AU2015100952A4 - Probiotic- and enzyme-containing compositions and uses thereof - Google Patents

Abstract

H:\mdt\Interwove\NRPortl\DCC\MD'IRO77983_1.dx-17/07/2015 Abstract Provided herein are compositions for improving gut function, for the therapeutic or prophylactic treatment of gut proinflammation and/or for the treatment or prevention of dysbiotic gut or a condition associated therewith, comprising one or more probiotic bacterial strains selected from Lactobacillus rhamnosus, Lactobacillus plantarum, Lactobacillus bulgaricus, Lactobacillus gasseri, Lactobacillus reuteri, Lactobacillus paracasei, Lactobacillus casei, Lactobacillus acidophilus, Lactobacillus fermentum, Lactobacillus salvarius, Lactococcus lactis, Streptococcus thermophilus, Bifidobacterium breve, Bifidobacterium bifidum, Bifidobacterium animalis subsp. lactis (B. lactis), Bifidobacterium animalis subsp. animalis, Bifidobacterium infantis, Bifidobacterium longum and Bifidobacterium pseudocatenulatum; and one or more digestive enzymes and/or digestive enzyme-containing extracts.

Description

H: ndt\Interwoven\NRPortbl\DCC\MDT\8077983_1.docx-17/07/2015 Probiotic- and enzyme-containing compositions and uses thereof Field of the Art [0001] The present disclosure relates generally to compositions and methods to provide combinations of enzyme supplements and probiotic strains useful for aiding digestion, relieving symptoms associated with indigestion, altered bowel movements, gastrointestinal discomfort and symptoms associated with an irritable bowel such as gas, bloating, constipation and loose stools. The combinations and methods also provide for the therapeutic and/or prophylactic treatment, amelioration and/or regulation of disease states or pathological conditions associated with dysfunction or dysbiosis of the gastrointestinal tract, such as disturbances in food digestion, assimilation and absorption. Background [0002] The digestive system serves in the digestion / absorption of nutrients, both macronutrients (for example proteins, lipids and carbohydrates) and micronutrients (for example vitamins and minerals), and the removal of catabolic / metabolic waste products from the gastrointestinal tract, and to subsequently maintain metabolic balance in the gastrointestinal tract. Failure to properly digest food may lead to inadequate nutrient assimilation that may ultimately lead to acute or chronic nutrient deficits, increasing the risk of disease. Dietary habits and trends in food production and consumption have health, environmental and social impacts. Diet has direct implications for gastrointestinal health. Gastrointestinal complications such as ulcerative colitis, Crohn's disease, irritable bowel syndrome and refractory coeliac disease result from overgrowth and imbalance of intestinal microbial flora, and have been related to different dietary food consumptions. This overgrowth and imbalance of intestinal microbial flora can significantly impact on nutrient absorption in the gastrointestinal tract, with the overall effect of these adverse factors being to increase the risk of disease, in particular in older age groups. [0003] Enzymes are essential to the body's absorption and complete assimilation of food products and there is a high demand for digestive enzymes following a meal. Digestive enzymatic activity begins in the mouth where salivary amylase, lingual lipase, and ptyalin initiate starch and fat digestion. In the stomach, hydrochloric acid activates pepsinogen to H: ndt\Interwoven\NRPortbl\DCC\MDT\8077983_1.docx-17/07/2015 -2 pepsin which breaks down protein, and gastric lipase begins the hydrolysis of fats. Without these initial proper enzyme productions, digesting ingested food becomes difficult, often resulting in a variety of chronic disorders. Poor eating habits, including inadequate chewing and eating on the run or quickly, may result in inadequate enzyme production and, hence, can lead to mal-absorption of food components. This may be significantly exacerbated by the aging process. Aging causes many people to experience problems with digestion, and digestive problems have been extensively linked to the infirmities of old age. It has been estimated that in older adults, after age 40, there is estimated to be a decrease in the body's ability to produce enzymes by a factor of 2 0

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3 0 %. [0004] The gastrointestinal system is primordial in chronic disease development and in the aged as it can be the source of over assimilation of nutrient absorption (e.g. obesity), or the source of under assimilation of nutrient absorption due to a deficit of digestive activity, for example as predicated by a loss of enzyme activity. The administration of specific enzymes in the form of supplements can assist to improve the efficiency of digestion and hence the absorption and utilization of nutrients. [0005] There is a need for new methods and compositions for improving organ function, for the treatment and prevention of obesity and its related chronic diseases and for the treatment and the prevention of conditions associated with or causative from obesity, such as dysbiosis of the gastrointestinal tract. Summary of the Disclosure [0006] In a first aspect the present disclosure provides a method for the therapeutic or prophylactic treatment of gut proinflammation and/or for improving gut function, the method comprising administering to a subject in need thereof: (i) an effective amount of one or more probiotic bacterial strains selected from Lactobacillus rhamnosus, Lactobacillus plantarum, Lactobacillus bulgaricus, Lactobacillus gasseri, Lactobacillus reuteri, Lactobacillus paracasei, Lactobacillus case, Lactobacillus acidophilus, Lactobacillus fermentum, Lactobacillus salvarius, Lactococcus lactis, Streptococcus thermophilus, Bifidobacterium breve, Bifidobacterium bifidum, Bifidobacterium animals subsp. lactis (B. lactis), H: ndt\Interwoven\NRPortbl\DCC\MDT\8077983_1.docx-17/07/2015 -3 Bifidobacterium animals subsp. animalis, Bifidobacterium infantis, Bifidobacterium longum and Bifidobacterium pseudocatenulatum; and (ii) an effective amount of one or more digestive enzymes and/or digestive enzyme containing extracts. [0007] The gut proinflammation may be associated with, or prognostic of susceptibility to and/or development of, a chronic disease. The chronic disease may be selected from, for example, ulcerative colitis, Crohn's disease, irritable bowel syndrome, refractory coeliac disease, obesity, type 2 diabetes mellitus, chronic kidney disease, and fatty liver disease e.g., Non Alcoholic Fatty Liver Disease [NAFLD]). [0008] Improving gut function may comprise facilitating or improving food or food product transit through the gastrointestinal tract, the absorption of nutrients from said food or food products, and/or the assimilation of nutrient s from said food or food products. [0009] Improving gut function may comprise relieving one or more symptoms associated with indigestion, altered bowel movements, gastrointestinal discomfort or one or more symptoms associated with an irritable bowel. Such symptoms associated with an irritable bowel include gas, bloating, constipation and loose stools. [0010] In particular embodiments the bacterial strains are selected from Lactobacillus rhamnosus, Lactobacillus acidophilus, Bipdobacterium bifidum and Bifidobacterium lactis. In a particular embodiment the method comprises administering a multi-strain combination of Lactobacillus rhamnosus, Lactobacillus acidophilus, Bifidobacterium bifidum and Bifidobacterium lactis. [0011] Typically the digestive enzymes are selected from an amylase, a protease and a lipase or a combination thereof In an exemplary embodiment, the amylase is obtained or derived from an Aspergillus sp., such as Aspergillus oryzae. In an exemplary embodiment, the protease is obtained or derived from an Aspergillus sp., such as Aspergillus oryzae. In an exemplary embodiment, the lipase is obtained or derived from a Rhizopus sp., such as Rhizopus oryzae.

H: ndt\Interwoven\NRPortbl\DCC\MDT\8077983_1.docx-17/07/2015 -4 [0012] The enzyme-containing extract may comprise, for example, papain or a bromelain. In an exemplary embodiment, the papain is obtained or derived from Carica papaya. In an exemplary embodiment, the bromelain is obtained or derived from Ananas comosus. [0013] The method may comprise the administration of a multi-strain combination of probiotic organisms and one or more digestive enzymes or digestive enzyme-containing extracts. [0014] The method may further comprise administration to the subject of an effective amount of one or more yeast strains. The yeast may be a Saccharomyces species, such as S. cerevisiae or S. boulardii. [0015] The method may further comprise administration to the subject of one or more prebiotic components. In an exemplary embodiment the prebiotic is FOS. The prebiotic may be administered in the same composition as the probiotic strain(s) or in a different composition. [0016] In a second aspect the present disclosure provides a composition for the therapeutic or prophylactic treatment of gut proinflammation and/or for improving gut function, wherein the composition comprises: (i) one or more probiotic bacterial strains selected from Lactobacillus rhamnosus, Lactobacillus plantarum, Lactobacillus bulgaricus, Lactobacillus gasseri, Lactobacillus reuteri, Lactobacillus paracasei, Lactobacillus case, Lactobacillus acidophilus, Lactobacillus fermentum, Lactobacillus salvarius, Lactococcus lactis, Streptococcus thermophilus, Bijidobacterium breve, Bipdobacterium bifidum, Bifidobacterium animals subsp. lactis (B. lactis), Bifidobacterium animalis subsp. animalis, Bifidobacterium infantis, Bipdobacterium longum and Bipdobacterium pseudocatenulatum; and (ii) one or more digestive enzymes and/or digestive enzyme-containing extracts.

H: ndt\Interwoven\NRPortbl\DCC\MDT\8077983_1.docx-17/07/2015 -5 [0017] The gut proinflammation may be associated with, or prognostic of susceptibility to and/or development of, a chronic disease. The chronic disease may be selected from, for example, ulcerative colitis, Crohn's disease, irritable bowel syndrome, refractory coeliac disease and obesity. [0018] Improving gut function may comprise facilitating or improving food or food product transit through the gastrointestinal tract, the absorption of nutrients from said food or food products, or the assimilation of nutrient s from said food or food products. [0019] Improving gut function may comprise relieving one or more symptoms associated with indigestion, altered bowel movements, gastrointestinal discomfort or one or more symptoms associated with an irritable bowel. Such symptoms associated with an irritable bowel include gas, bloating, constipation and loose stools. [0020] In particular embodiments the bacterial strains are selected from Lactobacillus rhamnosus, Lactobacillus acidophilus, Bipdobacterium bifidum and Bifidobacterium lactis. In a particular embodiment the composition comprises a multi-strain combination of Lactobacillus rhamnosus, Lactobacillus acidophilus, Bifidobacterium bifidum and Bifidobacterium lactis. [0021] Typically the digestive enzymes are selected from an amylase, a protease and a lipase or a combination thereof. In an exemplary embodiment, the amylase is obtained or derived from an Aspergillus sp., such as Aspergillus oryzae. In an exemplary embodiment, the protease is obtained or derived from an Aspergillus sp., such as Aspergillus oryzae. In an exemplary embodiment, the lipase is obtained or derived from a Rhizopus sp., such as Rhizopus oryzae. [0022] The enzyme-containing extract may comprise, for example, papain or a bromelain. In an exemplary embodiment, the papain is obtained or derived from Carica papaya. In an exemplary embodiment, the bromelain is obtained or derived from Ananas comosus.

H: ndt\Interwoven\NRPortbl\DCC\MDT\8077983_1.docx-17/07/2015 -6 [0023] The composition may comprise a multi-strain combination of probiotic organisms and one or more digestive enzymes or digestive enzyme-containing extracts. [0024] The composition may further comprise administration to the subject of an effective amount of one or more yeast strains. The yeast may be a Saccharomyces species, such as S. cerevisiae or S. boulardii. [0025] The composition may further comprise administration to the subject of one or more prebiotic components. In an exemplary embodiment the prebiotic is FOS. [0026] In a third aspect the present disclosure provides a method for the treatment or prevention of dysbiotic gut or a condition associated therewith, the method comprising administering to a subject in need thereof: (i) an effective amount of one or more probiotic bacterial strains selected from Lactobacillus rhamnosus, Lactobacillus plantarum, Lactobacillus bulgaricus, Lactobacillus gasseri, Lactobacillus reuteri, Lactobacillus paracasei, Lactobacillus case, Lactobacillus acidophilus, Lactobacillus fermentum, Lactobacillus salvarius, Lactococcus lactis, Streptococcus thermophilus, Bifidobacterium breve, Bifidobacterium bifidum, Bifidobacterium animals subsp. lactis (B. lactis), Bifidobacterium animalis subsp. animalis, Bifidobacterium infantis, Bifidobacterium longum and Bifidobacterium pseudocatenulatum; and (ii) an effective amount of one or more digestive enzymes and/or digestive enzyme containing extracts. [0027] The condition may be selected from, for example, ulcerative colitis, Crohn's disease, irritable bowel syndrome, refractory coeliac disease, obesity, type 2 diabetes mellitus, chronic kidney disease, and fatty liver disease (e.g., Non Alcoholic Fatty Liver disease [NAFLD]). [0028] The treatment may comprise relieving one or more symptoms of dysbiotic gut or a condition associated therewith. For example, in the case of an irritable bowel, symptoms include gas, bloating, constipation and loose stools.

H: ndt\Interwoven\NRPortbl\DCC\MDT\8077983_1.docx-17/07/2015 -7 [0029] In particular embodiments the bacterial strains are selected from Lactobacillus rhamnosus, Lactobacillus acidophilus, Bipdobacterium bifidum and Bifidobacterium lactis. In a particular embodiment the method comprises administering a multi-strain combination of Lactobacillus rhamnosus, Lactobacillus acidophilus, Bifidobacterium bifidum and Bifidobacterium lactis. [0030] Typically the digestive enzymes are selected from an amylase, a protease and a lipase or a combination thereof. In an exemplary embodiment, the amylase is obtained or derived from an Aspergillus sp., such as Aspergillus oryzae. In an exemplary embodiment, the protease is obtained or derived from an Aspergillus sp., such as Aspergillus oryzae. In an exemplary embodiment, the lipase is obtained or derived from a Rhizopus sp., such as Rhizopus oryzae. [0031] The enzyme-containing extract may comprise, for example, papain or a bromelain. In an exemplary embodiment, the papain is obtained or derived from Carica papaya. In an exemplary embodiment, the bromelain is obtained or derived from Ananas comosus. [0032] The method may comprise the administration of a multi-strain combination of probiotic organisms and one or more digestive enzymes or digestive enzyme-containing extracts. [0033] The method may further comprise administration to the subject of an effective amount of one or more yeast strains. The yeast may be a Saccharomyces species, such as S. cerevisiae or S. boulardii. [0034] The method may further comprise administration to the subject of one or more prebiotic components. In an exemplary embodiment the prebiotic is FOS. The prebiotic may be administered in the same composition as the probiotic strain(s) or in a different composition.

H: ndt\Interwoven\NRPortbl\DCC\MDT\8077983_1.docx-17/07/2015 [0035] In a fourth aspect the present disclosure provides a composition for the treatment or prevention of dysbiotic gut or a condition associated therewith, wherein the composition comprises: (i) one or more probiotic bacterial strains selected from Lactobacillus rhamnosus, Lactobacillus plantarum, Lactobacillus bulgaricus, Lactobacillus gasseri, Lactobacillus reuteri, Lactobacillus paracasei, Lactobacillus case, Lactobacillus acidophilus, Lactobacillus fermentum, Lactobacillus salvarius, Lactococcus lactis, Streptococcus thermophilus, Bifidobacterium breve, Bifidobacterium bifidum, Bifidobacterium animals subsp. lactis (B. lactis), Bifidobacterium animalis subsp. animalis, Bifidobacterium infantis, Bipdobacterium longum and Bipdobacterium pseudocatenulatum; and (ii) one or more digestive enzymes and/or digestive enzyme-containing extracts. [0036] The condition may be selected from, for example, ulcerative colitis, Crohn's disease, irritable bowel syndrome, refractory coeliac disease, obesity, type 2 diabetes mellitus, chronic kidney disease, and fatty liver disease (e.g., Non Alcoholic Fatty Liver Disease [NAFLD]). [0037] The treatment may comprise relieving one or more symptoms of dysbiotic gut or a condition associated therewith. For example, in the case of an irritable bowel, symptoms include gas, bloating, constipation and loose stools. [0038] In particular embodiments the bacterial strains are selected from Lactobacillus rhamnosus, Lactobacillus acidophilus, Bipdobacterium bifidum and Bifidobacterium lactis. In a particular embodiment the composition comprises a multi-strain combination of Lactobacillus rhamnosus, Lactobacillus acidophilus, Bifidobacterium bifidum and Bifidobacterium lactis. [0039] Typically the digestive enzymes are selected from an amylase, a protease and a lipase or a combination thereof. In an exemplary embodiment, the amylase is obtained or derived from an Aspergillus sp., such as Aspergillus oryzae. In an exemplary embodiment, the protease is obtained or derived from an Aspergillus sp., such as Aspergillus oryzae. In an H: ndt\Interwoven\NRPortbl\DCC\MDT\8077983_1.docx-17/07/2015 -9 exemplary embodiment, the lipase is obtained or derived from a Rhizopus sp., such as Rhizopus oryzae. [0040] The enzyme-containing extract may comprise, for example, papain or a bromelain. In an exemplary embodiment, the papain is obtained or derived from Carica papaya. In an exemplary embodiment, the bromelain is obtained or derived from Ananas comosus. [0041] The composition may comprise a multi-strain combination of probiotic organisms and one or more digestive enzymes or digestive enzyme-containing extracts. In one exemplary embodiment, the multi-strain probiotic combination comprises L. rhamnosus, L. acidophilus, B. lactis, and B. bifidum. [0042] The composition may further comprise administration to the subject of an effective amount of one or more yeast strains. The yeast may be a Saccharomyces species, such as S. cerevisiae or S. boulardii. [0043] The composition may further comprise administration to the subject of one or more prebiotic components. In an exemplary embodiment the prebiotic is FOS. [0044] Compositions according to the second and fourth aspects are typically in a form suitable for oral administration. The composition may be a solid or liquid composition. In one embodiment, the composition is in the form of capsules. The composition may be in the form of a beverage or food supplement. [0045] In accordance with methods of the present disclosure compositions disclosed herein may be administered to subjects in need thereof as food or drink supplements. The compositions may also be administered as an adjunct to one or more other treatments or therapies for a chronic disease, dysbiotic gut or conditions associated therewith. [0046] Also provided herein is the use of. one or more probiotic bacterial strains selected from Lactobacillus rhamnosus, Lactobacillus plantarum, Lactobacillus bulgaricus, H: ndt\Interwoven\NRPortbl\DCC\MDT\8077983_1.docx-17/07/2015 - 10 Lactobacillus gasseri, Lactobacillus reuteri, Lactobacillus paracasei, Lactobacillus case, Lactobacillus acidophilus, Lactobacillus fermentum, Lactobacillus salvarius, Lactococcus lactis, Streptococcus thermophilus, Bifidobacterium breve, Bifidobacterium bifidum, Bifidobacterium animals subsp. lactis (B. lactis), Bifidobacterium animals sub sp. animalis, Bifidobacterium infantis, Bifidobacterium longum and Bifidobacterium pseudocatenulatum; and one or more digestive enzymes or digestive enzyme-containing extracts, for the manufacture of a composition for treating or preventing dysbiotic gut or conditions associated therewith, or for treating or preventing gut proinflammation and/or for improving gut function. Detailed Description [0047] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, typical methods and materials are described. [0048] The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element. [0049] In the context of this specification, the term "about," is understood to refer to a range of numbers that a person of skill in the art would consider equivalent to the recited value in the context of achieving the same function or result. [0050] Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. [0051] In the context of this specification, the term "probiotic" is to be given its broadest H: mdt\lInterwoven\NRPortbl\DCC\MDT\8077983_1.docx-17/07/2015 - 11 construction and is understood to refer to a microbial cell population or preparation, or component of a microbial cell population or preparation, which when administered to a subject in an effective amount promotes a health benefit in the subject. [0052] As used herein the term "digestive enzyme" refers to any enzyme or molecule possessing enzymatic activity, or group of enzymes or molecules possessing enzymatic activity, that catalyse the breakdown of macromolecules, typically occurring as constituents of food. [0053] As used herein the term "extract", when used in the context of a digestive enzyme-containing extract, refers to a preparation comprising enzymatic activity, typically one or more enzymes or molecules possessing enzymatic activity, obtained or derived from a source such as a microbial organism, fungus or plant. An extract may be obtained by a process of "extraction" which will be understood by those skilled in the art as, in general terms, comprising treating originating material, such as a microbial organism culture or culture supernatant, a fungal culture or culture supernatant or a plant or plant material with a solvent, a liquid, or a supercritical fluid to dissolve the preparation and separate the same from residual unwanted material. [0054] As used herein the term "derived" in the context of a digestive enzyme or extract derived from an organism means that the enzyme may correspond to, originate from, or otherwise shares significant homology with a naturally occurring or native enzyme found in the organism. Those skilled in the art will also understand that by being "derived" from a naturally occurring or native enzyme, the derived enzyme need not be physically obtained from the organism, but may be chemically synthesised or generated by other molecular biology techniques known in the art. [0055] In the context of this specification, the term "prebiotic" is to be given its broadest construction and is understood to refer to any non-digestible substance that stimulates the growth and/or activity of bacteria in the digestive system. [0056] In the context of this specification, the terms "food", "foods", "beverage" or H: ndt\Interwoven\NRPortbl\DCC\MDT\8077983_1.docx-17/07/2015 - 12 "beverages" include but are not limited to health foods and beverages, functional foods and beverages, and foods and beverages for specified health use. When such foods or beverages of the present invention are used for subjects other than humans, the terms can be used to include a feedstuff. [0057] The term "subject" as used herein refers to any mammal, including, but not limited to, livestock and other farm animals (such as cattle, goats, sheep, horses, pigs and chickens), performance animals (such as racehorses), companion animals (such as cats and dogs), laboratory test animals and humans. Typically the subject is a human. [0058] As used herein, the term "effective amount" refers to an amount of a probiotic composition that is sufficient to effect one or more beneficial or desired outcomes. An "effective amount" can be provided in one or more administrations. The exact amount required will vary depending on factors such as the identity and number of individual probiotic strains employed, the subject being treated, the nature of any disease or condition suffered by the subject that is the treated and the age and general health of the subject, and the form in which the composition is administered. Thus, it is not possible to specify an exact "effective amount". However, for any given case, an appropriate "effective amount" may be determined by one of ordinary skill in the art using only routine experimentation. [0059] As used herein the terms "treating", "treatment" and the like refer to any and all applications which remedy, or otherwise hinder, retard, or reverse the progression of, an infection or disease or at least one symptom of an infection or disease, including reducing the severity of an infection or disease. Thus, treatment does not necessarily imply that a subject is treated until complete elimination of the infection or recovery from a disease. Similarly, the terms "preventing", "prevention" and the like refer to any and all applications that prevent the establishment of an infection or disease or otherwise delay the onset of an infection or disease. [0060] The term "improve gut function" means that a composition is administered to, or a method is used for, a subject for a period effective to improve function as determined by comparison with gut function in individuals not being administered the composition or H: mdt\lInterwoven\NRPortbl\DCC\MDT\8077983_1.docx-17/07/2015 - 13 using the method. Any suitable method of assessing gut function can be used to determine whether an improvement occurs. In one embodiment, gut function is assessed by the level(s) of one or more biomarkers in a tissue or fluid sample, for example systemic inflammation content of blood. [0061] The term "associated with" as used herein when used in the context of a disease or condition "associated with" dysbiotic gut means that the disease or condition may result from, result in, be characterised by, or be otherwise associated with a dysbiotic gut in the subject. Thus, the association between the disease or condition and the dysbiotic gut may be direct or indirect and may be spatially and/or temporally separated. [0062] The term "optionally" is used herein to mean that the subsequently described feature may or may not be present or that the subsequently described event or circumstance may or may not occur. Hence the specification will be understood to include and encompass embodiments in which the feature is present and embodiments in which the feature is not present, and embodiments in which the event or circumstance occurs as well as embodiments in which it does not. [0063] The gastrointestinal microflora has been shown to play crucial roles in maintaining gastrointestinal tract function and overall physiological health. For example the growth and metabolism of the many individual bacterial species inhabiting the gastrointestinal tract depend upon the substrates available to them, many of which are derived from the diet. Probiotic microorganisms are live microorganisms that confer a benefit when administered in adequate amounts to confer a health benefit on the host, often by inhibiting the growth of other biological organisms in the same corporeal environment. The best known probiotics are the lactic acid-producing bacteria (Lactobacilli) and Bifidobacteria, which are widely utilized in yoghurts and other dairy products. These probiotic organisms are non-pathogenic and nontoxigenic, retain viability during storage, and survive passage through the stomach and small intestine. Since probiotics do not permanently colonize the host, they typically need to be ingested regularly for any health promoting properties to persist.

H: ndt\Interwoven\NRPortbl\DCC\MDT\8077983_1.docx-17/07/2015 - 14 [0064] In addition, molecules such as amylase (from Aspergillus oryzae), protease (from Aspergillius oryzae), lipase (from Rhizopus oryzae), bromelains (from Ananas comosus), and papain (from Carica papaya) may augment the health of the gut individually and in combination with each other as well as with the administration of probiotic bacteria. This augmented health benefit may translate in a reduction of risk of chronic disease progression due to food ingestion and its improved digestion, assimilation and utilization, especially in older adults. [0065] Provided herein are methods for treating or preventing dysbiotic gut or conditions associated therewith, and for treating or preventing gut proinflammation and/or for improving gut function, comprising administering to a subject in need thereof: (i) an effective amount of one or more probiotic bacterial strains selected from Lactobacillus rhamnosus, Lactobacillus plantarum, Lactobacillus bulgaricus, Lactobacillus gasseri, Lactobacillus reuteri, Lactobacillus paracasei, Lactobacillus case, Lactobacillus acidophilus, Lactobacillus fermentum, Lactobacillus salvarius, Lactococcus lactis, Streptococcus thermophilus, Bifidobacterium breve, Bifidobacterium bifidum, Bifidobacterium animals subsp. lactis (B. lactis), Bifidobacterium animalis subsp. animalis, Bifidobacterium infantis, Bifidobacterium longum and Bifidobacterium pseudocatenulatum; and (ii) an effective amount of one or more digestive enzymes and/or digestive enzyme containing extracts. [0066] The gut proinflammation may be associated with a chronic disease. Those skilled in the art would understand the term chronic disease to refer to a disease or condition in which abnormalities of organ structure and function, have been present for greater than three months, or that are persistent or otherwise long-lasting in their effects, with implications for health. Examples of chronic diseases to which embodiments of the present disclosure are applicable include ulcerative colitis, Crohn's disease, irritable bowel syndrome, refractory coeliac disease and obesity. [0067] Improving gut function may comprise facilitating or improving food or food product transit through the gastrointestinal tract, the absorption of nutrients from said food H: ndt\Interwoven\NRPortbl\DCC\MDT\8077983_1.docx-17/07/2015 - 15 or food products, and/or the assimilation of nutrient s from said food or food products. [0068] Improving gut function may comprise relieving one or more symptoms associated with indigestion, altered bowel movements, gastrointestinal discomfort or one or more symptoms associated with an irritable bowel. Such symptoms associated with an irritable bowel include gas, bloating, constipation and loose stools. [0069] In particular embodiments the bacterial strains are selected from Lactobacillus rhamnosus, Lactobacillus acidophilus, Bifidobacterium bifidum and Bifidobacterium lactis. [0070] Typically the digestive enzymes are selected from an amylase, a protease and a lipase or a combination thereof. In an exemplary embodiment, the amylase is obtained or derived from an Aspergillus sp., such as Aspergillus oryzae, the protease is obtained or derived from an Aspergillus sp., such as Aspergillus oryzae, and the lipase is obtained or derived from a Rhizopus sp., such as Rhizopus oryzae. Those skilled in the art will appreciate that other sources of said enzymes may be employed. [0071] The enzyme-containing extract may comprise, for example, papain or a bromelain. In an exemplary embodiment, the papain is obtained or derived from Carica papaya. In an exemplary embodiment, the bromelain is obtained or derived from Ananas comosus. Those skilled in the art will appreciate that other digestive enzyme-containing extracts, or sources of said extracts, may be employed. [0072] In exemplary embodiments, the methods of the present disclosure comprise the administration of a combination of L. rhamnosus, L. acidophilus, B. bifidum and B. lactis strains and a combination of an amylase, a protease, a lipase, a papain and a bromelain. [0073] The one or more probiotic strains may be present in a composition as specially selected strains as a culture concentrate or as part of a multi-strain blend, optionally with a variety of excipients. Accordingly, novel probiotic compositions treating or preventing dysbiotic gut or conditions associated therewith, and for treating or preventing gut proinflammation and/or for improving gut function, are provided herein. The one or more H: ndt\Interwoven\NRPortbl\DCC\MDT\8077983_1.docx-17/07/2015 - 16 digestive enzymes or digestive enzyme-containing extracts may be formulated in the same composition as the one or more probiotic strains or in a different composition. [0074] Accordingly, also provided herein are compositions for treating or preventing dysbiotic gut or conditions associated therewith, and for treating or preventing gut proinflammation and/or for improving gut function, comprising: (i) one or more probiotic bacterial strains selected from Lactobacillus rhamnosus, Lactobacillus plantarum, Lactobacillus bulgaricus, Lactobacillus gasseri, Lactobacillus reuteri, Lactobacillus paracasei, Lactobacillus case, Lactobacillus acidophilus, Lactobacillus fermentum, Lactobacillus salvarius, Lactococcus lactis, Streptococcus thermophilus, Bifidobacterium breve, Bifidobacterium bifidum, Bifidobacterium animals subsp. lactis (B. lactis), Bifidobacterium animalis subsp. animalis, Bifidobacterium infantis, Bipdobacterium longum and Bipdobacterium pseudocatenulatum; and (ii) one or more digestive enzymes and/or digestive enzyme-containing extracts. [0075] Compositions of the present disclosure may further comprise, and methods disclosed herein may further comprise the administration of, a yeast strain such as Saccharomyces cerevisiae or Saccharomyces boulardii. [0076] The amounts of individual microbial strains to be administered to subjects or to be included in compositions disclosed herein will depend on a variety of factors including the identity and number of individual strains employed, the condition or disease to be treated against which the composition is designed to be used, and the form in which a composition is administered. For any given case, appropriate amounts may be determined by one of ordinary skill in the art using only routine experimentation. By way of example only, the amount of each microbial strain present in a single dose of a composition disclosed herein may be from about 1 x 10 2 cfu to about 1 x 10 1 cfu, and may be about 1 x 10 3 cfu, about 2.5 x 10 3 cfu, about 5 x 10 3 cfu, about 7.5 x 10 3 cfu, 1 x 104cfu, about 2.5 x 10 4 cfu, about 5 x 10 4 cfu, about 7.5x 10 4 cfu, about 1 x 10 5 cfu, about 2.5 x 10 5 cfu, about 5 x 10 5 cfu, about 7.5 x 10 5 cfu, about 1 x 10 6 cfu, about 2.5 x 10 6 cfu, about 5 x 10 6 cfu, about 7.5 x 10 6 cfu, about 1 x 10 7 cfu, about 2.5 x 10 7 cfu, about 5 x 10 7 cfu, about 7.5 x 10 7 cfu, about 1 x H: ndt\Interwoven\NRPortbl\DCC\MDT\8077983_1.docx-17/07/2015 - 17 10 8 cfu, about 2.5 x 10 8 cfu, about 5 x 10 8 cfu, about 7.5 x 10 8 cfu, about 1 x 10 9 cfu, about 2.5 x 10 9 cfu, about 5 x 10 9 cfu, about 7.5 x 10 9 cfu, about 1 x 10 1 0 cfu, about 2.5 x 10 1 0 cfu, about 5 x 10 1 0 cfu, about 7.5x 10 10 cfu, and about 1 x 10 11 cfu. [0077] Also contemplated by the present disclosure are variants of the microbial strains described herein. As used herein, the term "variant" refers to both naturally occurring and specifically developed variants or mutants of the microbial strains disclosed and exemplified herein. Variants may or may not have the same identifying biological characteristics of the specific strains exemplified herein, provided they share similar advantageous properties in terms of their ability to be used as probiotic strains for the treatment or prevention of a chronic disease, dysbiotic gut or compositions associated with dysbiotic gut. Illustrative examples of suitable methods for preparing variants of the microbial strains exemplified herein include, but are not limited to, culturing under selective growth conditions, gene integration techniques such as those mediated by insertional elements or transposons or by homologous recombination, other recombinant DNA techniques for modifying, inserting, deleting, activating or silencing genes, intraspecific protoplast fusion, mutagenesis by irradiation with ultraviolet light or X-rays, or by treatment with a chemical mutagen such as nitrosoguanidine, methylmethanesulfonate, nitrogen mustard and the like, and bacteriophage-mediated transduction. Suitable and applicable methods are well known in the art and are described, for example, in J. H. Miller, Experiments in Molecular Genetics, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1972); J. H. Miller, A Short Course in Bacterial Genetics, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1992); and J. Sambrook, D. Russell, Molecular Cloning: A Laboratory Manual, 3rd ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (2001), inter alia. [0078] Also encompassed by the term "variant" as used herein are microbial strains phylogenetically closely related to strains disclosed herein and strains possessing substantial sequence identity with the strains disclosed herein at one or more phylogenetically informative markers such as rRNA genes, elongation and initiation factor genes, RNA polymerase subunit genes, DNA gyrase genes, heat shock protein genes and recA genes. For example, the 16S rRNA genes of a "variant" strain as contemplated herein may share about H :ndt\lnterwoven\NRPortbl\DCC\MDT\8077983_1.docx-17/07/2015 - 18 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with a strain disclosed herein. [0079] The bacterial strains to be employed in accordance with the present disclosure may be cultured according to any suitable method known to the skilled addressee and may be prepared for addition to a composition by, for example, freeze-drying, spray-drying or lyophilisation. Thus, in embodiments of the present disclosure the bacterial strains may be in a dried form (such as lyophilized or sporulated form) in a suitable carrier medium, for example a FOS medium or other soluble fiber, sugar, nutrient or base material for the composition, with which the bacterial strains can be presented in an orally administrable form. One or more of the strains may be encapsulated in, for example, a suitable polymeric matrix to improve long-term stability and storage of the compositions. In one example, encapsulation may comprise alginate beads; although those skilled in the art will appreciate that any suitable encapsulation material or matrix may be used. Encapsulation may be achieved using methods and techniques known to those skilled in the art. [0080] The amounts of enzymes of enzyme-containing extracts to be administered to subjects or to be included in compositions disclosed herein will depend on a variety of factors including the activity or specific activity of the enzyme, the condition or disease to be treated against which the composition is designed to be used, and the form in which a composition is administered. For any given case, appropriate amounts may be determined by one of ordinary skill in the art using only routine experimentation. By way of example only, an amount of amylase may be employed so as to provide between about 500 to 20,000 amylase dextrinising units (DU), optionally between about 500 to 15,000 DU, between about 1,000 to 10,000 DU, or between about 1,000 to 5,000 DU. By way of example only, an amount of protease may be employed so as to provide between about 1,000 to 25,000 haemoglobin unit tyrosine base (HUT), between about 2,500 to 15,000 HUT or between about 5,000 to 10,000 HUT. By way of example only, an amount of lipase may be employed so as to provide between about 100 to 10,000 lipase units (lipU), between about 500 to 5,000 lipU or between about 750 to 2,500 lipU. By way of example only, papain and/or bromelain may be used in amounts of between about 1 to 1,000 mg, between about 10 to 500 mg or between about 50 to 250 mg.

H: ndt\Interwoven\NRPortbl\DCC\MDT\8077983_1.docx-17/07/2015 -19 [0081] In some embodiments compositions of the present disclosure may further comprise at least one prebiotic component. Suitable prebiotics include polydextrose, inulin, fructooligosaccharides (FOS), xylooligosaccharides (XOS),galactooligosaccharides (GOS), mannan oligosaccharides, protein-based green lipped mussel extract, and various prebioticcontaining foods such as raw onion, raw leek, raw chickory root and raw artichoke. In certain embodiments the prebiotic is a fructooligosaccharide. Those skilled in the art will appreciate that other sources of fibre and/or prebiotics may be added to the compositions. [0082] In accordance with particular embodiments of the invention the at least one prebiotic may be present in an amount of from about 1 mg to about 100 g, or more typically between about 5 mg to about 50 g. Alternatively, the composition may comprise about 10 mg, 100 mg, 1 g, 5 g, 10 g, 15 g, 20 g, 25 g, 30 g, 35 g, 40 g or 45 g of prebiotic. [0083] The compositions of the present disclosure may further comprise vitamins and/or minerals and/or amino acids. The vitamins and minerals may be selected from, but not limited to: vitamins A, BI, B2, B3, B5, B6, B9, B12, C, D, E and calcium, chromium, copper, fluorine, iodine, iron, magnesium, manganese, molybdenum, phosphorus, potassium, selenium, sodium and zinc. The amino acids may be selected from, but are not limited to: alanine, arginine, aspartic acid, cystine, glycine, histidine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan and tyrosine. [0084] Compositions of the present disclosure may further comprise one or more antioxidants or sources of antioxidant activity. Exemplary antioxidants may be water soluble or lipid soluble and include, but are not limited to, carotenes (e.g. beta-carotene, lycopene, lutein, zeaxanthin), flavonoids, tocopherols, tocotrienols, polyphenols (e.g. resveratrol, catechins), glutathione, anthocyanins, vitamins (e.g. vitamin A, vitamin C, vitamin E) and their derivatives, coenzymes (e.g. coenzyme Q10), and minerals (e.g. selenium, copper, zinc, manganese). Suitable sources of antioxidant activity include various plant extracts, herbal extracts and spices, as will be readily appreciated by those skilled in the art.

H: mdt\lInterwoven\NRPortbl\DCC\MDT\8077983_1.docx-17/07/2015 -20 [0085] Compositions of the present disclosure may further comprise a source of fibre. The source of fibre may comprise soluble fibre, insoluble fibre, or a combination of both soluble and insoluble fibre. Suitable sources of soluble fibre include, but are not limited to, psyllium, dextrins, fructans, oligosaccharides (e.g. inulins) and polysaccharides. Exemplary polysaccharides include arabinogalactans and resistant starches. [0086] The compositions may additionally include any suitable additives, carriers, additional therapeutic agents, bioavailability enhancers, side-effect suppressing components, diluents, buffers, flavouring agents, binders, preservatives or other ingredients that are not detrimental to the efficacy of the composition. In some embodiments, the probiotic strains may comprise from about 50% to about 90% by weight of the composition, based on the total weight of the composition including a carrier medium, or from about 60% to about 80% by weight of the composition. [0087] Compositions of the present disclosure can be readily manufactured by those skilled in the art using known techniques and processes. For example, the bacterial strains can be seeded from standard stock into a reactor and grown in standardized media until a predetermined CFU/g concentration is reached. The bulk material can then be drained from the reactor and dried by spray drying, lyophilization, or flatbed oven drying. The dried bacterial material can then be blended with the carrier medium and the resulting mixture can be pressed into tablets, filled into foil pouches as a granular solid, or introduced into gelatin capsules as a particulate material. [0088] Compositions of the present disclosure may be suitably formulated for oral administration, and may be prepared according to conventional methods well known in the pharmaceutical and nutraceutical industries, such as those described in Remington's Pharmaceutical Handbook (Mack Publishing Co., NY, USA) using suitable excipients, diluents and fillers. Exemplary additional ingredients include citric acid, magnesium oxide, silicon dioxide, etc. In general, oral compositions are prepared by uniformly and intimately bringing into association the components of the composition with a liquid carrier or finely divided solid carrier, or both and then, if necessary, shaping the product into the desired composition. Oral dosage forms may include soluble sachets, orally soluble forms, capsules, H: ndt\Interwoven\NRPortbl\DCC\MDT\8077983_1.docx-17/07/2015 - 21 tablets, chewable tablets, multi-layer tablets with, for example, time- and/or pH-dependent release, and granulates. [0089] Compositions suitable for oral administration may be presented as discrete units (i.e. dosage forms) such as gelatine or HPMC capsules, cachets or tablets, each containing a predetermined amount of each component of the composition as a powder, granules, as a solution or a suspension in an aqueous liquid or a non-aqueous liquid, or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. [0090] When the composition is formulated as capsules, the components of the composition may be formulated with one or more pharmaceutically acceptable carriers such as starch, lactose, microcrystalline cellulose and/or silicon dioxide. Additional ingredients may include lubricants such as magnesium stearate and/or calcium stearate. The capsules may optionally be coated, for example, with a film coating or an enteric coating and/or may be formulated so as to provide slow or controlled release of the composition therein. [0091] Tablets may be prepared by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the components of the composition in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant (for example magnesium stearate or calcium stearate), inert diluent or a surface active/dispersing agent. Moulded tablets may be made by moulding a mixture of the powdered composition moistened with an inert liquid diluent, in a suitable machine. The tablets may optionally be coated, for example, with a film coating or an enteric coating and/or may be formulated so as to provide slow or controlled release of the composition therein. [0092] The compositions may be provided to the user in a powder form. The compositions may be added in powder form by the user to any type of drink or food product (for example water, fruit juice or yoghurt) and consumed there after. In another embodiment, the compositions may simply be consumed as a powder in the absence of a drink or additional food product.

H: ndt\Interwoven\NRPortbl\DCC\MDT\8077983_1.docx-17/07/2015 -22 [0093] Compositions of the present disclosure may be conveniently incorporated in a variety of food and/or beverage products, nutraceutical products, probiotic supplements, food additives, pharmaceuticals and over-the-counter formulations. The food or food additive may be a solid form such as a powder, or a liquid form. Specific examples of the types of beverages or foods include, but are not limited to water-based, milk-based, yoghurt based, other dairybased, milk-substitute based such as soy milk or oat milk, or juice-based beverages, water, soft drinks, carbonated drinks, and nutritional beverages, (including a concentrated stock solution of a beverage and a dry powder for preparation of such a beverage); baked products such as crackers, breads, muffins, rolls, bagels, biscuits, cereals, bars such as muesli bars, health food bars and the like, dressings, sauces, custards, yoghurts, puddings, pre-packaged frozen meals, soups and confectioneries. [0094] Those skilled in the art will appreciate that single or multiple administrations of compositions disclosed herein can be carried out with dose levels and dosing regimes being determined as required depending on the circumstances and on the condition of the subject to be treated. The skilled addressee can readily determine suitable dosage regimes. A broad range of doses may be applicable. Dosage regimens may be adjusted to provide the optimum therapeutic response. Those skilled in the art will appreciate that the exact amounts and rates of administration of the probiotic microorganisms will depend on a number of factors such as the particular composition being administered, the age, body weight, general health, sex and dietary requirements of the subject, as well as any drugs or agents used in combination or coincidental with the compositions. For example, several divided doses may be administered hourly, daily, weekly, monthly or at other suitable time intervals or the dose may be proportionally reduced as indicated by the exigencies of the situation. Based on the teaching herein those skilled in the art will, by routine trial and experimentation, be capable of determining suitable dosage regimes on a case-by-case basis. [0095] In general, compositions of the present disclosure may be administered in any suitable dose amount that is effective as a health supplement, food supplement, food additive, and/or therapeutic agent to achieve the desired health outcome. In some embodiments, an effective dose of a composition may be in a range of from 1 g to 15 g for an adult subject, or between about 2 g and about 10 g. Pediatric dosages may be in the range H: ndt\Interwoven\NRPortbl\DCC\MDT\8077983_1.docx-17/07/2015 -23 of 15% to 90% of adult dosages. In therapeutic applications a constant dosage of the composition can be administered over time, for example, about 2 g to about 4 g per day, up to about 6 g to about 10 g per day, depending on the severity of the disease or condition to be treated. Once the disease or condition has been effectively ameliorated, the subject can in many instances decrease the dosage to about 2 g to about 4 g per day for maintenance purposes. [0096] Compositions and methods of the present disclosure may be employed as an adjunct to other therapies or treatments for chronic diseases, dysbiotic gut and conditions associated therewith. Accordingly compositions and methods disclosed herein may be coadministered with other agents that may facilitate a desired therapeutic outcome, for example, one more renal drugs. By "coadministered" is meant simultaneous administration in the same formulation or in two different formulations via the same or different routes or sequential administration by the same or different routes. By "sequential" administration is meant a time difference of from seconds, minutes, hours or days between the administration of the agents, compositions or treatments. Sequential administration may be in any order. [0097] The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates. [0098] The present disclosure will now be described with reference to the following specific examples, which should not be construed as in any way limiting the scope of the invention. Examples [0099] The following examples are illustrative of the invention and should not be construed as limiting in any way the general nature of the disclosure of the description throughout this specification.

H: ndt\lnterwoven\NRPortbl\DCC\MDT\8077983_1.docx-17/07/2015 - 24 Example 1 - Case studies [0100] Two overweight middle-aged male subjects diagnosed with gut dysfunction were administered a capsular probiotic composition comprising Lactobacillus rhamnosus (15.5 billion CFU), Lactobacillus plantarum (3.1 billion CFU), Lactobacillus case (9.5 billion CFU), Lactobacillus acidophilus (7.4 billion CFU), Lactobacillus fermentum (1.3 billion CFU), Bifidobacterium breve (1.3 billion CFU), Bifidobacterium bifidum (450 million CFU), Bifidobacterium lactis (4 billion CFU) and Staphylococcus thermophilus (2.2 billion CFU). After one month at a dose of 1 or 2 capsules per day, both subjects presented with improved gut symptoms as exemplified by reduced abdominal bloating, pain and discomfort. Example 2 - Gut dysfunction and tight junction proteins [0101] The intestinal barrier protects the body from the external environment and is formed by epithelial cells that line the gut luminal surface. The plasma membranes of these epithelial cells prevent free passage of hydrophilic molecules across the gut epithelial barrier. Tight junctions between cells at the apicolateral boundary layer seal the paracellular space, but are necessarily leaky, to allow absorption of essential nutrients and ions according to size and charge. However, intestinal mucosal barrier dysfunction in inflammatory gut conditions may lead to increased intestinal permeability. This partly results from irregular expression of certain intestinal epithelium tight junction proteins. Breakdown in barrier functions affects both absorption of uremic toxins into the blood stream, loss of tight junction proteins and increased leakage of serum proteins into the intestinal lumen. [0102] Human T84 enterocytes are seeded on Transwell plates and utilized when the transepithelial electrical resistance (TER) exceeds 10OOmQ/cm2 (using Millicell ERS-2) to ensure full polarization and tight junction formation. Confluent cells are incubated for 24h in media containing 0 (control), 5 (in normal range), 25 or 50mmol/L urea or urea plus urease (1 unit/tm urea) to simulate the presence of microbial flora. TER are re-measured. Effects on dissipation of TER are recorded. Pro-inflammatory cytokines (TNF-a, ILla, IFN-y) are analysed in protein from cells, and supernatants from luminal apical versus internal basolateral sides of Transwells, using Western blots or ELISA. Movement of the H: ndt\Interwoven\NRPortbl\DCC\MDT\8077983_1.docx-17/07/2015 -25 [0103] tight junction proteins occludin, ZO1 and 2, claudin-1 and JAM-A (JAM-1) are studied using Zeiss LCM 150 confocal fluorescence microscopy. Caveolae-mediated endocytosis and storage of tight junction proteins are measured using multi-fluorescence labelling and confocal microscopy. Transmission and immuno-electron microscopy are used to define changes in structure and co-localisation of tight junction proteins, especially at caveolae. Phosphorylation/activation of caveolin-1 are measured (Western immunoblots). Apoptosis, necrosis and mitosis are quantified using structure and microscopy of fixed cells grown on [0104] glass coverslips, with ApopTag/TUNEL enzymatic in situ stain for apoptosis and Ki67 immunohistochemistry for proliferation. [0105] A pilot probing clinical study is proposed with 20 participants diagnosed with gut dysbiosis and indigestion. The aim is to supplement participants in a cross over design with a multi-strain probiotic- and enzyme-containing composition (for example corresponding to, or similar to that presented in Example 3) to ameliorate gut function and indigestion as evidenced by an improvement in gut dysbiosis and digestion ability. This will be a 8 week prospective, randomized, double-blind, placebo-controlled, crossover trial of a multi-strain probiotic preparation / enzymic supplement mixture with otherwise healthy participants. Inclusion criteria: * >60 years of age e dysbiotic gastrointestinal tract * diagnosed with indigestion (e.g., dyspepsia) Exclusion criteria: * pregnant or nursing women; e antibiotic treatment at the time of screening or within 14 days before screening; * refusal to sign the informed consent form; e active illicit drug dependency or alcohol abuse; * HIV/AIDS/liver disease; e any medical, psychiatric, debilitating disease/disorder or social condition that in the judgment of the investigator would interfere with or serve as a contraindication to H: ndt\Interwoven\NRPortbl\DCC\MDT\8077983_1.docx-17/07/2015 - 26 adherence to the study protocol or ability to give informed consent current anticoagulant therapy. [0106] Once the eligibility criteria have been met, the participants will be randomized into two study arms, namely Group I and Group II. Group I to receive placebo and Group II to receive the multi-strain probiotic- and enzyme-containing composition. After 4 weeks, the crossover will be made and Group I will receive the multi-strain probiotic- and enzyme containing composition and Group II will receive the placebo. This study design was chosen as in an outpatient setting each participant can be considered to be a control subject in both arms of the study, thereby each participant acting as their own control. Example 3 - Exemplary compositions An exemplary multi-strain probiotic- and enzyme-containing composition according to the present disclosure has the following ingredients. The beneficial immune modulatory effects of probiotic L. rhamnosus strains have been extensively reported. Probiotic strains Lactobacillus rhamnosus 10 x 10' CFU/mL Lactobacillus acidophilus 10 x 10' CFU/mL Bifidobacterium bifidum 2.5 x 108 CFU/mL Bifidobacterium animals subsp lactis 2.25 x I0 9 CFU/mL Enzyme components Amylase (from Aspergillus oryzae) 1500 DU (300 mg) Protease (from Aspergillius oryzae) 7580 HUT (20 mg) Lipase (from Rhizopus oryzae) 1050 LipU (30 mg) Bromelain (from Ananas comosus) 60 mg Papain (from Carica papaya) 142.5 mg Carrier components: magnesium oxide magnesium gluconate H: ndt\Interwoven\NRPortbl\DCC\MDT\8077983_1.docx-17/07/2015 - 27 glutathione FOS Fructose Additional excipients: anhydrous citric acid flavouring colouring An exemplary multi-strain probiotic- and enzyme-containing composition according to the present disclosure comprises in capsule form: 17.5 billion CFU Lactobacillus rhamnosus, Lactobacillus acidophilus, Bifidobacterium bifidum and Bifidobacterium animals subsp lactis 483 mg enzyme blend of amylase, papain, lipase, bromelain, acid and alkali proteases

Claims (5)

1. A composition for improving gut function, for the therapeutic or prophylactic treatment of gut proinflammation and/or for the treatment or prevention of dysbiotic gut or a condition associated therewith, comprising: (i) one or more probiotic bacterial strains selected from Lactobacillus rhamnosus, Lactobacillus plantarum, Lactobacillus bulgaricus, Lactobacillus gasseri, Lactobacillus reuteri, Lactobacillus paracasei, Lactobacillus case, Lactobacillus acidophilus, Lactobacillus fermentum, Lactobacillus salvarius, Lactococcus lactis, Streptococcus thermophilus, Bifidobacterium breve, Bifidobacterium bifidum, Bifidobacterium animals subsp. lactis (B. lactis), Bifidobacterium animalis subsp. animalis, Bifidobacterium infantis, Bipdobacterium longum and Bipdobacterium pseudocatenulatum; and (ii) one or more digestive enzymes and/or digestive enzyme-containing extracts.

2. A composition according to claim 1, wherein the composition comprises a multi stain combination of probiotic bacterial strains comprising Lactobacillus rhamnosus, Lactobacillus acidophilus, Bifidobacterium bifidum, and Bifidobacterium animalis subsp. lactis.

3. A composition according to claim 1 or claim 2, wherein the digestive enzymes or digestive enzyme-containing extracts comprise amylase, protease, lipase, papain and bromelain.

4. A composition according to any one of claims 1 to 3, wherein the composition comprises Lactobacillus rhamnosus, Lactobacillus acidophilus, Bifidobacterium bifidum, Bifidobacterium animals subsp. lactis, amylase, acid and alkali proteases, lipase, papain and bromelain.

5. A method for improving gut function, for the therapeutic or prophylactic treatment of gut proinflammation and/or for the treatment or prevention of dysbiotic gut or a condition associated therewith, the method comprising administering to a subject: (i) one or more probiotic bacterial strains selected from Lactobacillus rhamnosus, H: ndt\Interwoven\NRPortbl\DCC\MDT\8077983_1.docx-17/07/2015 -29 Lactobacillus plantarum, Lactobacillus bulgaricus, Lactobacillus gasseri, Lactobacillus reuteri, Lactobacillus paracasei, Lactobacillus case, Lactobacillus acidophilus, Lactobacillus fermentum, Lactobacillus salvarius, Lactococcus lactis, Streptococcus thermophilus, Bifidobacterium breve, Bifidobacterium bifidum, Bifidobacterium animals subsp. lactis (B. lactis), Bifidobacterium animalis subsp. animalis, Bifidobacterium infantis, Bifidobacterium longum and Bipdobacterium pseudocatenulatum; and (ii) one or more digestive enzymes and/or digestive enzyme-containing extracts.