microbiome barrier ceases to act as a lipophilic shield, and the teeth begin to dissolve in acidic or extremely acidic media. Every mouth is different.Tooth mineral content and enamel thickness also vary between individuals. Other variables, such as salivary flow and salivary mineral saturation, collectively explain why some teeth will resist better than others, referred to as the critical pH (Dawes, 2003). In vitro conditions ignore living microorganisms and their ecosystems. These too may be large reservoirs of minerals, water, peptides, and metabolic resources that stop and prevent human teeth from dissolving. This theory is supported by the fact that, in the absence of dental plaque, even stimulating saliva would fail to promote mineral accumulation. In our view, a dysbiotic microbiome would render fruitless efforts to remineralize teeth by stimulating saliva or by supplementing with minerals or remineralizing agents, as some authors have begun to consider (Lussi & Carvalho, The future of fluorides, 2015). When teeth are physically scraped and worn down, the habitat is altered, revealing the initially hidden dentin and providing modulated support for the microbiome.

[0037] The more tooth wear and tooth structure loss, the greater the attack on the oral microbiota, which finds flatter and more altered tooth surfaces to attach to. In advanced cases of tooth wear, the interproximal area experiences loss of specific microbiota habitats, followed by the disappearance of all occlusal surfaces. Finally, chewing is impaired, leading to a shift to a softer diet and more severe oral dysbiosis due to further tooth loss, an example of the vicious cycle of dysbiosis described by the inventors.

[0038] Combating any form of dental plaque or dental biofilm by means of biocides, disinfectants, chemical, or physical debridement has not proven effective in eliminating periodontal conditions such as gingivitis or periodontitis and caries behind premature tooth loss. A growing number of patients treated with dental implants has given rise to a new condition called peri-implantitis. Implants placed in non-keratinized gingival sites, lacking a thick mucosal barrier, present the potential for specific peri-implant dysbiosis that cannot be prevented or treated with antibiotics. A rapidly growing group of patients receiving prosthetics or dental restorations and those undergoing orthodontic treatment can also suffer from oral dysbiosis as a result of an imbalanced microbiome resulting from habitat changes imposed by artificial materials.

[0039] As well as the oral cavity, the skin is home to an extensive microbiome with specific microflora for different skin types and sites. Like mucous membranes, the skin exhibits a high rate of desquamation and cell renovation. Depending on the degree of oily or aqueous secretion, we can find three different types of skin: -Oily areas include the scalp, forehead, back, postauricular creases, and alae of the nose. - Wet areas include the armpits, groin creases, buttock creases, soles of the feet, popliteal fossae, and cubital fossae. - Dry areas include various parts of the forearms, buttocks, and hands.

[0040] Inflammation and ulceration of different grades are the most common signs of skin diseases. When the skin loses its healthy status, it appears with impaired barrier function, cracking, and redness.

[0041] Among the everyday attacks on the skin, alcohols and detergents from soaps and creams can damage the integrity of the epidermal barrier by, among other mechanisms, removing lipids. This favors the colonization of some harmful bacteria (Staphylococcus aureus). This is the case in atopic dermatitis, where, during dermatitis inflammation, bacterial colonization shifts to low-diversity species incompatible with healthy skin. A similar situation applies to psoriasis.

[0042] There is a link between several medical conditions, such as chronic inflammatory conditions and cancer, and both the mucosal and skin microbiomes. In chronic inflammatory conditions such as type 2 diabetes, not only are the oral and skin microbiomes involved in the pathology and progression of this complex metabolic condition, but there is growing evidence that diabetes alters the environment of the oral, skin, and gut microbiome, leading to the establishment of diabetic dysbiosis. Diabetic oral dysbiosis is associated with a higher risk of caries, a higher prevalence and severity of periodontitis, and diabetic skin dysbiosis with foot ulceration, decreased skin elasticity, decreased sebaceous gland activity, and a lower lipid mantle.

[0043] Furthermore, skin and oral microbiomes have been associated with oncogenic changes leading to melanoma and oral cancer. On the other side of the scale, cancer dysbiosis occurs as a consequence of living with cancer. This cancer dysbiosis reconstitutes a cohort of signs and symptoms with low prevalence but a high negative impact on quality of life. Cancer oral dysbiosis may be characterized by, among other things, one, several, or all of the following: oral irritation, dysgeusia (altered taste), high rates of fractures, high rates of caries, angular cheilitis (cracks at the corners of the mouth), oral sores, and even eating disorders. Cancer skin dysbiosis may be characterized by, among other things, one, several, or all of the following: skin irritation, altered palpability, high rates of cracking, paronychia, pain, and functional disorders involving distal body parts, primarily the skin of the hands and feet, but also the skin of the back, legs, and trunk.

[0044] Oral mucosa, like any mucosa in the body, is similar in many ways to skin. It consists of two distinct layers: stratified squamous epithelium and the lamina propria. In some places in the oral cavity, the oral mucosa is attached to the underlying structures by a submucosal layer of loose connective tissue components. These three layers are analogous to the epidermal, dermal, and subcutaneous tissue layers of skin (see FIG. 1). In fact, conditions such as lichen planus and pemphigus affect both the skin and oral mucosa. Therefore, in the present invention, they are embodiments of both oral and skin dysbiosis.

[0045] Pulmonary dysbiosis follows a disruption of the lung microbiome, which causes a loss of homeostasis and initiates dysbiosis. The most common initiators of pulmonary dysbiosis are environmental changes, such as dehydration, drying due to oxygen therapy, temperature changes, pH changes, tobacco, tobacco substitutes (vaping), lifestyle habits, alcohol, diet, pollution, radiation, oxygen gradients, drug intake, diseases such as cancer, infections, and diabetes, obesity, and aging, among others. Interestingly, a decrease in the diversity and specificity of the microbiome of different microenvironments within the body has been found in elderly populations, explaining the increased vulnerability in aging associated with a loss of species richness.

[0046] Pulmonary dysbiosis can also occur as a result of mucosal penetration of bacteria, viruses, or fungi that encounter a microbiota with reduced diversity. For example, whether changes in the microbiome are the cause or consequence of the development of pneumonia, or whether they simply coexist with or are associated with disease status, remains a controversial question. However, in the present study's view, the vicious cycle of the microbiome and the perpetuation of dysbiosis in disease and disease in dysbiosis, described in the microbiome dynamics model of eubiosis and dysbiosis, explains why lung health is the outcome of a complex interaction between the host and the microbiome.

[0047] With all the above in mind, in specific embodiments of any aspect of the invention, "oral dysbiosis" includes, but is not limited to, halitosis dysbiosis, caries dysbiosis, periodontal dysbiosis, aphthous dysbiosis, peri-implantitis dysbiosis, lichen planus dysbiosis, pemphigus dysbiosis, sleep apnea dysbiosis, stress dysbiosis, tooth wear dysbiosis, diabetic oral dysbiosis, cancerous oral dysbiosis, and combinations thereof. Preferably, the oral dysbiosis is selected from caries dysbiosis, tooth wear dysbiosis, periodontal dysbiosis, aphthous dysbiosis, peri-implantitis dysbiosis, sleep apnea dysbiosis, diabetic oral dysbiosis, cancerous oral dysbiosis, and combinations thereof.

[0048] Similarly, in specific embodiments of any aspect of the invention, "skin dysbiosis" includes, but is not limited to, atopic dermatitis dysbiosis, acne vulgaris dysbiosis, psoriasis dysbiosis, xerosis dysbiosis, skin allergy dysbiosis, radiation dermatitis dysbiosis, sun dermatitis dysbiosis, contact dermatitis dysbiosis, seborrheic dermatitis dysbiosis, scalp dysbiosis (dandruff, alopecia), body malodor dysbiosis (armpits, feet), premature skin aging dysbiosis, lichen planus dysbiosis, pemphigus dysbiosis, and combinations thereof. Preferably, the skin dysbiosis is selected from atopic dermatitis dysbiosis, acne vulgaris dysbiosis, psoriasis dysbiosis, xerosis dysbiosis, body malodor dysbiosis, premature skin aging dysbiosis, scalp dysbiosis, and combinations thereof.

[0049] In specific embodiments of any aspect of the invention, "pulmonary dysbiosis" includes, but is not limited to, chronic pulmonary dysbiosis, chronic obstructive pulmonary dysbiosis (COPD), cystic fibrosis dysbiosis, asthma dysbiosis, tracheitis dysbiosis, bronchitis dysbiosis, and respiratory infectious dysbiosis.

[0050] In specific embodiments, the respiratory infection is a lower respiratory tract infection caused by bacterial colonization (e.g., Streptococcus), viral colonization (e.g., influenza, parainfluenza, coronavirus, coronavirus SARS-CoV-2, respiratory syncytial virus), or fungal colonization (e.g., Candida, Pneumocystis). More specifically, the respiratory infection is selected from the group consisting of cold, pneumonia, influenza, and coronavirus SARS-CoV-2 disease (Covid-19). Thus, in specific embodiments according to the invention, the pulmonary dysbiosis is cold dysbiosis, pneumonia dysbiosis, influenza dysbiosis, or coronavirus SARS-CoV-2 dysbiosis.

[0051] In a specific embodiment of the present invention, oral dysbiosis is assessed by clinical parameters (signs and symptoms), such as: gum bleeding with interdental brushing, tooth sensitivity, the presence of inflamed gums or inflamed papillae, malodor associated with dysbiosis, tooth discoloration, tooth wear (erosion, attrition, bruxism) and / or caries, mucosal desquamation, mucosal dehydration, ulceration, aphthous ulcers, pain, taste disturbance (altered or absent taste), lack of elasticity, peri-implantitis. Similarly, skin dysbiosis is assessed by clinical parameters, such as: skin dryness, itching, redness, desquamation, ulceration, pain, bleeding, lack of elasticity, lack of tactile sensitivity (modulated or absent tactile sensitivity), blisters or blisters after sun exposure.

[0052] In another specific embodiment of the invention, pulmonary dysbiosis is assessed by clinical parameters such as sputum, rhinorrhea, congestion, conjunctivitis, headache, muscle aches, aches and pains, cough, dryness, sore throat, roughness, hoarseness, dysgeusia-loss of taste, anosmia, impaired oxygenation levels, chest pain or pressure, shortness of breath, difficulty breathing, or / and fever.

[0053] Complex Covid-19 remains an unknown entity in both its origin and its treatment. However, growing evidence of the role of an altered microbiome in the disease process offers new perspectives for both prevention and treatment. The observed reduction in bacterial diversity in Covid-19 patients compared with healthy subjects, together with the fact that parallel and simultaneous reestablishment of the upper respiratory tract and gut microbiome occurs in most Covid-19 patients with mild disease, supports the theory of coronavirus disease-associated dysbiosis affecting more than the lungs. Furthermore, the reduced diversity in most microbiome environments of older individuals inherent to aging may ultimately explain the rapidly severe progression and high rate of fatal outcomes of Covid-19. In the present study's view, coronavirus dysbiosis exploits the blockage of the microbiome, which penetrates from the mucous membranes of the lungs to other mucous membranes, such as the digestive system, but also to the skin, a concrete example of the mouth-lung-gut-skin axis. In fact, 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 continually being updated. In any event, in the present invention, Covid-19 dysbiosis is considered a specific embodiment of pulmonary dysbiosis, since it was originally described as a respiratory infection.

[0054] Keeping in mind the order listed above, the signs and symptoms of coronavirus dysbiosis are: in the mouth, dry mucous membranes (dry mouth), loss or absence of taste (dysgeusia or ageusia), vesicle-like lesions, aphthous lesions, loss or absence of smell (anosmia); in the upper respiratory tract and lungs, dry respiratory mucous membranes (dry cough), speech disturbance, sore throat, difficulty breathing, and shortness of breath; in the intestines, diarrhea; and on the skin, skin rash, discoloration of the fingers and toes.

[0055] In a first aspect, the present invention relates to a composition comprising olive products, 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.

[0056] Compositions containing olive products, such as olive oil, betaine, and xylitol, are already known in the prior art, albeit for other unrelated uses. See, for example, EP2119477A1 and WO2019 / 025366A1. Specifically, the composition of EP2119477 can be used to treat xerostomia. Nothing in the prior art suggests that adequate salivary function would prevent dysbiosis from occurring, or that patients without xerostomia would not be at risk for dysbiosis. Sufficient saliva production is not a guarantee of eubiosis. Otherwise, caries, periodontitis, and other oral dysbiosis would be prevented by normal saliva flow. In fact, nothing has been written about the inhibitory effect of saliva flow on periodontitis, the most prevalent oral dysbiosis. The converse is also true: patients with xerostomia do not pose a higher risk of periodontitis. Similarly, patients with eating disorders or gastroesophageal reflux disease experience compensatory extravasation of saliva, yet suffer from the easily recognized tooth-wear oral dysbiosis, which consists of blockage of dental biofilm first on the lingual surfaces of the teeth, secondly on the occlusal (chewing) surfaces, and finally on the buccal surfaces. The teeth eventually become depleted of all lipophilic content, loosening the barrier effect of this dental biofilm and destroying the teeth. This cannot be remedied by means of any kind of mouthpiece.

[0057] The compositions of WO2019 / 025366A1 can be used to treat oncology treatment-induced oral gastrointestinal mucositis (OTIOM), a life-threatening condition for cancer patients undergoing chemotherapy and / or radiotherapy. OTIOM differs from oral and skin dysbiosis in the sense that it is self-limiting, does not affect the skin or teeth, and is not associated with the microbiome or pathogens of any origin. It is an acute blockage of oral gastrointestinal mucosal toxicity, the single most feared complication of cancer treatment, which cannot be treated with antibiotics, probiotics, or prebiotics. In fact, probiotics are strictly contraindicated during OTIOM due to the high risk of sepsis.

[0058] Interestingly, as shown in the examples, the composition of the present invention comprising olive products, betaine, and xylitol has a new medical use, since it is useful for the prevention and / or treatment of dysbiosis. Surprisingly, the composition comprising olive products, betaine, and xylitol shows an unexpected synergistic effect compared to a composition comprising only one of the ingredients or a combination of olive products and betaine (see Examples 1, 3, 4, and 8). Moreover, different examples demonstrate the usefulness of the composition of the present invention for the treatment and / or prevention of both mucosal dysbiosis and skin dysbiosis.

[0059] Specific and preferred embodiments of dysbiosis are described above and are applicable to all aspects of the present invention.

[0060] In a specific embodiment according to the first aspect of the present invention, the olive product is selected from olive oil, olive fruit extract, and their mixtures.The olive fruit extract can be olive fruit extract (also known as olive fruit liquid extract), olive fruit dry extract (also known as olive fruit dry powder extract), or their mixtures.Preferably, the olive fruit extract is olive fruit extract and olive fruit dry extract.

[0061] Olive fruit extract is known to those skilled in the art and is commercially available.Similarly, the method of extracting from olive fruit is well known.Examples of said method are disclosed in WO2008142178A1 and ES2051238A1.In a specific embodiment, the olive fruit extract is a hydroxytyrosol-rich olive fruit extract.More specifically, the olive fruit extract contains at least 20% (w / w) hydroxytyrosol.Examples of these extracts are available from Nutexa Inc. and Natac, among others.

[0062] Preferably, the olive product is olive oil. More preferably, the olive oil is selected from the group consisting of extra virgin olive oil and virgin olive oil. Even more preferably, the olive oil is extra virgin olive oil (EVOO), which has outstanding effects in treating and preventing dysbiosis, as shown in the examples.

[0063] Betaine may be used in any of its dosage forms, either as an aqueous solution or as a powder. In specific embodiments according to any one of the preceding embodiments, the betaine may be selected from the group consisting of trimethylglycine (TMG), cocamidopropyl betaine, dimethylamine betaine, alkyl (C 12 -C 18 ) Amidobetaine, Alkyl (C8-C 18 ) betaine, amidobetaine, alkylamidobetaine, sulfohydroxybetaine, and combinations thereof. Preferably, the betaine is trimethylglycine, which has outstanding effects in treating and preventing dysbiosis, as shown in the examples. More preferably, trimethylglycine is selected for formulations for mucous membranes and skin.

[0064] Olive oil is used in the food industry as a preservative due to its antibacterial, antifungal, and antiviral properties. It has been publicized as irritating, possessing a pungent taste and a barrier-blocking effect on stratum corneum integrity by means of increased transepidermal water loss (TEWL) after topical application to the skin in subjects with or without atopic dermatitis. On the skin, olive oil has been claimed to cause contact dermatitis and to have anti-inflammatory benefits but also irritating side effects, resulting in barrier blockage. Betaine, commonly used in mouthwashes for its antiseptic activity, carries the risk of disrupting the healthy balance of biofilms when used for over two weeks.

[0065] Xylitol is a well-known anti-carcinogenic ingredient and is increasingly commonly introduced to consumers. Xylitol has demonstrated anti-streptococcal activity, especially when used alone as a remineralizing agent. However, recent studies benefiting from modern computational science using rRNA gene sequencing have examined the impact of xylitol on the composition of the oral microbiota and found no evidence of previously documented caries-associated or caries-protective species following the use of either xylitol or sorbitol. This adds to the controversy surrounding the dental benefits of xylitol. Interestingly, when included in oral hygiene compositions, a demonstrated reduction in the anti-plaque effect of xylitol has been found when it is combined with other minerals and salts with remineralizing potential. Despite the possible beneficial effects of xylitol for humans when consumed orally at high rates or over long periods of time (it is highly toxic to animals), the subsequent digestive disturbances (bloating, diarrhea) may be a marker of undesirable gut microbiome imbalance, which returns to homeostasis upon cessation of ingestion (Storey, Lee, & Bornet, 2007). In skin and / or vaginal dysbiosis, high concentrations of xylitol are also undesirable because they can shift the phyla of Bacillus (Lactobacillus) and Streptococcus and Staphylococcus. Surprisingly, the compositions of the present invention do not exhibit any of these adverse effects. In fact, the compositions of the present invention preserve hydrophilic and lipophilic bacteria without exerting the antimicrobial properties of olive oil, betaine, and xylitol alone.

[0066] The compositions of the present invention, when applied topically, have been found to be effective in preventing mucosal and skin dysbiosis by forming 3D structures that help maintain the native microflora when hazards emerge.

[0067] The composition of the present invention provides a three-dimensional amphiphilic scaffold that incorporates water also from the atmosphere, humidifying the microbiome ecosystem and simultaneously humidifying human skin and mucous membranes, ultimately providing protection from external insults (among others, lack of moisture, pH shifts, temperature fluctuations, disinfectants, detergents, radiation), limiting the penetration of harmful agents, and providing a home for the necessities of cellular activity, namely water and nutrients.

[0068] The microbiome ecosystem is enhanced by the compositions of the present invention because it is improved for better attachment of the indigenous microflora due to the hydrophobic properties of olive oil, which captures moisture from the atmosphere, the water-retaining properties of betaine, and the moisturizing effect of xylitol, making it a more persistent moisturizer than a simple aqueous or two-phase solution.In fact, an emulsion of olive oil in the absence of betaine and xylitol cannot provide the desired moisturizing effect of a humectant on both the skin and mucous membranes.

[0069] The concept of epithelial homeostasis explains that there is a continuous replacement of cells by desquamation of more superficial cells, which has a positive effect in limiting microbial colonization and a negative effect when the indigenous microbiota is partially lost.

[0070] However, these living microorganisms require their ecosystem in order to become established.

[0071] Researchers intended to identify the good bacteria behind health and, conversely, the populations behind disease. Unfortunately, this simplification proved to be incorrect, as the same bacterial types are found in diseased individuals and controls, albeit in different proportions. It is not yet possible to conclude that the microbiota shift is the origin of the disease itself. An associative rather than a causal relationship is assumed, with the latter prevailing in infectious conditions. In other words, certain microbiota in disease appear to be more associated than originating from such a condition.

[0072] In nature, ecological changes in habitats initiate, leading to either the adaptation or extinction of certain species. Attempting to maintain a stable microbiome by acting through the microbiota has so far had controversial results. The inventors of the present invention view the ecosystem as the primary recipient of damage, which in turn causes microbiota shifts that are themselves the cause of environmental change. This is depicted by what we define as the microbiome dynamics model of eubiosis and dysbiosis (Figure 2).

[0073] Human evolution resulted in a natural symbiosis, or eubiosis, where health is the norm. However, when dysbiosis emerges, non-symbiotic microbial populations, together with a disturbed ecosystem, perpetuate vicious cycles such as obesity or depression. Both entities are now understood in relation to the dysbiotic microbiome, along with frustrating resistance to both dietary and psychological treatments.

[0074] Our bodies face daily insults, specifically stress, pollution, hyperconnectivity, Wi-Fi, chemicals, disinfectants, antibiotics, medications, cleaning products, radiation, oxidative stress, infectious agents, fast food, oral and skin hygiene, shampoos, feminine hygiene, wounds, eating disorders, mouth breathing, sleep apnea, and systemic and chronic conditions that have an impact on our microbiome.

[0075] Some individuals lack the necessary internal or external conditions to restore the microbiome, thus developing disease. Once the microbiome shifts, reestablishing a healthy population of bacteria requires health-promoting factors that can act directly on the microbiome or indirectly on the environment. Surprisingly, the compositions of the present invention can restore and promote a healthy microbiome and its ecosystem by enhancing support for a healthy environmental ecosystem. Our approach is directed toward enhancing environmental conditions and ecosystems that are favorable for the maintenance and re-establishment of a healthy microbiome, regardless of the site. The compositions enhance specific microbiome compartments, since it has not yet been possible to identify one or several microorganisms causally linked to most of the conditions and diseases studied so far. As shown in the examples, improving the human microbiome through ecosystem compartments is less site-specific. This mechanism is depicted in a schematic manner in Figure 3.

[0076] In a specific embodiment according to any one of the above embodiments, the composition does not contain any other vegetable oil.More specifically, it does not contain parsley oil.In this way, the use of lower quality oil, such as palm oil, is avoided.However, the composition can contain essential oil.Therefore, in a specific embodiment, with the exception of essential oil, the composition does not contain any other vegetable oil.

[0077] In specific embodiments according to any one of the preceding embodiments, the composition comprises 0.05% to 5.1% by weight of an olive product, preferably 0.05% to 4.1%, more preferably 0.05% to 2.6%. Preferably, when the olive product is or comprises olive fruit extract, the composition comprises 0.05% to 0.1% olive fruit extract, and when the olive product is or comprises olive oil, the composition comprises 0.1% to 5%, more preferably 0.1% to 4%, even more preferably 0.2% to 2.5% olive oil.

[0078] In another specific embodiment according to any one of the preceding embodiments, the composition comprises between 0.1% and 10% by weight of betaine, preferably between 1.0% and 6%, and more preferably between 1.20% and 5%.

[0079] In another specific embodiment according to any one of the preceding embodiments, the composition comprises xylitol, preferably 1% to 20% by weight xylitol, more preferably 1% to 15%. Advantageously, at smaller concentrations (e.g., ≦20%), xylitol acts as a moisturizer and refresher, helping to improve the prevention and treatment of dysbiosis.

[0080] Unless otherwise stated, all percentages given in this invention are given in weight per weight (w / w) of the total composition.

[0081] As shown in the examples, compositions comprising olive products, betaine, and xylitol in amounts within the ranges defined above are highly effective in treating and preventing dysbiosis. In another preferred embodiment, the composition of the present invention comprises olive products, betaine, and xylitol in the amounts defined in any one of the formulations described in the examples.

[0082] In a specific embodiment according to any one of the preceding embodiments, the composition comprises an antioxidant and / or vitamin. Preferably, the antioxidant is a natural antioxidant, more preferably an antioxidant from Olea europaea. Preferably, the antioxidant is selected from the group consisting of hydroxytyrosol, tyrosol, oleuropein, and mixtures thereof. Interestingly, hydroxytyrosol, tyrosol, and oleuropein appear to potentiate the anti-inflammatory and antioxidant activity of olive oil and stabilize the composition (i.e., reduce or even eliminate additional preservatives, which would make the formulation more tolerable to subjects). Therefore, in a preferred embodiment, the composition comprises hydroxytyrosol and / or tyrosol and / or oleuropein. Preferably, it comprises hydroxytyrosol, tyrosol, and oleuropein.

[0083] Depending on the desired dosage form / formulation, the composition will include all components necessary to provide the desired organoleptic and rheological profile. Thus, in specific embodiments according to any one of the preceding embodiments, the composition further comprises one or more components selected from the group consisting of: remineralizing agents, viscosity adjusting agents, humectants, preservatives, colorants, pH adjusting agents (buffering agents), sweeteners, emulsifiers, proteolytic enzymes, whitening agents, probiotics, abrasives, essential oils, scarring agents, aromas, animal or vegetable gelatins, rheological agents, solvents, excipients, and combinations thereof.

[0084] These additional components of the compositions of the present invention are commonly known to those skilled in the art, and non-limiting examples of said compounds are provided below. In specific embodiments according to any one of the preceding embodiments, these compounds are selected from the following examples: The remineralizing agent may be selected from fluoride anions, phosphate anions, calcium cations, potassium cations, and mixtures thereof. The rheological agent may be selected from the group consisting of gum arabic, tragacanth gum, xanthan gum, carboxymethylcellulose, carbopol-type polymers, pectin, mucin, and mixtures thereof. The humectant may be selected from the group consisting of glycerin, propylene glycol, sorbitol, and mixtures thereof, preferably glycerin. The preservative may be selected from the group consisting of sodium benzoate, potassium sorbate, benzoic acid, diazolidinyl urea, imidazolinyl urea, methylparaben sodium, propylparaben sodium, 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.

[0085] Recent studies have demonstrated a link between the use of biocides in toothpastes for general use and multiple and serious direct side effects in distant parts of the body. A multi-institutional university animal study demonstrated that triclosan, widely used in oral care products, can be detected in the blood following oral application and is directly related to several pathological conditions such as colitis, intestinal inflammatory changes, and colon cancer, the most common form of cancer, among others (Yang, Wang, & Romano, 2018). The study authors acknowledge the specificity of animal-human translational research, but caution medical and health authorities and experts, because they outline that the results obtained in the study occurred after small exposures to triclosan, which humans use extensively for oral hygiene three times a day over a long lifespan.

[0086] Antifungal drugs have proven effective in treating dandruff, but they cannot prevent recolonization by yeasts after several weeks. However, the compositions of the present invention can enhance the microbial balance by providing the necessary conditions for a scalp microhabitat, which will help prevent significant colonization by pathogenic microorganisms such as yeasts from the genus Malassezia.

[0087] Thus, in a specific embodiment according to any of the preceding embodiments, the composition of the invention does not include any additional active ingredients (e.g., antibiotics, antifungals). Specifically, it does not include triclosan.

[0088] The compositions of the present invention provide ideal physicochemical conditions (pH, barrier integrity, and nutrients) that support the maintenance and restoration of a healthy, balanced microflora of the skin and mucous membranes. Every ecological niche defines its own state, particularly by pH (Table 1). Depending on the body part, the pH will be adjusted to respect the specificity within the body. The pH will be adjusted by a buffering agent. Therefore, in a specific embodiment, the compositions of the present invention contain a buffering agent. Any buffering agent known in the prior art can be used in the compositions of the present invention. Specifically, the buffering agent can be selected from the group consisting of lactic acid, lactate salts, citric acid, citrate salts, malic acid and its salts, sodium hydroxide, potassium phosphate, sodium phosphate, potassium pyrophosphate, sodium pyrophosphate, and mixtures thereof.

[0089] [Table 1]

[0090] Surprisingly, whatever the pH requirements for different skin and / or mucous membrane locations, the compositions of the present invention maintain their beneficial effects.

[0091] Those skilled in the art can formulate the compositions of the present invention in any suitable dosage form that allows for simple use in preventing and / or treating dysbiosis. In specific embodiments according to any one of the preceding embodiments, the compositions are formulated as a facial and / or body moisturizer, a deodorant cream, a regenerative 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 gel for topical application to the vulva, an intranasal inhalant, an intranasal spray, an aerosol solution, an aerosol spray, an aerosol capsule, a toothpaste, a mouthwash, a chewing gum, a chewable tablet, a sucking capsule, a sucking lozenge, a palate sheet, a candy, an impregnated oral swab, an impregnated oral gauze, a lipstick, or a balm.

[0092] In a preferred embodiment, the gel is formed by using gelling agents such as agar, alginic acid, carrageenan, guar gum, pectic acid, tragacanth gum, carbomer, polymers, and silica.

[0093] Dried olive fruit extract is preferred for the formulation of lozenges or pastilles, while olive oil, preferably EVOO, and liquid or dried olive fruit extract are the preferred sources of olive products for the formulation of gels, toothpastes, mouthwashes, shampoos, conditioners, hair lotions, creams, masks, lipsticks, sprays, serums, deodorants, capsules, vaginal suppositories, and shower gels. Treatment of aphthous oral dysbiosis has a preferred embodiment in the form of a gel with EVOO as the olive product source, containing hydroxytyrosol for its powerful antioxidant properties and olive fruit flavor (without a tingling flavor). Recurrent aphthous ulcers (RAUs) benefit from preventive hygiene using the same approach in the form of toothpaste, which may also contain remineralizing agents, natural, non-irritating flavors, vitamins, and other essential ingredients for comfortable hygiene. Patients with inflammatory bowel disease (IBD) or Crohn's or gluten intolerance also suffer from aphthous dysbiosis and are candidates for the same treatment. For stress & tooth wear oral dysbiosis, as well as sleep apnea oral dysbiosis and oral dysbiosis associated with eating disorders or gastric reflux, the gel is ideally formulated to be applied topically to the oral tissues several times per day after oral hygiene, particularly before sleep and upon awakening.

[0094] Administration of the compositions of the present invention to prevent or treat pulmonary dysbiosis can be by any known route of administration, non-limiting examples being liquid dosage forms for nasal inhalants, nasal sprays, nasal aerosols, nasal gels, oropharyngeal syrups, and oropharyngeal gels, as well as solid dosage forms as aerosol capsules.

[0095] The compositions of the present invention can be incorporated into care and hygiene products for different skin and mucous membrane areas.

[0096] "Care" refers to the restoration, improvement, or protection of the necessary mucosal and skin microflora whenever a hazard compromises the natural and healthy microbiome (i.e., hygiene with caustic products or alcohol, detergents, etc.).

[0097] "Hygiene" refers to the act of eliminating excess residual cells and other naturally produced substances that are susceptible to causing disruption of the natural and healthy microbiome.

[0098] Depending on the area of ​​the body / on which the composition is to be applied, different formulations and bases and / or excipients should be used. Those skilled in the art know how to adapt each composition to each area of ​​the body, depending, inter alia, on the pH and other specific physicochemical properties of the tissue.

[0099] For example, some areas of the skin are oilier, wetter or drier than others, and care and hygiene products will be adapted to this characteristic.

[0100] In the same sense, different products will be adapted to different mucous membranes, just as those for the mouth and vagina are very different from each other.In a specific embodiment, when a cleanser is used for hygiene, as can be seen in the examples, the composition of the present invention continues to deliver beneficial effects to the ecosystem and restore eubiosis.In dosage forms that include whitening ingredients for either teeth or skin, the composition of the present invention exerts beneficial activity on the microbiome and also reduces the possible irritation, scaling, or sensitivity effects of the whitening ingredients.

[0101] On the human body surface, the microbiota has some specializations and is adapted to different habitats. According to the Human Microbiome Project, there are distinct microbial communities in 10 specific sites within the digestive tract, such as the buccal cavity, gingiva, and hard palate (group 1) and the saliva, tongue, tonsils, and throat (group 2) (Segata, Kinder Haake, & Mannon, 2012). This topographical variation is surprisingly high among different individuals. Similarly, the skin, with its oily sites (scalp, back, forearms) and moist sites, as well as the oral mucosa, have site-specific microbiota that also exhibit temporal variations but most often remain stable over time. Currently, the topographical and temporal behavior and abundance or abundance of these microbiota are being studied. Similarities have been found in the fact that lipophilic bacteria in the oral cavity are predominantly present in the hard palate, the lingual surfaces of the teeth, the keratinized gingiva, and the buccal mucosa. As observed by the present inventors, these bacteria not only exhibit more resistance to the acids of the digestive system and the passage of food through the bolus, but they also produce fatty acids by metabolizing triglycerides. They bathe the remainder of the oral cavity in a lipid mantle, which serves as protection, lubrication, and helps perpetuate the lipid-based component of oral biofilms. In the same manner, the present inventors propose a positive enhancement of this natural lipophilic protection by the present composition.

[0102] Whether high in diversity (oral mucosa) or low in diversity (scalp, back, and forearms, or vagina), this biofilm, when behaving in a symbiotic (healthy) manner, appears to perform valuable functions such as immune defense, nutrition, metabolism, and even growth and individuality of the spectator. It remains unclear when and why it shifts to dysbiosis (disease) due to a yet-to-be-discovered trigger. It could be a keystone pathogen, or a major environmental insult like stress, or, more strikingly, hygiene, as previously alleged.

[0103] The microbiome is under constant movement and renovation, while at the same time exhibiting resilience to change. Identifying the core microbiome of a given anatomical site or the key pathogens of a particular dysbiosis remains a monumental task, despite the advent of next-generation sequencing, which offers less bias than previous culture-based technologies. This is especially true for periodontitis, an oral dysbiosis that represents the most highly prevalent disease in the global population. Over the years, periodontists have evolved from believing that gram-negative bacteria cause periodontitis to accepting that gram-positive and gram-negative bacteria are behind the shift from primary gingivitis to mature periodontitis, and that the pathogenesis is associative, rather than truly causal, with oxygen-deficient (anaerobic) hemolytic bacteria ("red complex" bacteria; Treponema denticola, Tannerella forsythia, and Porphyromonas gingivalis) that benefit from what was originally thought to be secondary inflammation. To make matters more complicated, P. gingivalis, widely recognized as a landmark pathogen of periodontitis, initiates an inflammatory response by shifting the normal resident microbiota, which then transforms into a dysbiotic state, or even in low abundance conditions. Whether this pathogen exhibits symbiotic harmful behavior with so-called dormant, unculturable microorganisms only recently discovered remains a mystery. This is the case with Filifactor allosis, which appears to be involved in major oral dysbiosis because it is rarely found in healthy individuals. Surprisingly, F. allosis is a Gram-positive, non-saccharolytic, anaerobic bacterium that resides in the subgingival area with a low oxygen gradient and can subsist on short-chain fatty acids. When metabolized, it releases ammonium, increasing the pH to the neutral range. This, in turn, eliminates Gram-positive, oxygen-dependent bacteria with an acidic metabolism, such as Streptococcus mutans. This may be the reason behind patients who exhibit periodontal susceptibility rather than caries risk, and vice versa.If the ability of F. alocasia to thrive in highly oxidative conditions leads to further oxidative stress, it is not yet known whether other potentially dysbiotic environmental changes favor OLP or oncogenic changes.

[0104] In an unbalanced situation of dysbiosis, the modulated microbiota interacts with the human body in an altered environmental atmosphere (temperature, pH, moisture, and oxygen conditions), which tends to perpetuate the microbial shift.

[0105] Not only are microorganisms replaced, but the ecosystem is simultaneously altered, and this dual shift is detected clinically by means of negative conditions such as inflammation, barrier breakdown, bleeding, desquamation, irritation, dehydration, and possibly infectious or ultimately carcinogenic changes in the body.

[0106] The role of the human microbiome in skin and oral dysbiosis, such as the diseases mentioned herein, is now established by research but was previously suspected, because many of these negative conditions, of unknown origin, have been ameliorated by antibiotics (AB). Unfortunately, AB resistance and side effects are common drawbacks. As shown in the examples, the compositions of the present invention can reverse these negative conditions and improve health through ecosystem augmentation, ultimately achieving eubiosis. Therefore, in specific embodiments of the present invention according to any of the preceding embodiments, the composition does not contain antibiotics.

[0107] Attempts to improve health through the microbiome have mainly been made by modifying the microflora, usually by adding supposedly beneficial microorganisms, so-called probiotics, with controversial results. In any case, the present invention is compatible with prebiotics and probiotics. Therefore, in a specific embodiment according to any one of the preceding embodiments, the composition further comprises prebiotics and / or probiotics. In a preferred embodiment, the composition is a lozenge for licking, which comprises olive dried fruit extract, betaine, xylitol, and probiotics. More preferably, it also comprises the necessary ingredients for formulating it into a dry dosage form.

[0108] The composition of the present invention contains a lipid-lipophilic fraction (olive products) that adheres to the tissue for a longer period of time and prevents evaporation, and a hydrophilic fraction (betaine and xylitol) that attracts moisture within this scaffold, allowing the microbiome to interact with the host and its ecosystem. The microbiome ecosystem is enhanced by this composition because it is improved for better attachment of the indigenous microbiome.

[0109] As shown in the examples, the compositions of the present invention have unprecedented beneficial properties: they not only neutralize the negative effects of olive oil or betaine used topically, but also amplify unexpected benefits for the oral and skin microbiome when applied directly to the skin and mucous membranes.

[0110] Skin and mucous membranes provide an effective barrier against pathogens and water loss. Blockage of the skin and mucous membrane barrier leads to inflammatory redness, which represents vascular dilation and increased blood flow. The use of the composition of the present invention has been demonstrated to reduce inflammation and simultaneously regenerate damaged tissue. It is important to emphasize that other inflammation inhibitors cannot regenerate tissue, making this composition unique, as this property has not been achieved by any other composition in humans (Van Dyke, 2017) (see, for example, Example 4).

[0111] Bacterial selection occurs as a result of altered skin or mucous membranes. Gum inflammation increases collagen peptides, plasma proteins, and hemoglobin, which select for specific bacteria characterized by the use of essential amino acids and hemin as nutrients.

[0112] The compositions of the present invention reduce permeability, regenerate tissue, and prevent the release of nutrients that promote dysbiosis (collagen peptides, plasma proteins, and hemoglobin), thus achieving a natural and healthy equilibrium of tissue-dwelling bacteria. At the same time, preventing the release of these molecules helps maintain the natural, healthy color of either mucous membranes, teeth, and skin.

[0113] In the present invention, the compositions enhance, but do not eliminate, sufficient oral and skin biofilms to promote a balanced and diverse microflora, maintaining and restoring the native microbiome of the underlying tissues.

[0114] Furthermore, the discovery of the compositions of the present invention to treat and prevent oral and skin dysbiosis and enhance oral and skin homeostasis supports a competent environment for the oral and skin microbiome without exerting any pressure on resident microorganisms that may trigger or spread dysbiotic stimuli.

[0115] The composition of the present invention has a lipid-lipophilic fraction (olive products) that adheres to the tissue for a longer period of time and prevents evaporation, along with a hydrophilic fraction (betaine and xylitol) that attracts moisture within the scaffold, allowing the microbiome to interact with the host and its ecosystem. The microbiome ecosystem is enhanced by this composition because it is improved for better attachment of the native microbiome.

[0116] To the inventors' knowledge, nothing in the prior art anticipates the oral-cutaneous axis. Gingivitis frequently occurs in patients with acne vulgaris. In acne skin inflammation, patients also experience bleeding and swelling of the gums, sometimes even before skin breakdown. Both conditions usually occur in adolescents but also in minors and are not uncommon in adults. Both conditions are related to a Western diet and stress and are among the most common reasons for specialist visits. Severity ranges from open or closed comedones (blackheads and whiteheads) to distinct inflammatory lesions (pustules and even cysts) in acne, and from gingival inflammation to bleeding and ulceration (ulceronecrotic lesions). The current trend is to consider acne vulgaris as a skin dysbiosis, with Propionibacterium acnes colonization as a related factor, facilitated by altered environmental conditions on the skin. Gram-positive bacteria are also found in gingivitis. However, to date, no pathogen has been identified, and similar to acne, there is an increased response from the host that disrupts the barrier and allows colonization. As shown in the examples, improvement in the gums is associated with improvement in acne, consistent with this newly described oral-cutaneous axis.

[0117] Finally, nothing in the prior art has linked tooth wear to oral dysbiosis. However, in the view of the present invention, the imbalance in mineral exchange behind mineral loss in erosion damage can be prevented by restoring the appropriate barrier function of the oral microflora when in balance. As shown in the examples and explained in the previous discussion, a balanced microflora in a healthy ecosystem neutralizes acid attacks, and after using the compositions of the present invention, indirect improvement of tooth sensitivity occurs. Specifically, the use of the compositions of the present invention in the form of toothpaste and mouthwash prevents dysbiosis and restores homeostasis. When dysbiosis is present, all these conditions benefit from the external application of the compositions, ideally in the form of a gel or spray, to reverse eubiosis at the early onset of dysbiosis.

[0118] Today, the skin-gut axis is the focus of inter-university research aimed at explaining and describing the relationship between the gut microbiome and skin health, the so far elusive communication between these seemingly unconnected body parts, and the potential of translational research in improving the gut microbiome and skin treatments (Salem, Ramser, Isham, & Ghannoum, 2018)(Lee, Byun, & Kim, 2019)(Vaughn, Notay, Clark, & Sivamani, 2017)(Szanto, Dozsa, & Antal, 2019).

[0119] To the best of the present authors' knowledge, the prior art has not clearly addressed the oral microbiome and its systemic effects as a dysfunction of the mouth during sleep, referred to as sleep apnea or obstructive sleep apnea (OSA) and considered by the authors to be a dysbiosis. Sleep apnea ranges from snoring to severe forms of true interruptions in breathing, which negatively impact sleep quality through frequent awakenings and poor sleep during the night. Daytime irritability, lack of concentration, daytime sleepiness, depression, and anxiety, along with increased cardiovascular risk, are experienced by physicians and patients who refer patients to maxillofacial surgeons and dentists for invasive or non-invasive (removable mouth splint) mandibular advancement therapy as an alternative to sleep, often accompanied by mechanical continuous positive airway pressure (CPAP). The role of the oral microbiome in OSA, both as the origin of the problem and as a consequence of it, has not been addressed. The present invention contemplates that sleep apnea dysbiosis begins in an altered environment similar to that experienced by mouth breathers. Acute and prolonged changes in mucosal moisture conditions disrupt mucosal structural architecture and the microbiome compartment, which has a critical disruption of airflow pathways in OSA. Humidification by sipping water upon waking is only a short-term solution and leads to nocturia. OSA is associated with repeated sleep interruptions, poor nighttime sleep, and daytime consequences on the individual's social, psychological, and health aspects. The oral-brain axis connection has been described previously, and this may well be another example of such a connection. Patients using the composition of the present invention in the form of a spray applied before bedtime and upon waking at night show significant improvements in signs and symptoms associated with sleep apnea dysbiosis, such as nighttime sleep quality, daytime stimuli reactivity, nighttime waking episodes, and nighttime water sipping episodes. Compared with water spray, patients using CPAP with the composition had better compliance.

[0120] Finally, as explained above, the composition of the present invention is useful for preventing and / or treating dysbiosis. Advantageously, as shown in Example 5, it is also useful for preventing conditions that are promoted or exacerbated by dysbiosis. Moreover, it may be useful for treating said conditions, particularly as an adjuvant treatment. The condition may be exacerbated by dysbiosis because dysbiosis increases the number of episodes of the condition, or because dysbiosis exacerbates the signs and / or symptoms of the condition. The signs and / or symptoms may be exacerbated by dysbiosis in terms of variety, intensity, and / or duration. Therefore, the first aspect of the present invention also relates to a composition of the present invention as described in any of the above-mentioned embodiments for use in preventing and / or as an adjuvant treatment of conditions that are promoted or exacerbated by dysbiosis.

[0121] Recent studies have agreed that imbalances in the scalp microbiome are a major contributing factor to conditions such as dandruff or seborrheic dermatitis. There are links between several medical conditions, such as chronic inflammatory conditions and cancer, and both the mucosal and skin microbiomes. In fact, the skin and oral microbiomes have been associated with oncogenic changes leading to skin cancers (e.g., melanoma) and oral cancer.

[0122] In the lungs, similar to what occurs in any dysbiosis, the loss of beneficial resident bacteria implies diminished protection against opportunistic pathogens such as bacteria, fungi, and viruses, which would perpetuate the dysbiosis by colonization. Furthermore, at the same time, pulmonary dysbiosis, if present, can exacerbate conditions and diseases of a different nature that would otherwise have a normal course. Human lungs have evolved to prevent the penetration of airborne particles and pathogens, and the normal state is eubiosis and health enjoyed by young people and other age groups unless dysbiosis is present. This is true for young people exposed to coronavirus, who experience an asymptomatic course or mild cold symptoms as part of their common cold dysbiosis, returning to homeostasis within a few days. This younger population, which normally benefits from eubiosis, when faced with the coronavirus Covid-19, will in the majority of cases not suffer from severe forms and will experience a mild or even asymptomatic course that does not progress to true coronavirus disease, whereas if dysbiosis is present, as occurs in older populations, the coronavirus invasion will likely progress to more severe forms as a result of the deterioration caused by dysbiosis (e.g., more severe respiratory distress requiring multiple hospitalizations and the use of oxygen and / or ventilation). Coronaviruses are a large family of viruses known to cause illnesses ranging from the common cold to more severe diseases, such as Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS).

[0123] Oral, skin, and vaginal hygiene disrupt and even destroy biofilms, degrading the microbiome compartment. A neglected population of over 300 different facultative anaerobic bacteria (especially Streptococcus salivarius, S. mitis, S. aureus, S. epidermidis, and Corynebacterium) lives in the crypts on the dorsum of the tongue and possesses the unique property of reducing dietary nitrate to nitrite, the body's natural vasodilator and gastroprotective promoter. Surprisingly, despite the unquestioned role of the oral microbiome in blood pressure, platelet function, and bone marrow physiology, as well as cerebral blood flow and peripheral arterial disease, all these beneficial effects are strikingly abolished when antibacterial mouthwashes are used. Dramatically, in healthy subjects on a leafy greens-poor diet using antibacterial mouthwash, the significant increase in systolic and diastolic blood pressure, clearly related to the reduction in plasma nitrite, is not reflected in the necessary research yet to be done to prove whether chronic use of antibacterial mouthwash leads to increased blood pressure and consequently higher cardiovascular risk. Moreover, periodontal dysbiosis and cardiovascular disease often occur in the same patients who may also be using oral antibacterial medications (Hezel, 2004). & Weitzberg, 2015 ).

[0124] Thus, inter alia, the pathology promoted or exacerbated by dysbiosis may be selected from the group consisting of dandruff, seborrheic dermatitis, chronic inflammatory conditions, skin cancer (e.g., melanoma), oral cancer, and respiratory infections, the latter of which may be bacterial infections (e.g., caused by Streptococcus), viral infections (e.g., caused by influenza, parainfluenza, coronavirus, coronavirus SARS-CoV-2, respiratory syncytial virus), or fungal infections (e.g., caused by Candida, Pneumocystis).

[0125] In a preferred embodiment, the condition promoted or exacerbated 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 of the present invention surprisingly prevents colds, as it reduces the number of cold episodes.

[0126] A 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, where the olive product is olive oil and / or olive fruit extract, as well as the use of a composition comprising an olive product, betaine, and xylitol for the preparation of a medicament for the prevention of conditions promoted or exacerbated by dysbiosis or for the preparation of an adjuvant for the treatment of conditions promoted or exacerbated by dysbiosis.

[0127] A third aspect of the present invention relates to a method of treating dysbiosis, or a condition precipitated or exacerbated by dysbiosis, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising an olive product, betaine, and xylitol, wherein the olive product is olive oil and / or olive fruit extract.

[0128] A fourth aspect of the present invention relates to a method for preventing dysbiosis in a subject, comprising administering to the 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 a condition contributed to or exacerbated by dysbiosis in a subject, comprising administering to the 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.

[0129] Finally, recent publications clearly demonstrate that oral hygiene is the primary and most important cause of oral microbiome dysbiosis (Sudhakara, Gupta, & Bhardwaj, 2018). The same has been asserted by skin researchers regarding skin hygiene and skin dysbiosis, using reduced biodiversity as a marker of skin health deficiency and demonstrating the effects of synthetic ingredients in everyday cosmetics (Wallen-Russell, 2019). Therefore, a 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 oral, nasal, vaginal, and / or skin hygiene 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 oral, nasal, vaginal, and / or skin hygiene of the human body and / or for maintaining the natural moisturization of mucous membranes or skin of the human body. Similarly, it also relates to a method for oral, nasal, vaginal, and / or skin hygiene of the human body, comprising the administration of a composition as defined in any of the embodiments of the first aspect of the present invention. Similarly, the use of a composition as defined in any of the embodiments of the first aspect of the present invention for maintaining the natural moisturization of the mucous membranes and / or skin of the human body, and the composition as defined in any of the embodiments of the first aspect of the present invention for use in maintaining the natural moisturization of the mucous membranes and / or skin of the human body, are also objects of the present invention.Similarly, a method for maintaining the natural moisturization of the mucous membranes and / or skin of the human body is also an object of the present invention, comprising administering a composition as defined in any of the embodiments of the first aspect of the present invention.Preferably, the administration is external.Preferably, the mucous membrane is the oral mucous membrane.

[0130] Specific and preferred embodiments of the compositions of the invention, dysbiosis and conditions contributed to or exacerbated by dysbiosis described for the first aspect of the invention are applicable to the second, third, fourth and fifth aspects of the invention.

[0131] In a specific embodiment of the invention according to any one of the embodiments of all aspects of the invention, the administration protocol of the composition of the invention is as set out in the examples below. [Example]

[0132] Certain embodiments of the present invention are described in detail below that serve to illustrate the invention without limiting its scope.

[0133] Example 1.- Periodontal dysbiosis In the mouth, periodontal disease is a late consequence of oral dysbiosis. It is often preceded by inflammation and other changes that have been understood as normal, leading to its high incidence. We see symptoms such as bleeding gums, bad breath, tooth sensitivity, and others. In the following study, the signs and symptoms of dysbiosis were investigated in a population of outpatients with a history of periodontal dysbiosis. Subjects rated the intensity of their complaints on a scale of 0 to 10 initially and after 15 days of using the assigned composition. Several compositions formulated as toothpastes (Table 2) were applied as part of the normal hygiene routine by brushing the teeth with a toothbrush for 2 minutes, three times daily, followed by a water rinse. With the exception of interdental brushing, no other oral hygiene measures were performed during the study period. Table 2 shows the qualitative and quantitative composition of each comp. Dysbiosis was analyzed and the following signs / symptoms were assessed: 1. Gum and papilla inflammation (G, PI) 2. Redness or spots (R, B) 3. Bleeding with brushing (BB) 4. Bleeding with Interdental Brushing (BIB) 5. Sensitivity (S) 6. Presence of a foul odor detectable by a third party on exhaled breath (H) 7. Tooth discoloration (TD).

[0134] [Table 2]

[0135] The results as the mean intensity of gum, papilla inflammation (G, PI), redness or staining (R, B), bleeding with brushing (BB), bleeding with interdental brushing (BIB), sensitivity (S), presence of bad breath (H), and tooth discoloration (TD), rated from 0 to 10, for five patients in each group at the beginning of the study (t = 0) and after 15 days (t = 15) are shown in Table 3. The results as the mean intensity of complaints for different signs / symptoms rated from 0 to 10 for the five patients in each group at the beginning of the study (t=0) and after 15 days (t=15) are shown in Table 3.

[0136] [Table 3]

[0137] The results as change in intensity of complaints assessed for each composition between t=0 and t=15 days are shown in Table 4.

[0138] [Table 4]

[0139] When all signs / symptoms were considered together, the mean complaint reduction 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. Therefore, when comparing the reduction in signs and symptoms associated with oral dysbiosis obtained for each composition after 15 days of use, a statistically significant effect is shown for the composition of the present invention comprising olive oil, betaine, and xylitol.Surprisingly, an unexpected synergistic effect is obtained with composition (1.a) of the present invention compared to the other compositions (1.b-1.d). Amelioration of signs or symptoms indicates restoration of a balanced microbiome, thus shifting from dysbiosis to eubiosis. Hence, the compositions of the present invention are capable of treating dysbiosis and transforming dysbiosis into eubiosis.

[0140] Additionally, to determine the relevance of the detectable presence of the periodontal pathogen P. gingivalis, patients in groups 1.a and 1.d were asked to continue using their assigned toothpaste for another 15 days. At the end of this period, periodontal probing with a commercially available test for the detection of P. gingivalis was performed according to the manufacturer's instructions (PerioPOC® by Genspeed Biotech). Also, to detect any possible flare-up of dysbiosis and as an assessment of maintenance of eubiosis, patients were asked again to answer the same questions as before (gum strength, papilla inflammation, redness or staining, bleeding with brushing, bleeding with interdental brushing, sensitivity, presence of bad breath, tooth discoloration). The results of the screening for P. gingivalis can be seen in Table 5.

[0141] [Table 5]

[0142] Regarding the symptoms and signs of dysbiosis, no relapse from eubiosis to dysbiosis was observed in the group using the composition of the present invention, and none of the symptoms improved in the control group. The outcome of sustained use of the composition of the present invention for oral periodontal dysbiosis was found to be effective in treating dysbiosis and maintaining eubiosis, whereas in the control group, the dysbiotic condition perpetuated the condition despite the possible benefits of tooth brushing.

[0143] Example 2.- Atopic Dermatitis Dysbiosis To evaluate the capacity of the compositions of the present invention to improve signs and / or symptoms associated with skin dysbiosis, the compositions of the present invention were applied to the skin of seven patients diagnosed with atopic dermatitis, aged 6 to 14 years. Signs and symptoms were assessed by the patients before product application (t=0 day) and 15 days later. Subjects marked a vertical line on a 100 mm horizontal line to indicate the intensity of their complaints (visual analog scale (VAS)). The compositions formulated as moisturizing gels (Table 6) were applied by means of gentle manual dispensing three times daily as part of the normal moisturizing procedure. No other moisturizing or cosmetic creams were applied during the study period. Signs / symptoms to be analyzed: 1.Dry skin feeling 2. Itching 3. Redness 4. Desquamation.

[0144] [Table 6]

[0145] The results as the mean intensity of complaints of the seven patients at the beginning of the study (t=0) and after 15 days (t=15) are shown in Table 7 and the % change is shown in Table 8.

[0146] [Table 7]

[0147] [Table 8]

[0148] As shown in Table 8, all tested signs and symptoms were significantly improved after 15 days of using the moisturizing gel of the composition of the present invention. All tested signs and symptoms are directly or indirectly related to the skin microbiome. The reduction of signs or symptoms indicates the restoration of a balanced microbiome, thus shifting the skin from dysbiosis to eubiosis. Therefore, the composition of the present invention can treat skin dysbiosis and transform dysbiosis into eubiosis.

[0149] Example 3.- Xeroderma Dysbiosis In the skin, scaling, dryness, and other signs of skin dysbiosis have been understood to be normal due to their high prevalence. We refer to symptoms such as dryness, itching, redness, scaling, and irritation, among others. In the following study, signs and symptoms were investigated in a population of subjects with a history of xerosis dysbiosis. Subjects marked a value on a 0-10 scale giving their subjective rating at the beginning and after 15 days of using their assigned composition.

[0150] Several compositions (Table 9) formulated as moisturizing gels were applied twice daily after showering and before bed. Signs / symptoms to be analyzed: 1. Dry skin feeling (DS) 2. Itching (I) 3. Redness (R) 4. Desquamation (DQ) 5. Stimulus Reactivity (IR) 6. Cracked Skin (CS) 7. Calmness (SS) 8. Increased Elasticity (E) 9.Humidification (H)

[0151] [Table 9]

[0152] The results as the mean intensity of the indicated signs / symptoms for each group at the beginning of the study (t=0) and after 15 days (t=15) are shown in Table 10.

[0153] [Table 10]

[0154] The reduction in the intensity of the complaints assessed for each composition (indicated as int in the table) and the increase in the beneficial effect for each composition are shown in Table 11.

[0155] [Table 11]

[0156] Finally, the mean reduction in all complaints and the mean increase in all beneficial effects after 15 days of gel use are depicted for all groups in Table 12.

[0157] [Table 12]

[0158] conclusion Complaints, including signs and symptoms of skin dysbiosis, are significantly reduced when using the composition of the present invention containing olive products, betaine, and xylitol for 15 days. Beneficial effects are improved to a much greater extent after using the gel containing olive products, betaine, and xylitol for 15 days. When comparing the reduction in complaints and beneficial improvements obtained with each composition after 15 days of use, a beneficial synergistic effect can be seen with the composition of the present invention.

[0159] Example 4.- Aphthous oral dysbiosis Aphthous oral dysbiosis was assayed in a group of patients with symptoms such as pain and ulcers associated with aphthous oral dysbiosis. Pain and aphthous or ulcer healing were measured and compared among four groups using different compositions (Table 13). The product was formulated as a gel and applied every evening before dinner and before bed until aphthous effusion had subsided. Occasional application was also permitted in case of daytime pain.

[0160] [Table 13]

[0161] Sixteen patients were included in the study and randomly divided into four groups. Three parameters were recorded: 1. Time for remission 2. Pain during oral hygiene 3. Pain during speech.

[0162] The results, as the average number of days required for aphthous relief for the four groups, are shown in Table 14. As can be seen from the table, patients using the composition containing olive oil, betaine, and xylitol experienced a mean ulcer / aphthous healing time of 2.25 days, compared to 3.25 days for the group using the olive oil and betaine composition and 5 days for the group using the xylitol composition. The control group had to wait an average of 7 days more for their ulcers to heal. These findings correlate with measurements of the average intensity of pain during oral hygiene and speaking, which were measured at the beginning of the study (t=0) and after 24 hours of product use (t=24), and are depicted in Table 15 for the four groups.

[0163] [Table 14]

[0164] [Table 15]

[0165] The compositions of the present invention have a synergistic effect in oral dysbiosis, such as aphthous oral dysbiosis, with statistically significant improvements in ulcer healing and pain management compared to other compositions. The traditional management of aphthous dysbiosis is driven by topical analgesics and antiseptics. Hyaluronic acid or / and aloe vera preparations claim barrier protection for ulcers, but are combined with antiseptics such as alcohol at high concentrations. The composition of the present invention can restore mucosal barrier function in the absence of antiseptics and has immediate pain relief. Pain ceased immediately, and ability to brush and speak was measured after 24 hours of application. The compositions of the present invention provided immediate pain relief and showed a statistically significant positive sum effect for immediate pain relief when compared to compositions with olive products and betaine, and even more so when compared to compositions with xylitol as the only active ingredient (Table 16).

[0166] [Table 16]

[0167] Example 5.-Common cold Like any other mucosa, when the lung mucosa is in eubiosis and benefits from microbiome homeostasis, it enjoys the moisturizing effect of the microbiome and its defensive barrier effect against the penetration of harmful agents, experiencing the comfort of humidification, the absence of pain, and the absence of cough. Conversely, a sense of dehydration, the presence of a dry cough, and symptoms of a cold episode are associated with the presence of dysbiosis and a microbiome shift, which increases the risk of infection or worsening of infection. Age is an initiator of dysbiosis, as the microbiome loses specificity, making older patients more vulnerable to infection. A group of patients was tested for the preventive effect of the composition of the present invention, and the subjective sensation of moisturizing the mucous membranes and the number of respiratory episodes (colds) were measured using the composition of the present invention. Nineteen nuns, with an average age of 77 years, counted the number of cold episodes that occurred during the study period using a topical gel applied to the nose, mouth, and throat with the composition of the present invention (Table 17) and compared it to the number of episodes that occurred in the previous year. They also answered the question "Do you feel that your mucous membranes are more moist now? Yes or No" (Table 18).

[0168] [Table 17]

[0169] [Table 18]

[0170] Table 19 shows the number of cold episodes experienced by the 19 nuns during the study period compared to the previous year.

[0171] [Table 19]

[0172] As shown in Table 19, the difference in the number of episodes is statistically significant. The results of this study demonstrate that use of the compositions of the present invention can significantly prevent dysbiosis and help reduce the number of colds.

[0173] Example 6.- COPD Dysbiosis In the following study, the development of altered or absent taste (geusia disorder or loss of taste) was investigated in a group of eight patients diagnosed with chronic obstructive pulmonary disease (COPD), a common pulmonary dysbiosis. The patients were divided into two groups, each treated with two different tablets: one containing a composition of the present invention containing olive fruit dried extract, betaine, and xylitol, and one with a commercially available chewable tablet containing xylitol (Tables 20a and 20b).

[0174] [Table 20]

[0175] Subjects answered the question "Do you perceive the taste of food?" before using the tablets and after using them for 5 days. The results, as responses to questions at the beginning (t=0) and five days after (t=5) of sucking three tablets per day, are shown in Table 21.

[0176] [Table 21]

[0177] Patients with taste disturbance or loss, a common symptom of mucosal dysbiosis, particularly pulmonary dysbiosis, typically suck on candies and / or lozenges to mask or improve the taste. These tablets are usually flavored and sweet. In this study, the use of commercially available tablets with high concentrations of xylitol did not help restore taste to food after 5 days. In contrast, tablets containing the composition of the present invention had a surprisingly positive outcome in restoring taste in association with COPD dysbiosis.

[0178] Example 7.-OLP Dysbiosis Oral lichen planus (OLP) is a dysbiosis that can affect either the skin, the mouth, or both. It is treated with corticosteroids. Oral hygiene during the course of the disease is painful, and in patients with OLP, the progression of periodontitis is unsuccessful and severe. Inflammation of OLP can impair feeding and hygiene. This study analyzed whether the compositions of the present invention can improve the efficacy of corticoids when used to treat OLP. Twenty patients with OLP were included in the study. Two groups of 10 patients each were divided as follows: Group 1. - Patients treated with corticosteroids and with special hygiene measures using a composition according to the invention as toothpaste (composition 7.a of Table 22). Group 2. - Patients treated with corticosteroids and hygienic measures without the composition of the invention (composition 7.b of Table 22).

[0179] [Table 22]

[0180] Treatment lasted 30 days, and a 1 to 10 scale was collected 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.

[0181] [Table 23]

[0182] As shown in Table 23, treatment combining a toothpaste containing a composition of the present invention with a corticosteroid improves the efficacy of the corticosteroid after 15 and 30 days of treatment, as less pain was recorded by patients treated with the composition of the present invention.

[0183] Example 8.- Halitosis Dysbiosis Halitosis dysbiosis results from a shift in the oral microbiome toward anaerobic bacteria, such as Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia, among others. The microbiome shift results in an environment that causes inflammation and the production of volatile sulfur compounds (VSCs) as a result of protein degradation. Some of the known VSCs are hydrogen sulfide, methyl mercaptan, and dimethyl sulfide. It has been reported that VSC levels present in patients with periodontal dysbiosis are found to be eight times greater than in patients without periodontal dysbiosis. However, halitosis dysbiosis is also found in dietary restrictions and is associated with other oral dysbiosis. This study examines the effect of different compositions on halitosis dysbiosis after four weeks of use.

[0184] material and method Twenty patients diagnosed with halitosis dysbiosis were divided into four groups, each of which used one of four compositions (Table 24) in the form of a mouth spray, spraying them twice into the oral cavity three times a day.

[0185] [Table 24]

[0186] method Oral VSC was measured using a device that measures the amount of sulfur compounds. Normal (no bad breath dysbiosis): 0 to 100 ppb Mild halitosis Dysbiosis: 101 to 150 ppb Severe bad breath Dysbiosis: 151 to 300 ppb Very strong halitosis Dysbiosis: above 300 ppb Number of subjects and measurements Twenty patients were included in the study. Initial baseline VSC scores were measured, and four groups were formed, with the patients' scores allocated without allowing statistical differences between the groups. All patients were instructed to use the assigned product for four weeks. A final score was measured at the end of the study, and comparisons were made between the groups. Two measurements were taken one after the other, and the average of the two measurements was calculated.

[0187] result The mean VSC (ppb) for each group at the beginning and end of the study is shown in Table 25.

[0188] [Table 25]

[0189] With the compositions tested, a decrease in VSC after 4 weeks was observed for composition 8.a (122.2 ppb), composition 8.b (30 ppb), and composition 8.c (39 ppb), and a slight increase was observed for composition 8.d (10 ppb).

[0190] conclusion The composition of the present invention (comp 8.a) containing xylitol, olive oil, and betaine exhibits beneficial effects on halitosis dysbiosis. Surprisingly, the composition of the present invention provides a synergistic improvement compared to compositions 8.b and 8.c, which lack xylitol and olive oil, respectively.

[0191] Example 9.- Sleep Apnea and Tooth Wear Dysbiosis As explained in the description of the present invention, the microbiome protects teeth from attack in a symbiotic state. In oral dysbiosis caused by stress, tooth wear, and sleep apnea, as well as oral dysbiosis associated with eating disorders or gastric reflux, blocking or altering the microbiome leads to tooth sensitivity and demineralization. When the microbiome is altered or altered, sensitivity, demineralization, caries, and / or tooth wear occur (for example, due to bruxism, erosion, abfraction, or attrition), and teeth begin to dissolve in acidic or extremely acidic media, and the first symptom of these dysbiosis is sensitivity.

[0192] material and method Eight patients diagnosed with sleep apnea dysbiosis and exhibiting tooth wear and irritability were recruited and divided into two groups. The first group was treated with a conventional over-the-counter sensitivity gel and a mouthwash containing a fluoride source (sodium fluoride) and potassium nitrate. While the identity of these ingredients is known, the remainder of the quantitative composition is unknown. Therefore, it is not displayed in Table 26. The second group was treated with the composition of the present invention applied as a mouthwash and a gel. The compositions for both groups are shown in Table 26. Composition 9.a is a mouthwash made from the composition of the present invention, composition 9.b is a gel made from the composition of the present invention, composition 9.c is a commercially available mouthwash, and composition 9.d is a commercially available gel. Patients applied the mouthwash for 2 minutes after brushing, three times daily, and applied the gel topically to the mouth after rinsing in the morning and before bed. Treatment lasted 15 days for both groups.

[0193] [Table 26]

[0194] method Self-reported responses to the following questions were recorded: -Can I drink cold water? -Can I eat fruit slices from the refrigerator? -Do you experience sensitivity while brushing your teeth? -Does your mouth feel moist? -Do you grind your teeth at night?

[0195] result The answers to the questions are shown in Table 27 for both the pre- and post-15 day treatment groups, with the number of subjects answering yes or no indicated.

[0196] [Table 27]

[0197] conclusion The group using the composition of the present invention had a 100% improvement in symptom outcomes, while the group using the commercial product had either no improvement (humidification) or only a 25-50% improvement (remaining symptoms).

Claims

1. 1. A composition for use in the treatment and / or prevention of signs and / or symptoms associated with atopic dermatitis dysbiosis, xeroderma dysbiosis, or oral aphthous dysbiosis, the composition comprising an olive product, trimethylglycine, and xylitol, the composition comprising 0.05% to 4.1% by weight of the olive product, the olive product being olive oil and / or olive fruit extract.

2. 1. A composition for use in treating dysgeusia (taste disturbance or loss of taste) associated with mucosal and / or pulmonary dysbiosis, or for use in preventing dehydration, dry cough and / or colds associated with dysbiosis, the composition comprising an olive product, trimethylglycine and xylitol, the composition comprising 0.05% to 4.1% by weight of the olive product, the olive product being olive oil and / or olive fruit extract.

3. 3. The composition according to claim 1, wherein the olive fruit extract is a dried olive fruit extract and / or an olive fruit extract liquid.

4. the olive fruit extract contains at least 20% w / w hydroxytyrosol, and / or The composition of any one of claims 1 to 3, wherein the olive oil is extra virgin olive oil, virgin olive oil, or a combination thereof.

5. the composition comprises between 0.05% and 2.6% by weight of olive products; and / or the composition comprises 0.1% to 10% by weight of trimethylglycine, and / or The composition of any one of claims 1 to 4, wherein the composition comprises from 1% to 20% by weight of xylitol.

6. 6. The composition according to any one of claims 1 to 5, comprising 0.05% to 0.1% by weight of olive fruit extract and / or 0.2% to 2.5% by weight of olive oil.

7. The composition according to any one of claims 1 to 6, wherein the composition further comprises an antioxidant and / or a vitamin.

8. 8. The composition of claim 7, wherein the antioxidant is selected from hydroxytyrosol, tyrosol, oleuropein, and mixtures thereof.

9. 9. The composition of any one of claims 1 to 8, wherein the composition is formulated as a facial and / or body moisturizer, deodorant cream, regenerative barrier cream, body gel, shampoo, hair conditioner, hair lotion, skin ampoule, tonic, capsule, tablet, spray, gel, lubricating gel, topical vulvar gel, toothpaste, mouthwash, chewing gum, chewable tablet, suckable capsule, suckable lozenge, palate sheet, candy, impregnated oral swab, impregnated oral gauze, lipstick, balm, intranasal inhalant, intranasal spray, intranasal aerosol, intranasal gel, oropharyngeal syrup, oropharyngeal gel, or aerosol capsule.

10. The composition of any one of claims 1 to 9, wherein the composition comprises olive products, trimethylglycine, and xylitol as the only active ingredients.

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