Compositions and methods of treating gastrointestinal diseases and disorders

Abstract

Provided herein are methods for the treatment of gastrointestinal diseases and disorders or for improving gut health. In certain embodiments the methods comprise administering 5-18 active components selected from oregano (Origanum vulgare) oil, thyme oil, Salvia officinalis, Lemon Balm (Melissa officinalis), Peppermint Oil, Coptis chinensis, Berberis aristate, Berberis vulgaris, Scutellaria baicalensis, Zingiber officinale, Rheum officinale, Anethum graveolens, Glycyrrhiza glabra (Liquorice), L-Glutamine, Althaea officinalis L. (Marshmallow), Neem (Azadirachta indica), Quercetin and Zinc. Also provided are compositions and systems useful in the above methods.

Description

Compositions and methods of treating gastrointestinal diseases and disorders1 FIELD OF THE INVENTION

[0001] The present invention relates to compositions and methods for the treatment of gastrointestinal diseases or disorders, in particular for the treatment of irritable bowel syndrome or related conditions.2 BACKGROUND OF THE INVENTION

[0002] Gastrointestinal diseases and disorders and their symptoms are highly represented in the population and have a significant effect on quality of life. Irritable bowel syndrome (IBS) is a diagnosis given to patients having a range of intestinal symptoms where no other diagnosis exists. Common symptoms of IBS include bloating, abdominal pain, diarrhoea, constipation, flatulence, lethargy, nausea, heartburn (reflux).

[0003] IBS is categorized by the Rome IV Diagnostic Criteria for FGIDs (https: / / theromefoundation.oig / rome-iv / rome-iv-criteria / ) into IBS-D, IBS-C, IBS-M and IBS-U. IBS-D is IBS with predominant diarrhoea, IBS-C is IBS with predominant constipation, IBS-M is IBS with mixed bowel habits, while IBS-U is IBS unclassified. However, this classification is again a symptom-based classification, rather than a classification based on cause.

[0004] The causes of IBS are poorly understood. Theories of causes of include interactions between the brain and gut, or certain events such as stressful or difficult early life events, such as physical or sexual abuse, certain mental disorders such as depression, anxiety, and somatic symptom disorder, bacterial infections in the digestive tract, small intestinal bacterial overgrowth, an increase in the number or a change in the type of bacteria in your small intestine, and / or food intolerances or sensitivities, in which certain foods cause digestive symptoms. The causes of IBS are often considered to be different in different patients, (see https: / / www.niddk.nih.gov / health-information / digestive-diseases / irritable-bowel- syndrome / symptoms-causes) .

[0005] As a result of the lack of an understanding of the causes of IBS, reliable treatments are few, usually being lifestyle changes, such as abstaining from certain food groups (see for example the FODMAP (Fermentable, Oligosaccharides, Disaccharides, Monosaccharides and Polyols) diet (https: / / www.monashfodmap.com / ibs-central / i-have- ibs / starting-the-low-fodmap-diet / ), removal or management of stressful situations; portion control; dietary change (e.g. increasing fibre) etc.

[0006] Pharmaceutical solutions to IBS focus on the symptoms, for example to treat IBS with diarrhea, loperamide NIH, rifaximin (an antibiotic), eluxadoline (Viberzi) or alosetron(Lotronex) may be prescribed, while to treat IBS with constipation, fiber supplements, laxatives, lubiprostone (Amitiza), linaclotide (Linzess) and plecanatide (Trulance) may be recommended. Treatments of abdominal pain include antispasmodics, antidepressants and coated peppermint oil capsules (see https: / / www.niddk.nih.gov / health-information / digestive-diseases / irritable-bowel- syndrome / treatment) .

[0007] Small intestinal bacterial overgrowth (SIBO) is one suspected ‘cause’ of IBS or IBS-like symptoms although it could also be characterised as a separate disease. SIBO is an abnormal increase in the overall bacterial population in the small intestine. Common symptoms of SIBO include loss of appetite, abdominal pain, nausea, bloating, uncomfortable feeling of fullness after eating, diarrhoea, unintentional weight loss and malnutrition. Tests used in diagnosing SIBO include breath testing for hydrogen or methane, and small intestine aspirate and fluid culture. SIBO can be classified as hydrogen dominant, hydrogen sulfide dominant and methane dominant (sometimes classified as intestinal methanogen overgrowth).

[0008] First line treatments for SIBO include antibiotic treatment, in particular with rifaximin, which have limited effectiveness and / or high rates of relapse. See Lauritano et al Am J Gastroenterol . 2008 Aug;103(8):2031-5.

[0009] Small intestinal fungal overgrowth (SIFO) is another suspected ‘cause’ of IBS or IBS-like symptoms. SIFO is an abnormal growth of fungi, primarily Candida, in the intestines, similar to the overgrowth seen in the throat and genitalia post antibiotic or other treatment. The most common symptoms are belching, bloating, indigestion, nausea, diarrhoea, and gas. While SIFO is most well characterised in individuals having had antibiotic treatment or in immunocompromised individuals, there is nevertheless growing evidence of the role of fungal overgrowth in gastrointestinal symptoms. See Erdogan A, Rao SS. Curr Gastroenterol Rep. 2015 Apr;17(4): 16. The primary test for SIFO is a small bowel aspirate.

[0010] Various dietary supplements / altemative treatments exist for the treatment of IBS, SIBO and SIFO which in some cases have been shown to be effective for the short-term treatment, see for example Chedid V et al. Glob Adv Health Med. 2014 May;3(3): 16-24.

[0011] Food intolerances are an often-cited cause of IBS and IBS related symptoms. The FODMAP diet recited above is perhaps the most common medical recommendation for IBS and related disorders. It involves abstaining from certain food groups which are high in sugars which are not absorbed properly in the gut. The theory is that FODMAPs are fermented by intestinal bacteria causing gas and the intestinal wall to expand causing IBS symptoms. See https: / / www.monashfodmap.com / about-fodmap-and-ibs / . The full IBS diet is only suitable for about six weeks as it involves substantial limitations on foods before foods are graduallyreintroduced. See https: / / www.monashfodmap.com / ibs-central / i-have-ibs / starting-the-low- fodmap-diet / . However, in practice it is commonly used as a long-term treatment for keeping symptoms away. This can have other very harmful effects like nutritional deficiencies and lead to more problems in the gut.

[0012] Other food intolerances have also been cited considered as potential causes of IBS or IBS-like symptoms. Gluten intolerance (non-Coeliac related), fructose intolerance, lactose intolerance and a wide range of food groups have been cited as causing IBS or related symptoms (see Jansson-Knodell, Claire L. et al Clinical Gastroenterology and Hepatology, Volume 20, Issue 9, 2022, Pages 2121-2131.e3. In some cases these may overlap with the FODMAP foods. Like the FODMAP diet, patients with these intolerances often restrict long term intake of those foods, leading to a lower quality of life and potentially leading to nutritional deficiencies and further damage to the gut.

[0013] Thus, there remains a need for an effective and long-term treatment for IBS, SIBO, SIFO, food intolerances, and related disorders.3 SUMMARY OF THE INVENTION

[0014] Provided herein is a method of treating or preventing a gastrointestinal disorder or symptoms thereof, or improving gut health, in a subject in need thereof, comprising administering an effective amount of one or more active components. The method may comprise administering 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 , 17 and 18 active components, particularly 17 or 18 active components.

[0015] Active components can be selected from those described further below and in particular may be selected from oregano (Origanum vulgare) oil, thyme oil, Salvia officinalis, Lemon Balm (Melissa officinalis)' , Peppermint Oil, Coptis chinensis, Berberis aristate, Berberis vulgaris, Scutellaria baicalensis, Zingiber officinale, Rheum officinale, Anethum graveolens, Glycyrrhiza glabra (Liquorice), L-Glutamine, Althaea officinalis L. (Marshmallow), S(QQm(Azadirachta indica), Quercetin and Zinc. Active components can be administered in forms and effective amounts as further described herein.

[0016] The gastrointestinal disorder treated or prevented by the method may be irritable bowel syndrome, a gastrointestinal disorder associated with inflammation, small intestinal bacterial overgrowth (SIBO), small intestinal fungal overgrowth (SIFO), food intolerances and combinations thereof. Food intolerances may be selected from gluten intolerance, lactose intolerance, garlic intolerance, onion intolerance and / or intolerance to fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPS).

[0017] Symptoms of a gastrointestinal disorder which are treated or prevented by the method may include bloating, abdominal pain, diarrhoea, constipation, flatulence, lethargy, nausea, heartbum or reflux, loss of appetite, nausea, uncomfortable feeling of fullness after eating, unintentional weight loss and malnutrition.

[0018] The method may comprise administering 1, 2, 3 or more compositions comprising the active components.

[0019] Thus also provided herein is a composition comprising one or more active components. The compositions may be formulated for oral administration, for example as a capsule and may optionally be enterically coated. Compositions may further comprise one or more excipients.

[0020] Active components for use in the composition can be selected from those described further below and in particular may be selected from oregano (Origanum vulgare) oil, thyme oil, Salvia officinalis, Lemon Balm (Melissa officinalis)' , Peppermint Oil, Coptis chinensis, Berberis aristate, Berberis vulgaris, Scutellaria baicalensis, Zingiber officinale, Rheum officinale, Anethum graveolens, Glycyrrhiza glabra (Liquorice), L-Glutamine, Althaea officinalis L. (Marshmallow), S)QQm(Azadirachta indica), Quercetin and Zinc. Active components can be included in forms and amounts as further described herein.

[0021] One such composition comprises oregano (Origanum vulgare) oil, thyme oil, Salvia officinalis, lemon balm (Melissa officinalis) and peppermint oil.

[0022] Another such composition comprises Coptis chinensis, Berberis aristata, Berberis vulgaris, Scutellaria baicalensis, Zingiber officinale, Rheum officinale, Anethum graveolens and Glycyrrhiza glabra (Liquorice).

[0023] A further such composition comprises Glycyrrhiza glabra (Liquorice), L- Glutamine, Althaea officinalis L. (Marshmallow), Quercetin and Zinc.

[0024] Also provided herein is a kit comprising two or more compositions as defined herein. Particularly provided is a kit comprising three of the compositions described herein, optionally with instructions for administration.

[0025] Further provided herein are systems for treating or preventing a gastrointestinal disorder or symptoms thereof, or improving gut health. Thus provided herein is a system comprising a plurality of compositions, the plurality of compositions comprising one or more. The plurality of compositions may between them comprise 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 , 17 and 18 active components, particularly 17 or 18 active components. The active components may be spread across 2, 3, 4 or more compositions, for example across 3 or 4 compositions as described above.

[0026] Active components for use in the system can be selected from those described further below and in particular may be selected from oregano (Origanum vulgare) oil, thyme oil, Salvia officinalis, Lemon Balm (Melissa officinalis)' , Peppermint Oil, Coptis chinensis, Berberis aristate, Berberis vulgaris, Scutellaria baicalensis, Zingiber officinale, Rheum officinale, Anethum graveolens, Glycyrrhiza glabra (Liquorice), L-Glutamine, Althaea officinalis L. (Marshmallow), S)QQm(Azadirachta indica), Quercetin and Zinc. Active components can be included in forms and amounts as further described herein.

[0027] As used herein, where a method of treating or preventing is described, it should also be taken as describing the use of the active components, in the manufacture of a medicament, for that method of treating or preventing.4 DETAILED DESCRIPTION OF THE INVENTION

[0028] It is to be understood that this invention is not limited to particular embodiments described and, as such may, of course, vary.

[0029] All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety, to the same extent as if each were incorporated by reference individually. In case of conflict, the present specification, including definitions, will control. It is to be understood that, if any prior art publication is referred to herein, such reference does not constitute an admission that the publication forms a part of the common general knowledge in the art, in Australia or any other country.4.1 Definitions

[0030] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0031] Except where the context requires otherwise due to express language or necessary implication, the word “comprise” or variations such as “comprises” or “comprising” is used in an inclusive sense, i.e. to specify the presence of the stated feature but not to preclude the presence or addition of further features in various embodiments of the invention.

[0032] Reference to an element by the indefinite article "a" or "an" does not exclude the possibility that more than one of the element is present, unless the context clearly requires that there be one and only one of the elements. The indefinite article "a" or "an" thus usually means "at least one".

[0033] As used herein, where the term “about” is used in relation to a value, unless context requires otherwise, the value may vary by ±2%.

[0034] As used herein the term “component” or “active component” refers to an ingredient which has one or more effects on a biological process involved with gastrointestinal function. A component may be, for example, an element or mineral e.g. zinc, a molecule e.g. quercetin, a mixture isolated from a natural organism, e.g. from a plant or fungi, or a natural organism or part thereof (e.g. Ginger rhizome (Zingiber officinale)' . A “form” refers to a particular type of a component. Examples include an extract from a natural organism, salts and hydrates of a mineral or molecule as well as their elemental or pure forms.

[0035] One form of an active component, used interchangeably herein is an “oif’or “essential oil”. An “essential oil” as used herein is a volatile oil or essence derived from vegetation and characterized by distinctive odors and a substantial measure of resistance to hydrolysis.

[0036] An “effective amount” or “efficacious amount” refers to the amount of a component, or combined amounts of two or more components, that, when administered, is sufficient to effect the desired biological effect for that component. The “effective amount” will vary depending on the component(s), the form of the component and the biological effect desired.

[0037] The terms “subject,” “host,” “individual,” and “patient” are as used interchangeably herein to refer to human and veterinary subjects, for example, humans, animals, non-human primates, dogs, cats, sheep, mice, horses, and cows. In some embodiments, the subject is a human.

[0038] The invention has been described broadly and generically herein. Each of the narrower species and sub-generic groupings falling within the generic disclosure also form part of the invention. This includes the generic description of the invention with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein.4.2 Factors in gastrointestinal disorders

[0039] Without wishing to be bound by the theory, the inventors have developed a theory that IBS and related gastrointestinal disorders are caused in part by damage to the gut and migrating motor complex and a less diverse gut microbiome, resulting in a weaker gut microbiome.4.2.1 Lack of microbial diversity causes risk of damage.

[0040] The drivers of lack of diversity include many factors such as lifestyle, antibiotic use, an over-cleanliness of food and / or changing food practices that expose us to less diversity in bacteria, increased overuse of antiseptics and antibacterials in the home - again exposing us to less diversity of bacteria, and an increase in consumption of processed or packaged foods. This leaves the gut in a compromised or weaker state when it encounters potentially harmful invaders.

[0041] The lack of diversity in the modern-day gut can leave the gut in a compromised place, resulting in high levels of damage to the intestinal cells when the body has to mount an immune response in defence of a potential invader (such as Campylobacter, salmonella or other).

[0042] The inventors theorise that a healthy gut can avoid a certain level of infection without having to engage the systemic immune system, potentially due to its diverse and stable microbial population outcompeting pathogens. However, when challenged, a gut with lowered diversity is no longer used to, or not robust enough to fend off the bacteria without calling upon other mechanisms in the body. The failure of this first line of defence means the pathogens can release CdtB (Cytolethal distending toxin subunit B) toxins that cause damage to the cells of the gut lining. In addition, the hosts own systemic immune / inflammatory response can have the unintended effect of harming the gut lining and causing retardation of microvilli.4.2.2 Damage to intestinal cells, mucosal lining, and the Migrating Motor Complex

[0043] This damage to the cells and microvilli in turn results in a retardation of the migrating motor complex (MMC). The MMC is a wave like motion that sweeps through the small intestine roughly every 90 minutes to avoid a buildup of bacteria and debris and keep motility running smoothly. Damage to the intestinal villi means the gut is now compromised in one of its natural mechanisms for keeping things moving through effectively and maintaining a healthy level of bacteria in the small intestine. The inventors theorise that this is a key reason why many people end up relapsing again at varying time frames - the worse the damage, the worse the body is at regulating this, the faster the relapse.

[0044] Damage to cells and the MMC can also be caused by other stressors in the modem environment, in particular the modem diet. Many additives now used in food can damage the MMC or other parts of the gut. For example, artificial sugars such as xylitol, now common in the Western diet can reduce the frequency of the MMC and gastric emptying. This additional damage also needs to be addressed.

[0045] Lack of diversity and damage to the MMC form a feedback loop, whereby when the MMC is not working properly, the healthy diversity in the gut is impeded, thereby further damaging the MMC.4.2.3 Fermentation in the Gut

[0046] Bacteria buildup in the gut, as is present with SIBO, or when the gut is in a state of dysbiosis (imbalance in the gut microbiome) can cause fermentation in the small intestine or an abnormal place like the stomach, which produces gas that stretches the intestines in an unnatural way and can lead to a host of other painful symptoms.

[0047] The inventors theorise this stretching is causing the loosening of tight junctions, leading to intestinal permeability, which lets particles enter the bloodstream, which aside from being harmful in themselves, result in the body mounting an immune / inflammatory response. This immune / inflammatory response is responsible for a number of the symptoms of IBS and / or SIBO.

[0048] The inventors theorise that this same stretching will also compromise the delicate mucus membrane.

[0049] To further accelerate the issues as a key driver of IBS, the modern-day diet and certain food additives have now been found to damage the structural integrity of the gut.4.2.4 Fungal overgrowth

[0050] Candida and other fungal overgrowth can be observed in the mouth and genitals after exposure to antibiotics. Given the high rates of antibiotic use and inability to access standardised testing for Candida overgrowth, the inventors consider this to be an undiagnosed problem that is likely being caught in the catch-all diagnosis of IBS.4.2.5 Histamine issues

[0051] Histamine produces an acute inflammatory state which in turn can cause cell damage and impaired cell or tissue function. This likely to be occurring in the gut in IBS or IBS related disorders, resulting both in some of the symptoms of these disorders - directly as a result of the inflammatory response, and damage to the cells and / or tissue function of the gut. Thus, the histamine mediated inflammatory response may need to be reduced.

[0052] Dysbiosis (a change to the composition of resident commensal communities relative to the community found in healthy individuals) in the gut is a likely a driving force of the increase in allergies and inflammatory response.

[0053] Histamine is stored in cytoplasmic granules in mast cells and is a primary driver of inflammatory response. Degranulation and release of histamine can occur in presence of allergens, for example in food, and other factors. Gut microbiology influences mast cells, as evidenced for example by the increased production of serotonin by mast cells where fermentation in the gut is occurring. It is theorised that dysbiosis, bacterial or fungal overpopulation, and / or damage to the structural integrity of the gut / gut lining may result inincreased migration of mast cells to the gut and / or increased degranulation and release of histamine. It is further theorised that dysbiosis may result in spontaneous production of histamine by mast cells (i.e. without the presence of a defined allergen), resulting in some of the symptoms of IBS.

[0054] In addition, certain species of bacteria themselves produce histamine, thus overpopulation of these species of bacteria may further exacerbate the inflammatory response.

[0055] Dysbiosis may also be linked to a deficiency in the gut’s ability to produce the DAO (diamine oxidase) enzyme that neutralises histamines in food.

[0056] The above factors are all interlinked and treatment of just one aspect, while it may achieve temporary relief, is likely to result in relapse. For example antibiotic treatment of bacterial overgrowth (SIBO) may treat the immediate issue, but without treating the underlying state of dysbiosis and damage to the MMC, the symptoms are likely to reoccur. Similarly treatment of the inflammatory response, for example by anti-histamines, without treatment of dysbiosis may treat some of the immediate symptoms, but relapse is likely to occur once the treatment is discontinued.4.2.6 Multi-factorial approach

[0057] Taking all of the above theory into account, the inventors recognised that in order to be successful and avoid relapse, a treatment of IBS or SIBO or related gastrointestinal disorders would need to be multi-factorial. Factors include:1. Killing potential overgrowth of both fungus and bacteria in the small intestine or other undesirable areas of the gastrointestinal system;2. Shifting / rebalancing / recomposing the gut microbiome from its current state;3. Encouraging the gut to move as it should despite a potentially compromised state;4. Reducing inflammatory responses in the gut, both to avoid immediate symptoms, and to avoid damage to cells and gut function;5. Restoring and rebuilding cells and gut functions damaged by multiple factors leading to a manifestation of symptoms; and6. Alleviating the symptoms of IBS / SIBO / SIFO.

[0058] Applying the above, the inventors arrived at an approach that uses multiple active components in order to provide a multi-factoral, systematic, synergetic and clinically appropriate approach to gastrointestinal issues.4.3 Active components

[0059] Active components are components which have one or more effects on a biological process involved with gastrointestinal function. Preferably the biological process is one involved with the theorised mechanisms or symptoms of IBS or related disorders. Active components are preferably naturally derived. Certain active components may have more than one effect or property. Components for use in accordance with the present invention include:4.3. 1 Components with prokinetic or motility properties

[0060] Components with prokinetic or motility properties include:4.3. 1.1 Chinese rhubarb ( e.g. Rheum officinale) -

[0061] Rhubarb root and rhizome regulates gastrointestinal motility issues, increases intestinal blood perfusion, removes oxygen-free radicals, and reduces inflammation.See:Science Direct Topic- Rhubarb: https: / / www.sciencedirect.com / topics / pharmacology-toxicology- and-pharmaceutical-science / rhubarbXiang H et al Chin Med. 2020 Aug 26; 15: 88.Yu, M et al, World J Gastroenterol. 2005 May 7; 11 ( 17):2670-3.4.3. 1.2 Ginger rhizome (Zingiber officinale)

[0062] Ginger has been shown to have a prokinetic effect. Studies on rats show an increased food transit time through the stomach.See:Hopkins Medicine. - Ginger benefits. (2023, October 4). Johns Hopkins Medicine. https: / / www.hopkinsmedicine.org / health / wellness-and-prevention / ginger- benefits#:~:text=Health%20Benefits%20of%20Ginger&text=Gingerol%2C%20a%20natural%2 0component%20of,Nausea%20reliefHu, ML et al World J Gastroenterol. 2011 Jan 7; 17( 1): 105 -10.Wu, KL, Eur J Gastroenterol Hepatol. 2008 May;20(5):436-40.Nikkhah Bodagh M, et al Food Sci Nutr. 2018 Nov 5 ;7( 1):96- 108.4.3. 1.3 Dill (Anethum graveolens)

[0063] Dill seed aids peristaltic action by eliminating wastes from the body, making it an effective constipation treatment.See:Science Direct Topic - Dill: https: / / www.sciencedirect.com / topics / agricultural-and-biological- sciences / dillBordbar G et al, Gastroenterol Res Pract. 2020 May 27;2020:8213082.Ben-Noun (Nun), Liubov. (2022). HEALTH EFFECTS OF DILL. https: / / www.researchgate.net / publication / 358346291_HEALTH_EFFECTS_OF_DILL4.3. 1.4 Lemon Balm (Melissa officinalis)'

[0064] Lemon balm may effectively treat gastrointestinal bloating and flatulence due to their spasmolytic mode of action.See:Aubert, P et al, J Med Food. 2019 Jul;22(7):653-662.4.3. 1.5 Peppermint oil

[0065] Peppermint is well established as a potent prokinetic herb in that it contains unique constituents (like menthol) that stimulate receptors in the gut to help promote motility.Science Direct Topic - Peppermint Oil: https: / / www.sciencedirect.com / topics / nursing-and- health-professions / peppermint-oilChumpitazi BP et a Alimeni Pharmacol Ther. 2018 Mar;47(6):738-752.4.3. 1.6 Berberine

[0066] Berberine improves intestinal motility.See:Chen C et a\PLoS One. 2015 Dec 23;10(12):e0145556.Li L et eAFront Pharmacol. 2020 Aug 31 ; 11 : 1210.4.3.2 Components with antimicrobial properties and / or which disrupt biofdms

[0067] Components with antimicrobial properties and / or which disrupt biofdms include:4.3.2. 1 Oregano ( e.g. Origanum vulgare)

[0068] Oregano oil (e.g. Origanum vulgare ) is a biofdm buster with two active compounds that may be useful in SIBO and SIFO (small intestinal fungal overgrowth). It has antibacterial and antifungal effects.See:Leyva-Lopez N et al Molecules. 2017 Jun 14;22(6):989.PasterN ct al. J Food Prot. 1995 Jan;58(l):81-85.Zhan X et alFoo ds. 2022 Aug 1; 11(15):2296. dos Santos Rodrigues, J B et al Food Control, Volume 73, Part B, 2017, Pages 1237-1246.Hacioglu M et al, Z Naturforsch C J Biosci. 2021 Apr 29;76(ll-12):443-450.4.3.2.2 Sage (Salvia officinalis)'

[0069] Sage exerts a range of therapeutic activities, including antibacterial, antiviral, antifungal, and antioxidant effects. Sage also contains anti-inflammatory properties and aids in the smooth functioning of the digestive system.See:Hamidpour, M et af JTradit Complement Med. 2014 Apr;4(2):82-8.Wijesundara NM et al, Molecules. 2019 Mar 24;24(6): 1165.Pejcic M et alFood and Chemical Toxicology, Volume 141, 2020, 111431.4.3.2.3 Lemon Balm (Melissa officinalis)

[0070] Lemon Balm is a gastro-protective and active ingredient that has antiinflammatory effects and has been shown to improve digestive symptoms. It is an antibacterial and antifungal agent.See:Ehsani A et al Vet Res Forum. 2017 Summer;8(3):223-229.Sales G et al, Scientia Pharmaceutica. 2022; 90(2):31.Carvalho F et al, Food Bioscience, Volume 44, Part B, 2021, 101437.4.3.2.4 Ginger Zingiber officinale)

[0071] Ginger (rhizome) contains several constituents which have antibacterial and antifungal effects.See:Rahmani AH et al, Int J Physiol Pathophysiol Pharmacol. 2014 Jul 12;6(2): 125-36.4.3.2.5 Berberine

[0072] Berberine can fight microbes, tumors, inflammation, high cholesterol, diabetes, and mitochondrial problems. Researchers have discovered that fungal mitochondria have unique DNA / proteins, which makes them a promising target for antifungal treatments.See:Mahmoudv H et al ISRN Pharmacol. 2014 Mar 10;2014:602436.4.3.2.6 Thyme (Thymus vulgaris)

[0073] Thyme oil has strong antimicrobial properties that can help kill off bacterial and fungal overgrowth and is also effective against biofilms. It has been shown as effective in SIBO treatment as the most effective western medical treatment option.See:Foumomiti M et al, Microb Ecol Health Dis. 2015 Apr 15;26:23289.Vassiliou E et al, IntJMol Sci. 2023 Apr 8;24(8):6936.Kowalczyk A et al, Molecules. 2020 Sep 9;25(18):4125.Kavanaugh NL et al, Appl Environ Microbiol. 2012 Jun;78(ll):4057-61. doi: 10.1128 / AEM.07499-11.4.3.2.7 Chinese skullcap (Scutellaria baicalensis)

[0074] Baicalin and baicalein, two chemicals found in high concentrations in Chinese Skullcap root, have many biological functions including anti-oxidation, antipyretic, analgesic, anti-inflammatory, antiallergic, antimicrobial, immunomodulatory, and antitumor effects.See:Yin B et al, Animals. 2021 Apr 7; 11(4): 1039.4.3.2.8 Chinese Liquorice (e.g. Glycyrrhiza uralensis)

[0075] More than 20 triterpenoids and nearly 300 flavonoids have been isolated from Chinese liquorice. Recent studies have shown that these metabolites possess many pharmacological activities, such as antiviral, antimicrobial, anti-inflammatory, antitumor and other activities.See:Wang L et al, Acta Pharm Sin B. 2015 Jul;5(4):310-5.4.3.2.9 Chinese Rhubarb (e.g. Rheum officinale)

[0076] Rhubarb root and rhizome is also an effective antimicrobial. It has a broad antibacterial range, and it can overcome antibiotic resistance by preventing bacterial biofilm formation The main chemical compositions of rhubarb include anthraquinones, anthrones, stilbenes, tannins, polysaccharides etc.See:Cao Y J et al, Chin Med. 2017 Dec 28;12:36.Xiang H et al, Chin Med. 2020 Aug 26; 15: 88.Oluwole OM. Afr J Infect Dis. 2022 Aug 17;16(2 Suppl):59-71.4.3.2. 10 Indian barberry

[0077] Indian barberry root has potent antimicrobial activity against major gastrointestinal pathogens.See:Jahan F et al, Pharmacological Research - Modern Chinese Medicine, Volume 5, 2022.4.3.2.11 Marshmallow (Althea officinalis)

[0078] Marshmallow root has antimicrobial effects.See:Banaee M et al, Vet Res Forum. 2017 Spring;8(2): 145-153.4.3.2.11 Peppermint

[0079] Peppermint oil has antibacterial and antibiofilm effects.See:Ashrafudoulla M et al. / Food Sci. 2023 Sep;88(9):3935-3955.Kang J, LWT, Volume 101,2019, Pages 639-645,Neagu R et al, Antibiotics. 2023; 12(7): 1191.4.3.2.12 Quercetin

[0080] Quercetin can prevent biofdm formation and reduce bacterial virulence by lowering stress levels and quorum sensing.Kim YK, Food Control, Volume 137, 2022, 108964.Memariani H et al, World J Microbiol Biotechnol. 2019 Sep 6;35(9): 143.4.3.3 Components to improve tight junctions and / or reduce intestinal permeability

[0081] Components to improve tight junctions and / or reduce intestinal permeability include:4.3.3. 1 Oregano (e.g. Origanum vulgare)

[0082] Oregano oil may benefit gut health by assisting in the restoration of the tight junctions of the intestine. SIBO and other related gut conditions cause micro-cracks in the gut lining, leading to a condition called leaky gut.See:ZouY et al, Biomed Res Int. 2016;2016:5436738.Xin Y, Frontiers in Marine Science Vol 9, 2022Jia L et al, Front Immunol. 2022 Jul 12; 13 : 908015.Feng, J et al. / Animal Sci Biotechnol 12, 72 (2021).4.3.3.2 Berberine

[0083] Due to its intracellular stabilising effects, Berberine helps re-fuse tight junctions, leading to gut lining repair.See:Cheng H et al, J Pharm Anal. 2022 Aug;12(4):541-555.Gu L et al, J Infect Dis. 2011 Jun l;203(ll): 1602-12.Gong J et al, Front Pharmacol. 2017 Feb 3;8:42.Zhang L et al, Front Cell Infect Microbiol. 2021 Feb 19; 10:588517.Li Y, Life Sciences, Volume 261, 2020, 118460.4.3.3.4 Glutamine

[0084] L-Glutamine nourishes and supports gut cell regeneration, which occurs every 48 hours and significantly decreases intestinal permeability.See:Rao R et al, J Epithel Biol Pharmacol. 2012 Jan;5(Suppl l-M7):47-54.Wang B et al , JNutr. 2016 Mar;146(3):501-8.Wang H et al, J Nutr. 2015 Jan;145(l):25-31.McRae MP. Biomed Rep. 2017 May;6(5):576-584.4.3.3.5 Quercetin

[0085] Quercetin can enhance intestinal barrier function and modulate gut microbiota composition. The activities of tight junction proteins at the gut epithelium enhance barrier functions and reduce inflammation, protecting the host from colonic diseases.See:Suzuki T et al, J Nutr Biochem. 2011 May;22(5):401-8.Gamero-Estevez E et al, IntJMol Sci. 2019 Oct 2;20(19):4889.Amasheh M et al J Nutr. 2008 Jun;138(6): 1067-73.Suzuki T et al, J Nutr. 2009 May; 139(5) : 965 -74.4.3.3.6 Marshmallow (Althaea officinalis)

[0086] Marshmallow root extracts contain compounds that help stimulate the growth of cells in the lining of the body's internal organs. These findings may support traditional uses of Marshmallow preparations for treating irritated mucous membranes and may promote tissue regeneration.See:Deters A et al, J Ethnopharmacol. 2010 Jan 8; 127( 1) :62-9.4.3.3.7 Chinese skullcap (Scutellaria baicalensis)

[0087] Chinese skullcap root can reduce the proximal colonic lesions, intestinal permeability and release levels of related inflammatory factors to achieve anti-hypertensive effect.See:Song, JW. et al, Chin Med 15, 102 (2020).4.3.3.8 Ginger rhizome (Zingiber officinale)'

[0088] Ginger is a spice commonly used in Indian cooking that can help people with leaky gut syndrome. It has anti-inflammatory and antioxidant properties which can reduce gut inflammation. Ginger can also improve digestion, helping to break down food and absorb nutrients.See:Shen CL et al, Front Pharmacol. 2022 Jul 8: 13Wang R et al, Nutrients. 2022 Oct 19;14(20):4384.Gumbarewicz E et al, IntJMol Sci. 2022 Dec 8;23(24): 15545.4.3.3.9 Zinc

[0089] Studies have shown that zinc can assist in tightening a leaky gut.See:Skrovanek S et al, World J Gastrointest Pathophysiol. 2014 Nov 15 ;5(4):496-513.Wan Y et al, Biomolecules. 2022 Jun 27;12(7):900.4.3.4 Components to assist in the formation of / repair the mucous membrane

[0090] Components to assist and / or help repair the mucous membrane in the intestine include but are not limited to:4.3.4. 1 Liquorice (Glycyrrhiza glabra)Liquorice, e,g, deglycyrrhizinated liquorice / DGL was found to increase the production of mucus. This mucus could act as a protective barrier against acid in the stomach and esophagus.Murray MT. Glycyrrhiza glabra (Licorice). Textbook of Natural Medicine. 2020:641-647.e3.4.3.4.2 L-Glutamine

[0091] Glutamine can help improve blood flow in the lining of the intestines, which may lead to reduced damage and activity of diamine oxidase (DAO). This could ease the permeability of the intestinal lining.See:Wang ZE ct a m JTransl Res. 2018 Nov 15;10(l l):3833-3846.Shu XL et al, Exp Ther Med. 2016 Dec;12(6):3499-3506.4.3.5 Components to assist in bacterial balance

[0092] Components to assist in bacterial balance include but are not limited to:4.3.5. 1 Chinese Rhubarb ( e.g. Rheum officinale)

[0093] Rhubarb root and rhizome can assist in restoring gut microbiota balance, restore disrupted flora, and prevent microbiota shift.See:Lai F et al, Evid Based Complement Alternat Med. 2015 ;2015 : 131283.Science Direct Topics: Rheum officinale https: / / www.sciencedirect.com / topics / agricultural-and- biological-sciences / rheum -officinalePeng Y et al, Exp Anim. 2014;63(4):415-22.Jiao J et al, J Agric Food Chem. 2018 Jan 31;66(4): 1047-1057.Ji C et al, Front Pharmacol. 2020 Jul 29; 11 : 1092.4.3.5.2 Ginger (Zingiber officinale)

[0094] Ginger rhizome can assist in maintaining bacterial balance.See:Wang X et al Front Microbiol. 2021 Feb 23: 11:576061.Wang J et al, Nutrients. 2020 Oct 19; 12( 10): 3194.4.3.5.3 Quercetin

[0095] Studies suggest that quercetin affects the progress of microbiota-associated diseases. Notably, quercetin supplementation increased gut microbial diversity, which may improve gut protection.See:Lin R et al, Front Microbiol. 2019 May 16; 10: 1092.Feng J et al Poult Sci. 2023 Mar;102(3): 102433.Uyanga VA et al, Nutrients. 2021 Oct 25; 13(11):3782.4.3.5.4 Coptis (e.g. Coptis chine ns is)

[0096] Coptis root and rhizome has been used to promote healthy digestive and microbial environments. Berberine alkaloids in Coptis have been researched for their influence on microbes in the gut.See:Wang J et al, Pharm Biol. 2019 Dec;57(l): 193-225.Wu J et al, J Cell Mol Med. 2019 Dec;23(12):7946-7960.Tang T et A ronl Microbiol. 2023 May 25; 14: 1180368.4.3.5.5 Berberine

[0097] Berberine affects the concentration of specific gut microbes, reducing Gastrointestinal Microbiota variety.Cheng H et al, JPharm Anal. 2022 Aug; 12(4):541-555.Zhang L et al Front Cell Infect Microbiol. 2021 Feb 19; 10: 588517.4.3.5.6 Neem (Azadirachta indica)

[0098] Neem leaf has been shown to influence beneficial bacteria in the gut. Neem is a scrub for intestinal villi, an antagonist to bacterial biofilm accumulation, and is naturally cleansing and detoxing for the blood, skin, and liver. It supports the proliferation of good intestinal bacteria without supporting the growth of bad intestinal bacteria.See:Harjai K et al, Pathog Dis. 2013 Oct;69(l):62-65.Polaquini SR et al, Arch Oral Biol. 2006 Jun;51(6):482-90.Lopez D et al, Cold Spring Harb Perspect Biol. 2010 Jul;2(7):a000398.KumarVS et al, Asian Pac J Prop Biomed. 2013 Jul;3(7):505-14.Alzohairy MA. Evid Based Complement Alternat Med. 2016;2016:7382506.Subapriya R, Nagini S. Curr Med Chem Anticancer Agents. 2005 Mar;5(2): 149-6.4.3.5.7 L-Glutamine

[0099] L-Glutamine can help to promote the growth of beneficial gut bacteria, which are essential for maintaining gut health.See:Perna S et al, IntJMol Sci. 2019 Oct 22;20(20):5232.4.3.5.8 Oregano

[0100] Oregano oil can inhibit “bad” bacteria, it can also increase the growth of beneficial bacteria.See:Jia L et al, Front Immunol. 2022 Jul 12; 13 : 908015.Guangxin G et Aquaculture , Volume 547, 2022, 737442.4.3.6 Components to assist in gastric emptying

[0101] Components which assist in gastric emptying include but are not limited to:4.3.6. 1 Peppermint

[0102] Peppermint oil enhances gastric emptying, and can be used for patients with functional gastrointestinal disorders.See:Inamori M et al, J Gastroenterol. 2007 Jul;42(7):539-42.4.3.6.2 Ginger (Zingiber officinale)

[0103] Ginger rhizome accelerates gastric emptying and stimulates antral contractions in healthy individuals.See:Bodagh MN et al, FoodSciNutr. 2018 Nov 5;7(l):96-108.Wu, KL et al, Eur J Gastroenterol Hepatol. (2008) May; 20. 436-40.4.3.7 Components to improve intestinal cell health

[0104] Components which improve intestinal cell health include but are not limited to:4.3.7. 1 L-Glutamine

[0105] Glutamine is crucial for the cells lining the intestines and the immune system. It has anti-inflammatory properties.See:Rhoads JM et al, Am J Physiol. 1997 May;272(5 Pt l):G943-53.Blachier F et al, Am JClin Nutr 2009 Sep;90(3):814S-821S4.3.7.2 Berberine

[0106] Recent studies have shown that berberine has beneficial effects on the immune cells of the intestinal immune system and affects the expression of several intestinal immune factors.See:Zhang L et al, Front Cell Infect Microbiol. 2021 Feb 19; 10: 588517.4.3.7.3 Sage (Salvia officinalis)'

[0107] Sage leaf may also have an effect on fuelling intestinal cells.See:Salomon R et al, Front Immunol. 2021 May 14;12:670279.4.3.8 Components for alleviating commonly occurring histamine issues / or reduced DAO

[0108] Components which assist with commonly occurring histamine issues or reduced DAO enzymes.4.3.8. 1 Chinese skullcap (Scutellaria haicalensis)

[0109] Baical skullcap root (Chinese skullcap root) is a potent herb with antiviral, antimicrobial, and anti-allergy properties. It stabilizes mast cells and inhibits histamine release, making it effective against anaphylactic-like reactions.See:Shin HS et al, Molecules. 2014 Feb 21; 19(2) :2536-45.Jung HS et al, J Ethnopharmacol. 2012 May 7; 141( 1) :345-94.3.8.2 Ginger (Zingiber officinale)

[0110] Ginger rhizome is a histamine blocker or antihistamine but is also beneficial for the immune system.See:Kawamoto Y et al, JNutr Biochem. 2016 Jan:27: 112-22.Yamprasert R et al, BMC Complement Med Ther. 2020 Apr 20;20(l): 119.4.3.8.3 Thyme (Thymus vulgaris)

[0111] Thyme oil is a herb with high levels of vitamin C and anti-inflammatory compounds. It blocks histamine and prevents its release from mast cells.See:Fachini-Queiroz FC et al, Evid Based Complement Alternat Med. 2012;2012:657026.Yu H et al Foo ds. 2021 Oct 18;10(10):2491.4.3.8.4 Quercetin

[0112] Quercetin can stabilize cells that release histamine, acting as an anti-inflammatory and antihistamine.See:Mlcek J et A. Molecule . 2016 May 12;21(5):623.Jafarinia M et al, Allergy Asthma Clin Immunol. 2020 May 14; 16: 36.4.3.8.5 Peppermint

[0113] Peppermint oil is known to have anti-inflammatory and antiallergenic properties, which could help mitigate the release of histamines and their subsequent effects on the body.See:Raskov H et al Gut Microbes. 2016 Sep 2;7(5):365-83.Inoue T et al, Biol Pharm Bull. 2001 Jan;24(l):92-5.4.3.9 Components to assist mast cell function

[0114] Components to assist in mast cell function include but are not limited to:4.3.9. 1 Chinese Liquorice (e.g. Glycyrrhiza uralensis)

[0115] Chinese liquorice root extract contains anti-pseudo-allergic components that can effectively inhibit mast cell degranulation and calcium influx.See:Wang L et al, Chin J Nat Med. 2022 Jun;20(6):421-431.Yang R et al, Pharm Biol. 2017 Dec;55(l):5-18.Haggag EG et al, J Herb Pharmacother. 2003;3(4):41-54.4.3.9.2 Chinese skullcap (Scutellaria baicalensis)

[0116] Chinese skullcap root is a potent herb with antiviral, antimicrobial, and antiallergy properties. It stabilizes mast cells and inhibits histamine release, making it effective against anaphylactic-like reactions.See:Shin HS et Al, Molecules . 2014 Feb 21 ; 19(2) :2536-45.Jung HS et al, J Ethnopharmacol. 2012 May 7; 141( 1) :345-94.3.9.3 Quercetin

[0117] Quercetin stabilizes mast cell membranes, reducing histamine release. It suppresses anaphylactic responses in rats and inhibits asthmatic inflammation in guinea pigs and rats.See:Science Direct topic: Quercetin https: / / www.sciencedirect.com / topics / nursing-and-health- professions / quercetinShaikY et al, Cent Eur J Immunol. 2018;43(4):476-481.4.3.10 Components to assist with diarrhoea or constipation

[0118] Components to assist with diarrhoea or constipation include but are not limited to:4.3.10.1 Chinese Rhubarb (e.g. Rheum officinale)

[0119] Rhubarb root and rhizome is used for diagnostic procedures and digestive issues such as constipation, diarrhoea, heartbum, stomach pain, GI bleeding.See:Cao YJ et al, ChinMed. 2017 Dec 28;12:36.QinY et al, J Ethnopharmacol. 2011 Feb 16; 133(3): 1096-102.4.3.10.2 Peppermint

[0120] Peppermint oil aids digestion by reducing constipation by relaxing the intestinal wall muscles.See:AlammarN et al, BMC Complement Altern Med. 2019 Jan 17; 19( 1):21.Irritable Bowel Syndrome: What helps and what doesn’t? https : / / www.ncbi .nlm .nih.gov / books / NBK279415 / #_ncbi_dlg_citbx_NBK2794154.3.10.3 Indian barberry

[0121] Indian barberry root is used to treat diarrhoea, reduce fever, improve appetite, relieve upset stomach, and promote vigour, as well as a sense of well-being.See:Neag MA et al, Front Pharmacol. 2018 Aug 21;9:557.Zarei A et al, Avicenna J Phytomed. 2015 Nov-Dec;5(6):485-97.4.3.10.4 Dill (Anethum graveolens)

[0122] Dill’s high fibre content aids peristaltic action by eliminating wastes from the body, making it an effective constipation treatment. Additionally, the herb’s antacid characteristic reduces the creation of excessive acids in the stomach, which helps cure indigestion, ulcers, and gastritis while promoting improved nutritional absorption.See:Oshaghi EA et al, Iran J Med Sci. 2016 Jul;41(4):328-33.Bota, S et Journal of Pharmaceutical Research International. (2021) 168-1794.3. 10.5 Ginger (Zingiber officinale)'

[0123] Ginger rhizome works by blocking the toxic bacteria that causes diarrhoea and preventing fluid from accumulating in the intestines. This has an antidiarrheal effect on the body. See:Khodaie L et al, Jundishapur J Nat Pharm Prod. 2015 Jan 17;10(l):el8402.Chen JC et al, J Agric Food Chem. 2007 Oct 17;55(21): 8390-7.4.3.10.6 Quercetin

[0124] Quercetin reduces diarrhoea and intestinal damage by improving antioxidative capacity and gut bacteria function.See:Gong T et al Virology, 2024 Jan; 589; 109923,4.3.10.7 Zinc

[0125] Zinc supplementation can reduce the severity and duration of diarrhoea, prevent future episodes, but its mechanism is not fully understood.See:Bajait C, Thawani V. Indian J Pharmacol. 2011 May;43(3):232-5.Qadir MI et al, WorldJClin Cases. 2013 Jul 16;1(4): 140-2.4.3.11 Components with anti-inflammatory properties

[0126] Components with anti-inflammatory properties include but are not limited to:4.3.11.1 Lemon Balm (Melissa officinalis)

[0127] Lemon Balm leaf extract is a gastro-protective and active ingredient that has antiinflammatory effects and has been shown to improve digestive symptoms. It is an antibacterial and antifungal agent.See:Draginic N et al, Iran JPharm Res. 2022 May 5;21( 1) :e 126561.Ehsani A et al, Vet Res Forum. 2017 Summer; 8(3) :223 -229.4.3.11.2 Sage (Salvia officinalis)

[0128] Sage extract has anti-inflammatory properties and aids in smooth functioning of the digestive system.See:Brindisi M et al, Antioxidants (Basel). 2021 Feb 19; 10(2):311.Hamidpour M et al, JTradit Complement Med. 2014 Apr;4(2):82-8. doi: 10.4103 / 2225- 4110.130373.4.3.11.3 Chinese skullcap (Scutellaria baicalensis)

[0129] Chinese Skullcap contains baicalin and baicalein which have various biological functions such as anti-oxidation, antipyretic, analgesic, anti-inflammatory, antiallergic, antimicrobial, immunomodulatory, and antitumor effects.See:Shin HS et al, Molecules. 2014 Feb 21; 19(2) :2536-45.Yin B et al, Animals (Basel). 2021 Apr 7; 11 (4): 1039.4.3.11.4 Coptis (Coptis chinensis. containing berberine)

[0130] Coptis root and rhizome extract is widely used traditionally in East Asia for their antioxidant, anti-inflammatory, and antimicrobial abilities.See:Wu J et al, J Cell Mol Med. 2019 Dec;23(12):7946-7960.Yang Z et al, Evid Based Complement Alternat Med. 2012;2012:4914964.3.11.5 Chinese Liquorice (e.g. Glycyrrhiza uralensis)

[0131] Chinese liquorice contains more than 20 triterpenoids and almost 300 flavonoids with various pharmacological activities, such as anti-inflammatory, antiviral, antimicrobial, and antitumor properties.See:Wang L et al, Acta Pharm Sin B. 2015 Jul;5(4):310-5.Yang R et al, Pharm Biol. 2017 Dec;55(l):5-18.4.3.11.6 Chinese Rhubarb (e.g.Rheum officinale)

[0132] Rhubarb root and rhizome contains anthraquinones, anthrones, stilbenes, tannins, and polysaccharides. These compounds have many health benefits, such as regulating the digestive system, fighting cancer and inflammation, and protecting against heart and brain diseases.See:Cao YJ et al, ChinMed. 2017 Dec 28;12:36.HuY ct al. J Ethnopharmacol. 2021 Jun 12;273: 114027.4.3.11.7 Neem (Azadirachta indica)

[0133] Neem leaf is clinically proven to treat SIBO and IBS due to its antibacterial and anti-inflammatory properties, which help to eliminate harmful bacteria in the stomach and improve digestion.See:Schumacher M et al, Genes Nutr. 2011 May;6(2): 149-60.Alzohairy MA. Evid Based Complement Alternat Med. 2016;2016:7382506.4.3.11.7 Marshmallow

[0134] Marshmallow root coats the digestive tract with protective lining to balance gut inflammation.See:Deters A et al, J Ethnopharmacol. 2010 Jan 8;127(l):62-9.Bonaterra GA et al, Front Pharmacol. 2020 Mar 17; 11 :290.4.3.11.8 Quercetin

[0135] Quercetin can improve gut barrier function and microbiota composition. Tight junction proteins enhance barriers and reduce inflammation.See:Li Y et al, Nutrients. 2016 Mar 15;8(3): 167.David AVA et al, Pharmacogn Rev. 2016 Jul-Dec; 10(20): 84-89.4.3. 12 Components for stool consistency

[0136] Components for stool consistency include, but are not limited to:4.3. 12. 1 Ginger (Zingiber officinale)'

[0137] Ginger root and rhizome can improve IBS symptoms, including abdominal pain, bloating, and stool consistency.See: van Tilburg MAL et al, Complement Ther Med. 2014 Feb;22(l): 17-20.4.3.12.2 Chinese Rhubarb (e.g. Rheum officinale)

[0138] Supplementing with rhubarb extract helps improve stool frequency and consistency over time, in a dose-dependent manner.See:Neyrinck AM et al, IntJMol Sci. 2022 Nov 24;23(23): 14685.Gao H et al, Front Pharmacol. 2022 Dec 5; 13 : 1048134.4.3.12.3 Zinc

[0139] Oral zinc supplementation has a promising role in reducing the duration of diarrhoea and improving stool consistency in children with acute diarrhoea.See:Bajait C and Thawani V. Indian J Pharmacol. 2011 May;43(3):232-5.Laghari GS et al, Cureus. 2019 Mar 11 ; 11 (3) :e4217.4.3. 13 Components to improve reflux (multiple root causes)

[0140] Components to improve reflux include:4.3.12.1 Liquorice (Glycyrrhiza glabra)

[0141] Liquorice root extract e.g. deglycyrrhizinated licorice, can relieve symptoms of GERD, such as acid reflux and heartbum. A study found that taking liquorice root was more effective in reducing symptoms than antacids in 58 people with GERD over two years.See:Science Direct Topic - Glycyrrhiza Glabra Root https: / / www.sciencedirect.com / topics / medicine- and-dentistry / glycyrrhiza-glabra-rootSetright, R. Prevention of symptoms of gastric irritation (GERD) using two herbal formulas: An observational study. Journal of the Australian Traditional-Medicine Society, 23(2), 68-71.4.3.12.2 Marshmallow

[0142] Marshmallow root is a soothing herb traditionally used to treat reflux, heartbum, and mild inflammation of the gastric mucosa.See:Hage-Sleiman R et al, Pharm Biol. 2011 Mar;49(3):327-33.Zaghlool SS et al, Antioxidants (Basel). 2019 Oct 25;8(11):512.Harvard Health - Herbal remedies for heartbum: https: / / www.health.harvard.edu / diseases-and- conditions / herbal-remedies-for-heartbum4.4 Sources and forms of active components

[0143] Various sources and forms of the active components can be used in the methods and compositions herein.4.4.1 Oregano

[0144] A variety of plants are known as Oregano including Hedeoma patens, Lippia graveolens, Lippia palmeri, Lippia alba, Origanum diciamnus. Origanum hirium. Origanum onites and Origanum vulgare. Although Origanum vulgare is exemplified and preferred, other species, especially those within the genera Oreganum may also be employed.

[0145] Various forms of oregano may be used as an active component herein. However, oregano is preferably utilised in the form of an oil, e.g. from the leaves. Methods of preparing essential oils of oregano are known.4.4.2 Thyme

[0146] A variety of plants of the genus Thymus are referred to as Thyme including Thymus citriodorus. Thymus herba-barona, Thymus praecox and Thymus vulgaris. Although Thymus vulgaris is exemplified and preferred, other species of thyme may also be used.

[0147] Various forms of thyme may be used as an active component herein. However thyme is preferably utilised in the form of an oil, e.g. from the leaves. Methods of preparing essential oils of thyme are known.4.4.3 Sage

[0148] A variety of plants of the genus Salvia are referred to as Sage. Although common sage Salivia officianalis is exemplified and preferred, other species of sage may also be used.

[0149] Various forms of sage can be used as active components. Sage is preferably used as an aqueous extract from the leaves. Most preferably the sage is a extracted using an cthanokwatcr mix, for example a 20:80 ethanokwater mix. The extract can be provided as an extra dry concentrate. In order to aid in formulation, the extract can be combined with an excipient such as maltodextrin.4.4.4 Lemon balm

[0150] The active component Lemon balm, of the species of plant Melissa officinalis, may be used in a variety of forms. An aqueous extract from the leaves of lemon balm is preferred, for example an extract made with an ethanol to water mix. In particular the leaves can be extracted using an ethanol to water 70:30 extract may be used. The extract can be provided as an extra dry concentrate. In order to aid in formulation, the extract can be combined with an excipient such as maltodextrin.4.4.5 Peppermint

[0151] The active component peppermint, from the species of plant Mentha piperita may be used in a variety of forms. Peppermint is preferably utilized as oil, e.g. from the leaves. Methods of making peppermint oil are known.4.4.6 Coptis

[0152] The active component Coptis, i.e. Coptis chinensis may be used in a variety of forms. An extract, e.g. an aqueous extract, from the root and / or rhizome is preferred. In particular the root and / or rhizome can be extracted using an ethanokwater 30:70. The extract can be provided as an extra dry concentrate. In order to aid in formulation, the extract can be combined with an excipient such as maltodextrin.4.4.7 Indian barberry

[0153] The active component Indian barberry, the plant species Herberts aristata, can be used in a variety of forms. An extract, e.g. an aqueous extract from the root is preferred. In particular the root and / or rhizome can be extracted using 100% water. The extract can be provided as an extra dry concentrate. In order to aid in formulation, the extract can be combined with an excipient such as maltodextrin.4.4.8 Berberine

[0154] The active component berberine is an alkaloid compound which is able to be isolated from a number of plants, most notably Berberis vulgaris. It can be utilised in a variety of forms, for example as the raw compound, in salt form, especially the HC1 salt, or as part of an extract, e.g. an ethanokwater extract, from a plant with high levels of berberine. Preferred ia a 95:5, ethanol: water extract. The preferred plant is Berberis vulgaris especially the root of Berberis vulgaris.4.4.9 Chinese skullcap

[0155] Chinese skullcap, the plant Scutellaria baicalensis, can be used in a variety of forms. An extract, e.g. an aqueous extract from the root is preferred. The root can be extracted using a 20:80 ethanol; water mix. The extract can be provided as an extra dry concentrate. In order to aid in formulation, the extract can be combined with an excipient such as maltodextrin.4.4.10 Ginger

[0156] Ginger, as used herein, refers to the root and / or rhizome of Zingiber officinale. Ginger can be used in a variety of forms. An extract, e.g. an aqueous extract is preferred. In particular the extract can be an ethanol: water 20:80 extract on the rhizome. The extract can be provided as an extra dry concentrate. In order to aid in formulation, the extract can be combined with an excipient such as maltodextrin.4.4.11 Dill

[0157] As used herein dill refers to the Anethum graveolens species of plant. A range of parts of the dill plant may be used in different forms. A particularly preferred form uses the seeds of the dill plant. The seeds can be extracted, for example by using an aqueous extraction process, preferably using an ethanol: water 20:80 mix. The extract may be dried and optionally may be combined with an excipient such as maltodextrin.4.4.12 Liquorice

[0158] Liquorice (Glycyrrhiza glabra) can be used in a range of forms. Particularly preferred forms utilise the root of Glycyrrhiza glabra. The root can be subject to an aqueousextraction process, for example in 100% water. The extract may be dried and optionally may be combined with an excipient such as maltodextrin.

[0159] In certain cases the liquorice used herein can be deglycyrrhizinated liquorice (DGL), i.e. liquorice with the glycyrrhizin chemical removed.4.4.13 Marshmallow

[0160] Marshmallow as used herein refers to the marshmallow plant, Althaea officinalis L. Particular forms of marshmallow used herein utilise the root of the plant. In particular an aqueous extract of marshmallow root can be used, for example an extraction with a 20:80 ethanol: ater mix. Optionally the extract can be dried.4.4.14 L-Glutamine

[0161] L-glutamine is an amino acid. A range of sources and forms of L-glutamine can be used. Preferably, the L-glutamine is substantially pure or isolated L-glutamine.4.4.15 Quercetin

[0162] Quercetin is a flavonoid available from a range of plant sources. Preferably the quercetin used herein is in an isolated or pure form. Salt or complex forms of quercetin may also be used. A particularly preferred form of quercetin is quercetin dihydrate.4.4.16 Zinc

[0163] Zinc can be utilised in a range of forms. Particularly preferred are salts of Zinc, for example Zinc oxide.4.4.17 Chinese rhubarb

[0164] Chinese rhubarb, as used herein refers to several members of the Rheum genus of plants, for example Rheum palmatum, Rheum officinale, and Rheum tangguticum. Particularly preferred is Rheum officinale. Preferred forms relate to the root and / or rhizomes of the plant, in particular extracts from the root and / or rhizomes, e.g. aqueous extracts. Extraction of the roots can be, for example, with an 20:80 ethanol: ater mix. The extract may be dried. In certain cases excipients are also added for formulation.4.4.18 Neem

[0165] Neem refers to the plant Azadir ach ta indica. A range of forms of the plant may be used in the invention, in particular the leaf. Extracts, for example aqueous extracts of Neem leaf are a preferred form.4.5 Compositions

[0166] According to one aspect, provided herein are compositions comprising at least one active component selected from 4.3.1 to 4.3.12 above.

[0167] The composition preferably comprises two or more active components, still more preferably three or more active components, still more preferably four or more active components and yet more preferably five or more active components selected from the above.

[0168] Particularly preferably the component or components are present in an effective amount.4.5.1 Composition 1

[0169] In one embodiment provided herein is a first composition comprising oregano (e.g. Origanum vulgare), thyme, Sage (Salvia officinalis), Lemon Balm (Melissa officinalis) and Peppermint.

[0170] In certain embodiments Oregano is present as an oil of Origanum vulgare. The oil may be present in the composition an amount of from about 80 to about 120mg, more preferably from about 90 to about HOmg, still more preferably from about 95 to about 105mg. Most preferably oregano oil is present in the composition in an amount of about lOOmg.

[0171] In certain embodiments Oregano oil (e.g. Origanum vulgare oil) may be present in an amount of from about 10% to about 35% by weight of the active components in the composition, preferably about 15% to about 30%, most preferably about 18% to about 27% by weight. Particularly the oregano oil can be present in an amount of about 24% by weight of the active ingredients.

[0172] Thyme may be present as an oil in an amount of from about 30% to about 70% by weight of the active components in the composition, preferably about 40% by weight to about 60% by weight; more preferably about 45% by weight to about 55% by weight of the active components. Particularly the thyme oil can be present in amount of about 48% by weight of the active ingredients.

[0173] In certain embodiments thyme oil is present in the composition in an amount of from about 160 to about 240mg, more preferably from about 180 to about 220mg, still more preferably from about 190 to about 21 Omg. Most preferably thyme oil is present in an amount of about 200mg.

[0174] A variety of forms of sage (Salvia officinalis) may be suitable for use in the composition. Preferably Salvia officinalis is present in an amount equivalent to the dry leaf of from about 300 to about 500mg, more preferably from about 350 to about 450mg, still morepreferably from about 375 to about 425mg. Most preferably Salvia officinalis is present in an amount equivalent to about 412.5mg of the dry leaf. Preferably Salvia officinalis is included as an extract, for example of the leaf. Preferably the extract is a dry concentrate 5.5: 1 in ethanol: water 20:80. Preferably the Salvia officinalis extract is present in an amount of from about 7% by weight to about 25% by weight of the active ingredients in the composition; more preferably about 10% to about 20% by weight; still more preferably from about 15 to about 19% by weight of active ingredients. Particularly the Salvia officinalis is present in an amount of about 18% by weight of active components in the composition.

[0175] A variety of forms of Lemon Balm (Melissa officinalis) may be suitable for use in the composition. Preferably the Lemon Balm is present in an amount equivalent to the dry leaf of from about 150 to about 400mg, more preferably from about 200 to about 300mg, still more preferably from about 225 to about 275mg. Most preferably Lemon Balm (Melissa officinalis) is present in an amount equivalent to about 250mg of the dry leaf. The Lemon balm can be included as an extract, for example of the leaf. Preferably the extract is a dry concentrate 10: 1 in ethanobwater 70:30. Preferably the lemon balm extract is present in an amount of from 3% to about 10% by weight of the active components in the composition, preferably from 5% to 7% by weight. Particularly the lemon balm extract can be present in an amount of about 6% by weight of the active components in the composition.

[0176] Peppermint can be included as an oil in an amount from about 5 to about 35mg, more preferably from about 10 to about 30mg, still more preferably from about 15 to about 25mg. Most preferably peppermint oil can be included in an amount of about 20mg.

[0177] In other embodiments, the peppermint oil can be present in an amount of about 1% to about 8% by weight of the active components in the composition, preferably in an amount of about 2% to about 7% by weight, more preferably about 3% to about 6% by weight. Particularly the peppermint oil can be present in amount of about 5% by weight of the active components in the composition.

[0178] It is to be understood that where the form of the component varies, the amount present in the composition may also be varied in order to achieve the same effect.4.5.2 - Composition 2

[0179] In another embodiment, provided herein is a composition comprising Coptis chinensis. Berberis cristate. berberine, Scutellaria baicalensis, Zingiber officinale, Rheum officinale, Anethum graveolens, Glycyrrhiza glabra and optionally Neem (Azadirachta indica)\caf.

[0180] A variety of forms of Coptis chinensis may be suitable for use in the composition. Preferably the Coptis chinensis is present at an amount equivalent to the dry root of from about 40 to about 80mg, more preferably from about 50 to about 70mg, still more preferably from about 55 to about 65mg. Most preferably Coptis chinensis is present in an amount equivalent to the dry root of about 60mg. Coptis chinensis can be included as an extract, for example of the root. Preferably the extract is a dry concentrate 4: 1 in ethanol :water=30:70. Preferably the Coptis chinensis extract is present in an amount of from about 1% to about 8% by weight of active components; preferably in an amount of from about 2% to about 7% by weight of active components; still more preferably in an amount of from about 3% to about 6% by weight of active components. Particularly the Coptis chinensis extract can be present in an amount of about 5% by weight of active components.

[0181] A range of forms of Berheris aristata may be suitable for use in the composition. Preferably the Berheris aristata is present in an amount equivalent to the dry root of from about 200 to about 400mg, more preferably from about 250 to about 350mg, still more preferably from about 275 to about 375mg. Most preferably Berheris aristata is present in an amount equivalent to the dry root of about 300mg.

[0182] Berheris aristata can be included as an extract, for example of the root. Preferably the extract is a dry concentrate 20: 1 in 100% water or a 10: 1 extract in 100% water. Preferably the Berheris aristata extract is present in an amount of from about 1% to about 8% by weight of active components; preferably in an amount of from about 2% to about 7% by weight of active components; still more preferably in an amount of from about 3% to about 6% by weight of active components. Particularly the Berheris aristata extract can be present in an amount of about 5% by weight of active components.

[0183] Berberine is preferably present as berberine HC1 for example 97% berberine HC1. The berberine is preferably present as a powder, preferably a powder with a small particle size, preferably a particle size that passes 100% through size 80 mesh. It has been found that a smaller particle size of berberine achieves a better therapeutic effect. It is thought that a small particle size aids in the dispersion of the berberine into different parts of the gut.

[0184] Berberine can be obtained from a range of sources. One source of Berberine is Berheris vulgaris. A range of forms of Berheris vulgaris may be suitable for use in the composition. Preferably the Berheris vulgaris is present in an amount equivalent to the dry root of from about 5 to about 8g, more preferably from about 5.5 to about 7.5g, still more preferablyfrom about 6 to about 7g. Most preferably Berberis vulgaris is present in an amount equivalent to about 6.798g of the dry root.

[0185] Berberis vulgaris can be included as an extract, for example of the dry root. Preferably the extract is a dry concentrate 33: 1 extract in ethanobwater 95:5 or a dry concentrate 30: 1 extract in ethanohwater 30:70. Preferably the Berberine vulgaris extract is an extract which is 97% berberine HC1.

[0186] Preferably the Berberis vulgaris extract is present in an amount of from about 45% to about 75% by weight of active components in the composition, preferably in an amount of from about 50% to about 70%; more preferably in an amount of from about 60 to about 65% by weight of the active components in the composition. Particularly the Berberis vulgaris extract is present in an amount of about 64% by weight of the active components of the composition.

[0187] A range of forms of Scutellaria baicalensis may be suitable for use in the composition. Preferably the Scutellaria baicalensis is present in an amount equivalent to the dry root of from about 200 to about 400mg, more preferably from about 250 to about 350mg, still more preferably from about 275 to about 375mg. Most preferably Scutellaria baicalensis is present in an amount equivalent to about 300mg of the dry root.

[0188] Scutellaria baicalensis can be included as an extract, for example of the root. Preferably the extract is a dry concentrate 20: 1 in ethanohwater 20:80. Preferably the Scutellaria baicalensis extract is present in an amount of from about 1% to about 8% by weight of active components; preferably in an amount of from about 2% to about 7% by weight of active components; still more preferably in an amount of from about 3% to about 6% by weight of active components. Particularly the Scutellaria baicalensis extract can be present in an amount of about 5% by weight of active components.

[0189] A range of forms of Zingiber officinale may be suitable for use in the composition. Preferably the Zingiber officinale is present in an amount equivalent to the dry rhizome of from about 130 to about 200mg, more preferably from about 150 to about 180mg, still more preferably from about 160 to about 170mg. Most preferably Zingiber officinale is present in an amount equivalent to about 165mg of the dry rhizome.

[0190] Zingiber officinale can be included as an extract, for example of the rhizome. Preferably the extract is a dry concentrate 11: 1 in ethanohwater 20:80 or a 10: 1 extract in ethanol: water 20:80. Preferably the Zingiber officinale extract is present in an amount of from about 1% to about 8% by weight of active components; preferably in an amount of from about 2% to about 7% by weight of active components; still more preferably in an amount of fromabout 3% to about 6% by weight of active components. Particularly the Zingiber officinale extract can be present in an amount of about 5% by weight of active components.

[0191] A range of forms of Rheum officinale may be suitable for use in the composition. Preferably Rheum officinale is present in an amount equivalent to the dry root and rhizome of from about 10 to about 20mg, more preferably from about 12 to about 18mg, still more preferably from about 14 to about 16mg. Most preferably Rheum officinale is present in an amount equivalent to about 15mg of the dry root and dry rhizome.

[0192] Rheum officinale can be included as an extract, for example of the root and rhizome. Preferably the extract is a dry concentrate 1 : 1 in ethanobwater 20:80. Preferably the Rheum officinale extract is present in an amount of from about 1% to about 8% by weight of active components; preferably in an amount of from about 2% to about 7% by weight of active components; still more preferably in an amount of from about 3% to about 6% by weight of active components. Particularly the Rheum officinale extract can be present in an amount of about 5% by weight of active components.

[0193] A range of forms of Anethum graveolens may be suitable for use in the composition. Preferably Anethum graveolens is present in an amount equivalent to dry seed of from about 10 to about 40mg, more preferably from about 15 to about 35mg, still more preferably from about 20 to about 30mg. Most preferably Anethum graveolens is present in an amount equivalent to about 25mg of the dry seed. In other embodiments the Anethum graveolens is present in an amount equivalent to the dry seed of about 40mg to about 400mg, preferably about lOOmg to about 300mg, more preferably 200 to 300mg. Most preferably the Anethum graveolens is present in an amount equivalent to about 250mg of the dry seed.

[0194] Anethum graveolens can be included as an extract, for example of the seed. Preferably the extract is a dry concentrate 1 : 1 in ethanol:water=20:80 or a 10: 1 extract in ethanol: water 20:80. Preferably the Anethum graveolens extract is present in an amount of from about 2% to about 11% by weight of active components; preferably in an amount of from about 3% to about 10% by weight of active components; still more preferably in an amount of from about 3% to about 9% by weight of active components. Particularly the Anethum graveolens extract can be present in an amount of about 8% by weight of active components.

[0195] A range of forms of Glycyrrhiza glabra (Liquorice) may be suitable for use in the composition. Preferably the liquorice is deglycyrrhizinated liquorice. Preferably the Glycyrrhiza glabra (Liquorice) is present in an amount equivalent to about 100 to about 300mg of the dry root, more preferably from about 150 to about 250 mg, still more preferably fromabout 175 to about 225mg. Most preferably the Glycyrrhiza glabra is present in an amount equivalent to about 195mg based on the dry root.

[0196] Glycyrrhiza glabra (Liquorice) can be included as an extract, for example of the root. Preferably the extract is a dry concentrate 13: 1 in 100% water or a 10: 1 extract in 100% water. Preferably the Glycyrrhiza glabra extract is present in an amount of from about 1% to about 8% by weight of active components; preferably in an amount of from about 2% to about 7% by weight of active components; still more preferably in an amount of from about 3% to about 6% by weight of active components. Particularly the Glycyrrhiza glabra extract can be present in an amount of about 5% by weight of active components. It is to be understood that where the form of the component varies, the amount present in the composition may also be varied in order to achieve the same effect.

[0197] A range of forms of Neem (Azadirachta indica) may be suitable for use in the composition. Preferably the Neem is present in an amount equivalent to about 5 to about 50mg of the dry leaf, more preferably from about 10 to about 40 mg, still more preferably from about 20 to about 30mg. Most preferably the Neem is present in an amount equivalent to about 23.12mg based on the dry leaf. Preferably Neem is present as powdered dry leaf.4.5.3 Composition s

[0198] In a still further embodiment, provided herein is a composition comprising Glycyrrhiza glabra (Liquorice), L-Glutamine, Althaea officinalis L. (Marshmallow), Quercetin Dihydrate and Zinc.

[0199] A range of forms of Glycyrrhiza glabra may be suitable for use in the composition. Preferably the liquorice is deglycyrrhizinated liquorice. Preferably the Glycyrrhiza glabra (Liquorice) is present in an amount equivalent to about 100 to about 300mg of the dry root, more preferably from about 150 to about 250 mg, still more preferably from about 175 to about 225mg. Most preferably the Glycyrrhiza glabra is present in an amount equivalent to about 195mg based on the dry root.

[0200] Glycyrrhiza glabra can be included as an extract, for example of the root. Preferably the extract is a dry concentrate 13: 1 in 100% water or a 10: 1 extract in 100% water. Preferably the Glycyrrhiza glabra extract is present in an amount of from about 0.5% to about 5% by weight of active components; more preferably in an amount of from about 1% to about 4% by weight of active components; still more preferably in an amount of from about 2% to about 3% by weight of active components. Particularly the Glycyrrhiza glabra extract can be present in an amount of about 2.5% by weight of active components.

[0201] Preferably the L-glutamine is present in an amount of from about 250 to about 750mg, more preferably from about 350 to about 650mg, still more preferably from about 450 to about 550mg. Most preferably L-glutamine is present in an amount about 500mg.

[0202] L-Glutamine can be present in an amount of from 70% to about 95% by weight of active components, preferably from 80% to about 92% by weight of active components, still more preferably in an amount of 85-90% by weight of active components. Particularly the L- Glutamine is present in an amount of about 89% by weight of active components.

[0203] A range of forms of Althaea officinalis L. (Marshmallow) may be suitable for use in the composition. Preferably the Althaea officinalis L is present in an amount equivalent to the dry root of from about 100 to about 400mg, more preferably from about 180 to about 300mg, still more preferably from about 200 to about 250mg. Most preferably Althaea officinalis L. is present in an amount equivalent to about 221mg of the dry root.

[0204] Althaea officinalis L. (Marshmallow) can be included as an extract, for example of the root. Preferably the extract is a dry concentrate 13: 1 in ethanol:water=20:80 or a 10: 1 extract in ethanol:water=20:80. Preferably the Althaea officinalis L extract is present in an amount of from about 0.5% to about 5% by weight of active components; more preferably in an amount of from about 1% to about 4% by weight of active components. Particularly the Althaea officinalis L extract can be present in an amount of about 3% by weight of active components.

[0205] A range of forms of quercetin can be present in the composition, including in the pure form or as hydrate such as the dihydrate. Preferably the quercetin is present in an amount equivalent to the pure form of from about 10 to about 40mg, more preferably from about 15 to about 35mg, still more preferably from about 20 to about 30mg. Most preferably Quercetin is present in an amount equivalent to about 24.7mg of the pure form.

[0206] Quercetin can be included as the dihydrate form as a 95% powder. It is believed that the quercetin dihydrate has greater bioavailability than the pure form. Preferably the quercetin dihydrate is present in an amount of from about 1% to about 10% by weight of active components; more preferably in an amount of from about 2% to about 8% by weight of active components, still more preferably from about 4% to about 6% by weight of active components. Particularly the quercetin dihydrate can be present in an amount of about 5% by weight of active components.

[0207] Zinc can be present in a range of forms, for example as biologically acceptable salts such as zinc oxide. Preferably the zinc is present in an amount equivalent to the elemental form of zinc of from about 1 to about lOmg, more preferably from about 2 to about 8mg, stillmore preferably from about 3 to about 5mg. Most preferably zinc may be present in an amount equivalent to about 3.6mg of the elemental form.

[0208] Zinc can be included as zinc oxide or other suitable form. Preferably the zinc oxide is present in an amount from about 0.5 to about 1.5% by weight of active components, preferably in an amount of from about 0.7% to about 1.1% by weight of active components. Particularly, the zinc oxide can be present in an amount of about 0.8% by weight of active ingredients.

[0209] It is to be understood that where the form of the component varies, the amount present in the composition may also be varied in order to achieve the same effect.4.5.4 Excipients

[0210] The compositions provided herein may further comprise excipients. Suitable excipients include maltodextrin, lecithin, yellow bees wax, soya oil, microcrystalline cellulose, colloidal anhydrous silica and magnesium stearate.4.5.5 Formulation

[0211] The compositions are preferably formulated as an oral dosage form, in particular as a capsule. Capsules may be either hard or soft capsules such as a gel capsule.

[0212] In certain embodiments the capsule may be enterically coated so as to be dispersed in the intestine. In other embodiments the capsule is not enterically coated.4.6 Kit

[0213] In certain instances it may be difficult to formulate all active components into a single composition, either for reasons dosage size, or as a result of incompatible ingredients.

[0214] Thus in another aspect, the provided herein is a kit comprising two or more different compositions as described herein. In certain embodiments the kit comprises three different compositions. In certain embodiments the kit comprises compositions 1, 2 and 3 as described hereinbefore. In still further embodiments the kit comprises instructions for administration.4.7 System

[0215] According to certain embodiments, provided herein is a system comprising a plurality of compositions, the plurality of compositions comprising 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 , 17 and 18 active components selected from oregano (Origanum vulgare) oil, thyme oil, Salvia officinalis, Lemon Balm (Melissa officinalis), Peppermint Oil, Coptis chinensis, Berberis aristata, Berberine, Scutellaria baicalensis, Zingiber officinale, Rheum officinale,Anethum graveolens, Glycyrrhiza glabra (Liquorice), L-Glutamine, Althaea officinalis L. (Marshmallow), S)QQm(Azadirachta indicd), Quercetin and Zinc.

[0216] In certain embodiments the system comprises at least one component from each of categories 4.3.1 to 4.3.13.

[0217] Preferably the system comprises Glycyrrhiza glabra, L-Glutamine, Althaea officinalis L. (Marshmallow), Quercetin and Zinc.

[0218] Preferably the plurality of compositions comprise oregano (Origanum vulgare) oil, thyme oil, Salvia officinalis, Lemon Balm (Melissa officinalis)' , Peppermint Oil, Coptis chlnensls, Berberls arlstata, Berberine, Scutellaria balcalensls, Zingiber officinale, Rheum officinale, Anethum graveolens, Glycyrrhiza glabra (Liquorice), L-Glutamine, Althaea officinalis L. (Marshmallow), Quercetin and Zinc.

[0219] Still more preferably the plurality of compositions further comprise Neem (Azadlractha indicd).

[0220] The active components can be included in the forms, dosages and amounts discussed further in relation to compositions above.4.8 Methods of treatment

[0221] In a further aspect, provided herein are methods of treating or preventing gastrointestinal disorders or symptoms thereof, or improving gut health in a subject in need thereof, comprising administering an effective amount of a composition or kit as described herein before.

[0222] In a still further aspect, provided herein are methods of treating or preventing gastrointestinal disorders or symptoms thereof, or improving gut health in a subject in need thereof, comprising administering an effective amount of one or more of the active components described herein. Preferably the method comprises administering 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 of the active components described herein. In particular the method comprises administering oregano (Origanum vulgare) oil, thyme oil, Salvia officinalis, Lemon Balm (Melissa officinalis), Peppermint Oil, Coptis chinensis, Berberls arlstata, Berberine, Scutellaria baicalensis, Zingiber officinale, Rheum officinale, Anethum graveolens, Glycyrrhiza glabra (Liquorice), L-Glutamine, Althaea officinalis L. (Marshmallow), Quercetin and Zinc. Preferably the method comprises administering Glycyrrhiza glabra (Liquorice), L-Glutamine, Althaea officinalis L. (Marshmallow), Quercetin and Zinc. In certain embodiments the method further comprises administering Neem (Azadirachta indicd).

[0223] In certain embodiments the method comprises administering at least one component from each of categories 4.3.1 to 4.3.13.

[0224] In certain embodiments the gastrointestinal disease is irritable bowel syndrome (IBS). In still further embodiments the IBS is IBS -constipation (IBS-c), IBS-diarrhoea (IBS-d), IBS-mixed (IBS-m) or IBS-undefined (IBS-u).

[0225] In certain embodiments the methods provided herein treat or prevent the symptoms of IBS. Symptoms include bloating, abdominal pain, diarrhoea, constipation, flatulence, lethargy, nausea, heartbum (reflux).

[0226] In certain embodiments the gastrointestinal disorder comprises small intestinal bacterial overgrowth (SIBO) or small intestinal fungal overgrowth (SIFO). In certain embodiments the SIBO is a result of gastrointestinal surgery, SIBO as a result of structural defects in the small intestine including intestinal adhesions, and intestinal diverticulosis, SIBO as a result of Crohn’s disease, radiation enteritis, scleroderma, coeliac disease, diabetes or other conditions that can slow motility through the small intestine. In certain embodiments the SIBO is classified as hydrogen dominant, hydrogen sulfide dominant or methane dominant.

[0227] In certain embodiments the methods herein treat or prevent one or more symptoms of small intestinal bacterial overgrowth including loss of appetite, abdominal pain, nausea, bloating, uncomfortable feeling of fullness after eating, diarrhoea, unintentional weight loss, malnutrition.

[0228] In certain embodiments the methods described herein reduce histamine production in the instetine. Thus in certain embodiments the gastrointestinal disorder is a gastrointestinal disorder associate with inflammation or allergy.

[0229] In certain embodiments the methods herein treat or prevent food intolerances. Exemplary food intolerances are gluten intolerance (e.g. non-Coeliac related gluten intolerance), lactose intolerance, garlic intolerance, onion intolerance, garlic intolerance and / or intolerance to fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPS).

[0230] In certain embodiments the methods provided herein treat IBS or SIBO after stomach or gastrointestinal surgery.

[0231] There is growing evidence of a causal relationship between poor gut health, e.g. dysbiosis and a wide range of other diseases or conditions. Accordingly, the methods provided herein, which address poor gut health and dysbiosis, may also be used for these diseases or conditions. Such conditions include depression, anxiety, and other mental disorders, skindisorders such as acne, eczema and psoriasis and inflammatory disorders such as joint pain or fibromyalgia.

[0232] Recent evidence also shows that poor gut health can be a cause or aggravating factor in a range of diseases, disorders or conditions of the female reproductive system. Accordingly, the methods provided herein may be used to treat or alleviate the symptoms of diseases, disorders or conditions of or related to the female reproductive system. These may include endometriosis, fibroids, recurrent bladder, urinary tract or vaginal infections (including bacterial and fungal infections), abnormal menstruation, including dysmenorrhea, menorrhagia, amenorrhea and premenstrual syndrome (PMS) and perimenopausal symptoms. Many of these disorders are linked to female infertility. Thus the methods provided herein may also be used to treat female infertility.

[0233] Without wanting to be bound by a particular theory, poor gut health and / or gut health is believed to have effects beyond the gut by way of various mechanism. One such mechanism is that gut dybiosis can result in intestinal leakage, which in turn results in an inflammatory response, which can cause or exacerbate inflammatory disorders. The guts role in regulating hormonal balance, especially estrogen clearance and estrogen / proge sterone balance is also well documented. An unhealthy gut can effect estrogen clearance, which effects the estrogen / progesterone balance and can be responsible for a range of disorders of the female reproductive system.

[0234] In a further aspect, provided herein is the use of the components, compositions and kits provided hereinbefore, in the manufacture of a medicament for the treatment or prevention of a disorder according to a method as described above.

[0235] In a still further aspect, provided herein is a composition for use in the method as provided above.4.8.1 Dosages

[0236] Effective amounts or dosages of the components for use in the methods described herein can be determined by the person skilled in the art.

[0237] Oregano (Origanum vulgare) oil can be administered at a dose of from about 80 to about 120mg, more preferably from about 90 to about HOmg, still more preferably from about 95 to about 105mg. Most preferably oregano oil can be administered at a dose of about lOOmg.

[0238] Thyme oil can be administered at a dose of from about 160 to about 240mg, more preferably from about 180 to about 220mg, still more preferably from about 190 to about 210mg. Most preferably thyme oil can be administered at a dose of about 200mg.

[0239] Salvia officinalis can be administered at a dose equivalent to the dry leaf of from about 300 to about 500mg, more preferably from about 350 to about 450mg, still more preferably from about 375 to about 425mg. Most preferably Salvia officinalis can be administered at a dose of about 412.5mg.

[0240] Lemon Balm (Melissa officinalis)' can be administered at a dose equivalent to the dry leaf of from about 150 to about 400mg, more preferably from about 200 to about 300mg, still more preferably from about 225 to about 275mg. Most preferably Lemon Balm (Melissa officinalis) can be administered at a dose of about 250mg.

[0241] Peppermint oil can be administered at a dose of from about 5 to about 35mg, more preferably from about 10 to about 30mg, still more preferably from about 15 to about 25mg. Most preferably peppermint oil can be administered at a dose of about 20mg.

[0242] Coptis chinensis can be administered at a dose equivalent to the dry leaf of from about 40 to about 80mg, more preferably from about 50 to about 70mg, still more preferably from about 55 to about 65mg. Most preferably Coptis chinensis can be administered at a dose of about 60mg.

[0243] Berheris aristata can be administered at a dose equivalent to the dry root of from about 200 to about 400mg, more preferably from about 250 to about 350mg, still more preferably from about 275 to about 375mg. Most preferably Berheris aristata can be administered at a dose of about 300mg.

[0244] Berberine can be administered from, for example, Berheris vulgaris, at a dose equivalent to the dry root of from about 5 to about 8g, more preferably from about 5.5 to about 7.5g, still more preferably from about 6 to about 7g. Most preferably Berheris vulgaris can be administered at a dose of about 6.798g.

[0245] Scutellaria baicalensis can be administered at a dose equivalent to the dry root of from about 200 to about 400mg, more preferably from about 250 to about 350mg, still more preferably from about 275 to about 375mg. Most preferably Scutellaria baicalensis can be administered at a dose of about 300mg.

[0246] Zingiber officinale can be administered at a dose equivalent to the dry rhizome of from about 130 to about 200mg, more preferably from about 150 to about 180mg, still morepreferably from about 160 to about 170mg. Most preferably Zingiber officinale can be administered at a dose of about 165mg.

[0247] Rheum officinale can be administered at a dose equivalent to the dry root and rhizome of from about 10 to about 20mg, more preferably from about 12 to about 18mg, still more preferably from about 14 to about 16mg. Most preferably Rheum officinale can be administered at a dose of about 15mg.

[0248] Anethum graveolens can be administered at a dose equivalent to dry seed of from about 10 to about 40mg, more preferably from about 15 to about 35mg, still more preferably from about 20 to about 30mg. Most preferably Anethum graveolens can be administered at a dose of about 25mg. In other embodiments the Anethum graveolens can be administered in an amount equivalent to the dry seed of about 40mg to about 400mg, preferably about lOOmg to about 300mg, more preferably 200 to 300mg. Most preferably the Anethum graveolens is administered at a dose equivalent to about 250mg of the dry seed.

[0249] Glycyrrhiza glabra can be administered at a dose equivalent to the dry root of from about 100 to about 900mg, more preferably from about 200 to about 700mg, still more preferably from about 300 to about 600mg. Most preferably Glycyrrhiza glabra can be administered at a dose of about 585mg. In certain embodiments Glycyrrhiza glabra may be included in two or more dosage forms, for example in three dosage forms of about 195mg based on the dry root.

[0250] L-glutamine can be administered at a dose of from about 500 to about 1500mg, more preferably from about 700 to about 1300mg, still more preferably from about 900 to about 1 lOOmg. Most preferably L-glutamine can be administered at a dose of about lOOOmg. In certain embodiments L-glutamine may be included in two or more dosage forms, for example in two dosage forms for simultaneous administration at a dosage of about 500mg.

[0251] Althaea officinalis L. (Marshmallow) can be administered at a dose equivalent to the dry root of from about 200 to about 600mg, more preferably from about 300 to about 500mg, still more preferably from about 400 to about 500mg. Most preferably Althaea officinalis L. can be administered at a dose of about 442mg. In certain embodiments Althaea officinalis L. may be included in two or more dosage forms, for example in two dosage forms for simultaneous administration at a dosage of about 221mg.

[0252] Quercetin can be administered at a dose equivalent to the pure form of from about 20 to about 80mg, more preferably from about 30 to about 70mg, still more preferably from about 40 to about 50mg. Most preferably quercetin can be administered at a dose of about49.4mg. In certain embodiments quercetin may be included in two or more dosage forms, for example in two dosage forms for simultaneous administration at a dosage of about 24.7mg.

[0253] Zinc can be administered at a dose equivalent to the elemental form of from about 2.5 to about 20mg, more preferably from about 5 to about 15mg, still more preferably from about 6 to about lOmg. Most preferably zinc can be administered at a dose of about 7.2mg. In certain embodiments zinc may be included in two or more dosage forms, for example in two dosage forms for simultaneous administration at a dosage of about 3.6mg.

[0254] Neem (Azadirachta indica) can be administered in an amount equivalent to about 5 to about 50mg of the dry leaf, more preferably from about 10 to about 40 mg, still more preferably from about 20 to about 30mg. Most preferably the Neem leaf is present in an amount equivalent to about 23.12mg based on the dry leaf. Preferably Neem is present as powdered dry leaf.

[0255] The active components can be administered in the forms described in relation to the compositions and elsewhere above.4.8.2 Dosage regimen

[0256] In certain embodiments the dosages described herein are administered 1, 2 or 3 times daily.

[0257] In certain embodiments the dosages described herein are administered for a period of 6-14 weeks, 6-8 weeks, 10-14 weeks or 14-16 weeks continuously. In certain embodiments this initial treatment is followed by a reduced maintenance dose.

[0258] The dosage regimen may depend on the severity of the gastrointestinal disorder.

[0259] Where the subject has mild gut issues and / or has had issues for less than three months, the doses are administered twice daily. Furthermore, where the subject has mild gut issues and / or has had issues for less than three months dosage is the doses are administered for 6- 8 weeks continuously. The initial treatment may be followed by a maintenance dose, for example of administration of the doses once daily, or of half a dose once daily.

[0260] Where the subject has moderate gut issues and / or has had issues for 3-10 months, the doses are administered twice daily. Furthermore, where the subject has moderate gut issues and / or has had issues for 3-10 months, the doses are administered for 10-14 weeks continuously. The initial treatment may be followed by a maintenance dose, for example of administration of the doses once daily.

[0261] Where the subject has severe gut issues and / or has had issues for greater than 11 months the doses are administered three times daily. Furthermore, where the subject has severe gut issues and / or has had issues for greater than 11 months the doses are administered for 14-16 weeks continuously. The initial treatment may be followed by a maintenance dose, for example of administration of the doses once or twice daily.

[0262] The invention will now be described with reference to the following, non-limiting examples.5 EXAMPLESExample 1: Composition 1 (Fix 1)

[0263] Composition 1 is a soft gel capsule for oral administration. Each capsule has a net weight of 600mg (±7.5%) and a gross weight of 853 mg (±7.5%) and has a disintegration time of not more than 30 minutes. Active ingredients are set out in table 1 :Table 1:

[0264] The capsule further comprises excipients lecithin, yellow bees wax and soya oil to a total amount of 180 mg / unit.

[0265] The capsule shell comprises gelatin, glycerol and purified water to a shell weight subtotal of 253.Example 2: Composition 2 (Fix 2)

[0266] Composition 2 is a hard shell capsule for oral administration. Each capsule has a net weight of 550mg (±7.5%) and a gross weight of 668mg mg (±7.5%) and has a disintegration time of not more than 30 minutes. Active ingredients are set out in table 2:Table 2:

[0267] The capsule further comprises excipients microcrystalline cellulose, colloidal anhydrous silica and magnesium stearate to a total amount of 229 mg / unit.

[0268] The capsule shell is a hard vegetable capsule with a total amount of 118 mg / unit.

[0269] In certain cases this composition may further comprise neem.

[0270] In an alternative formulation the Anethum graveolens ext. dry cone, 1 : 1 in E:W=20:80 is substituted with Anethum graveolens ext. dry cone, 10: 1 in E:W=20:80 in an amount of 2.5mg, being also equivalent to 25mg of the dry seed.Example 3: Composition 3 (Gut fix repair)

[0271] Composition 3 is a hard shell capsule for oral administration. Each capsule has a net weight of 550mg (±7.5%) and a gross weight of 668mg mg (±7.5%) and has a disintegration time of not more than 30 minutes. Active ingredients are set out in table 2:Table 3:

[0272] The capsule further comprises excipients microcrystalline cellulose, colloidal anhydrous silica and magnesium stearate to a total amount of 137.5 mg / unit.

[0273] The capsule shell is a hard vegetable based capsule with a total amount of 118 mg / unit.Example 4: Administration regime

[0274] The compositions are administered based on severity and length of time with conditions.1 Mild issuesFor a subject with mild gut issues (issues for less than 3 months) the recommended dosage is 6-8 weeks without a break at the following dosage. All doses are administered orally:MORNING lx Capsule of composition 1 lx Capsule of composition 22x Capsules of composition 3NIGHT lx Capsule of Composition 1 lx Capsule of Composition 22x Capsules of composition 3Maintenance dose:Halve the dose and take only AM or PM.If issues were very mild before the course only composition 3 may be required for a maintenance dose.For patients who historically had any issues with daily bloating, food sensitivities, constipation, or diarrhoea, even if for less than three months, a half dose AM or PM of Composition 1, 2 and 3 is recommended.2 Moderate issuesFor a subject with moderate gut issues (issues for 3-10 months) the recommended dose is 10-14 weeks without a break at the following dosage:MORNING lx Capsule of composition 1 lx Capsule of composition 22x Capsule of composition 3NIGHT lx Capsule of composition 1 lx Capsule of composition 22x Capsule of composition 3*dose can be upped to 3 times a day if necessary and issues lean towards the more severe sideMaintenance dose:Once daily lx Capsule of composition 1 lx Capsule of composition 22x Capsule of composition 33 Severe issuesFor a subject with severe gut issues (issues for 11+ months) the recommended dose is 14-16 weeks without a break at the following dosage:MORNING lx Capsule of composition 1 lx Capsule of composition 22x Capsule of composition 3MIDDAY lx Capsule of composition 1 lx Capsule of composition 22x Capsule of composition 3NIGHT lx Capsule of composition 1 lx Capsule of composition 22x Capsule of composition 3Maintenance dose:Compositions 1 and 2 x1 and composition 3 x 2 once or twice a day, depending on your needs.Compositions 1 and 2x1 and composition 3x2 once or twice a day. Some cases may require 3x a day for a longer period of time

[0275] In the case studies and examples that follow, the participants had severe issues and followed the regimen for severe issues unless specified otherwise.Example 5: Case study 1

[0276] A 30-year-old female presenting with daily severe bloating, intolerances to gluten, lactose, garlic, and onion, regular fatigue, and breakout in psoriasis when eating certain foods for the most part of her young adult life. The individual saw numerous General practitioners, did numerous stool tests, saw varied naturopaths who prescribed different diets including elimination diet and provided several different supplements to take, none of which made any significant changes.

[0277] The individual suspected SIBO via a process of elimination based on the following symptoms reactive to foods high in fibre shortly after eating, causing gas build up, distension and pain in the upper abdominal region, in conjunction with other reported symptoms. The individual did not have access to breath testing, and local GP claimed never to have heard of SIBO. The individual first opted for antibiotic treatment and was prescribed rifaximin. Rifaximin provided minimal short-term relief before the individual returned to their baseline level of symptoms again.

[0278] The individual began trialling the fixBIOME System (Composition 1, Composition 2 and Composition 3) at a dosage of 3 times daily. They found that after only three days their bloating had significantly reduced and a significant improvement in eneigy levels. After 12 weeks of the fixBIOME system, the individuals’ issues had completely resolved. 5 months post taking the supplements the individual still has no gut issues.Example 6: Case study 2

[0279] A 26-year-old female presenting with IBS diagnosed by their GP, issues involving daily uncomfortable bloating, self-diagnosed gluten and lactose intolerance and irregular bowel movements. The individual has tried numerous probiotics, Inner Health Plus, Low FODMAP diet and other elimination diets with little to no difference noted after taking them.

[0280] After about three weeks of taking the fixBIOME system (Composition 1, Composition 2 and Composition 3), they started to notice they had decreased bloating towards the end of the day and also noticed they could tolerate eating gluten and dairy without reacting.After six weeks of taking the fixBIOME system the individual reported having no bloating and being able to tolerate eating gluten and dairy again fully.Example 7: Case study 3

[0281] A 55 year old female presenting with diagnosed IBS-d would have daily liquid bowel movements needing to go to the bathroom 5-10 times per day. The individual had their gallbladder removed in the mid 30s.

[0282] Within three days of taking the fixBIOME system (Composition 1, Composition 2 and Composition 3), the individual went from going to the bathroom 5-10 times per day to 1-2 times per day and their stool went from type 6-7 on the Bristol stool chart to 4-5. The individual also lost 10 kgs, had better appetite control, less carbohydrate cravings and overall far greater energy. The individual took the system for 6-8 weeks.Example 8: Case study 4

[0283] In this example, a 40 year old female presenting with general undiagnosed gut issues has irregular bowel movements, with a mix of very loose stool and going to the bathroom 4+ times per day, as well as periods of constipation. The individual also struggles with frequent uncomfortable bloating and poor energy levels.

[0284] This individual tried a different dietary supplement to which they saw some mild changes in bowel movements, being slightly more regular with some decrease in bloating also noted. This supplement was taken for 6 weeks.

[0285] The individual then tried another the fixBIOME system as described above ( 2x Fix 1 capsules , 2 x Fix 2 capsules and 4 x Gut fix capsules ), on this occasion they noticed significant changes within 3 days. After some initial stomach discomfort, the individual had regular daily bowel movements and a significant reduction in intensity and frequency of bloating. The individual also took this variant for 6 weeks.Example 9: Case study 5

[0286] In this example, an individual presents with numerous food and histamine intolerances. When eating certain foods, predominately the individual would have histamine reactions resulting in watery eyes and runny nose. They were on a very restrictive diet as a result.

[0287] The individual took the fixBIOME system (2x Fix 1 capsules , 2 x Fix 2 capsules and 4 x Gut fix capsules ) for 8 weeks. Within a couple of weeks they began to notice a reduced reaction to trigger foods and were slowly able to reintroduce trigger foods. After the 8 weeks the individual was able to eat all foods again with no histamine reactions occurring when doing so.Example 10: IBBSI-J

[0288] Clinically meaningful improvements as a result of IBS treatment can be evaluated using the IBSSI. In this example the Japanese version of the IBSSI was used based on Ida, M., Nishida, A., Akiho, H. et al. Evaluation of the irritable bowel syndrome severity index in Japanese male patients with irritable bowel syndrome with diarrhea. BioPsycho Social Med 11, 7 (2017).

[0289] Participants are asked to rate the following from 0 - 100 (100 being the worst) before and after treatment with the fixBIOME system:• Severity of abdominal pain• Frequency of abdominal pain• Intensity of abdominal distention / bloating• Dissatisfaction with bowel habits• Interference with quality of life (QOL)

[0290] All five components contribute to the score equally, yielding overall scores ranging from 0 to 500. IBS severity is graded as mild (75-174), moderate (175-299), or severe (300-500) on the basis of overall scores. Patients who had at least a 50% reduction from baseline (>50% reduction) in IBSSI-J overall score were defined as responders at each evaluation point.

[0291] The results are presented in table 3 :Table 3Discussion

[0292] All participants had IBS graded as severe prior to treatment. All participants showed a substantial reduction in all individual criteria and the overall score following treatment. Moreover, all participants were classed as responders with an overall percentage reduction over >79%.Example 11 : Bristol Stool Chart

[0293] The Bristol Stool Chart (or Bristol Stool Form Scale) is also used as a common tool for assessing efficacy of a treatment for IBS. Participants were asked to rate their stool based on the following:• Type 1 : Separate hard lumps, like nuts (hard to pass)• Type 2: Sausage-shaped, but lumpy• Type 3 : Like a sausage but with cracks on its surface• Type 4: Like a sausage or snake, smooth and soft• Type 5 : Soft blobs with clear cut edges (passed easily)• Type 6: Fluffy pieces with ragged edges, a mushy stool• Type 7 : Watery, no solid pieces, entirely liquid

[0294] Types 3 and 4 are considered normal. Type 1 and Type 2 indicate constipation, type 5 may be indicative of diarrhoea while type 6 and 7 are indicative of diarrhoea. IBS can be categorised into IBS-c (IBS-constipation), IBD-d (IBS -diarrhoea) of IBS-m (IBS-mixed) based on this according to the Rome IV criteria (see Rome IV Criteria - Rome Foundation (theromefoundation.org)).

[0295] Results are set out in table 4.Table 4:Discussion:

[0296] Participants were mixed in their before treatment stool type, suggesting IBS-c (participants 1 and 6), IBS-d (participants 2 and 4) and IBS-m (participants 3, 5 and 7). Despite this, following treatment the participant stool type was universally in the normal range. Thus treatment with the fixBIOME system is effective over all IBS types.Example 12: - IBS General Survey

[0297] Participants were asked to answer a general survey in relation to their gastrointestinal symptoms before and after treatment with the fixBIOME system. Results are set out in table 5 below.Table 5:1Ratings in order of symptom described where 0 is completely relieved, 1 is considerably relieved, 2 is somewhat relieved, 3 is unchanged and 4 is worsened.2Ratings in order of intolerance described where 0 is completely relieved, 1 is considerably relieved, 2 is somewhat relieved, 3 is unchanged and 4 is worsened.Discussion

[0298] The participants all showed a range of IBS or IBS related symptoms which were relieved at least somewhat by the fixBIOME system. Of particular note is the reduction in food intolerances. According to mainstream theories, food intolerances are considered to be a cause of IBS. The effectiveness of the fixBIOME system in reducing these intolerances would suggest that these could be seen as a symptom of IBS rather a cause and further supports the inventors’ theory of the root causes of IBS.

[0299] The effectiveness against food intolerances further suggests that the fixBIOME system may be effective in the treatment of food intolerances in patients who have not been diagnosed with IBS.Example 13: Treatment of SIBO

[0300] A subject undertook hydrogen and methane breath tests for bacterial overgrowth before and after treatment with fixBIOME. Before treatment the methane and hydrogen results indicated the subject was positive for SIBO. Post-treatment results showed a substantial reduction in the amount of both hydrogen and methane, with the subject now being classified as negative for SIBO.Discussion

[0301] Hydrogen and methane breath tests are key criteria in the diagnosis of small intestinal bacterial overgrowth (SIBO). The reduction in hydrogen and methane indicates the effectiveness of fixBIOME in treating SIBO.Example 14: Disorders of the female reproductive system

[0302] Subjects taking the fixBIOME system have reported effects beyond those purely in the gastroinstestinal tract. A significant portion of adult female subjects taking fixBIOME, especially those with difficult periods, have reported reduced menstrual pain, reduced menstrual cramps and / or reduced menstrual bleeding.

[0303] The effect on menstruation is likely attributable to a relationship between the gut health and the female reproductive system, whereby poor gut health can cause or exacerbate a range of disorders of the female reproductive system. Thus use of the fixBIOME system is likely to be suitable for the treatment of or alleviating the symptoms of a range of disorders or conditions of the female reproductive system including endometriosis, fibroids, recurrent bladder, urinary tract or vaginal infections (including bacterial and fungalinfections), abnormal menstruation, including dysmenorrhea, menorrhagia, amenorrhea and premenstrual syndrome (PMS), and perimenopausal symptoms.

[0304] Although the invention is described in detail with reference to specific embodiments thereof, it will be understood that variations which are functionally equivalent are within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description and accompanying drawings. Such modifications are intended to fall within the scope of the appended claims. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

Claims

CLAIMSThe claims defining the invention are as follows:1 A method of treating or preventing a gastrointestinal disorder or symptoms thereof, or improving gut health, in a subject in need thereof, comprising administering an effective amount of 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 , 17 and 18 ofthe active components selected from oregano (Origanum vulgare) oil, thyme oil, Salvia officinalis, Lemon Balm (Melissa officinalis), Peppermint Oil, Coptis chinensis, Berberis aristata, Berberis vulgaris, Scutellaria baicalensis, Zingiber officinale, Rheum officinale, Anethum graveolens, Glycyrrhiza glabra (Liquorice), L-Glutamine, Althaea officinalis L. (Marshmallow), S(QQm(Azadirachta indica). Quercetin and Zinc.2 The method of claim 1, wherein the method comprises administering 17 of the active components.3 The method of claim 1, wherein the method comprises administering 18 of the active components.4 The method according to any one of claims 1 to 3, wherein the gastrointestinal disorder is irritable bowel syndrome (IBS).5 The method according to any one of claims 1 to 4, wherein the gastrointestinal disorder is small intestinal bacterial overgrowth (SIBO) or small intestinal fungal overgrowth (SIFO).6 The method according to any one of claims 1 to 5, wherein the gastrointestinal disorder is associated with inflammation.7 The method according to any one of claims 1-6 wherein the symptom is bloating, abdominal pain, diarrhoea, constipation, flatulence, lethargy, nausea, heartbum or reflux, loss of appetite, nausea, uncomfortable feeling of fullness after eating, unintentional weight loss or malnutrition.8 The method according to any one of claims 1-7 for the treatment or prevention of food intolerances.9 The method of claim 8 wherein the food intolerances are selected from gluten intolerance, lactose intolerance, garlic intolerance, onion intolerance and / or intoleranceto fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPS). A composition comprising oregano (Origanum vulgare) oil, thyme oil, Salvia officinalis, lemon balm (Melissa officinalis)' and peppermint oil. The composition of claim 10, wherein Oregano oil is present in an amount of from about 80 to about 120mg, more preferably from about 90 to about HOmg, still more preferably from about 95 to about 105mg. The composition of claim 11, wherein the oregano oil is present in an amount of about lOOmg. The composition of any one of claims 10 to 12, wherein the Thyme oil is present in an amount of from about 160 to about 240mg, more preferably from about 180 to about 220mg, still more preferably from about 190 to about 21 Omg. The composition of claim 13 wherein the thyme oil is present in amount of about 200mg. The composition of any one of claims 10 to 14, wherein the Salvia officinalis is present as an extract, preferably wherein the extract is a dry concentrate of a 5.5: 1 extract in ethanobwater 20:

80. The composition of any one claims 10 to 15, wherein the Salvia officinalis is present in an amount equivalent to the dry leaf of from about 300 to about 500mg, more preferably from about 350 to about 450mg, still more preferably from about 375 to about 425mg. The composition according to claim 16, wherein the Salvia officinalis is present in an amount equivalent to about 412.5mg of the dry leaf. The composition according to any one of claims 10 to 17, wherein the lemon balm is present as an extract, preferably as a dry concentrate of a 10: 1 extract in ethanoFwater 70:

30. The composition according to any one of claims 10 to 18, wherein the lemon balm is present in an amount equivalent to the dry leaf of from about 150 to about 400mg, morepreferably from about 200 to about 300mg, still more preferably from about 225 to about 275mg. The composition according to claim 18 or 19, wherein the lemon balm is present in an amount equivalent to about 250mg of the dry leaf. The composition according to any one of claims 10 to 20, wherein the peppermint oil is present in an amount from about 5 to about 35mg, more preferably from about 10 to about 30mg, still more preferably from about 15 to about 25mg. The composition according to claim 21, wherein the peppermint oil is present in an amount of about 20mg. A composition comprising Coptis chinensis, Berberis aristata. Berberis vulgaris, Scutellaria baicalensis. Zingiber officinale, Rheum officinale, Anethum graveolens and Glycyrrhiza glabra (Liquorice). The composition according to claim 23, wherein the Coptis chinensis can be included as an extract, preferably the extract is a dry concentrate of a 4: 1 extraction in ethanol : water=30:

70. The composition according to claim 23 or 24, wherein the Coptis chinensis is present at an amount equivalent to the dry root of from about 40 to about 80mg, more preferably from about 50 to about 70mg, still more preferably from about 55 to about 65mg. The composition according to claim 24 or 25, wherein the Coptis chinensis is present in an amount equivalent to the dry root of about 60mg. The composition according to any one of claims 23 to 26, wherein Berberis aristata is included as an extract, preferably wherein the extract is a dry concentrate of a 20: 1 extract in 100% water or a 10: 1 extract in 100% water. The composition according to any one of claims 23 to 27, wherein the Berberis aristata extract is present in an amount equivalent to the dry root of from about 200 to about 400mg, more preferably from about 250 to about 350mg, still more preferably from about 275 to about 375mg. The composition according to claim 28, wherein the Berberis aristata extract is present in an amount equivalent to the dry root of about 300mg.The composition according to any one of claims 23 to 29 wherein the berberine is present as berberine HC1.The composition according to claim 30, wherein the berberine HC1 is 97% berberine HC1 with a particle size that passes 100% through size 80 mesh.The composition according to any one of claims 23 to 29, wherein the berberine is as Berberis vulgaris or an extract thereof, preferably wherein the extract is a dry concentrate of a 33: 1 extract in ethanol: water 95:5 or a dry concentrate of a 30: 1 extract in ethanol: water 30:70.The composition according to claim 32, wherein the Berberis vulgaris extract in an amount equivalent to the dry root of from about 5 to about 8g, more preferably from about 5.5 to about 7.5g, still more preferably from about 6 to about 7g.The composition according to claim 33, wherein the Berberis vulgaris is present in an amount equivalent to about 6.798g of the dry root.The composition according to any one of claims 23 to 34, wherein the Scutellaria baicalensis can be included as an extract, preferably the extract is a dry concentrate of a 20: 1 extract in ethanol :watcr 20:80.The composition according to any one of claims 23 to 35, wherein the Scutellaria baicalensis is present in an amount equivalent to the dry root of from about 200 to about 400mg, more preferably from about 250 to about 350mg, still more preferably from about 275 to about 375mg.The composition according to claim 36, wherein the Scutellaria baicalensis present in an amount equivalent to about 300mg of the dry root.The composition according to any one of claims 23 to 37, wherein the Zingiber officinale can be included as an extract, preferably the extract is a dry concentrate of an 11: 1 extract in ethanohwater 20:80 or a 10: 1 extract in ethanohwater 20:80.The composition according to any one of claims 23 to 37, wherein the Zingiber officinale in an amount equivalent to the dry rhizome of from about 130 to about 200mg, more preferably from about 150 to about 180mg, still more preferably from about 160 to about 170mg.The composition according to claim 39, wherein the Zingiber officinale is present in an amount equivalent to about 165mg of the dry rhizome.The composition according to any one of claims 23-40, wherein the Rheum officinale can be included as an extract, preferably wherein the extract is a dry concentrate of a 1: 1 extract in ethanol: ater 20:

80. The composition according to any one of claims 23 to 41, wherein the Rheum officinale is present in an amount equivalent to the dry root and rhizome of from about 10 to about 20mg, more preferably from about 12 to about 18mg, still more preferably from about 14 to about 16mg. The composition according to claim 42, wherein the Rheum officinale is present in an amount equivalent to about 15mg of the dry root and dry rhizome. The composition according to any one of claims 23-43 wherein Anethum graveolens can be included as an extract, preferably wherein the extract is a dry concentrate of a 1 : 1 extract in ethanol : water=20 : 80, or a dry concentrate of a 10 : 1 extract in ethanol:water=20:

80. The composition according to any one of claims 23-44, wherein the Anethum graveolens is present in an amount equivalent to dry seed of from about 10 to about 40mg, more preferably from about 15 to about 35mg, still more preferably from about 20 to about 30mg. The composition according to claim 44, wherein the Anethum graveolens is present in an amount equivalent to about 25mg of the dry seed. The composition of any one of claims 23-46, wherein the Glycyrrhiza glabra can be included as an extract, preferably wherein the extract is a dry concentrate or a 13: 1 extract in 100% water or a 10: 1 extract in 100% water. The composition according to any one of claims 23 to 47, wherein the Glycyrrhiza glabra is present in an amount equivalent to about 100 to about 300mg of the dry root, more preferably from about 150 to about 250 mg, still more preferably from about 175 to about 225mg. The composition according to claim 48 wherein Glycyrrhiza glabra is present in an amount equivalent to about 195mg based on the dry root. The composition according to any one of claims 23 to 49, further comprising Neem (Azadirachta indica).The composition according to claim 50, wherein the Neem is present in an amount equivalent to about 5 to about 50mg of the dry leaf, more preferably from about 10 to about 40 mg, still more preferably from about 20 to about 30mg.The composition according to claim 51, wherein the Neem is present in an amount equivalent to about 23.12mg based on the dry leaf.The composition according to any one of claims 50 to 52, wherein the Neem is present as powdered dry leaf.A composition comprising Glycyrrhiza glabra, L-Glutamine, Althaea officinalis L. (Marshmallow), Quercetin Dihydrate and Zinc.The composition according to claim 54, wherein the Glycyrrhiza glabra can be included as an extract, preferably wherein the extract is a dry concentrate of a 13: 1 extract in 100% water or a 10: 1 extract in 100% water.The composition of claim 54 or 55, wherein the Glycyrrhiza glabra is present in an amount equivalent to about 100 to about 300mg of the dry root, more preferably from about 150 to about 250 mg, still more preferably from about 175 to about 225mg.The composition of claim 56, wherein the Glycyrrhiza glabra is present in an amount equivalent to about 195mg based on the dry root.The composition of any one of claims 54 to 57, wherein L-Glutamine is present in an amount of from about 250 to about 750mg, more preferably from about 350 to about 650mg, still more preferably from about 450 to about 550mg. Most preferably L- glutamine is present in an amount about 500mg.The composition of claim 58, wherein the L-Glutamine is present in an amount about 500mg.The composition of any one of claims 54-59 wherein the Althaea officinalis L. (Marshmallow) is included as an extract, preferably wherein the extract is a dry concentrate 13: 1 in ethanol: water=20: 80 or a 10: 1 extract in ethanol:water=20:80.The composition of any one of claims 54 to 60, wherein the Althaea officinalis L is present in an amount equivalent to the dry root of from about 100 to about 400mg, more preferably from about 180 to about 300mg, still more preferably from about 200 to about 250mg.62 The composition of claim 61, wherein the Althaea officinalis L. is present in an amount equivalent to about 22 Img of the dry root.63 The composition of any one of claims 54 to 62, wherein quercetin is included as the Dihydrate form as a 95% powder.64 The composition according to any one of claims 54 to 63, wherein the quercetin is present in an amount equivalent to the pure form of from about 10 to about 40mg, more preferably from about 15 to about 35mg, still more preferably from about 20 to about 30mg.65 The composition according to claim 64, wherein the quercetin is present in an amount equivalent to about 24.7mg of the pure form.66 The composition according to any one of claims 54-65, wherein zinc is included as zinc oxide.67 The composition according to claim 54 to 65, wherein the zinc is present in an amount equivalent to the elemental form of zinc of from about 1 to about 1 Omg, more preferably from about 2 to about 8mg, still more preferably from about 3 to about 5mg.68 The composition according to claim 67, wherein, the zinc present in an amount equivalent to about 3.6mg of the elemental form.69 The composition according to any one of claims 10 to 68 which is formulated for oral administration.70 The composition according to any one of claims 10 to 69, further comprising one or more excipients.71 The composition according to any one of claims 10 to 70, wherein the composition is in the form of a capsule.72 The composition according to any one of claims 10-71, wherein the composition is enterically coated.73 A kit comprising two or more of the compositions as defined in any one of claims 10 to 72.74 The kit according to claim 73 comprising: a. a composition as defined in any one of claims 10 to 22;b. a composition as defined in any one of claims 23 to 53; and c. a composition as defined in any one of claims 54 to 68.75 The kit of claim 73 or 74, further comprising instructions for administration.76 A system comprising a plurality of compositions, the plurality of composition comprising 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 , 17 and 18 active components selected from oregano (Origanum vulgare) oil, thyme oil, Salvia officinalis, Lemon Balm (Melissa officinalis)' , Peppermint Oil, Coptis chinensis, Berberis aristata., Berberis vulgaris, Scutellaria baicalensis, Zingiber officinale, Rheum officinale, Anethum graveolens, Glycyrrhiza glabra, L-Glutamine, Althaea officinalis L. (Marshmallow), Neem (Azadirachta indica), Quercetin and Zinc.77 The system of claim 76, wherein the plurality of compositions comprise oregano (Origanum vulgare) oil, thyme oil, Salvia officinalis, Lemon Balm (Melissa officinalis), Peppermint Oil, Coptis chinensis, Berberis aristata, Berberis vulgaris, Scutellaria baicalensis, Zingiber officinale, Rheum officinale, Anethum graveolens, Glycyrrhiza glabra, L-Glutamine, Althaea officinalis L. (Marshmallow), Quercetin and Zinc.78 The system of claim 77 wherein the plurality of compositions further comprise Neem (Azadirachta indica).79 A method of treating or preventing a gastrointestinal disorder or symptoms thereof , or improving gut health in a subject in need thereof, comprising administering an effective amount of a composition of any one of claims 10 to 68.80 A method of treating a disease, disorder or condition associated with poor gut health and / or alleviating symptoms thereof, in a subject in need thereof, comprising administering an effective amount of a composition of any one of claims 10 to 68.81 The method of claim 80, wherein the disease, disorder or condition associated with poor gut health is a mental disorder, a skin disorders, an inflammatory disorder or a disease, disorder or condition of the female reproductive tract.82 The method according to claim 81 wherein the mental disorder is anxiety or depression.83 The method according to claim 81, wherein the skin disorder is selected from acne, psoriasis or eczema.The method according to claim 81, wherein the inflammatory disease, disorder or condition is selected from as joint pain or fibromyalgia. The method according to claim 81, wherein the disease, disorder or condition of the female reproductive system is selected from endometriosis, fibroids, recurrent bladder, urinary tract or vaginal infections (including bacterial and fungal infections), abnormal menstruation, including dysmenorrhea, menorrhagia, amenorrhea and premenstrual syndrome (PMS), perimenopausal symptoms and female infertility. The method according to any one of claims 79 to 85 which comprises: a. administration of a composition as defined in any one of claims 10 to 23 ; b. administration of a composition as defined in any one of claims 24 to 53 ; and c. administration of a composition as defined in any one of claims 54 to 68. The method according to claim 86, wherein steps a, b and c are conducted twice daily. The method according to claim 87, wherein steps a, b and c are conducted three times daily. A method of treating or preventing a a disease, disorder or condition associated with poor gut health and / or alleviating symptoms thereof, in a subject in need thereof, comprising administering an effective amount of 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 , 17 and 18 of the active components selected from oregano (Origanum vulgare) oil, thyme oil, Salvia officinalis, Lemon Balm (Melissa officinalis)' , Peppermint Oil, Coptis chinensis, Berberis aristata, Berberis vulgaris, Scutellaria baicalensis, Zingiber officinale, Rheum officinale, Anethum graveolens, Glycyrrhiza glabra (Liquorice), L- Glutamine, Althaea officinalis L. (Marshmallow), S)QQm(Azadirachta indica), Quercetin and Zinc. The method of claim 1, wherein the method comprises administering 17 of the active components. The method of claim 1, wherein the method comprises administering 18 of the active components. The method of claims 89-91, wherein the disease, disorder or condition associated with poor gut health is a mental disorder, a skin disorders, an inflammatory disorder or a disease, disorder or condition of the female reproductive tract.The method according to claim 92 wherein the mental disorder is anxiety or depression. The method according to claim 92, wherein the skin disorder is selected from acne, psoriasis or eczema. The method according to claim 92, wherein the inflammatory disease, disorder or condition is selected from as joint pain or fibromyalgia. The method according to claim 92, wherein the disease, disorder or condition of the female reproductive system is selected from endometriosis, fibroids, recurrent bladder, urinary tract or vaginal infections (including bacterial and fungal infections), abnormal menstruation, including dysmenorrhea, menorrhagia, amenorrhea and premenstrual syndrome (PMS), perimenopausal symptoms and female infertility.

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