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, to the use of said composition for preparing a medicament for the prevention and / or treatment of dysbiosis, and further to a method for preventing and / or treating dysbiosis, wherein said composition is administered to a subject in need thereof.

Description

Technical Field

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

Background Art

[0002] Microbiome and microbiota are sometimes used as similar terms. Microbiota means a set of microorganisms composed of bacteria, fungi, archaea, viruses, and parasites that live in or on our body, and microbiome is a broader term that refers to the entire habitat that includes 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 scaffold of the biofilm and, in the view of the inventors, is the key to the onset of dysbiosis and the restoration of health (eubiotic). This scaffold not only has chemical properties, but it also physically contributes to the shape of this microcosm and provides protection from environmental assaults (especially changes in humidity, pH shifts, temperature fluctuations, disinfectants, antibacterial agents, stress). Ideally, it should also house the necessities for cell activity, namely water and nutrients, and limit the penetration of harmful factors.

[0003] Biofilm is understood as a specific microbiota and its ecosystem that live on different parts of the body attached to a specifically structured surface in three dimensions. Examples of biofilms are oral, dental, skin, and vaginal biofilms.

[0004] The microbiome gradually establishes itself inside or on the body surface through childbirth, depending on the delivery route (vaginal or cesarean section), the mother's microbiome, nutritional type, geography, habits, psychology, and lifestyle. It bestows individual characteristics upon the host, establishing a bidirectional dialogue between the host and the microbiome, and vice versa. It is well known that lifestyle, stress, education, personality, age, geography, and climate alter the microbiome and its ecosystem, and at the same time, the microbiome can alter the ecosystem, and from there, ultimately, the individual. Drugs, tobacco, as well as alcohol, stress, wounds, mouth breathing, sleep apnea, eating disorders, and other systemic diseases, such as cancer and diabetes in particular, have a negative impact on the microbiome of the mucous membranes of the body in different parts of the body, 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 tubules leading to the outside, primarily the membranes of the respiratory, digestive, and urogenital systems. These include, among others, the mouth, nose, eyelids, trachea, lungs, stomach, intestines, ureters, urethra, vagina, and the connections between different locations. The body's mucous membranes line all blood vessels and organs, sharing common histological features and mucus secretion, which acts as a barrier and is adapted to different sites (papillae, microvilli, etc.). The skin throughout the body also exhibits common histological features and possesses barrier functions with several adaptive specificities depending on its location (hair, sweat glands, etc.). Mucous membranes and skin are the largest microbiome habitats and are most susceptible to microbiome imbalances or dysbiosis connecting 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 oro-gut axis, oro-liver axis, oro-lung axis, oro-gut-liver axis, oro-brain axis, oro-cardiovascular axis, gut-lung axis, gut-cutaneous axis, oro-joint axis, oro-mammary axis (Lira-Junior & Bostrom, 2018), and the oro-cutaneous axis, which is newly described herein (see below).

[0007] Regarding the oral-lung axis, periodontitis dysbiosis as a source of inflammatory mediators has been linked to the exacerbation of lung disease (Paju & Scannapieco, 2007). Growing evidence regarding the role of the lung microbiome and its impact on the progression and severity of lung disease is being studied in various groups, including pneumonia, the common cold, influenza, cystic fibrosis, pulmonary fibrosis, and chronic obstructive pulmonary disease (COPD).

[0008] Evidence of a gut-skin axis linking inflammatory skin diseases associated with gut microbiome imbalance has so far been used to translate research into recognition of the potential benefits of probiotics for improving skin conditions through the gut microbiome (Atarashi, Wataru, & Chengwei, 2017). Transplantation measures have recently emerged from attempts to replicate this microbiome from a healthy individual (donor) to a diseased target (receptor). Similarly, some clinicians advocate for skin microbiome transplantation from healthy subjects to improve the symptoms and clinical course of atopic dermatitis as an alternative to antibiotics against the pathogen S. aureus. Unfortunately, microbiome transplantation therapy appears to require further development, seems like an expensive approach, has so far few practical applications left in a hospital setting, and seems far from becoming a routine practice.

[0009] To date, attempts to correct dysbiotic microbiome hazards through replacement or transplantation (probiotics) or eradication (antibiotic therapy) have demonstrated uncertain safety and efficacy issues. Therefore, there remains a need for improved treatments for the prevention and management 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 [Overview of the Initiative] [Means for solving the problem]

[0011] The first aspect of the present invention relates to a composition comprising an olive product, betaine, and xylitol for use in preventing and / or treating dysbiosis, wherein the olive product is olive oil and / or olive fruit extract.

[0012] The second aspect of the present invention relates to the use of a composition comprising an olive product, betaine, and xylitol for the preparation of a medicament for preventing and / or treating dysbiosis, wherein the olive product is olive oil and / or olive fruit extract.

[0013] The 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] The fourth aspect of the present invention relates to a method of preventing dysbiosis in a subject, which comprises 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] The fifth aspect of the present 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 humidification 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 be apparent to those skilled in the art from the following description and the appended claims.

Brief Description of the Drawings

[0017] [Figure 1] A schematic drawing of the skin and mucosal (oral mucosa) structures highlighting the similarities and parallels between the skin and mucous membranes. [Figure 2]A microbiome dynamics model of eubiosis and dysbiosis. Ecosystems are part of the microbiome's self-healing cycle to promote symbiosis (health) and prevent dysbiosis (disease), but they are also actors in the vicious cycle of the microbiome that perpetuates dysbiosis. [Figure 3] Microbiome dynamics according to the composition of the present invention. The composition of the present invention enhances ecosystem resilience and promotes a healthy environment, microbial balance, and eubiosis. [Modes for carrying out the invention]

[0018] Unless the context explicitly indicates otherwise, the singular forms “a,” “an,” and “the” as used herein encompass their corresponding plural forms. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by practitioners of the art to which this invention belongs. To facilitate the understanding of certain terms in the context of this invention and to clarify their meaning, the following definitions and specific and preferred embodiments thereof are provided, applicable to all embodiments of different aspects of this invention.

[0019] As used herein, “microbiome” refers to both the microorganisms that live persistently and transiently within and on the surface of the human body, as well as their genetic content, encompassing eukaryotes, archaea, bacteria, and viruses (including bacterial viruses (i.e., phages)). “Genetic content” includes genomic DNA, RNA, e.g., ribosomal RNA, epigenome, plasmids, and all other types of genetic information. A healthy microbiome provides the host with several benefits, including resistance to colonization of a broad spectrum of pathogens, essential nutrient biosynthesis and absorption, and immune stimulation that maintains healthy epithelium and appropriately 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 contrast to eubiosis, dysbiosis occurs as a result of a loss of balance within the microbiome, caused by either a shift in the microbial flora or a change in the microbiome ecosystem.

[0021] "Dysbiosis" refers to a state of the microbiome in any area of ​​the body, including mucous membranes and skin surfaces, where the normal diversity or function of the ecological network is disrupted. Therefore, in specific embodiments, dysbiosis may be mucosal dysbiosis, cutaneous dysbiosis, or a combination thereof. Any disruption of the microbiome from a favorable (e.g., ideal, normal) state may be considered dysbiosis, even if such dysbiosis does not result in a detectable decrease in health. This state of dysbiosis may be unhealthy, it may be unhealthy only under certain conditions, or it may prevent the subject from becoming healthier. Dysbiosis may simultaneously be a cause or consequence of disease, and may exacerbate and / or worsen the course of disease. Dysbiosis may be caused by reduced diversity, excessive growth of one or more pathogens or pathogenics, symbionts that can cause disease only when certain genetic or environmental conditions are present in the patient, or a shift to an ecological network that no longer provides beneficial functions to the host and thus no longer promotes health. Dysbiosis can be induced by disease (diabetes, cancer, infection, obesity, depression), treatment with active substances (e.g., antibiotics, e.g., antibiotics that reduce the normal flora) (e.g., abuse), or other environmental factors (pH changes, inflammation, diet, medications).

[0022] In a state of "dysbiosis" or disrupted symbiosis, microbiome function is lost or disrupted, which can lead to increased susceptibility to pathogens, a mutated metabolic profile, or induction of pro-inflammatory signals that may result in localized or systemic inflammation or autoimmunity.

[0023] In a specific embodiment according to any one aspect of the present invention, the dysbiosis is selected from mucosal dysbiosis, cutaneous dysbiosis, or a combination thereof.

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

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

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

[0027] "Vaginal dysbiosis" refers to a condition called vaginitis.

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

[0029] The term “prevent” or “prevention” means to prevent, delay, and / or reduce the severity of a disease and / or signs and / or symptoms associated with the disease.

[0030] "Prophylactically effective dose" means the amount delivered that, when delivered, prevents, delays, and / or reduces the severity of the disease and / or signs and / or symptoms associated with the disease.

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

[0032] "Therapeutic dose" refers to the amount that is effective in reducing or eliminating a disease and / or signs and / or symptoms associated with the disease.

[0033] Specifically, in this invention, a disease is a dysbiosis, or a condition exacerbated or worsened by dysbiosis.

[0034] The Human Oral Microbiome Database (HOMD) describes oral taxons and phyla, strains, reaching nearly 620 taxons. Of these, 65% have been cultured to date, compared to barely 1% in other parts of the body. Firmicutes, Bacteroidetes, Proteobacteria, Actinobacteria, Spirochetes, and Fusobacteria account for 95%. In the skin, the four dominant phyla are Actinobacteria, Proteobacteria, Firmicutes, and Bacteroidetes. Both the skin and the oral cavity exhibit diverse topographic populations associated with different microenvironments. In the mouth, the palatal and lingual surfaces of the teeth are referred to as subgingival or buccal or lingual, respectively, due to their parallelism with the oily environment of the upper part of the body to the phyla of the skin, which have greater diversity in the stratified and lower parts of the body. Both the skin and oral cavity exhibit high geomorphological diversity determined by the environment, as previously mentioned, and show high temporal variability within individuals, but are fairly stable throughout an individual's lifetime. The abundances that have attracted attention from many researchers in recent years are now considered only relative markers of disease, because every individual will likely exhibit Staphylococcus, Propionibacterium, and Corynebacterium in the skin, and Streptococcus mutans and Porphyromonas gingivalis in the mouth. Current research supports the idea that applying pressure to a Firmicutes phylum inhabiting either the skin (Streptococcus epidermidis) or the mouth (Streptococcus mutans) makes it possible for another Firmicutes of the Staphylococcus phylum to exploit the inflammatory state to penetrate the skin. In the mouth, the shift imposed by anticarious agents that reduce the Streptococcus mutans population will lead to a decrease in acidic metabolites from these bacteria, enhancing the increase in pH. This will be exploited by sugar-non-degrading bacteria that prefer higher pH and lower oxygen gradients, meaning anaerobic subgingival Gram-negative bacteria that lead to periodontitis.Periodontitis is commonly associated with Staphylococcus permeation 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. Twenty to 35 percent of OLP patients also have lesions on the skin, scalp, and / or vagina.

[0035] The most common microbiome in the oral cavity consists of Streptococcus, Lactobacillus, and Prevotella. Respiratory bacterial analysis of patients with pneumonia at risk of aspiration has shown that oral Streptococcus is 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 are in different compartments along the entire length of both tissues. For symbiotic, dualistic host-microbe interactions, a minimal separation between the microbiome and host epithelial cells is required. When the skin or mucous membrane is blocked, as seen in wounds or inflammatory conditions, the mechanism leads to a dysbiotic relationship between the host and microbiome, resulting not only in a world of dysbiotic inflammatory diseases but ultimately even carcinogenesis. Today, oral studies are consistent with the finding that oral dysbiosis and dysbiotic biofilms are behind common, highly prevalent diseases such as caries and periodontitis. In the view of the researchers, teeth, insofar as they are symbiotic, possess their own microbiome that protects them from attack. At the same time, teeth themselves, when healthy, are a barrier against the maxilla from the moment they penetrate the oral mucosa during eruption. Barrier function is essential for human survival, so when teeth are eventually lost, the mucous membrane takes their place and fills the gap. As previously stated about skin and mucous membranes, teeth and their microbiomes are both in different compartments that are physically and chemically attached to each other, and the integrity of both compartments is essential for health and barrier function. When the microbiome is damaged because, for example, the separation and integrity of both compartments is lost, blocked, or disappears, a new dysbiotic relationship between the host and the microbiome leads to a non-symbiotic inflammatory state (periodontitis dysbiosis) and / or increased tooth permeability (hypersensitivity, demineralization, and loss of tooth structure). When this microbiome is lost, blocked, or damaged, the tooth barrier is lost. Hypersensitivity, demineralization, caries, and toothwear of either physical, chemical, or mixed origins (bruxism, acid erosion, abfraction, attrition) occur. A blocked microbiome barrier ceases to act as a lipophilic shield, and teeth begin to dissolve in acidic or extremely acidic media. Every mouth is different.Tooth mineral content and enamel thickness also vary from person to person. Other variables, such as salivary flow and salivary mineral saturation, together explain why some teeth will be more resistant than others, a point known as critical pH (Dawes, 2003). In vitro conditions ignore living microorganisms and their ecosystems. These, too, can be large reservoirs of minerals, water, peptides, and the metabolism they possess that stop and prevent human teeth from dissolving. This theory is supported by the fact that in the absence of plaque, even stimulating saliva would not be able to promote mineral accumulation. In our view, a dysbiotic microbiome makes efforts to remineralize teeth by stimulating saliva or by supplementing with minerals or remineralizers fruitless, as some authors have begun to explore (Lussi & Carvalho, The future of fluorides, 2015). When teeth are physically rubbed and worn down, the initially hidden dentin is exposed, so the habitat is altered and provides modified support to the microbiome.

[0037] The greater the tooth wear and tooth structure loss, the more extensive the attack on the oral microbiome, which finds flatter and more altered tooth surfaces for attachment. In advanced cases of tooth wear, the interdental areas follow the disappearance of all occlusal surfaces and have loss of specific microbiome habitats. Finally, chewing is impaired, leading to a shift towards softer foods 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 plaque or dental biofilm by means of biocides, disinfectants, or chemical or physical debridement has not proven effective in eliminating caries behind periodontal conditions such as gingivitis or periodontitis and premature tooth loss. The growing number of patients treated with dental implants has given rise to a new condition called peri-implantitis. Implants lacking a thick mucosal barrier, placed in areas of non-keratinized gingiva, exhibit the potential for certain peri-implantitis dysbiosis that cannot be prevented or treated with antibiotics. The rapidly growing group of patients with prostheses or dental restorations, and patients undergoing orthodontic treatment, may also suffer from oral dysbiosis as a consequence of an unbalanced microbiome resulting from habitat changes imposed by artificial materials.

[0039] The skin, like the oral cavity, is a habitat for a large microbiome with specific microflora for different skin types and areas. Skin exhibits high desquamation and cellular renewal rates, similar to mucous membranes. Depending on the degree of oily or watery secretion, we can identify three different skin types: - Oily areas include the scalp, forehead, back, creases behind the ears, and nasal folds. - Moist areas include the armpits, groin folds, buttock folds, soles of the feet, popliteal fossa, and elbow fossa. - The dry areas include the forearms, buttocks, and various parts of the hands.

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

[0041] Among the everyday attacks on the skin, alcohol and cleansing agents from soaps and creams can damage the integrity of the epidermal barrier by removing lipids, among other mechanisms. This promotes the colonization of several harmful bacteria (Staphylococcus aureus). This is true in atopic dermatitis, where, during inflammation, bacterial colonization triggers a shift to low-diversity species incompatible with healthy skin. A similar situation applies to psoriasis.

[0042] There are links between several medical conditions, such as chronic inflammatory states and cancer, and both the mucosal and skin microbiomes. In chronic inflammatory states like type II diabetes, the oral and skin microbiomes are not only involved in the pathology and course of this complex metabolic state, but there is also evidence that diabetes alters the environment of the oral, skin, and gut microbiomes, leading to an increasing establishment of diabetic dysbiosis. Diabetic oral dysbiosis progresses to a higher caries risk, a higher prevalence and severity of periodontitis, while diabetic cutaneous dysbiosis progresses to foot ulceration, decreased skin elasticity, reduced sebaceous gland activity, and a less lipid-rich cloak.

[0043] Furthermore, the skin and oral microbiome are associated with carcinogenic 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 reassembles a cohort of signs and symptoms that have a low incidence but a high negative impact on quality of life. Cancer oral dysbiosis has a striking similarity to the skin, particularly characterized by one, some, or all of the following: burning in the mouth, altered taste (altered flavor), high fracture rate, high caries rate, angular cheilosis (cracks at the corners of the mouth), mouth pain, and even feeding difficulties. Cancer cutaneous dysbiosis is characterized by one, some, or all of the following: burning in the mouth, altered palpability, high crack rate, paronychia, pain, and one, some, or all of the following functional impairments, particularly affecting the skin of the distal parts of the body, mainly the hands and feet, but also the skin of the back, legs, and torso.

[0044] The oral mucosa, like any other mucous membrane in the body, is similar in many ways to the skin. The oral mucosa consists of two distinct layers: stratified squamous epithelium and the lamina propria mucosa. In some parts of the oral cavity, the oral mucosa is attached to the underlying structure by a submucosa of loose connective tissue components. These three layers are analogous to the epidermis, dermis, and subcutaneous tissue layers of the skin (see Figure 1). In fact, conditions such as lichen planus and pemphigus affect both the skin and the oral mucosa. Therefore, in this invention, they are embodiments of both oral dysbiosis and cutaneous dysbiosis.

[0045] Pulmonary dysbiosis follows a disruption of the pulmonary microbiome, which leads to a loss of homeostasis and the initiation of dysbiosis. The most common initiators of pulmonary dysbiosis are, among other things, 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, infection and diabetes, obesity, and aging. Interestingly, a decrease in the diversity and specificity of the microbiome of different microenvironments within the body is found in aging populations, explaining the increased vulnerability in aging associated with a loss of biodiversity.

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

[0047] With all the above in mind, in specific embodiments of any aspect of the present 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, toothwear dysbiosis, diabetic oral dysbiosis, cancer oral dysbiosis, and combinations thereof. Preferably, oral dysbiosis is selected from caries dysbiosis, toothwear dysbiosis, periodontal dysbiosis, aphthous dysbiosis, peri-implantitis dysbiosis, sleep apnea dysbiosis, diabetic oral dysbiosis, cancer oral dysbiosis, and combinations thereof.

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

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

[0050] In specific embodiments, 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, respiratory infection is selected from the group consisting of the common cold, pneumonia, influenza, and coronavirus SARS-CoV-2 disease (Covid-19). Therefore, in specific embodiments according to the present invention, pulmonary dysbiosis is common cold dysbiosis, pneumonia dysbiosis, influenza dysbiosis, or coronavirus SARS-CoV-2 dysbiosis.

[0051] In specific embodiments of the present invention, oral dysbiosis is evaluated by clinical parameters (signs and symptoms), e.g.: gingival bleeding upon interdental brushing, tooth sensitivity, presence of inflamed gums or inflamed papillae, malodor associated with dysbiosis, tooth discoloration, toothwear (acid erosion, attrition, bruxism) and / or caries, mucosal desquamation, mucosal dehydration, ulceration, aphthous ulcers, pain, taste disturbance (altered or absent taste), lack of elasticity, and peri-implantitis. Similarly, cutaneous dysbiosis is evaluated by clinical parameters, e.g.: dry skin, itchiness, redness, desquamation, ulceration, pain, bleeding, lack of elasticity, lack of tactile sensitivity (modified or absent tactile sensation), and blistering or vesicles after sun exposure.

[0052] In another specific embodiment of the present invention, pulmonary dysbiosis is evaluated by clinical parameters such as sputum, runny nose, congestion, conjunctivitis, headache, muscle pain, dull ache and pain, cough, dryness, sore throat, irritation, hoarseness, taste disturbances—loss of taste, anosmia, impaired oxygenation levels, chest pain or pressure, shortness of breath, difficulty breathing, and / or fever.

[0053] The complex reality of Covid-19 remains largely unknown, both in its origin and treatment. However, growing evidence of the role of the mutated microbiome in the course of the disease offers new perspectives for both prevention and treatment. The reduction in bacterial diversity found in Covid-19 patients compared to healthy subjects, coupled with the fact that parallel and simultaneous re-establishment of the upper respiratory tract and gut microbiome occurs in most mild Covid-19 patients, supports the theory of dysbiosis associated with coronavirus disease affecting beyond the lungs. Furthermore, the reduced diversity in most of the microbiome environments of older individuals inherent in aging may finally explain the rapid progression to severe disease and the high rate of fatal outcomes in Covid-19. In the view of the researchers, coronavirus dysbiosis exploits the disruption of the microbiome, which allows for intrusion from the mucous membranes of the lungs to other mucous membranes such as the digestive system, but also into the skin, as exemplified by 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 continuously being updated. In any case, in this invention, Covid-19 dysbiosis is considered a specific embodiment of pulmonary dysbiosis, because it was originally described as a respiratory infection.

[0054] Note the order listed above, the signs and symptoms of coronavirus dysbiosis are: in the mouth, dry mouth, loss or absence of taste, vesicular lesions, aphthous lesions, loss or absence of smell; in the upper respiratory tract and lungs, dry cough, voice changes, 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 present invention") for use in the prevention and / or treatment of dysbiosis. In light of Example 7, it also relates to the composition of the present invention for use as an adjuvant for 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, although for other unrelated uses. See, for example, EP2119477A1 and WO2019 / 025366A1. Specifically, the composition of EP2119477 can be used in the treatment of xerostomia. Nothing in the prior art suggests that adequate salivary function will prevent dysbiosis from occurring, nor that patients without xerostomia are not at risk of dysbiosis. Sufficient saliva production is not a guarantee of eubiosis. Otherwise, caries, periodontitis, and other oral dysbiosis would be prevented by normal salivary flow. In fact, nothing is written about the preventive effect of salivary flow in the most prevalent oral dysbiosis, periodontitis. The reverse is also true; patients with xerostomia do not show a higher risk of periodontitis. Similarly, patients with eating disorders or gastroesophageal reflux disease experience compensatory salivary overflow, but still suffer from easily recognizable toothwear oral dysbiosis consisting of the disruption of the tooth biofilm, firstly on the lingual surface of the teeth, secondly on the occlusal surface (masticatory surface), and finally on the buccal surface. The teeth eventually lose all their lipophilic content, weakening the barrier effect that this tooth biofilm should provide and leading to tooth destruction. This cannot be relieved by any type of mouthguard.

[0057] The composition of WO2019 / 025366A1 may be used for the treatment of oral gastrointestinal mucositis (OTIOM), a life-threatening condition induced by oncological treatment in cancer patients undergoing either chemotherapy and / or radiotherapy. This OTIOM differs from oral and cutaneous dysbiosis in that it is self-limiting, does not affect the skin or teeth, and is not associated with any microbiome or pathogen of any origin. It is an acute blockade of toxicity of the oral gastrointestinal mucosa, which is the single most feared complication of cancer treatment, and is not treated with antibiotics, probiotics, or prebiotics. In fact, probiotics are absolutely contraindicated during OTIOM due to the high risk of sepsis.

[0058] Interestingly, as the examples show, the compositions of the present invention, comprising olive products, betaine, and xylitol, have novel medical uses as they are useful for the prevention and / or treatment of dysbiosis. Surprisingly, the compositions comprising olive products, betaine, and xylitol exhibit unexpected synergistic effects compared to compositions comprising only one of the aforementioned components or a combination of olive products and betaine (see Examples 1, 3, 4, and 8). Moreover, different examples demonstrate the usefulness of the compositions of the present invention for the treatment and / or prevention of both mucosal dysbiosis and cutaneous dysbiosis.

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

[0060] In specific embodiments according to the first aspect of the present invention, the olive product is selected from olive oil, olive fruit extract, and mixtures thereof. The olive fruit extract may be olive fruit extract (also known as olive fruit liquid extract), olive fruit dry extract (also known as olive fruit dry powder extract), or a mixture thereof. 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, methods for extracting from olive fruit are well known. Examples of such methods are disclosed in WO2008142178A1 and ES2051238A1. In specific embodiments, 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, among others, from Nutexa Inc. and Natac.

[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 either an aqueous solution or a powder in any of its dosage forms. In a specific embodiment according to any one of the preceding embodiments, betaine may be trimethylglycine (TMG), cocamidopropyl betaine, dimethylamine betaine, alkyl (C 12 -C 18 ) Amidobetaine, alkyl (C8-C 18 The betaine is selected from the group consisting of betaine, amide betaine, alkylamide betaine, 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 chosen 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 is publicly reported to be irritating, with a pungent taste and a barrier-breaking effect on keratin integrity due to increased transepidermal water loss (TEWL) after topical application to the skin in subjects with or without atopic dermatitis. On the skin, olive oil is claimed to cause contact dermatitis and has anti-inflammatory benefits but also irritating side effects, resulting in barrier-breaking consequences. Betaine, commonly used in mouthwashes due to its disinfectant activity, carries the risk of disrupting the healthy balance of biofilms when used for two weeks.

[0065] Xylitol is a well-known anti-carcinogenic ingredient and is increasingly being introduced to consumers. Xylitol has demonstrated anti-Streptococcus activity, particularly 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 microbiome and have not shown evidence of previously established caries-related or caries-protective organisms after the use of either xylitol or sorbitol. This is a new controversy regarding the dental benefits of xylitol. Interestingly, when incorporated into oral hygiene compositions, a proven reduction in the anti-plaque effect of xylitol has been found when it is combined with other minerals and salts that have remineralizing potential. Despite the potential beneficial effects of xylitol for humans when consumed orally in high percentages or over extended periods (though highly toxic to animals), subsequent digestive disturbances (swelling, diarrhea) can be a marker of undesirable gut microbiome imbalance, which returns to homeostasis upon discontinuation of intake (Storey, Lee, & Bornet, 2007). High concentrations of xylitol are also undesirable in cutaneous dysbiosis and / or vaginal dysbiosis (vaginosis) because it can shift Bacillus (Lactobacillus) and Streptococcus and Staphylococcus type phyla. Surprisingly, the compositions of the present invention do not exhibit any of these harmful effects. In fact, the compositions of the present invention retain hydrophilic and lipophilic bacteria without exercising the antimicrobial properties of olive oil, betaine, and xylitol alone.

[0066] The compositions of the present invention have been found to be effective in preventing mucosal and skin dysbiosis by forming a 3D structure that helps maintain the existing microbiome when hazards arise, when applied topically.

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

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

[0069] The concept of epithelial homeostasis explains that the continuous replacement of cells through desquamation of more superficial cells has both a positive effect of limiting microbial colonization and a negative effect of partial loss of the indigenous microbiome.

[0070] However, these living microorganisms require their respective ecosystems to establish themselves.

[0071] Researchers intended to identify the beneficial bacteria behind health and, conversely, the populations behind disease. Unfortunately, this simplification proved incorrect, as the same bacterial types were found in different proportions in diseased individuals and controls. It has not yet been concluded that a shift in the microbiome is the origin of the disease itself. A more related relationship than a causal one is suspected, with the latter being dominant in infectious conditions. In other words, certain microbiomes in disease appear to be more related than simply originating from the condition itself.

[0072] In nature, ecological changes in a habitat begin, followed by either adaptation or extinction of certain species. Attempting to maintain a stable microbiome by acting through the microbial community has so far yielded controversial results. The inventors of this invention view ecosystems as the primary recipients of damage. This, in turn, causes microbial shifts that themselves are the cause of environmental change. This is illustrated by what the inventors define as a microbiome dynamics model of eubiosis and dysbiosis (Figure 2).

[0073] Human evolution has led to a natural symbiosis or eubiosis where health is the norm. However, when dysbiosis emerges, non-symbiotic microbial communities, along with the mutated ecosystem, perpetuate vicious cycles such as obesity or depression. Both entities are now understood in relation to the dysbiotic microbiome, along with the frustrating resistance to both diet and psychotherapy.

[0074] Our bodies are constantly exposed to everyday threats, specifically stress, pollution, hyperconnectivity, Wi-Fi, chemicals, disinfectants, antibiotics, drugs, cleansers, radiation, oxidative stress, infectious pathogens, fast food, oral and skin hygiene, shampoos, feminine hygiene, wounds, eating disorders, mouth breathing, sleep apnea, and systemic and chronic conditions that impact our microbiome.

[0075] Certain individuals lack the necessary internal or external conditions to restore their microbiome, and therefore develop disease. Once the microbiome shifts, rebuilding a healthy bacterial population 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 the support for a healthy environment ecosystem. Our approach is to enhance environmental conditions and ecosystems that are favorable for maintaining and re-establishing a healthy microbiome, whatever the site. The compositions enhance specific microbiome compartments, as it has still been impossible to identify one or more microorganisms that have a causal relationship with most of the conditions and diseases studied so far. Improving the human microbiome through ecosystem compartments is less site-specific, as illustrated by the example. This mechanism is schematically depicted in Figure 3.

[0076] In a specific embodiment following any one of the preceding embodiments, the composition does not contain any other vegetable oils. More specifically, it does not contain parsley oil. Thus, the use of lower quality oils, such as palm oil, is avoided. However, the composition may contain essential oils. Therefore, in a specific embodiment, with the exception of essential oils, the composition does not contain any other vegetable oils.

[0077] In a specific embodiment following any one of the preceding embodiments, the composition contains 0.05% to 5.1% by weight of olive products, preferably 0.05% to 4.1%, more preferably 0.05% to 2.6% of olive products. Preferably, when the olive products are or contain olive fruit extract, the composition contains 0.05% to 0.1% of olive fruit extract, and when the olive products are or contain olive oil, the composition contains 0.1% to 5%, more preferably 0.1% to 4%, and even more preferably 0.2% to 2.5% of olive oil.

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

[0079] In another specific embodiment following any one of the preceding embodiments, the composition comprises xylitol, preferably 1% to 20% by weight, more preferably 1% to 15%. Advantageously, at lower 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 terms of weight per unit weight (w / w) of the total composition.

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

[0082] In specific embodiments following 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 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 further preservatives, which would make the formulation more tolerable depending on the subject). Therefore, in preferred embodiments, 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 includes all the components necessary to provide the desired functional and rheological form. Therefore, in a specific embodiment following any one of the preceding embodiments, the composition further includes one or more components selected from the group consisting of: remineralizers, viscosity modifiers, humectants, preservatives, colorants, pH adjusters (buffers), sweeteners, emulsifiers, proteolytic enzymes, whitening agents, probiotics, abrasives, essential oils, scar-forming agents, aromas, animal or plant gelatin, rheological agents, solvents, excipients, and combinations thereof.

[0084] These further components of the compositions of the present invention are commonly known to those skilled in the art, and non-limiting examples of the compounds are given below. In specific embodiments according to any one of the preceding embodiments, these compounds are selected from the following examples: Remineralizers may be selected from fluoride anions, phosphate anions, calcium cations, potassium cations, and mixtures thereof. Rheological agents may be selected from the group consisting of gum arabic, tragacanth gum, xanthan gum, carboxymethylcellulose, carbopol-type polymers, pectin, mucin, and mixtures thereof. Humectants may be selected from the group consisting of glycerin, propylene glycol, sorbitol, and mixtures thereof, preferably glycerin. Preservatives may be selected from the group consisting of sodium benzoate, potassium sorbate, benzoic acid, diazolidinyl urea, imidazolinyl urea, sodium methylparaben, sodium propylparaben, and mixtures thereof. Sweeteners 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. Emulsifiers 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 toothpaste for general use and multiple serious direct side effects in distant parts of the body. Multi-institutional university animal studies have shown that triclosan, widely used in oral care products, is detected in the blood upon oral application and is directly associated with several pathological conditions, particularly colitis, inflammatory changes in the intestines, and colon cancer, the most common form of cancer (Yang, Wang, & Romano, 2018). While the authors of the study acknowledge the peculiarities of animal-human translational research, they are warning medical and health authorities and experts because they outline that the results obtained in the studies occurred after small exposures to triclosan, which humans use extensively for oral hygiene three times a day over a long lifespan.

[0086] While antifungal agents have proven effective in treating dandruff, they cannot prevent re-establishment by yeast after several weeks. However, the compositions of the present invention can enhance the microbial balance by providing the necessary conditions for scalp microhabitats, which will help prevent significant establishment by pathogenic microorganisms such as yeast from the Malassezia genus.

[0087] Therefore, in specific embodiments according to any of the preceding embodiments, the composition of the present invention does not contain any additional active ingredients (e.g., antibiotics, antifungal agents). Specifically, it does not contain triclosan.

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

[0089] [Table 1]

[0090] Remarkably, the composition of the present invention maintains its beneficial effects regardless of the pH required for different skin and / or mucous membrane locations.

[0091] Those skilled in the art may formulate the compositions of the present invention in any preferred dosage form that allows for simple use for the prevention and / or treatment of dysbiosis. In specific embodiments according to any one of the preceding embodiments, the compositions are formulated as facial and / or body moisturizers, deodorant creams, regenerative barrier creams, body gels, shampoos, hair conditioners, hair lotions, skin ampoules, tonics, capsules, tablets, sprays, gels, lubricating gels, topical gels for the vulva, intranasal inhalants, intranasal sprays, aerosol solutions, aerosol sprays, aerosol capsules, toothpaste, mouthwash, chewing gum, chewable tablets, lickable capsules, lickable lozenges, palatal sheets, candies, impregnated oral swabs, impregnated oral gauze, lipsticks, and balms.

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

[0093] Dried olive fruit extract is preferred for lozenge or pastille formulations, olive oil, preferably EVOO, and liquid or dried fruit extract are preferred sources of olive products for formulations 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 source of olive products, having hydroxytyrosol due to its potent antioxidant properties and having an olive fruit flavor (without a tingling taste). Recurrent aphthous ulcers (RAU) benefit from preventive hygiene using the same approach in the form of toothpaste, which may also have remineralizing agents, natural non-irritating flavors, vitamins, and other necessities 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- and toothwear oral dysbiosis, as well as sleep apnea oral dysbiosis and oral dysbiosis associated with eating disorders or gastric reflux, the gel is formulated to be applied topically to oral tissues, ideally several times a day, after oral hygiene, especially before bedtime and upon waking.

[0094] The compositions of the present invention for preventing or treating pulmonary dysbiosis may be administered by any known route of administration. Examples, not limited to, include liquid dosage forms for intranasal inhalants, intranasal sprays, intranasal aerosols, intranasal gels, oropharyngeal syrups, and oropharyngeal gels, as well as solid dosage forms such as aerosol capsules.

[0095] The compositions of the present invention may 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 mucous membrane and skin microbiota whenever a hazard threatens the natural and healthy microbiome (i.e., hygiene with caustic products or alcohol, cleaning agents, etc.).

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

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

[0099] For example, some areas of the skin are oilier, more moist, or drier than others. Care and hygiene products should be adapted to these characteristics.

[0100] In the same sense, just as oral and vaginal products are very different from each other, different products will be adapted to different mucous membranes. In specific embodiments, when a cleansing agent is incorporated for hygiene, as seen in the examples, the compositions of the present invention continue to deliver beneficial effects to the ecosystem and restore eubiosis. In dosage forms incorporating a whitening ingredient for either teeth or skin, the compositions of the present invention exert beneficial activity on its microbiome and also reduce the possible irritation, desquamation, or sensitivity effects of the whitening ingredient.

[0101] On the human body surface, the microbiome exhibits several specific characteristics and is adapted to different habitats. According to the Human Microbiome Project, there are distinct microbial communities among 10 different specific sites within the digestive tract, such as the buccal, gingiva, and hard palate (Group 1), as well as among the saliva, tongue, tonsils, and throat (Group 2) (Segata, Kinder Haake, & Mannon, 2012). This topographical variation is surprisingly higher among different individuals. Similarly, the skin has oily areas (scalp, back, forearms) and moist areas, as well as site-specific microbiomes that, while exhibiting temporal variation, remain stable for most long periods. Today, their topographical and temporal behavior and abundance or abundance are being studied. Similarities have been found in the fact that lipophilic bacteria of the oral cavity are prominently present on the hard palate, lingual surfaces of teeth, keratinized gingiva, and buccal mucosa. As observed by the authors of this invention, these bacteria not only exhibit greater resistance to digestive acid and food bolus passage, but they also produce fatty acids by metabolizing triglycerides. They immerse the oral residue in a lipid mantle, which serves as protection and lubrication and helps to permanentize the lipid components of the oral biofilm. In the same manner, the inventors of this invention propose a positive enhancement of this natural lipophilic protection by the present composition.

[0102] Whether highly diverse (oral mucosa) or less diverse (scalp, back, and forearms, or vagina), when behaving in a symbiotic (healthy) manner, this biofilm appears to perform valuable functions such as immune defense, nutrition, metabolism, and even growth and individuality. When and why it shifts dysbiotic (disease-prone) due to a still-undiscovered trigger remains unclear. It could be a keystone pathogen, a major environmental attack such as stress, or, more impressively, hygiene as previously alleged.

[0103] Microbiota are under constant movement and renovation, while simultaneously exhibiting resilience to change. Identifying the core microbiome of certain anatomical sites or key pathogens of specific dysbiosis remains a tremendous task, despite the advent of next-generation sequencing, which offers less bias than earlier culture-based technologies. This is true of periodontitis, an oral dysbiosis that constitutes one of the most highly prevalent diseases in the world's population. Over the years, periodontists have progressed from believing that Gram-negative bacteria cause periodontitis to accepting that Gram-positive and Gram-negative bacteria are behind the shift from initial gingivitis to developed periodontitis, and that the onset is not truly causal but related to oxygen-deficient (anaerobic) hemo-dependent bacteria ("red complex" bacteria; Treponema denticola, Tannerella forsythia, and Porphyromonas gingivalis), benefiting from what was originally thought to be secondary inflammation. To complicate matters further, P. gingivalis, widely recognized as a landmark pathogen of periodontitis, initiates an inflammatory response by shifting the normal commensal microbiome, which then transforms dysbiotically. Whether this pathogen exhibits symbiotic toxicity, even under low-abundance conditions, alongside the recently discovered dormant, so-called hard-to-culture microorganisms, remains largely ignored. This applies to F. allosis, which appears to be involved in large-scale oral dysbiosis because it is rarely found in healthy individuals. Surprisingly, F. allosis is a Gram-positive, sugar-non-degrading anaerobic bacterium that lives in the subgingival area with a low oxygen gradient and can survive on short-chain fatty acids. These release ammonium when metabolized, increasing the pH to a neutral range. This, in turn, eliminates Gram-positive, oxygen-dependent bacteria with acidic metabolism, such as Streptococcus mutans. This is the reason behind patients exhibiting periodontal susceptibility rather than caries risk, and vice versa.It remains unknown whether the ability of F. allosis to thrive under highly oxidative conditions leads to further oxidative stress, and whether potentially other dysbiotic environmental changes favor OLP or carcinogenic changes.

[0104] In dysbiotic imbalances, the mutated microbiome interacts with the human body in altered environmental conditions (temperature, pH, humidity, and oxygen levels), which tends to perpetuate the microbial shift.

[0105] Not only are microorganisms replaced, but ecosystems are simultaneously altered, and this dual shift is clinically detected by negative conditions such as inflammation, barrier breakdown, bleeding, desquamation, irritation, dehydration, and, in some cases, infection of the body or even carcinogenic changes.

[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 doubted. This is because many of these negative conditions, which have unknown origins, were improved by antibiotics (ABs). Unfortunately, AB resistance and side effects are common drawbacks. As illustrated by the examples, the compositions of the present invention can reverse these negative conditions, improve health through ecosystem enhancement, and ultimately achieve eubiosis. Therefore, in specific embodiments of the present invention according to any of the prior embodiments, the compositions do not contain antibiotics.

[0107] Attempts to enhance health through the microbiome have primarily involved modifying the microbial flora, usually by adding presumably beneficial microorganisms, so-called probiotics, which have yielded controversial results. In any case, the present invention is compatible with prebiotics and probiotics. Therefore, in specific embodiments following 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 components for formulating it as a dry dosage form.

[0108] The composition of the present invention comprises a lipid-lipophilic fraction (olive product) that adheres to tissues for a longer period and prevents evaporation, and a hydrophilic fraction (betaine and xylitol) that attracts moisture within this scaffold, thereby enabling microbial interaction with the host and its ecosystem. The microbiome ecosystem is enhanced by this composition because it is improved for better adhesion of the intrinsic microbial community.

[0109] As illustrated by the examples, the compositions of the present invention possess unprecedented beneficial properties. These not only neutralize the negative effects of olive oil or betaine used externally, but also amplify the unexpected benefits to the oral and cutaneous microbiome when applied directly to the skin and mucous membranes.

[0110] The skin and mucous membranes provide an efficient barrier against pathogens and water loss. Blockage of the skin and mucous membrane barrier leads to inflammatory redness, which manifests as vasodilation and increased blood flow. The use of the compositions of the present invention has demonstrated the reduction of inflammation and, simultaneously, the regeneration of damaged tissue. It is important to emphasize that this property has not been obtained in humans with any other composition, and that other anti-inflammatory agents cannot regenerate tissue, making this composition unique (Van Dyke, 2017) (see, for example, Example 4).

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

[0112] The composition of the present invention reduces permeability, avoids the release of nutrients (collagen peptides, plasma proteins, and hemoglobin) that regenerate tissue and promote dysbiosis, and thus achieves a natural and healthy balance of bacteria residing in the tissue. At the same time, avoiding the release of these molecules helps maintain the natural, healthy color of mucous membranes, teeth, and skin.

[0113] In the present invention, the composition enhances sufficient oral and skin biofilms without causing loss, promoting a balanced and diverse microbiome, and maintaining and restoring the microbiome inherent in the underlying tissues.

[0114] Furthermore, the discovery of the compositions of the present invention for treating and preventing oral and cutaneous dysbiosis, as well as enhancing oral and cutaneous homeostasis, supports a sufficient environment for the oral and cutaneous microbiome without exercising any pressure on commensal microorganisms that could trigger or spread dysbiotic irritation.

[0115] The composition of the present invention has a lipid-lipophilic fraction (olive product) that adheres to tissues for a longer period and prevents evaporation, together with a hydrophilic fraction (betaine and xylitol) that attracts moisture within the scaffold, thereby enabling microbial interaction with the host and its ecosystem. The microbiome ecosystem is enhanced by this composition because it is improved for better adhesion of the intrinsic microbial community.

[0116] To the best of our knowledge, nothing in the prior art anticipates the oral-skin 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 occur, usually in adolescence, but also in minors and are not uncommon in adults. Both conditions are associated with Western diets and stress, and are among the most common reasons for visiting a specialist. Severity ranges from open or closed comedones (blackheads and whiteheads) to clearly inflammatory lesions (pustules, and even cysts) and from gum inflammation to bleeding and ulceration (ulcerative necrotic lesions). The current trend is to consider acne vulgaris as a cutaneous dysbiosis in which the colonization of Propionibacterium acnes is a contributing factor exacerbated by changes in the environmental conditions of the skin. Gram-positive bacteria are also found in gingivitis. However, to date, the pathogen has not been identified, and there is an increased host response similar to acne, allowing for barrier disruption and colonization. As shown in the example, gingival improvement is associated with acne improvement, which is consistent with this newly described orocutaneous axis.

[0117] Finally, nothing in the prior art has linked toothwear to oral dysbiosis. However, in the view of the present invention, the imbalance in mineral exchange behind mineral loss in acid erosion damage can be prevented by restoring the proper barrier function of the oral microbiome when it is in equilibrium. As shown in the examples and explained in the preceding discussion, a balanced microbiome in a good ecosystem neutralizes acid attack, and after using the compositions of the present invention, an indirect improvement in 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. Where dysbiosis is present, all these conditions are beneficial, ideally from topical application of the compositions in the form of gel or spray, to reverse to eubiosis at the early stages of dysbiosis.

[0118] Today, the skin-gut axis is the focus of intercollegiate research aiming to explain and describe the relationship between the gut microbiome and skin health, the previously misunderstood communication between these seemingly unconnected body parts, and the potential for translational research to improve 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 authors' knowledge, nothing has been explicitly stated in the prior art regarding the oral microbiome and the systemic effects that occur as a dysfunction of the mouth during sleep, known as sleep apnea or obstructive sleep apnea (OSA), which the authors consider dysbiosis. Sleep apnea ranges from snoring to severe forms of true respiratory interruption, and these negatively impact sleep quality through frequent nighttime awakenings and poor sleep. Daytime irritability, lack of concentration, daytime sleepiness, depression, and anxiety, along with a high 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 prognathism as a sleep alternative, often linked to mechanical continuous positive airway pressure (CPAP). Nothing has been written about the role of the oral microbiome in OSA, either as the origin or consequence of the problem. This invention considers that sleep apnea dysbiosis begins in a modulated environment similar to that which occurs in mouth breathers. Drastic and prolonged changes in mucosal moisture conditions impair the mucosal structural architecture and microbiome compartments that have collapsed pathways for air inflow in OSA. Humidification by sipping water upon waking is only a short-term solution and compels nocturia. OSA progresses through repeated sleep interruptions, poor nighttime sleep, and daytime consequences in the social, psychological, and health aspects of the individual. The oral-brain axis connection has been described as previously mentioned, and this is certainly 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 nighttime awakenings show significant improvement in signs and symptoms associated with sleep apnea dysbiosis, such as quality of nighttime sleep, daytime stimulus responsiveness, episodes of nighttime awakening, and episodes of nighttime water sipping. Patients using CPAP with the composition had better compliance when compared with a water spray.

[0120] Finally, as described above, the compositions of the present invention are useful for preventing and / or treating dysbiosis. Advantageously, as shown in Example 5, they are also useful for preventing conditions that are exacerbated or worsened by dysbiosis. Moreover, they can be used specifically as adjuvant treatments for the treatment of such conditions. Such conditions can be worsened by dysbiosis because dysbiosis increases the number of episodes of the condition, or because dysbiosis worsens the signs and / or symptoms of the condition. Signs and / or symptoms can be worsened by dysbiosis in terms of variety, intensity, and / or duration. Therefore, a first aspect of the present invention also relates to compositions of the present invention described in any of the embodiments mentioned above for use in preventing and / or as adjuvant treatments for conditions that are exacerbated or worsened by dysbiosis.

[0121] Recent research agrees that imbalances in the scalp microbiome are a major contributing factor to conditions such as dandruff or seborrheic dermatitis. Links exist between several medical conditions, such as chronic inflammatory conditions and cancer, and both the mucous membrane and skin microbiomes. In fact, the skin and oral microbiomes have been associated with carcinogenic changes leading to skin cancer (e.g., melanoma) and oral cancer.

[0122] In the lungs, similar to what occurs in any dysbiosis, the loss of beneficial commensal bacteria implies diminished protection against opportunistic pathogens such as bacteria, fungi, and viruses that, by colonizing, would perpetuate the dysbiosis. Moreover, pulmonary dysbiosis, if present, can exacerbate conditions and diseases of different natures that would otherwise have a normal course. The 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 the young population exposed to coronavirus, who experience an asymptomatic course or mild cold symptoms as part of cold dysbiosis and revert to homeostasis within days. This younger group, which normally benefits from eubiosis, will, in most cases, not suffer from severe forms of coronavirus Covid-19 and will experience a mild or even asymptomatic course that does not progress to true coronavirus disease. However, if dysbiosis is present, as occurs in the older group, coronavirus infection will take on a more severe course as a result of the exacerbation caused by dysbiosis (e.g., more severe dyspnea requiring multiple hospitalizations and the use of oxygen and / or ventilation). Coronaviruses are a large family of viruses, and it is well known that they cause illnesses ranging from the common cold to more severe illnesses, such as Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS).

[0123] Oral, skin, and vaginal hygiene can disrupt and even destroy biofilms, degrading microbiome compartments. A neglected population of over 300 different facultative anaerobic bacteria (particularly Streptococcus salivarius, S. mitis, S. aureus, S. epidermidis, and Corynebacterium) lives in the crypts on the dorsal surface of the tongue, possessing the unique property of reducing dietary nitrates to nitrites, the body's natural vasodilator and gastric protectant. Remarkably, the role of the oral microbiome in blood pressure, platelet function, and bone marrow physiology, as well as in cerebral blood flow and peripheral artery disease, is unquestionable, yet, impressively, all these beneficial effects vanish when antibacterial mouthwash is used. Dramatically, in healthy subjects on a green leafy-deficient diet using antibacterial mouthwash, a significant increase in systolic and diastolic blood pressure, clearly related to a reduction in plasma nitrite, is not reflected in the essential, yet-to-be-done research to prove whether chronic use of antibacterial mouthwash leads to elevated blood pressure and, consequently, a higher cardiovascular risk. Moreover, periodontal dysbiosis and cardiovascular disease often occur in the same patients who may be using antibacterial drugs orally (Hezel & Weitzberg, 2015).

[0124] Therefore, in particular, conditions that are exacerbated or worsened 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 may be bacterial infections (e.g., by Streptococcus), viral infections (e.g., by influenza, parainfluenza, coronavirus, coronavirus SARS-CoV-2, respiratory syncytial virus), or fungal infections (e.g., by Candida, Pneumocystis).

[0125] In preferred embodiments, the condition exacerbated or worsened by dysbiosis is a respiratory infection. More preferably, the respiratory infection is the common cold, Covid-19, or pneumonia. As shown in Example 5, the use of the compositions of the present invention remarkably prevents the common cold, as it reduces the number of common cold episodes.

[0126] A second aspect of the present invention relates to the use of a composition comprising olive products, betaine, and xylitol for the preparation of a pharmacopoeia for the prevention and / or treatment of dysbiosis, wherein the olive products are olive oil and / or olive fruit extract. Similarly, it relates to the use of a composition comprising olive products, betaine, and xylitol for the preparation of a pharmacopoeia for the prevention of a condition exacerbated by dysbiosis, or for the preparation of an adjuvant for the treatment of a condition exacerbated by dysbiosis.

[0127] A third aspect of the present invention relates to a method for treating dysbiosis, or a condition exacerbated or worsened by dysbiosis, in a subject in need, comprising administering a therapeutically effective amount of a composition comprising olive products, betaine, and xylitol to the subject, wherein the olive products are 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 olive products, betaine, and xylitol, wherein the olive products are olive oil and / or olive fruit extract. Similarly, it relates to a method for preventing a condition exacerbated or worsened by dysbiosis in a subject, comprising administering to the subject a prophylactically effective amount of a composition comprising olive products, betaine, and xylitol, wherein the olive products are olive oil and / or olive fruit extract.

[0129] Finally, recent publications have indicated that oral hygiene is the primary and most important cause of oral microbiome dysbiosis (Sudhakara, Gupta, & Bhardwaj, 2018). The same is claimed 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 compositions defined in any embodiment of the first aspect of the present invention for oral, nasal, vaginal, and / or skin hygiene of the human body, and compositions defined in any embodiment 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 use in maintaining the natural humidification of mucous membranes or skin of the human body. Similarly, it also relates to methods for oral, nasal, vaginal, and / or skin hygiene of the human body, including the administration of compositions defined in any embodiment of the first aspect of the present invention. Similarly, the use of compositions defined in any of the embodiments of the first aspect of the present invention for maintaining the natural humidification of mucous membranes and / or skin of the human body, and compositions defined in any of the embodiments of the first aspect of the present invention for use in maintaining the natural humidification of mucous membranes and / or skin of the human body, are also objects of the present invention. Similarly, a method for maintaining the natural humidification of mucous membranes and / or skin of the human body is also an object of the present invention, and includes the administration of compositions defined in any of the embodiments of the first aspect of the present invention. Preferably, the administration is done externally. Preferably, the mucous membrane is the oral mucosa.

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

[0131] In a specific embodiment of the present invention according to any one of the embodiments of the present invention, the administration protocol of the composition of the present invention is as described in the example below. [Examples]

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

[0133] Example 1. - Periodontal dysbiosis In the mouth, periodontal disease is a late-stage consequence of oral dysbiosis. This is often preceded by inflammation and other changes that have been understood as normal due to their high prevalence. We refer to symptoms such as bleeding gums, bad breath, tooth sensitivity, and others. The following study investigated the signs and symptoms of dysbiosis in a group of outpatients with a history of periodontal dysbiosis. Participants rated the severity of their complaints on a scale of 0 to 10 at the beginning and 15 days later using an assigned composition. Several compositions formulated as toothpaste (Table 2) were applied three times a day as part of a normal hygiene procedure, by brushing teeth with a toothbrush for two minutes. This was followed by rinsing with water. 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 composition (comp). Dysbiosis was analyzed, and the following signs / symptoms were evaluated: 1. Gum and papillitis (G, PI) 2. Redness or blemishes (R, B) 3. Bleeding caused by brushing (BB) 4. Bleeding due to interdental brushing (BIB) 5. Sensitivity (S) 6. Presence of detectable malodorous odor in the breath of a third party (H) 7. Tooth discoloration (TD).

[0134] [Table 2]

[0135] Table 3 shows the results as the mean intensity of gum, papillitis (G, PI), redness or staining (R, B), bleeding on brushing (BB), bleeding on 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 start of the study (t=0) and 15 days later (t=15). Table 3 shows the results as the mean intensity of complaints for different signs / symptoms, rated from 0 to 10, for five patients in each group at the start of the study (t=0) and 15 days later (t=15).

[0136] [Table 3]

[0137] The results, as changes in the intensity of complaints evaluated 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 reduction in complaints was 4.97 for composition 1.a, 1.34 for composition 1.b, 0.46 for composition 1.c, and 0.09 for composition 1.d. Therefore, when comparing the reduction in symptoms and signs associated with oral dysbiosis obtained for each composition after 15 days of use, a statistically significant effect is shown with the composition of the present invention containing olive oil, betaine, and xylitol. Surprisingly, an unexpected synergistic effect is obtained with composition (1.a) of the present invention compared with the other compositions (1.b to 1.d). Improvement in signs or symptoms signifies the restoration of a balanced microbiome, and thus a shift from dysbiosis to eubiosis. Therefore, the compositions of the present invention can treat dysbiosis and transform it into eubiosis.

[0140] In addition, to measure the association of the detectable presence of the periodontal pathogen Porphyromonas gingivalis, patients in groups 1.a and 1.d were asked to continue using their assigned toothpaste for another 15 days. At the end of this period, periodontal probing was performed using commercially available tests to detect P. gingivalis, following the manufacturer's instructions (PerioPOC® by Genspeed Biotech). Furthermore, to detect any possible relapse of dysbiosis and to assess the maintenance of eubiosis, patients were again asked to answer the same questions as before (gum strength, papillitis, redness or discoloration, bleeding during brushing, bleeding during interdental brushing, sensitivity, presence of bad breath, tooth discoloration). The results of the screening for P. gingivalis are shown 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, while none of the symptoms improved in the control group. The outcomes of sustained use of the compositions of the present invention for oral periodontal dysbiosis were found to be effective in treating dysbiosis and maintaining eubiosis, whereas in the control group, the dysbiotic condition became permanent despite the possible benefits of brushing teeth.

[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 cutaneous dysbiosis, the compositions were applied to the skin of seven patients aged 6 to 14 years diagnosed with atopic dermatitis. Signs and symptoms were evaluated by the patients before application of the product (t=0 day) and 15 days later. Subjects were marked with a vertical line indicating the intensity of complaints on a 100 mm horizontal line (Visual Analog Scale (VAS)). The composition, formulated as a humidifying gel (Table 6), was applied three times a day as part of a normal humidification procedure by gentle distribution by hand. No other humidifying or cosmetic creams were applied during the study period. Signs / symptoms that should be analyzed: 1.Dry skin feeling 2. Itching 3. Redness 4. Desquamation.

[0144] [Table 6]

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

[0146] [Table 7]

[0147] [Table 8]

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

[0149] Example 3. - Xerosis dysbiosis In the skin, desquamation, dryness, and other signs of cutaneous dysbiosis have been understood as normal due to their high prevalence. We refer, in particular, to symptoms such as dryness, itchiness, redness, desquamation, and irritation reactivity. The following study investigated signs and symptoms in a population of subjects with a history of xerosis dysbiosis. Subjects marked their subjective ratings on a 0-10 scale, giving them their initial and 15-day ratings after using the assigned composition.

[0150] Several compositions formulated as humidifying gels (Table 9) were applied twice a day, after showering and before going to bed. Signs / symptoms that should be analyzed: 1. Dry skin feeling (DS) 2. Itching (I) 3. Redness (R) 4. Desquamation (DQ) 5. Stimulus Response (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 in each group at the beginning of the study (t=0) and 15 days later (t=15), are shown in Table 10.

[0153] [Table 10]

[0154] Table 11 shows the reduction in the severity of complaints (indicated as "int" in the table) and the increase in beneficial effects for each composition.

[0155] [Table 11]

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

[0157] [Table 12]

[0158] conclusion Complaints, including signs and symptoms of cutaneous dysbiosis, are significantly reduced when the composition of the present invention, containing olive products, betaine, and xylitol, is used for 15 days. After using the gel containing olive products, betaine, and xylitol for 15 days, the beneficial effects are greatly improved. When comparing the reduction in complaints and beneficial improvements obtained by each composition after 15 days of use, advantageous synergistic effects may be observed 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 before dinner and before bedtime each day until aphthous ulcers were relieved. Assisted application was also permitted for 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] Table 14 shows the results for the four groups as the mean number of days required for aphthous remission. As can be seen from the table, patients using compositions 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 more than 7 days for ulcer healing. These findings correlate with measurements of mean pain intensity during oral hygiene and speech. This was measured at the beginning of the study (t=0) and after 24 hours of product use (t=24), and is illustrated 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, and exhibit statistically significant improvements in ulcer healing and pain management compared to other compositions. Conventional management of aphthous dysbiosis is driven by topical analgesics and disinfectants. Hyaluronic acid and / or aloe vera preparations claim barrier protection for ulcers, but are often combined in high concentrations with disinfectants such as alcohol. The composition of the present invention can restore mucosal barrier function in the absence of disinfectants and provides immediate pain relief. The pain subsided immediately, and the ability to brush and speak was measured 24 hours after application. The compositions of the present invention provided immediate pain relief, showing a statistically significant positive sum effect of immediate pain relief when compared with compositions containing olive products and betaine, and even more so when compared with compositions containing xylitol alone as the active ingredient (Table 16).

[0166] [Table 16]

[0167] Example 5.-Common cold The lung mucosa, like any other mucous membrane, benefits from the moisturizing effect and protective barrier effect of the microbiome against the permeation of harmful factors when in eubiosis and benefiting from microbiome homeostasis, experiencing comfort such as humidification, absence of pain, and absence of cough. Conversely, a feeling of dehydration, the presence of a dry cough, and symptoms of a common cold episode are associated with the presence of dysbiosis and microbiome shift, which carries an increased risk of infection or exacerbation of infection. Age is an initiator of dysbiosis, as the microbiome loses its specificity, making older patients more vulnerable to infection. A group of patients tested the preventive effect of the composition of the present invention, measuring their subjective sense of mucosal humidification and the number of respiratory episodes (colds) using the composition of the present invention. Nineteen hermit nuns, with an average age of 77, counted the number of cold episodes that occurred during the study period and were compared to the number of episodes that occurred in the previous year, using a topical gel applied to the nose, mouth, and throat with the composition of the present invention (Table 17). They also answered the question, "Do you now feel that your mucous membranes are more humidified? Yes or No" (Table 18).

[0168] [Table 17]

[0169] [Table 18]

[0170] Table 19 shows the number of influenza episodes that occurred among 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 the use of the composition of the present invention can significantly prevent dysbiosis and help reduce the number of colds.

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

[0174] [Table 20]

[0175] Participants answered the question, "Do you perceive the taste of food?" before using the tablets and after using them for 5 days. Table 21 shows the results as responses to the initial (t=0) and 5-day (t=5) questions, given that participants took three tablets per day.

[0176] [Table 21]

[0177] Patients with mucosal dysbiosis, specifically pulmonary dysbiosis, who have taste disorders or loss of taste as a common symptom, typically suck on candies and / or lozenges to mask the altered taste or improve it. 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 the taste of food after 5 days. In contrast, tablets with the composition of the present invention had a remarkable positive outcome in taste restoration in relation to COPD dysbiosis.

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

[0179] [Table 22]

[0180] The treatment lasted 30 days, and pain levels were collected on a 1-10 scale 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 toothpaste containing the composition of the present invention with a corticosteroid improves the efficacy of the corticosteroid after 15 and 30 days of treatment. This is because patients treated with the composition of the present invention reported less pain.

[0183] Example 8. - Halitosis dysbiosis Halitosis dysbiosis arises from a shift in the oral microbiome to anaerobic bacteria, such as Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia, among others. This microbiome shift involves an inflammatory environment and volatile sulfur compounds (VSCs) as a consequence of protein degradation. Some known VSCs include hydrogen sulfide, methyl mercaptan, and dimethyl sulfide. It has been reported that VSC levels in patients with periodontal dysbiosis are eight times higher than those 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 effects of different compositions on bad breath dysbiosis after 4 weeks of use.

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

[0185] [Table 24]

[0186] method The VSC of the mouth was measured using a device that measures the amount of sulfur compounds. VSC Result Interpretation Normal range (no halitosis dysbiosis): 0 to 100 ppb Mild bad breath dysbiosis: 101 to 150 ppb Severe bad breath dysbiosis: 151 to 300 ppb Extremely strong bad breath dysbiosis: above 300 ppb. Number of subjects and measurement Twenty patients were included in the study. Initial baseline VSC scores were measured, and four groups were formed, with patients assigned to each group without allowing for statistically significant differences between groups. All patients were instructed to use their assigned product for four weeks. Final scores were measured at the end of the study, and comparisons were made between groups. Two measurements were taken sequentially, and the mean of the two measurements was calculated.

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

[0188] [Table 25]

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

[0190] conclusion The composition of the present invention (comp 8.a), comprising xylitol, olive oil, and betaine, exhibits beneficial effects against bad breath dysbiosis. Surprisingly, the composition of the present invention showed synergistic improvements compared to compositions 8.b and 8.c, which lacked xylitol and olive oil, respectively.

[0191] Example 9. - Sleep apnea and toothwear dysbiosis As described in the present invention, the microbiome protects teeth from attack in a symbiotic state. In oral dysbiosis associated with stress, toothwear, and sleep apnea, as well as oral dysbiosis associated with eating disorders or gastric reflux, disruption or modulation of the microbiome leads to tooth hypersensitivity and demineralization. When the microbiome is modulated or disrupted, hypersensitivity, demineralization, caries, and / or toothwear occur (e.g., due to teeth grinding, erosion, abfraction, and attrition), and the teeth begin to dissolve in acidic or extremely acidic media, with hypersensitivity being the primary symptom of these dysbiosis.

[0192] material and method Eight patients diagnosed with sleep apnea dysbiosis and exhibiting toothwear and irritability were recruited and divided into two groups. The first group was treated with a conventional commercially available hypersensitivity gel and a mouthwash containing a fluoride source (sodium fluoride) and potassium nitrate. While the components are known, the remaining quantitative composition is unknown and therefore not shown in Table 26. The second group was treated with the compositions of the present invention applied in the form of mouthwash and gel. Compositions from both groups are shown in Table 26. Composition 9.a is a mouthwash according to the compositions of the present invention, composition 9.b is a gel according to the compositions of the present invention, composition 9.c is a commercially available mouthwash, and composition 9.d is a commercially available gel. The patient applied the mouthwash for 2 minutes three times a day after brushing, and applied the gel externally to the mouth after rinsing in the morning and before bedtime. The treatment lasted 15 days for both groups.

[0193] [Table 26]

[0194] method I recorded my self-reported answers to the following questions: -Can you drink cold water? -Can I eat slices of fruit from the refrigerator? - Do you experience any sensitivity while brushing your teeth? -Do you feel like your mouth is being moistened? 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 participants who answered yes or no indicated.

[0196] [Table 27]

[0197] conclusion The group using the composition of the present invention showed a 100% improvement in symptom outcomes, while the group using the commercially available product showed no improvement (humidification) or only a 25 to 50% improvement (residual symptoms).

Claims

1. A composition for use in the treatment and / or prevention of dysbiosis, wherein the composition comprises an olive product, trimethylglycine and xylitol, wherein the composition comprises 0.05% to 4.1% by weight of the olive product, the olive product is olive oil and / or olive fruit extract, and the dysbiosis is periodontal dysbiosis.

2. The composition according to claim 1, wherein the olive fruit extract is olive fruit dry extract and / or olive fruit extract solution.

3. The olive fruit extract contains at least 20% w / w hydroxytyrosol, and / or The composition according to claim 1 or 2, wherein the olive oil is extra virgin olive oil, virgin olive oil, or a combination thereof.

4. The composition contains 0.05% to 2.6% by weight of olive products, and / or The composition contains 0.1% to 10% by weight of trimethylglycine, and / or The composition according to any one of claims 1 to 3, wherein the composition comprises 1% to 20% by weight of xylitol.

5. A composition according to any one of claims 1 to 4, comprising 0.05% to 0.1% by weight of olive fruit extract and / or 0.2% to 2.5% by weight of olive oil.

6. The composition according to any one of claims 1 to 5, wherein the composition further comprises an antioxidant and / or a vitamin.

7. The composition according to claim 6, wherein the antioxidant is selected from hydroxytyrosol, tyrosol, oleuropein, and mixtures thereof.

8. The composition according to any one of claims 1 to 7, wherein the composition is formulated as a capsule, tablet, spray, gel, lubricating gel, toothpaste, mouthwash, chewing gum, chewable tablet, lickable capsule, lickable lozenge, palatal sheet, candy, impregnated oral swab, impregnated oral gauze, lipstick, balm, oropharyngeal syrup, oropharyngeal gel, or aerosol capsule.

9. The composition according to any one of claims 1 to 8, wherein the composition comprises olive products, trimethylglycine, and xylitol as the sole active ingredients.

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