Riboprine for use in the (a) maintenance; (b) improvement; or (c) dietary management of gut barrier function (gut barrier integrity)

Abstract

The present invention relates to the use of riboprine in the maintenance, improvement, or dietary management of gut barrier function. The riboprine may be formulated in an oral composition such as dietary supplement, a food product, a food for special medical purpose (FSMP) or a food for special dietary use (FSDU).

Description

[0001] GUT BARRIER COMPOSITIONS1. TECHNICAL FIELDThe present invention relates to the use of riboprine in the maintenance, improvement, ordietary management of gut barrier function. The riboprine may be formulated in an oralcomposition such as dietary supplement, a food product, a food for special medical purpose(FSMP) or a food for special dietary use (FSDU). The composition can be administered to asubject in need of maintenance or improvement of gut barrier function, or to a subject suspected of being in need of maintenance or improvement of gut barrier function. Accordingly, the invention also relates to methods and uses in a subject that may or may nothave impaired gut barrier function and / or a symptom thereof.2. BACKGROUNDThe gastrointestinal barrier plays a fundamental defensive role as a functional barrierseparating the inside of the body from the external environment, i.e. the contents of the intestinal lumen comprising microbiota, dietary components and environmental toxins. Nevertheless, it must also function to allow the absorption of desired nutrients while excluding potentially harmful substances such as certain macromolecules, antigens andpathogenic organisms. This activity is known as the gut barrier function or gut barrier integrity,and a dysregulated or altered gut barrier function is known to be associated with a number of clinical conditions and / or predisposition to disease. Additionally the gut barrier function is known to play a role in immunity regulation and hormone balance. Thus, not only is the improvement or restoration of the gut barrier function in subjects with altered function of interest, but also its maintenance and protection in potentially asymptomatic subjects to optimize health and wellbeing. Accordingly, there is a need for compositions and therapies that maintain, protect, restore and / or improve gut barrier function.3. SUMMARYThis section summarizes certain aspects of the present invention, while additional aspects aredescribed in the Detailed Description, Examples, Drawings, and Claims. Although separatesections, the disclosure of each is intended to be read in the context of the entirety. That is, each section is intended to be read in explicit conjunction with the other sections, such that the various aspects and embodiments, whether disclosed in the same or separate sections, can be combined. All such combinations are intended to fall within the scope of the presentinvention, which is based on the surprising discovery that riboprine can positively affect gut barrier function, including improving or maintaining at least mucus production and intestinal epithelial integrity. Accordingly, the present invention relates to riboprine, and methods comprising itsadministration, for use in the maintenance, improvement, or dietary management of gutbarrier function. The provided methods and uses are not limited to cases wherein the subject exhibits impaired or altered gut barrier function, but may also be implemented when it is desired or deemed necessary that gut barrier function is to be supported (e.g. maintained) or improved whether the subject exhibits one or more symptoms of impaired gut barrier function or not. Thus, the methods and uses provided herein may be used where the subject has gut barrier function otherwise falling within normal / standard physiological parameters. The need for the support, improvement, or dietary management of the gut barrier functioncan determined by an attending physician or team of physicians according to standardpractices in the art. However, the methods and uses of the invention need not be under medical supervision.The gastrointestinal barrier is composed of a mucus layer and an intestinal epithelial barrier(IEB), both of which function to allow the passage of desired nutrients and prevent the passage of, e.g. commensal bacteria, pathogens, and food antigens from the lumen. Thus, both themucus layer and the IEB contribute to gut barrier function. Accordingly, the maintenance,improvement or dietary management of gut barrier function encompasses the maintenance, improvement or dietary management of one or both of the mucus layer (e.g. mucus production) and the intestinal epithelial barrier (and / or their function).Gut barrier function, including its response to riboprine according to the invention, can beassessed by any means known in the art or described herein. For example, as known in the art, determination of gut barrier permeability can be used as an indicator of gut barrierfunction, e.g. gut barrier integrity and / or the activity / protective capacity of the IEB. Methodsto assess gut barrier permeability and or activity may comprise the assessment of passage ofone or more markers through / across one or both of the mucus layer and IEB. Such methodsmay be in vivo or in vitro, e.g. by the use of models as is known in the art and / or describedherein. Therefore, exemplary methods may comprise the assessment / determination of the passage or one or more markers from the lumen through the gut barrier (e.g. one or more of the mucus layer and IEB), for example, into intestinal tissue, gut tissue, the peritoneum, the abdominal cavity and / or systemic circulation, or comprise such assessment / determination ina model of intestinal lumen and the gut barrier. The passage of one or more markers throughthe gut barrier or part thereof (e.g. through one or more of the mucus layer and IEB) according to the invention is not limited to any mechanism and includes without limitation the translocation of the one or more markers across the gut barrier or part thereof. As is knownin the art, such methods may also determine the potential for passage across the gut barrieror one or more parts thereof. Thus, the maintenance, improvement or dietary management of gut barrier function encompasses the maintenance, improvement or dietary management of the passage, passage activity, and / or potential for passage (including without limitation the translocation, translocation activity and / or potential for translocation) of one or more markers through the gut barrier or one or more parts thereof. The measurement / determination / assessment of the one or more markers may be qualitative or quantitative.Markers of use according to the invention include biomarkers such as, but not limited to,pathogens (or markers thereof), commensal bacteria (or markers thereof), cytokines, chemokines, growth factors, angiogenic factors, enzymes, proteases, adhesion molecules, cell signaling molecules, and hormones or sugars. However, the markers of use according to theinvention need not be biomarkers but may be other molecules as known in the art, e.g.derived from sources external to the subject such as allergens, toxic compounds and / or sugars (e.g. as obtained from ingestion). In one non-limiting method, gut barrier function can be assessed by measuring or determining the passage of a marker (e.g. lactulose or manitol) into the blood circulation. Alternately or additionally, gut barrier function may be assessed by measuring or determining the passage of one or more markers (e.g. lactulose or mannitol) by excretion in urine.As is recognized, gut barrier function is selective, that is, allowing the passage of certaincompounds and limiting or prohibiting the passage of others. Accordingly, depending on themarker selected and the particular assay, e.g. improved, gut barrier function may be associated with an increased or decreased level of the marker. Similarly, again depending on the marker selected and particular assay, e.g. maintained gut barrier function may beassociated with a maintained, increased or decreased level of the biomarker.It is also recognized that as dependent on the activity of the intestinal epithelial barrier, gut barrier function can also be assessed by the measurement / determination of one or morebiomarkers associated with the function of the barrier or barrier components (e.g. cells of theIEB), such as but not limited to, biomarkers associated with intestinal epithelial cell viability, intestinal epithelial barrier repair, epithelial barrier structure, and tight junction structure. Non-limiting examples of biomarkers associated with such repair and / or structure include tight junction proteins such as tight junctional adhesion molecules (JAMs), tricellulin, angulinsintracellular scaffolding proteins (such as zonula occludens proteins (ZOs)), claudins, occludin,ZO-1, and E-cadherin proteins. Alternately or additionally, gut barrier function can be assessed my macroscopic pathological determinations as known in the art, such as presence and grading of intestinal ulcers or wounds. In addition or alternative to biomarkers associated with the function or activity of the intestinal epithelial barrier, gut barrier function can also be assessed by measurement or determination of one or more biomarkers associated with the function or activity of the intestinal mucus layer. For example, the amount or relative expression levels of one or more mucins, at the protein (either intracellular or extracellular) or mRNA level can be determined.In nonlimiting embodiments, the mucin is one or more of MUC1, MUC2, MUC3 (includingMUC3A), MUC4, MUC5 (including MUC5AC and MUC5B), MUC6, MUC7, MUC8, MUC12,MUC13, MUC15, MUC16, MUC17, MUC19, MUC20, MUC21, and MUC22. Mucins are alsoknown to be expressed in various isoforms. Accordingly, the biomarkers for the methods anduses herein also encompass one or more of an isoform of MUC1, MUC2, MUC3 (includingMUC3A), MUC4, MUC5 (including MUC5AC and MUC5B), MUC6, MUC7, MUC8, MUC12,MUC13, MUC15, MUC16, MUC17, MUC19, MUC20, MUC21, and MUC22 as known in the art.Provided is riboprine, and methods of its administration, for use in the improvement of gutbarrier function. Improvement as used herein in understood to indicate an increase in anymarker, index, or parameter of normal gut barrier function. For example, where gut barrierfunction is assessed according to the invention by monitoring intestinal barrier integrity, e.g. intestinal barrier permeability, improvement may be demonstrated by the increased passageof one or more compounds, substances or markers that are desired or that normally cross theintestinal epithelial barrier in a subject having a healthy gut barrier (e.g. a desired nutrient or marker associated with the passage of a desired nutrient) as determined by any method known in the art or provided herein. The increase in passage across the IEB (or one or morepart thereof) is not limited and may be determined by a value at least 5%, at least 10%, atleast 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 100%, at least 1.5 fold, at least 2 fold, at least 2.5 fold or at least 3 fold greater than a control value established (a) in the subject prior to exposure to or administration of riboprine; or (b) in a similarly situated subject or similarly situated group (two or more) of subjects prior to exposure to or administration of riboprine. Alternately or additionally, the improvement due to the uses and methods of the invention may be demonstrated by the decreased passage of one or more compounds, substances or markersthat are not desired to or that do not normally passage through the intestinal epithelial barrierin a subject with a healthy gut barrier (e.g. without limitation, a pathogen, allergen or toxiccompound, or a marker of the passage thereof). The decrease in passage across the IEB (orone or more part thereof) is not limited and may be determined by a value, e.g. at least 5%,at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 100%, at least 1.5 fold, at least 2 fold, at least 2.5 fold or at least 3 fold less than a control value established (a) in the subject prior to exposure to or administration of riboprine; or (b) in a similarly situated subject or similarly situated group (two or more) of subjects prior to exposure to or administration of riboprine. The invention provides uses and methods directed to improving gut barrier function in subjects in need thereof, that is, uses and methods directed to restoring normal gut barrier function. Improvement need not be associated with a quantitative or qualitative change in any index, parameter or indicator of gut barrier function, but can be assessed based on improvement of one or objective or subjective (i.e. report of the subject) symptom of altered gut barrier function. The restoration may also be determined by a change in the value of anyone or more indices, parameters or indicators of gut barrier function toward a value indicativeof or associated with normal gut barrier function. The degree of restoration is not limited and may indicated by a value of the index, parameter of indicator during or subsequent toriboprine administration that is within at least 5%, at least 10%, at least 20%, at least 30%, atleast 40%, at least 50%, at least 60% of the control value as determined in a subject or groupof subjects similarly situated and having normal gut barrier function (i.e. a healthy gut barrier).As disclosed herein, improvement can also be demonstrated or assessed by the increase inone or more markers (including biomarkers) associated with the function of the gut barrier,such as but not limited to, markers associated with intestinal epithelial cell viability, intestinalepithelial barrier repair, epithelial barrier structure, tight junction structure and mucinproduction. Accordingly, improvement can be determined or assessed by an increase of, innon-limiting examples, levels or amounts of tight junction proteins tricellulins, angulinsintracellular scaffolding proteins, claudins, occludins, ZO-1, E-cadherin proteins and mucins.The improvement associated increase in the level, expression or amount of the one or more biomarkers associated with gut barrier function is not limited and may be an assessed by achange of at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, atleast 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 100%, at least 1.5 fold, at least 2 fold, at least 2.5 fold or at least 3 fold relative to a control value (a) established in the subject prior to exposure to or administration of riboprine; or (b) previously determined in one or more of a group of similarly situated subjects prior to exposure to or administration of riboprine. The improvement in gut barrier function can also be assessed as a restoration of gut barrier function. In a non-limiting example, the value of any index, parameter or indicatorassociated with normal gut barrier function during or subsequent to riboprine administrationmay be within at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60% of the control value as determined in a subject or group of subjects similarly situated and having normal gut barrier function (i.e. a healthy gut barrier). The improvement due to the uses and methods of the invention may be a reduction in local gut inflammation or systemic inflammation. In a nonlimiting embodiment, the reduction in systemic inflammation may be a reduction in one or more inflammatory cytokines as determined in a biological sample such as a tissue or blood sample, including but not limited to whole blood, plasma or serum. The blood sample may be a peripheral blood sample. The one or more inflammatory cytokines may include, but are not limited to CRP, TNF-α, IL-1β, IL- 2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-13, IL-15, IL-21, IL-22, IL-23, IL-27, IPNγ, G- CSF, GM-CSF, IP-10, KC, LIF, LIX, MCP-1, M-CSF, , MIG, MIP-1α, MIP-1β, MIP-2, MIP-3, RANTES, RANKL and VEGF. The reduction may be determined relative to a control level established in the subject prior to exposure to or administration of riboprine, or may be relative to that previously determined in one or more of a group of similarly situated subjects prior to exposure to or administration of riboprine. Accordingly the decrease in the one or morecytokines as indicative of improved gut barrier function is not limited and may be a decreaseof at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 100%, relative such a to a control value (a) established in the subject prior to exposure to or administration of riboprine; or (b) previously determined in one or more of a group of similarly situated subjects prior to exposure to or administration of riboprine. Provided is also riboprine, and methods of its administration, for use in the maintenance of gut barrier function. Maintenance as used herein in understood to indicate that any one ormore marker, index, or parameter of gut barrier function (such as has been disclosed hereinabove), whether lower, higher or equal to the value established for normal gut barrier function, remains unchanged or is not substantially changed as understood in the art (e.g. within the standard deviation of a relevant accepted assay). It is also understood that maintenance as used herein is not absolute, so that the maintenance of gut barrier function can indicate that the level, expression or amount of one or more marker is within at least 5%,at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60% of a controlvalue established in the subject prior to exposure to or administration of riboprine. It is preferred that the maintenance of gut barrier function according to the uses and methods of the invention is associated with reduction in the level, expression or amount of one or more markers associated with normal gut barrier function by no more than 5%, 10%, 20%, 30%, 40%, 50%, or 60% relative to a control value established in the subject prior to exposure to oradministration of riboprine. In some embodiments, maintenance need not be associated witha quantitative or qualitative change in any index, parameter or indicator of gut barrierfunction, but can be determined by a lack of objective or subjective (i.e. report of the subject) progression or substantial progression of one or symptoms of altered gut barrier function.The presence or lack of one or more markers according to the methods and uses herein canbe determined in any relevant biological sample known or believed to contain luminalcontents or the marker (or a fragment, component, break-down product or indicator thereof)subsequent to passage through / across the IEB or part thereof. Thus, non-limiting examples ofbiological samples for determination of the presence or lack of such one or more markers include tissue samples (e.g. samples of the small intestine), and body fluids (including, without limitation, blood (which may be peripheral blood and includes whole blood, serum and plasma) and urine). The improvement or maintenance of gut barrier function are encompassed within the treatment of gut barrier function, e.g. the treatment of a disease or condition associated with altered gut barrier function (or a symptom thereof). As used herein the terms “treatment”, “treating” and analogous terms generally mean obtaining a desired pharmacological and / or physiological effect. The effect may be prophylactic in terms of completely or partiallypreventing or resolving a symptom associated with altered gut barrier function (or a symptomof a disease associated with altered gut barrier function). The effect may also be prophylactic in terms of at least partially curing a disease or condition (and / or an adverse effect attributedto the disease or condition) associated with altered gut barrier function. The effect may alsobe therapeutic in terms of partially or completely resolving the altered gut barrier function, disease associated with altered gut barrier function, and / or adverse effect attributed to adisease or condition (associated with altered gut barrier function). The term “treatment” asused herein covers any treatment of a disease or condition in a subject and includes: (a) preventing and / or ameliorating a disease or condition (or symptom thereof) from occurringin a subject, where the subject is known or believed to have the disease or condition, or ispredisposed to develop the disease or condition; (b) inhibiting the disease or condition, i.e., arresting its development; (c) relieving the disease or condition, i.e. causing regression of the disease; and / or (d) preventing, inhibiting or relieving any symptom or adverse effect associated with the disease or condition. The term “treatment”, "treating" and analogous terms as used herein therefore cover any treatment of altered gut barrier function including (a) preventing and / or ameliorating altered gut barrier function or a disease associated withaltered gut barrier function from occurring in a subject that may be predisposed to altered gutbarrier function or disease associated therewith; (b) inhibiting progression of alteration of gutbarrier function or inhibiting progression of a disease associated therewith, i.e. arresting itsdevelopment; (c) relieving existing altered gut barrier function or a disease associatedtherewith, e.g. causing regression of the altered barrier function or disease associatedtherewith; and / or (d) preventing, inhibiting or relieving any symptom or adverse effectassociated with altered barrier function and / or a disease or condition associated therewith.The term “treatment” also includes the amelioration, e.g. improvement or lessening of, of one or more indicators, signs, or symptoms of a disease, disorder, or condition. In particular, the term “treatment” also includes the amelioration, .g. improvement or lessening of, any symptom or adverse effect associated with altered barrier function and / or a disease or condition associated therewith. Thus, the term “treatment” can include a delay or slowing in the progression or severity of one or more indicators of a condition or disease. The progression or severity of indicators may be determined by subjective or objective measures, which are known to those skilled in the art. Accordingly, the term “treatment” and analogousterms as used herein may relate to intervention of an already manifested disorder (whetherdiagnosed or not) or may relate to intervention in a subject predisposed to manifest the disorder (e.g. asymptomatic subject not yet exhibiting altered gut barrier function or any symptom associated therewith). The intervention may be medical intervention, e.g. under the supervision of a medical professional, but need not be. The intervention may be the dietary management of the disease, disorder, or condition associated with altered barrier function, or the dietary management of an adverse event or one or more symptoms associated with such a disease disorder or condition.The uses and methods herein may encompass improvement of gut barrier function. Suchimprovement includes, but is not limited to, recovery of the gut barrier integrity (includingrecovery of intestinal epithelial barrier integrity), repair of a disrupted barrier (including adisrupted mucus layer or a disrupted intestinal epithelial cell layer), reduction of permeabilityof the gut barrier (such as on inflammatory challenge), and mucosal repair. Improvement ofgut barrier function also includes improvement of gut barrier structure, such as, but notlimited to, strengthening of the gastrointestinal barrier, integrity of the gastrointestinalbarrier, tight junction structure, and intestinal epithelial lining integrity. Improvement of gut barrier function also includes, but is not limited to, improvement of gut barrier resistance,reduction of gut barrier permeability (such as reduction of pathogen, commensal bacteria,allergen, or toxic compound migratory activity from the gut through the intestinal barrier) andreduction of disease susceptibility. Improvement of gut barrier function also includes improvement of gut barrier protection, such as (but not limited to) prevention of gut barrier dysfunction, prevention of gut barrier leakiness, protection of intestinal epithelial tight junction structure, and protection of the intestinal epithelial lining integrity.Riboprine for the use and / or methods of the invention in the context of improvement,maintenance or treatment of gut barrier function may be provided as a pharmaceutical composition. The term “pharmaceutical composition” can be used interchangeably with “medicament” and generally relates to a composition for administration to a subject. Thepharmaceutical composition as disclosed herein may be administered by any suitable way todeliver a therapeutically effective amount of riboprine to the subject, but is preferablydelivered through enteral delivery, i.e. wherein the compound is delivered through the enteral mucosa. Such compositions can be formulated according to well-known conventional means and include syrups and solid oral dosage forms, such as tablets, capsules, and the like, andmay further comprise a pharmaceutically acceptable carrier. The pharmaceuticalcompositions can be provided at a suitable dose, e.g. determined by the attending physician and clinical factors. As is well known in the medical arts, dosages for any one patient depend upon many factors, including the patient’s size, body surface area, age, the particularcompound to be administered, sex, time and route of administration and general health. Suchcompositions are typically administered to the subject under medical supervision; however,medical supervision is not required. In certain embodiments, riboprine is the only activeingredient in the pharmaceutical composition.The invention also provides riboprine for the management of altered gut barrier function orone or more symptom thereof, e.g. the dietary management of gut barrier function. As used herein, dietary management is understood to mean the exclusive or partial feeding of a subject who because of a disease, disorder or medical condition has limited or impairedcapacity to digest, absorb or otherwise metabolize certain foods or certain nutrientscontained therein; or has determined nutrient requirements. Thus, it is understood thatdietary management as used herein provides riboprine to a subject deemed to be in needthereof, e.g. as a component of a nutritional composition. The subject may be determined to be in need of improvement of maintenance of gut barrier function according to the standard practice in the art, or may be believed to be or suspected to be at risk of developing impairedgut barrier function and / or a disease or condition associated with altered gut barrier function.Thus, the subject may or may not exhibit one or more symptoms of altered gut barrier function, or a disease or condition associated with altered gut barrier function; and / or may or may not exhibit altered expression, levels or amounts of one or more biomarkers associated with normal gut barrier function as disclosed herein. Thus, the dietary management of gut barrier function according to the invention is understood to relate to the minimization or prevention of one or more existing or expected symptoms of (a) altered gut barrier function; (b) a disease or condition associated with altered gut barrier function in a subject determined to have or suspected to be at risk of altered gut barrier function; and / or (c) one or symptomsuch altered gut barrier function or disease / condition associated therewith. Riboprine for thedietary management according to the methods and used of the invention may be formulated according to well-known and standard practices in the art and may be any suitable nutritionalcomposition known in the art, including formulation as a food product, food supplement, afunctional beverage product, nutritional supplement, dietary supplement, over-the-counter (OCT) supplement, medical food, Enteral Formula for Special Medical Use, Food for Specified Health Uses, Food for Special Medical Purposes (FSMP), Food for Special Dietary Use (FSDU),and a Medical Food. In certain embodiments, isolated and / or purified riboprine is used in thepreparation of the nutritional composition for the uses and methods according to theinvention. In certain embodiments, riboprine is the only active ingredient or agent in thenutritional composition for the uses and methods according to the invention.The maintenance or management (including dietary management) of gut barrier function mayinclude “preventive treatment” or “prevention” of alteration of gut barrier function (includingprevention of a decrease in gut barrier function or a slowing of a decrease in gut barrier function), of one or more symptom of altered barrier function (including a slowing of theprogression of one or more symptom of altered gut barrier function), and / or of a disease orcondition associated with altered gut barrier function (including prevention of such disease of condition in a subject at risk or believed to be at risk for the development of the disease or condition, whether diagnosed with such risk or not). "Preventive treatment," "prevention" and analogous terms means treatment given or action taken to diminish the risk of onset orrecurrence of altered gut barrier function, a disease or condition associated with alteredbarrier function, or a symptom thereof. The prevention may occur by addressing underlyingnutritional needs of the subject (e.g. dietary management) or through other mechanisms.Therefore, where the maintenance, improvement, treatment or management (includingdietary management) of gut barrier function according to the invention includes theprevention or preventative treatment of dysregulation of gut barrier function (e.g. gut barrier dysregulation), it includes the prevention or reduction in severity or frequency of one or more symptoms of a disease or condition, including ameliorating one or more existing symptoms of a disease or condition, preventing one or more existing symptoms of disease or condition, preventing one or more underlying causes of a disease or condition, ameliorating one or more underlying cause of a disease or condition, reducing the prevalence of one or more symptoms of a disease or condition, and / or reducing the occurrence of one or more symptoms of a disease or condition. Improving or maintaining gut barrier function will also be understood to include stabilizing a disease or condition and preventing progression of a disease or condition. Diseases and conditions that are associated with altered gut barrier function include, but are not limited to, obesity, metabolic syndrome, insulin-deficiency or insulin-resistance related disorders, diabetes mellitus, glucose intolerance, abnormal lipid metabolism, hyperglycaemia,barrier function diseases (including inflammatory bowel disease, e.g. Crohn's disease andulcerative colitis), irritable bowel syndrome, gut contractility disorder, hypercholesterolemia, atherogenic dyslipidemia, leaky gut, malnutrition, chronic inflammation, cardiovascular disease, functional dyspepsia, gastrointestinal infection, food allergy, ageing, menopause, recovery from antibiotic treatment, recovery from surgery, a neurodegenerative disorder, and autoimmune disease or kidney disease. Suitable subjects of the present invention include mammalian subjects, but are preferablyhuman or companion animals (including without limitation, dogs and cats). The mammaliansubject according to the present invention includes, but is not limited to a human, canine,feline, lagomorph, mustelid, rodent, bovine, caprine, equine, camelid, ovine, porcine, primate,and a simian. The subject according to the present invention may be avian.In some embodiments, in the different uses and / or methods of the invention, the riboprine isadministered or used at a concentration of at least 5µM, preferably at least 8 µM, morepreferably at least 10 µM or 10 µM to 10 µM-500 µM or 10 µM to 10 µM-100 µM.Accordingly, the invention is directed to the following items,[1] Riboprine for use in the maintenance of gut barrier function.[2] The riboprine for the use according to item 1, wherein said use is in a subject in need ofmaintenance of gut barrier function.[3] A method for the maintenance of the gut barrier function in a subject in need thereof,comprising administering a therapeutically effective amount of riboprine.[4]. The riboprine for the use according to item 1 or 2, or the method according to item 3,wherein said riboprine is formulated as an oral composition, a dietary supplement, afood product, a functional beverage product, a medical food, a food for specified health uses, a food for special medical purposes (FSMP) or a food for special dietary use (FSDU).[5] The riboprine for the use according to any one of items 1, 2 and 4, or the methodaccording to any one of items 3 to 4, wherein said maintenance of gut barrier functionis the maintenance of barrier structure, barrier protection, tight junction structure,intestinal epithelial integrity, or the quantity of mucin produced by the intestinal epithelia.[6] The riboprine for the use according to any one of items 1, 2 and 4 to 5, or the methodaccording to any one of items 3 to 5, wherein said maintenance of gut barrier function,includes the lack of progression of barrier dysfunction, intestinal ulcers, intestinal wounds, or lack of increased passage of luminal contents into systemic circulation.[7] The riboprine for the use according to any one of items 1, 2 and 4 to 6, or the methodaccording to any one of items 3 to 6, wherein the maintenance of gut barrier function isa) the lack of increased passage of luminal contents into systemic circulation,wherein the luminal contents comprise or consist of a lipopolysaccharide (LPS), a pathogen, an allergen, and / or a test compound; and / orb) the lack of alteration in level of LPS binding protein (LBP) in a biological sample.[8] The riboprine for the use according to item 7, or the method according to item 7,wherein said lack of increased passage or lack of alteration is relative to a control that isa) to be determined in a subject prior to the exposure or administration of riboprine;or b) a level as previously determined in one or more of a group of similarly situatedsubjects prior to exposure or administration of riboprine.[9] The riboprine for the use according to any one of items 1, 2 and 4 to 8, or the methodaccording to any one of items 3 to 8, wherein the maintenance of gut barrier function isa lack of increased local gut inflammation or systemic inflammation in a subject.

[0010] The riboprine for the use according to item 9, or the method according to item 9,wherein said subject is characterized as having systemic inflammation by having a level of one or more inflammatory cytokines above a predetermined threshold.

[0011] The riboprine for the use according to any one of items 1, 2 and 4 to 10, or the methodaccording to any one of items 3 to 10, wherein the maintenance of gut barrier functionis for the treatment of obesity, metabolic syndrome, insulin-deficiency or insulin- resistance related disorders, diabetes mellitus, glucose intolerance, abnormal lipid metabolism, hyperglycaemia, barrier function diseases (including inflammatory bowel disease, Crohn's disease and ulcerative colitis), irritable bowel syndrome, gut contractility disorder, hypercholesterolemia, atherogenic dyslipidemia, leaky gut, malnutrition, chronic inflammation, cardiovascular disease, functional dyspepsia, gastrointestinal infection, food allergy, ageing, menopause, recovery from antibiotic treatment, recovery from surgery, a neurodegenerative disorder, and autoimmune disease or kidney disease.

[0012] The riboprine for the use according to any one of items 1, 2 and 4 to 11, wherein saidsubject to be treated is a mammal.

[0013] The method according to any one of items 3 to 11, wherein said subject is a mammal.

[0053] The riboprine for the use according to item 1, 2 and 4 to 12, or the method accordingto item 3 to 11, and 13, wherein the riboprine is administered or used at a concentration of atleast 5µM, preferably at least 8 µM, more preferably at least 10 µM or 10 µM to 10 µM-500µM or 10 µM to 10 µM-100 µM.The invention is also directed to the following items:

[0014] Riboprine for use in the improvement of gut barrier function.

[0015] The riboprine for the use according to item 14, wherein said use is in a subject in needof improvement of gut barrier function.

[0016] A method for the improvement of the gut barrier function in a subject in need thereofcomprising administering a therapeutically effective amount of riboprine.

[0017] The riboprine for the use according to item 14 or 15, or the method according to item16, wherein said riboprine is formulated as an oral composition, a dietary supplement,a food product, a functional beverage product, a medical food, a food for specified health uses, a food for special medical purposes (FSMP) or a food for special dietary use (FSDU).

[0018] The riboprine for the use according to any one of items 14, 15 and 17, or the methodaccording to any one of items 16 to 17, wherein said improvement of gut barrier functionis the improvement of barrier structure, barrier protection, tight junction structure, intestinal epithelial integrity, or the quantity of mucin produced by the intestinal epithelia.

[0019] The riboprine for the use according to any one of items 14, 15 and 17 to 18, or themethod according to any one of items 16 to 18, wherein said improvement of gut barrierfunction, includes the reduction of barrier dysfunction, intestinal ulcers, intestinal wounds, or passage of luminal contents into systemic circulation.

[0020] The riboprine for the use according to any one of items 14, 15 and 17 to 19, or themethod according to any one of items 16 to 19, wherein the improvement of gut barrierfunction is a) the reduction of passage of luminal contents into systemic circulation, wherein theluminal contents comprise or consist of a lipopolysaccharide (LPS), a pathogen, an allergen, and / or a test compound; and / or b) the alteration in the level of LPS binding protein (LBP) in a biological sample.

[0021] The riboprine for the use according to item 20, or the method according to item 20,wherein said reduction or alteration is relative to a control that is a) to be determined in a subject prior to the exposure or administration of riboprine;or b) a level as previously determined in one or more of a group of similarly situatedsubjects prior to exposure or administration of riboprine.

[0022] The riboprine for the use according to any one of items 14, 15 and 17 to 21, or themethod according to any one of items 16 to 21, wherein the improvement of gut barrierfunction is the reduction of local gut inflammation or systemic inflammation in a subject.

[0023] The riboprine for the use according to item 22, or the method according to item 22,wherein said subject is characterized as having systemic inflammation by having a level of one or more inflammatory cytokines above a predetermined threshold.

[0024] The riboprine for the use according to any one of items 14, 15 and 17 to 23, or themethod according to any one of items 16 to 23, wherein the improvement of gut barrierfunction is for the treatment of obesity, metabolic syndrome, insulin-deficiency or insulin-resistance related disorders, diabetes mellitus, glucose intolerance, abnormal lipid metabolism, hyperglycaemia, barrier function diseases (including inflammatory bowel disease, Crohn's disease and ulcerative colitis), irritable bowel syndrome, gut contractility disorder, hypercholesterolemia, atherogenic dyslipidemia, leaky gut, malnutrition, chronic inflammation, cardiovascular disease, functional dyspepsia, gastrointestinal infection, food allergy, ageing, menopause, recovery from antibiotic treatment, recovery from surgery, a neurodegenerative disorder, and autoimmune disease or kidney disease.

[0025] The riboprine for the use according to any one of items 14, 15 and 17 to 24, whereinsaid subject to be treated is a mammal.

[0026] The method according to any one of items 16 to 24, wherein said subject is a mammal.

[0054] The riboprine for the use according to item 14, 15 and 17 to 25, or the methodaccording to item 16 to 24, and 26, wherein the riboprine is administered or used at aconcentration of at least 5µM, preferably at least 8 µM, more preferably at least 10 µM or 10µM to 10 µM-500 µM or 10 µM to 10 µM-100 µM.The invention is also directed to the following items,

[0027] Riboprine for use in the dietary management of gut barrier function.

[0028] The riboprine for the use according to item 27, wherein said use is in a subject in needof maintenance, improvement, or management of gut barrier function.

[0029] A method for the dietary management of gut barrier function in a subject in needthereof, comprising administering a therapeutically effective amount of riboprine.

[0030] The riboprine for the use according to item 27 or 28, or the method according to item29, wherein said riboprine is formulated as an oral composition, a dietary supplement,a food product, a functional beverage product, a medical food, a food for specified health uses, a food for special medical purposes (FSMP) or a food for special dietary use (FSDU).

[0031] The riboprine for the use according to any one of items 27, 28 and 30, or the methodaccording to any one of items 29 to 30, wherein said dietary management improves barrier structure, barrier protection, tight junction structure, intestinal epithelial integrity, or the quantity of mucin produced by the intestinal epithelia.

[0032] The riboprine for the use according to any one of items 27, 28 and 30 to 31, or themethod according to any one of items 29 to 31, wherein said dietary management reduces barrier dysfunction, intestinal ulcers, intestinal wounds, or passage of luminalcontents into systemic circulation.

[0033] The riboprine for the use according to any one of items 27, 28 and 30 to 32, or themethod according to any one of items 29 to 32, wherein the dietary managementa) reduces passage of luminal contents into systemic circulation, wherein the luminalcontents comprise or consist of a lipopolysaccharide (LPS), a pathogen, an allergen, and / or a test compound; and / or b) alters the level of LPS binding protein (LBP) in a biological sample.

[0034] The riboprine for the use according to item 33, or the method according to item 33,wherein said reduction or alteration is relative to a control that is a) to be determined in a subject prior to the exposure or administration of riboprine;or b) a level as previously determined in one or more of a group of similarly situatedsubjects prior to exposure or administration of riboprine.

[0035] The riboprine for the use according to any one of items 27, 28 and 30 to 34, or themethod according to any one of items 29 to 34, wherein the dietary managementreduces local gut inflammation or systemic inflammation in a subject.

[0036] The riboprine for the use according to item 35, or the method according to item 35,wherein said subject is characterized as having systemic inflammation by having a level of one or more inflammatory cytokines above a predetermined threshold.

[0037] The riboprine for the use according to any one of items 27, 28 and 30 to 36, or themethod according to any one of items 29 to 36, wherein the dietary management is themanagement of obesity, metabolic syndrome, insulin-deficiency or insulin-resistance related disorders, diabetes mellitus, glucose intolerance, abnormal lipid metabolism, hyperglycaemia, barrier function diseases (including inflammatory bowel disease, Crohn's disease and ulcerative colitis), irritable bowel syndrome, gut contractilitydisorder, hypercholesterolemia, atherogenic dyslipidemia, leaky gut, malnutrition, chronic inflammation, cardiovascular disease, functional dyspepsia, gastrointestinal infection, food allergy, ageing, menopause, recovery from antibiotic treatment, recovery from surgery, a neurodegenerative disorder, and autoimmune disease or kidney disease.

[0038] The riboprine for the use according to any one of items 27, 28 and 30 to 37, whereinsaid subject to be treated is a mammal.

[0039] The method according to any one of items 29 to 37, wherein said subject is a mammal.

[0055] The riboprine for the use according to item 27, 28, and 30 to 38, or the methodaccording to item 29 to 37, and 39, wherein the riboprine is administered or used at aconcentration of at least 5µM, preferably at least 8 µM, more preferably at least 10 µM or 10µM to 10 µM-500 µM or 10 µM to 10 µM-100 µM.The invention is also directed to the following items,

[0040] Riboprine for use in the treatment of altered or dysregulated gut barrier function.

[0041] The riboprine for the use according to item 40, wherein said treatment is in a subject inneed of maintenance, or improvement of gut barrier function.

[0042] A method for the treatment of altered or dysregulated gut barrier function in a subjectin need thereof, comprising administering a therapeutically effective amount of riboprine.

[0043] The riboprine for the use according to item 40 or 41, or the method according to item42, wherein said riboprine is formulated as an oral composition, a dietary supplement, a food product, a functional beverage product, a medical food, a food for specified health uses, a food for special medical purposes (FSMP) or a food for special dietary use (FSDU).

[0044] The riboprine for the use according to any one of items 40, 41 and 43, or the methodaccording to any one of items 42 to 43, wherein said treatment improves barrier structure, barrier protection, tight junction structure, intestinal epithelial integrity, or the quantity of mucin produced by the intestinal epithelia.

[0045] The riboprine for the use according to any one of item 40, 41 and 43 to 44, or the methodaccording to any one of items 42 to 44, wherein said treatment reduces barrierdysfunction, intestinal ulcers, intestinal wounds, or passage of luminal contents intosystemic circulation.

[0046] The riboprine for the use according to any one of items 40, 41 and 43 to 45, or themethod according to any one of items 42 to 45, wherein said treatmenta) reduces passage of luminal contents into systemic circulation, wherein the luminalcontents comprise or consist of a lipopolysaccharide (LPS), a pathogen, an allergen, and / or a test compound; and / or b) alters the level of LPS binding protein (LBP) in a biological sample.

[0047] The riboprine for the use according to item 46, or the method according to item 46,wherein said reduction or alteration is relative to a control that is a) to be determined in a subject prior to the exposure or administration of riboprine;or b) a level as previously determined in one or more of a group of similarly situatedsubjects prior to exposure or administration of riboprine.

[0048] The riboprine for the use according to any one of items 40, 41 and 43 to 47, or themethod according to any one of items 42 to 47, wherein said treatment reduces localgut inflammation or systemic inflammation in a subject.

[0049] The riboprine for the use according to item 48, or the method according to item 48,wherein said subject is characterized as having systemic inflammation by having a level of one or more inflammatory cytokines above a predetermined threshold.

[0050] The riboprine for the use according to any one of items 40, 41 and 43 to 49, or themethod according to any one of items 42 to 49, wherein said treatment is a treatmentfor obesity, metabolic syndrome, insulin-deficiency or insulin-resistance related disorders, diabetes mellitus, glucose intolerance, abnormal lipid metabolism, hyperglycaemia, barrier function diseases (including inflammatory bowel disease, Crohn's disease and ulcerative colitis), irritable bowel syndrome, gut contractility disorder, hypercholesterolemia, atherogenic dyslipidemia, leaky gut, malnutrition, chronic inflammation, cardiovascular disease, functional dyspepsia, gastrointestinal infection, food allergy, ageing, menopause, recovery from antibiotic treatment, recovery from surgery, a neurodegenerative disorder, and autoimmune disease or kidney disease.

[0051] The riboprine for the use according to any one of items 40, 41 and 43 to 50, whereinsaid subject to be treated is a mammal.

[0052] The method according to any one of items 42 to 50, wherein said subject is a mammal.

[0056] The riboprine for the use according to item 40, 41, and 43 to 51, or the methodaccording to item 42 to 50, and 52, wherein the riboprine is administered or used at aconcentration of at least 5µM, preferably at least 8 µM, more preferably at least 10 µM or 10µM to 10 µM-500 µM or 10 µM to 10 µM-100 µM.

[0002] 4. BRIEF DESCRIPTION OF FIGURESFigure 1. Structure of the compound N6-Isopentenyladenosine, i.e. "riboprine" as used herein. Figure 2A and B. Dose-response curves of Muc2 intracellular production in response toriboprine from 2 different experiments (N1 (Fig.2A) and N2 (Fig 2B)). The concentration of thechemical compound (cpd) riboprine is expressed as log (base 10) in moles per liter. Normalizedproduction is reported based on basal and maximum production determined in negative (no treatment) and positive (30 µM TNFα) control cultures, respectively, according to the formula (x-basal) / (max-basal)*100. Figure 3. Intracellular production of Muc2 protein, expressed with respect to the control (CTL)group (in %). Normalized Muc2 protein production is expressed as the percentage of Muc2with respect to the value of the control group (average value) according to the formula(x / control)*100. The results were analyzed by a one-way ANOVA test and p values areindicated for each comparison (p<0.05 is considered statistically significant). Negative controlgroup is 0.1% DMSO; 10 µM forskolin was used as a positive control for Muc2 proteinproduction. The graph corresponds to a pool of 2 distinct experiments (n= 24).Figure 4. Viability of cells exposed to different concentrations of riboprine over 24 hours. Datawere analyzed by a one-way ANOVA test. The control culture (CTL) contained 0.1% DMSOwithout riboprine. The graph corresponds to a pool of two distinct experiments (n= 4-23). Figure 5. Representation of intestinal permeability as assessed by the passage of FITC-dextranacross the intestinal epithelium of C. elegans at day 8 of age. Values are expressed relative tothe average in the control group. Student t test was used to compare groups and p<0.05 wasconsidered statistically significant. Representation of 2 experiments (n=24).Figure 6. Representation of the intestinal permeability as assessed by the passage of FITC-Dextran across the intestinal epithelium of C. elegans at day 8 of age. The worms had been challenged at L4 for 14 to 15 hours with salmonella LPS. Values are expressed as relative to the average in the control group. One-way Anova followed by Dunnet’s multiple comparison tests were used to compare groups and p<0.05 was considered statistically significant. Representation of 2 experiments (n=24). Figure 7. Comparative analysis of intracellular production of Muc2 protein betweenriboprine and adenosine. Different batches of each compound were tested in 4replicates per condition. Both batches of riboprine at 10 µM concentration increasedbetween 1.4-1.5 times the production of Muc2 as compared to the vehicle. None of thebatches of adenosine promoted Muc-2 protein production. The results are expressed in fold-change respect to the vehicle group (0.1% DMSO) and were analyzed by a one-wayANOVA test. P values are indicated for each comparison (p<0.05 is considered statisticallysignificant; ns indicates not significant). Positive control conditions were 10 µM TNF-α and10 µM forskolin. The graphs correspond to a pool of 3-8 independent experiments (n= 12-36).

[0003] 5. DETAILED DESCRIPTIONAll references cited in this disclosure are hereby incorporated by reference in their entireties. In addition, any manufacturers’ instructions or catalogues for any products cited or mentionedherein are incorporated by reference. Documents incorporated by reference into this text, orany teachings therein, can be used in the practice of the present invention. Documents incorporated by reference into this text are not admitted to be prior art.The invention provides methods of use of riboprine for maintaining or improving gut barrierfunction. Also provided are methods of dietary management of gut barrier function comprising the use of riboprine. The invention is based on the recognition for the first timethat riboprine positively affects gut barrier function, including at least gut barrier integrity andmucus production. As used herein the term "riboprine" refers to the compound N6-isopentenyladenosine (e.g. commercially available at ChemScene, CS-W011925, CAS n°: 7724-76-7, Figure 1).Gut barrier function (also known as intestinal barrier function) regulates transport and hostdefense mechanisms at the intestinal mucosal interface with the external world, specifically ingested contents of the intestinal luminal space. Transcellular and paracellular fluxes are tightly controlled by membrane pumps, ion channels and tight junctions, adaptingpermeability to physiological needs. Disturbance at any level, but particularly alterations inpermeability, in particular, increased permeability, can result in tissue damage andinflammation due to introduction of, e.g. toxins, allergens, bacterial components (e.g. lipopolysaccharide (LPS) and other inflammatory compounds from the luminal space.The passage of undesired substances from the luminal side of the intestine through or acrossthe intestinal barrier to intestinal tissue and / or systemic circulation is inhibited in part by thefunctioning of the epithelial cell barrier (IEB), e.g. mediated by tight junctions. Tight junctions,or zonula occludens, are the closely associated areas of two epithelial cells whose membranes join together forming a virtual impermeable barrier to fluid, thereby separating the vascularsystem from the lumen of the digestive tract. Alteration of the tight junction barrier function,specifically reduction, has been demonstrated to result in an increased passage of undesirablesubstances from intestinal lumen into the circulating system. The present invention provides uses and methods of maintaining, improving or managing gut barrier function (including the dietary management thereof) in a subject, specifically comprising the use of riboprine. Gut barrier function is also known as gut barrier integrity and the terms may be used interchangeably. The terms are also recognized to apply to barrierfunctionality, specifically, of the intestine. Accordingly, the uses and methods provided herein are preferably directed to effects and / or benefits obtained in the intestine or directed to effects on and benefits for intestinal barrier function. High gut barrier function / high gutbarrier integrity (which includes, e.g. a lack of intestinal permeability to undesired substancessuch as pathogens, toxins, allergens) is also recognized as normal (i.e. healthy) gut barrier function / gut barrier integrity. Thus, the invention provides methods of maintaining, improving or managing healthy (i.e. normal) gut barrier function (including the dietary managementthereof). The uses and methods provided herein may be used in the prevention, treatment ormanagement of altered gut barrier function (also known as gut barrier dysregulation) in a subject diagnosed or otherwise recognized to have altered barrier function; or is considered or believed to be at risk for development of altered gut barrier function. The uses and methods provided herein may also be used in the management of gut barrier function (e.g. the dietary management thereof) in a subject, whether the subject has been deemed to be in need ofsuch management or not, and whether the subject has altered gut barrier function (or asymptom thereof) or not. Accordingly, the uses and methods of the invention apply to a subject deemed in need of improvement or maintenance of gut barrier function, e.g. that (a) has been diagnosed as having altered gut barrier function, a symptom of altered gut barrier function, or a disease or condition (or symptom thereof) of altered gut barrier function; (b) is suspected as having altered gut barrier function, a symptom of altered gut barrier function, ora disease or condition (or symptom thereof) of altered gut barrier function (whetherdiagnosed or not); or (c) is believed to be at risk for development of altered gut barrier function, a symptom of altered gut barrier function, or a disease or condition (or symptom thereof) of altered gut barrier function. Accordingly, the methods and uses of the invention apply to a subject that may or may not have altered gut barrier function or a disease associated with altered gut barrier function; or that may or may not exhibit a symptom of a disease or condition associated with altered gut barrier function. Thus, the uses and methods of theinvention also apply to an otherwise normal, e.g. healthy, subject.Gut barrier function can be assessed by the determination, e.g. measurement, of one or moremarkers associated with gut barrier function, e.g. gut barrier permeability, in a biologicalsample from the subject. In a nonlimiting embodiment, the biological sample is a tissue orbody fluid sample (such as a blood sample, including but not limited to whole blood, serum or plasma)). The marker can be used to assess the level or status of gut barrier function in a subject, or the change therein. For example, relative gut barrier function / gut barrier integrity can be assessed by determining the level or amount of one or more markers as known in the art or defined herein and compared to a control level or amount, e.g. (a) that established in asimilarly situated but otherwise healthy subject or population of such subjects (or otherwisehaving normal gut barrier function); or (b) that established in a similarly situated subject orpopulation of subjects known to have altered gut barrier function or a disease associated withaltered barrier function. Such assessment can for example be used to determine whether the subject is in need of improvement, maintenance or management (including dietarymanagement) of gut barrier function. Change in gut barrier function, e.g. improvement, canalso be assessed in non-limiting examples by determining the level or amount of one or morebiomarkers as known in the art or defined herein and compared to a control level or amount, e.g. (a) that established in the subject at an earlier point in time, e.g. prior to exposure to oradministration of riboprine; or (b) that established in a similarly situated subject or populationof subjects known to have altered gut barrier function or a disease associated with altered barrier function, but prior to exposure to or administration of riboprine. However, the methods and uses of the invention are not dependent on such a medical assessment. Thus, improvement according to the invention need not necessarily comprise the comparison of oneor more markers taken from the same individual at two points in time, but can be determinedby comparison with a relevant control value. Depending on the marker, sample and assay, the level or amount of a marker may increase or decrease as gut barrier function / gut barrier integrity improves as is known in the art, e.g.indicating an increase in gut barrier integrity and / or a decrease in gut barrier permeability.Similarly, depending on the marker, sample and assay, the level or amount of a marker mayincrease or decrease as gut barrier function / gut barrier integrity decreases. In non-limitingexamples, the marker is selected from a pathogen (or a marker thereof), commensal bacteria (or a fragment, component, or marker thereof, including level of lipopolysaccharide (LPS) and / or determination of LPS activity), an allergen, a toxic compound, an ingested sugar or a biomarker (including in non-limiting examples a cytokine, a chemokine, a growth factor, anangiogenic factor, an enzyme, a protease, an adhesion molecule, a cell signaling molecule, ahormone and a sugar). As described herein, the biomarker may also itself be a marker of thepresence of the marker of gut barrier function. For example, the biomarker may belipopolysaccharide binding protein (LBP), which is an acute phase protein that is also modulated in response to LPS, i.e. is an indirect marker of gut barrier function. Significantchanges in LPSBP either higher or lower (e.g. as determined in a biological sample using ELISAas described herein), when compared to a control, may also be used as an indicator ofincreased intestinal permeability and can confirm a reduced gut barrier integrity as describedherein. The biomarker may also be one or more proteins associated with epithelial barrierstructure or protection, epithelial tight junction structure or function, or one or more proteins known to be involved in the regulation of intestinal epithelial cell barrier permeability, such as, but not limited to, tight junction proteins, tight junction adhesion molecules (JAMS), tricellulins, angulins, intracellular scaffolding proteins (such as zona occludens proteins), claudins, and E-cadherin proteins. One exemplary marker is lipopolysaccharide (LPS). Oneexemplary biomarker is plasma citrulline An increase in the in blood level (including levels inone or more of whole blood, serum or plasma) of LPS or a reduction in the blood level(including levels in one or more of whole blood, serum or plasma) of citrulline corresponds toan increase in gut barrier permeability, and thus a decreased gut barrier function. The uses and methods of the invention also encompass the management or improvement of gut or systemic inflammation, for example, uses and methods of reducing the level and / or activity of at least one inflammatory cytokine. Accordingly, the one or more biomarker that may be assessed according to the invention includes inflammatory cytokines such as, but not limited to, CRP, TNF-α, IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-13, IL-15, IL-21, IL-22, IL-23, IL-27, IPNγ, G-CSF, GM-CSF, IP-10, KC, LIF, LIX, MCP-1, M-CSF, , MIG, MIP- 1α, MIP-1β, MIP-2, MIP-3, RANTES, RANKL and VEGF. Any suitable assay known in the art or described herein can be used for the determination or assessment of the one or more markers (including biomarkers) in a biological sample from the subject according to the invention. Suitable assays include at least immunohistochemicalstaining and ELISA. Techniques and kits for immunohistochemical assays and ELISA are wellknown in the art. Suitable biological samples include at least blood (e.g. whole blood, plasma, or serum) or tissue, and may also include other body fluids such as saliva or urine. As a non-limiting example, the presence and / or levels of LPS and LBP can be determined using readily available commercial kits, such as LBP ELISA Kit (e.g. LBP ELISA Kit from Antibodiesonline with catalogue number: ABIN414694), LPS ELISA Kit (e.g. LPS ELISA Kit from Antibodiesonline with catalogue number: ABIN6975836). LPS activity / content can be measured by usingbiological activity assays, such as limulus amebocyte lysate (LAL) and LAL-like activity assays, fluorescence assays (such as ENDOLISA®, PYROGENE™, or ENDOZYME®), enzymatic tests (suchas HEK-BLUE™ LPS detection kit / HEK-BLUE™ hTLR4 cells, ELISA), and mass assays (such as 3-hydroxymyristate (3HM) quantitation by GC / MS, HPLC / MS / MS). A further non-limiting example of an assay for the assessment of gut barrier function includes the oral administration of a marker such as an insoluble sugar (such as sucralose, mannitol,lactulose, sucrose, sucralose, or a combination thereof) collection of a bodily fluid such asurine or blood after one or more defined periods of time, and measurement of the marker (e.g. the insoluble sugar or break down product thereof) contained in the bodily fluid through standard clinical analytical techniques. Additional or alternative exemplary assays include invitro assays, such as by trans-epithelial electrical resistance (TEER); e.g. as disclosed inSrinivasan et al., J Lab Autom 20(2015), 107-126. It is recognized that the mucus layer also impacts gut barrier function / gut barrier integrity. Thus, the one or more biomarker for the use and methods of the invention may be or includeone or more biomarkers associated with mucus production or mucus layer function. In nonlimiting examples, the one or more biomarker associated with mucus production or mucus layer function may be the amount, level or relative expression level of one more mucins, whichare known to be integral membrane proteins that span the entirety of the cell membrane, e.g.are transmembrane proteins. Mucins form a gateway to permit / prevent the transport ofspecific substances across the membrane and are known to exist / be expressed as multipledifferent isoforms. The level, amount or change in mucin, mucin production or mucinexpression may be determined by any suitable method known in the art, such as at the protein level (whether intracellular or extracellular), or at the expression level (e.g. assessing mRNAlevels or amount). The one or more mucins can include but are not limited to one or more ofMUC1, MUC2, MUC3 (including MUC3A), MUC4, MUC5 (including MUC5AC and MUC5B),MUC6, MUC7, MUC8, MUC12, MUC13, MUC15, MUC16, MUC17, MUC19, MUC20, MUC21,and MUC22, or one or more isoforms thereof, The one or more marker for the use and methods according to the invention may also be markers of mucosal layer function and / or mucosal healing, which are normally determined by macroscopic observation or microscopic analysis of intestinal tissue samples obtained by endoscopy. Such characteristics and, thus, markers according to the invention include, but arenot limited to, erythema, loss of vascular pattern, friability, bleeding, erosions and ulcers. Inorder to evaluate the presence or absence of characteristics associated with altered gut barrier function (and / or mucosal layer function / healing), in particular using endoscopic methods, various endoscopic scoring systems have been developed. These parameters orindices allow for the determination of improvements of endoscopic lesions, even when a rigidendpoint of complete mucosal healing or total disappearance of all mucosal ulcerations is not met. The endoscopic component of the clinical Mayo score, introduced in 1987, is currently the most used score of the mucosal layer in clinical practice and includes the variables erythema, loss of vascular pattern, friability, bleeding, erosions and ulcers, and ranges from 0 to 3. Thus, improvement or management of the gut barrier function may refer to mucosal layer function / healing, such as amelioration or prevention intestinal ulcers or wounds, and / or reduction or improvement of intestinal inflammatory, ulcer or wound score. Apart from endoscopic methods, other measures of assessing mucosal layer function are wellknown in the art are also encompassed by the invention, including the measurement ofbiomarkers C-reactive protein and calprotectin. As is understood, an advantage of using invitro biomarker assays for the assessment of mucosal healing is that such assays are typicallyfar less invasive for the subject.Riboprine for the use and methods of the invention may be provided or administered to thesubject for medical use in the form of a pharmaceutical composition. In the pharmaceuticalcomposition, riboprine acts as an active pharmaceutical ingredient (API) and is present in apharmaceutically acceptable or pharmaceutically effective amount. As used herein, the term“pharmaceutically-effective amount” means an amount sufficient to manage, treat, orimprove, e.g. reduce and / or alleviate one or more effects or symptoms or altered gut barrierfunction and / or a disease or condition associated with altered gut barrier function. In someembodiments, the pharmaceutical composition does not comprise any additional activeagent, e.g. an additional pharmaceutically active agent. The form of the pharmaceuticalcomposition is not particularly limited, and examples include tablets, pills, powders, solutions,suspensions, emulsions, granules, capsules, syrups, and the like. Additives widely used as pharmaceutical carriers for suitable pharmaceutical compositions, in particular oral compositions and oral dosage forms as described herein, such as excipients, binders, disintegrating agents, lubricants, stabilizers, corrigents, diluents, and surfactants can also beused. In certain embodiments, the pharmaceutical composition is a nutritional composition.The invention also encompasses uses and methods of providing riboprine to a subject in acomposition outside of the context of a pharmaceutical composition and / or outside of thecontext of supervision of medical personnel. In some embodiments, the composition does notcomprise any additional active agent, e.g. any additional pharmaceutically active agent.Riboprine can be provided in any suitable form as determined according to standard methodsin the art, e.g. as a nutritional composition for the dietary management of gut barrier function.Non-limiting examples of a nutritional composition, whether also pharmaceutical compositionor not (i.e. a "composition") include a food supplement, a dietary supplement, a nutritionalsupplement, an over-the-counter (OCT) supplement, a food product, a medical food, an Enteral Formula for Special Medical Use, a Food for Specified Health Uses, a Food for SpecialMedical Purposes (FSMP), a Food for Special Dietary Use (FSDU), a Medical Nutrition or aMedical Food. Nutritional compositions may or may not be administered to the subject undermedical supervision.Accordingly, the invention encompasses methods directed to the use of riboprine for themaintenance, improvement or management (including dietary management) of gut barrierfunction which may be the use of riboprine in pharmaceutical compositions in a therapeuticmethod for the maintenance or improvement of gut barrier function (including the prevention or improvement of a disease or condition (or a symptom thereof) associated with altered gutbarrier function; or the use of riboprine in a composition (e.g. a nutritional composition) forthe dietary management of gut barrier function, e.g. supporting, maintaining, or improving gut barrier function.The riboprine pharmaceutical compositions or riboprine compositions can be formulated fororal delivery to a subject in need thereof according to standard practices known in the art. Inone embodiment, a pharmaceutical composition is formulated to deliver riboprine to a subjectin need thereof. In another embodiment, a composition is formulated to deliver riboprine toa subject in need thereof. The riboprine pharmaceutical composition or the riboprinecomposition is preferably formulated to such that the riboprine substantively first acts in theintestine or that the first tissue of the gastrointestinal tract exposed to the riboprine isintestinal tissue. That is, it is preferred that on ingestion of a riboprine pharmaceuticalcomposition or riboprine composition, apart from the unavoidable exposure to esophageal orstomach tissue that may occur as the pharmaceutical composition or composition travelsthrough the gastrointestinal tract, the riboprine does not act or only minimally acts in theesophagus or stomach or has only minimal effect in / on esophageal or stomach tissues. Pharmaceutical compositions and compositions for oral administration can be, in non-limitingexamples, in solid, semi-solid, micro-emulsion, gel, or liquid form including tablets, capsules,powders and liquids.The oral administration form can be any suitable form produced by any suitable methodknown in the art such as a push-fit capsule made of gelatin, or a soft, sealed capsule made ofgelatin and a plasticizer, such as glycerol or sorbitol. Tablets can be made by compression ormolding, optionally with one or more accessory ingredients such as a filler. Compressedtablets can be prepared by compressing in a suitable machine the active ingredient riboprinein a free-flowing form such as a powder or granules, optionally mixed with binders, inertdiluents, preservatives, antioxidants, disintegrants, or lubricating, surface active or dispersing agents. Molded tablets can be made by molding in a suitable machine a mixture of thepowdered active agent, riboprine, moistened with an inert liquid diluent. The tablets canoptionally be coated or scored and can be formulated so as to provide slow or controlledrelease of the active ingredient therein, in particular, for optimized release in the intestine or subsequent to passage through the stomach such as with an enteric coating, e.g. providing release in parts of the gut (e.g., colon, lower intestine) other than the stomach. Such enteric coating can be stable at low pH (such as in the stomach) and can dissolve at higher pH (for example, in the small intestine). Material that can be used in enteric coatings includes, for example, alginic acid, cellulose acetate phthalate, plastics, waxes, shellac, and fatty acids (e.g., stearic acid, palmitic acid). The enteric coating can also be an aqueous enteric coating. Examples of polymers that can be used in enteric coatings include, for example, shellac,cellulose acetate phthalate, polyvinylacetate phthalate, and methacrylic acid.Where the oral formulation is a push-fit capsule, it can contain riboprine in admixture withfiller such as lactose, binders such as starches, and / or lubricants such as talc or magnesiumstearate and, optionally, stabilizers. In soft capsules, the riboprine can be dissolved orsuspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.In addition, stabilizers can be added. Dragee cores can be provided with suitable coatings. Forthis purpose, concentrated sugar solutions can be used, which can optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments can be added to the tablets or dragee coatings for identification.Riboprine pharmaceutical compositions and riboprine compositions for oral use can also bepresented as hard gelatin capsules wherein the riboprine is mixed with an inert solid diluent,for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsuleswherein the riboprine is mixed with water soluble carrier such as polyethylene glycol or an oilmedium, for example peanut oil, liquid paraffin, or olive oil.Riboprine pharmaceutical compositions and riboprine compositions for oral use can also beformulated as aqueous or oily suspensions, solutions, emulsions syrups or elixirs, or can be presented as a dry product for reconstitution with water or other suitable vehicle before use.Such liquid preparations can contain conventional additives, such as suspending agents, forexample sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, acacia; nonaqueous vehicles (which can include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydoxybenzoate or sorbic acid, and, if desired, conventional flavoring or coloring agents.The riboprine pharmaceutical compositions and riboprine compositions for provided hereincan be in unit-administration forms or multiple-administration forms. Unit-administrationforms, as used herein, refer to physically discrete units suitable for administration to a subjectin need thereof and packaged individually. Each unit-administration can contain a predetermined quantity of riboprine, e.g. in the context of a pharmaceutical composition, inan amount sufficient to produce a desired therapeutic effect. Examples of unit-administrationforms include, but are not limited to, ampoules, syringes, and individually packaged tablets and capsules. Unit-administration forms can be administered in fractions or multiples thereof. A multiple-administration form is a plurality of identical unit-administration forms packaged in a single container, which can be administered in segregated unit-administration form. Examples of multiple-administration forms include, but are not limited to, vials, bottles of tablets or capsules, or bottles of pints or gallons.The riboprine pharmaceutical compositions and riboprine compositions provided herein forthe use and method of the invention may also be formulated as a nutritional composition. As used herein a nutritional composition means a substance or composition that satisfies at leasta portion of a subject's nutrient requirements and is intended to supplement a diet, inparticular of subjects having, being suspected of having or being at risk of developing altered gut barrier function (e.g. impaired gut barrier or gut barrier dysfunction) or a disease or condition (or symptom thereof) associated with altered gut barrier function. A nutritional composition may refer to liquids, powders, solutions, gels, pastes, solids, concentrates, suspensions, ready-to-use forms of enteral formulas, oral formulas, or formulas for infants, pediatric subjects, or children. Examples for nutritional compositions include supplements (such as dietary supplements) and medical foods. The term supplement, in particular a dietary supplement, refers to a substance that is not a conventional food and that is manufactured to be administered to a subject over a period of time, wherein the substance is an addition to the subject's diet. The supplement may, forexample, be in the form of a food or drink, or formulated to be added to a food or drink, suchthat it otherwise supplements the regular intake of food. From a regulatory standpoint, adietary supplement is generally a composition that can be purchased and used without aprescription. For example, in the United States, per the Food and Drug Administration and TheDietary Supplement Health and Education Act of 1994, a dietary supplement is "a productintended to supplement the diet that bears or contains one or more of the following dietaryingredients: a vitamin, a mineral, an herb or other botanical, an amino acid, a dietarysubstance for use by man to supplement the diet by increasing the total dietary intake, or aconcentrate, metabolite, constituent, extract, or combination of any of the ingredients justdescribed." In the context of the invention a riboprine supplement, such as a riboprine dietarysupplement, is intended to supplement the diet of a subject having, being suspected of having or being at risk of developing altered gut barrier function (e.g. impaired gut barrier or gut barrier dysfunction) or a disease or condition (or symptom thereof) associated with alteredgut barrier function. However it needs not to be used under medical supervision.The riboprine dietary supplement for the uses and methods according to the invention mayencompass any formulation for oral delivery. For example, the riboprine compositions of theinvention may be ingested in liquids, for example, being formulated in any number ofbeverage formats, including infused water, sports drinks, energy drinks, teas, fruit juices, ormeal replacement beverages. Alternately or additionally, the riboprine compositions of theinvention are formulated as a powder which may be dissolved in water, or other drinks suchas fruit juice, coffee, or tea. The powder formulation may be packaged in individual packetsor vials at a measured dose. The powder formulation may be packaged with a scoop whichmeasures the correct dose for mixing with liquid and instructions for doing so at a specified frequency.The riboprine dietary supplement may also be formulated as a capsule, tablet, or chewabletablet. They may be ingested as a component of an edible item, for example, beingincorporated into gummies, cookies, snack bars, meal replacement bars and other bars, cereals, biscuits, crackers, confectionery items, and probiotic formulations including yogurt, and other food items. The nutritional composition for the uses and methods according to the invention may also be a medical food. A medical food refers to a formula food specially processed and prepared in order to meet special needs for nutrient or diet of those suffering from, suspected to suffer from or at risk of suffering from a disease or disorder of digestive absorption, in particular inthe context of the present invention altered gut barrier function. Medical foods are speciallydeveloped by clinicians and nutritionists, may be used alone or together with other foods, and may be used with or without the guidance or supervision of a doctor or clinical nutritionist. Medical foods are special dietary food, not medicine, but not ordinarily eaten by normalpeople. Medical foods are intended for the dietary management of a disease, state, disorder,or condition, or one or more symptoms thereof. In the context of the invention the nutritional composition or medical food is for use in the dietary management of gut barrier function in asubject having, being suspected of having or being at risk of developing altered gut barrierfunction (e.g. impaired gut barrier or gut barrier dysfunction) or a disease or condition (or symptom thereof) associated with altered gut barrier function. The term "medical food" maybe used interchangeably with the terms "food for specified health uses," "food for specialmedical purposes (FSMP)" or "food for special dietary use (FSDU)."The riboprine pharmaceutical compositions or riboprine compositions for the uses andmethods of the invention may be ingested or administered according to a selected health ortreatment regimen and / or a specified dosage schedule. Doses may be ingested oradministered for a selected period of time, e.g. a period of days, weeks, or months. In someimplementations, in particular in the context of preventative uses and methods, chronic, long-term ingestion or administration is contemplated for management of gut barrier function, e.g.maintaining beneficial, therapeutic, or preventative effects. In a non-limiting exemplary embodiment, the administration is daily with one or more dosages ingested or administered per day. Multiple such dosages may be administered during the day, to arrive a cumulative dosage near, at, or above the biologically effective or therapeutically effective daily dosage, forexample, two, three, four, or more doses per day. Dosage forms (e.g. capsules, packets ofdissolvable powder for drinks, scoops for measuring such powder, etc.) may be configured forfractions of the daily dose. In some embodiments, two or more dosages are delivered per day,for example, a morning and an evening dose, a dosage administered before or after each meal, a dosage delivered every four hours, six hours, twelve hours, or at other selected timeintervals. Alternatively, riboprine pharmaceutical compositions or riboprine compositionsmay be consumed or administered at less than daily frequency, for example, once a week,twice a week, three times a week, etc.Where the riboprine pharmaceutical composition or riboprine composition for the uses andmethods of the invention is provided as a nutritional composition, the composition may comprise a source of protein. The protein may be present in any suitable amount, for example, below 2.0 g per 100 kcal, e.g. between 1.8 to 2 g / 100kcal, or below 1.8 g per 100 kcal. Wheer the composition is a formula, the protein may be in an amount between 1.6 to 3 g per 100kcal (e.g. when the composition is an infant formula); or between 2.4 and 4 g / 100kcal or morethan 3.6 g / 100kcal (e.g. when the composition is a formula for premature infants).The protein source may be any protein source suitable for use in the nutritional composition. The protein(s) in the nutritional composition may be intact or hydrolysed or a mixture of intactand hydrolysed proteins. Non-limiting examples of protein sources include those based onwhey, casein, soy and mixtures thereof. With respect to whey, the protein source may bebased on acid whey or sweet whey or mixtures thereof and may include alpha-lactalbumin and beta-lactoglobulin in any desired proportions.The riboprine pharmaceutical composition or riboprine composition for the uses and methodsof the invention that is a nutritional composition may also additionally or alternativelycomprise at least one carbohydrate. A “carbohydrate” refers to a sugar or polymer of sugars.The terms “saccharide,” “polysaccharide,” “carbohydrate,” and “oligosaccharide” can be used interchangeably. The carbohydrate may be present in any suitable amount. For example, thecarbohydrate content may be in the range 9 to 14 g carbohydrate per 100 kcal (e.g. in thecontext of a composition that is an infant formula). Suitable carbohydrate sources include, butare not limited to lactose, sucrose, saccharose, maltodextrin, starch and mixtures thereof.Most carbohydrates are aldehydes or ketones with many hydroxyl groups, usually one on eachcarbon atom of the molecule. Carbohydrates generally have the molecular formula CnH2nOn. A carbohydrate can be a monosaccharide, a disaccharide, trisaccharide, oligosaccharide, or polysaccharide. The most basic carbohydrate is a monosaccharide, such as glucose, sucrose, galactose, mannose, ribose, arabinose, xylose, and fructose. Disaccharides are two joinedmonosaccharides. Exemplary disaccharides include sucrose, maltose, cellobiose, and lactose.Typically, an oligosaccharide includes between three and six monosaccharide units (e.g., raffinose, stachyose), and polysaccharides include six or more monosaccharide units. Exemplary polysaccharides include starch, glycogen, and cellulose. Carbohydrates may contain modified saccharide units such as 2ʹ-deoxyribose wherein a hydroxyl group is removed, 2ʹ-fluororibose wherein a hydroxyl group is replace with a fluorine, or N- acetylglucosamine, a nitrogen-containing form of glucose (e.g., 2ʹ-fluororibose, deoxyribose, and hexose). Carbohydrates may exist in many different forms, for example, conformers, cyclic forms, acyclic forms, stereoisomers, tautomers, anomers, and isomers.The riboprine pharmaceutical composition or riboprine composition for the uses and methodsof the invention that is a nutritional composition may also additionally or alternativelycomprise at least one lipid. As used herein a “lipid” includes fats, oils, triglycerides, cholesterol,phospholipids, fatty acids in any form including free fatty acids. Example fats include sunflower oil, low erucic acid rapeseed oil, safflower oil, canola oil, olive oil, coconut oil, palm kernel oil,soybean oil, fish oil, palm oleic, high oleic sunflower oil and high oleic safflower oil, andmicrobial fermentation oil containing long chain, polyunsaturated fatty acids. The fat may alsobe in the form of fractions derived from these oils, such as palm olein, medium chain triglycerides (MCT) and esters of fatty acids such as arachidonic acid, linoleic acid, palmiticacid, stearic acid, docosahexaeonic acid, linolenic acid, oleic acid, lauric acid, capric acid,caprylic acid, caproic acid, and the like. Further example fats include structured lipids (i.e.lipids that are modified chemically or enzymatically in order to change their structure). Oils containing high quantities of preformed arachidonic acid (ARA) and / or docosahexaenoic acid(DHA), such as fish oils or microbial oils, may be added. Long chain polyunsaturated fatty acids,such as dihomo-γ-linolenic acid, arachidonic acid (ARA), eicosapentaenoic acid and docosahexaenoic acid (DHA), may also be added. The essential fatty acids linoleic and α-linolenic acid may also be added, as well small amounts of oils containing high quantities of preformed arachidonic acid and docosahexaenoic acid such as fish oils or microbial oils. The fat source may have a ratio of n-6 to n-3 fatty acids ofabout 5:1 to about 15:1; for example about 8:1 to about 10:1. The fats, oils and fatty acids canbe saturated, unsaturated (cis or trans) or partially unsaturated (cis or trans).The riboprine pharmaceutical composition or riboprine composition for the uses and methodsof the invention that is a nutritional composition may also additionally or alternativelycomprise at least one supplemental mineral or mineral source. For example, the nutritionalcomposition may contain all vitamins and minerals understood to be essential in the daily dietand in nutritionally significant amounts. The riboprine pharmaceutical composition orriboprine composition for the uses and methods of the invention that is a nutritionalcomposition may also additionally or alternatively comprise at least one supplemental vitamin. The at least one vitamin can be fat-soluble or water soluble vitamins. Suitable vitamins include but are not limited to vitamin C, vitamin A, vitamin E, vitamin B12, vitamin K, riboflavin, niacin, vitamin D, vitamin B6, folic acid, pyridoxine, thiamine, pantothenic acid, and biotin. Suitable forms of any of the foregoing are salts of the vitamin, derivatives of the vitamin, compounds having the same or similar activity of the vitamin, and metabolites of thevitamin. Minimum requirements have been established for certain vitamins and minerals. Examples of minerals, vitamins and other nutrients optionally present include vitamin A, vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin E, vitamin K, vitamin C, vitamin D, folic acid, inositol, niacin, biotin, pantothenic acid, choline, calcium, phosphorous, iodine, iron, magnesium, copper, zinc, manganese, chlorine, potassium, sodium, selenium, chromium, molybdenum, taurine, and L-carnitine. Minerals are usually added in salt form. The presence and amounts of specific minerals and other vitamins will vary depending on the intended subject. Slightly soluble mineral salts, insoluble mineral salts, chelated minerals, mineral complexes, non-reactive minerals such as carbonyl minerals, and reduced minerals, andcombinations thereof can be used according to standard methods.The uses and methods of the invention for the maintenance, improvement or management (including dietary management) of gut barrier function may be directed to the maintenance, improvement or management of any disease or condition associated with altered gut barrier function (or a symptom thereof), including but not limited to obesity, metabolic syndrome, insulin-deficiency or insulin-resistance related disorders, diabetes mellitus, glucose intolerance, abnormal lipid metabolism, hyperglycaemia, barrier function diseases (including inflammatory bowel disease, Crohn's disease and ulcerative colitis), irritable bowel syndrome, gut contractility disorder, hypercholesterolemia, atherogenic dyslipidemia, leaky gut, malnutrition, chronic inflammation, cardiovascular disease, functional dyspepsia, gastrointestinal infection, food allergy, ageing, menopause, recovery from antibiotic treatment, recovery from surgery, a neurodegenerative disorder, and autoimmune disease or kidney disease. The subject to be treated by the methods and uses disclosed herein can be a mammal, including, but not limited to, domesticated animals (e.g., cows, sheep, cats, dogs, and horses),rabbits, rodents (e.g., mice and rats) and primates (e.g., humans and non-human primatessuch as monkeys). Accordingly, the subject may be a human, domestic or farm animal,including but not limited to humans, canines, felines, lagomorphs, mustelids, rodents,bovines, caprines, equines, camelids, ovines, porcines, primates, simians or avians.Accordingly, in some cases, the riboprine pharmaceutical compositions or riboprinecompositions are formulated as products for non-human animals, such as chow, feed, treatsor snacks, or supplemented pet food. Where administered to animals, oral gavage may beused.It is preferred that the subject to be treated is a human. In particular, the subject to betreated has, is suspected of having or being at risk of developing altered gut barrier function(e.g. impaired gut barrier or gut barrier dysfunction) or a disease or condition (or symptom thereof) associated with altered gut barrier function. Altered gut barrier function as used herein, may encompass any pathological process, pathological state, disease, or dysfunction of the gut barrier, including but not limited to an altered or dysfunctional intestinal epithelial cell layer or intestinal mucus layer. Administration “in combination” or the use “together” with other known therapiesencompasses the administration of the riboprine pharmaceutical composition or riboprinecomposition as disclosed herein before, during, after or concurrently with any of the co- therapies disclosed herein or known in the art. Such combination therapies noted above encompass combined administration (where two or more therapeutic agents are included in the same or separate formulations), and separate administration. In a non-limiting example,as part of a combination therapy, the riboprine pharmaceutical composition or riboprinecomposition and the additional therapeutic agent may be administered within about onemonth, or within about one, two or three weeks, or within about one, two, three, four, five, or six days of each other. The specific set of disorders as disclosed herein are characterized by gut barrier dysfunction. The term gut barrier dysfunction is meant to be the partial or complete disruption of thenatural function of the intestinal gut barrier of a subject and may include disruption of theepithelial intestinal cell barrier / layer and / or the intestinal mucus layer. The methods and uses of the invention may have a beneficial or restorative effect on barrier function diseases, including anti-inflammatory properties, so they may be useful in thediseases such as inflammatory bowel disease(including Crohn's disease and ulcerative colitis).In this context, in some embodiments, the invention provides uses and methods of maintaining, improving or managing gut barrier function by preventing ulcerations and / orbleeding in the intestine, e.g. in connection with IBD, Crohn's disease, colitis and / or ulcerativecolitis. The uses and methods of the invention may also reducing at least one side effect ofIBD, Crohn's disease. colitis and / or ulcerative colitis such as ulcerations and / or bleeding. IBDis known to accompany many other diseases or conditions, such as cardiovascular disease, neuropsychological disorders, and metabolic syndrome. Thus, the uses and methods of the invention also encompass the maintenance, improvement or management of one or more diseases or conditions that accompany IBD.It is also recognized that signs of intestinal inflammation associated with altered gut barrierfunction are detectable before the clinical onset of many autoimmune disorders, such as type1 diabetes (T1D). Similarly, increased gut permeability appears before the development ofinsulitis in diabetes-prone rats in comparison with diabetes-resistant rats. Thus, it is evidentthat the breakage of gut barrier integrity with subsequent increased, e.g. antigen, traffickingand occurrence of low-grade intestinal inflammation precede the onset of T1D and are directly related to its pathogenesis, rather than secondary to diabetes-induced metabolic alterations (i.e., hyperglycemia). Thus, maintenance, improvement or management of gut barrier function according to the methods and uses of the invention consequentially provided the maintenance, improvement or management of autoimmune disorders, including, withoutlimitation, T1D, arthritis (such as rheumatoid arthritis, osteoarthritis, psoriatic arthritis, orjuvenile idiopathic arthritis), multiple sclerosis, psoriasis, and systemic lupus erythematosus(SLE). In some embodiments, in the different uses and / or methods of the invention, the riboprine isadministered or used at a concentration of at least 5µM, preferably at least 8 µM, morepreferably at least 10 µM or 10 µM to 10 µM-500 µM or 10 µM to 10 µM-100 µM.Accordingly, when the uses or the methods refer to a composition (e.g. nutritionalcomposition, riboprine composition, pharmaceutical composition or the like), the compositioncomprises at least 5µM, preferably at least 8 µM, more preferably at least at least 10 µM or10 µM to 10 µM-500 µM or 10 µM to 10 µM-100 µM riboprine. Alternatively, the compositioncomprises riboprine at a concentration such that when the composition is administered orconsumed, a concentration of at least 5µM, preferably at least 8 µM, more preferably at least10 µM or 10 µM to 10 µM-500 µM or 10 µM to 10 µM-100 µM of riboprine is administered orconsumed. In the foregoing detailed description of the invention, a number of individual elements, characterizing features, techniques and / or steps are disclosed. It is readily recognized that each of these has benefit not only individually when considered or used alone, but also when considered and used in combination with one another. Accordingly, to avoid exceedingly repetitious and redundant passages, this description has refrained from reiterating every possible combination and permutation. Nevertheless, whether expressly recited or not, it is understood that such combinations are entirely within the scope of the presently disclosed subject matter. All technical and scientific terms used herein, unless otherwise defined, are intended to have the same meaning as commonly understood by one of ordinary skill in the art. Reference to techniques employed herein are intended to refer to the techniques as commonly understood in the art, including variations on those techniques or substitutions of equivalent techniques that would be apparent to one of skill in the art. All amino acid sequences provided herein are presented starting with the most N-terminal residue and ending with the most C-terminal residue (N^C), as customarily done in the art, and the one-letter or three-letter code abbreviations as used to identify amino acids throughout the present invention correspond to those commonly used for amino acids. In this specification, a number of documents including patent applications and manufacturer’s manuals are cited. The disclosure of these documents, while not considered relevant for thepatentability of this invention, is herewith incorporated by reference in its entirety. Morespecifically, all referenced documents are incorporated by reference to the same extent as if each individual document was specifically and individually indicated to be incorporated by reference. The present invention is further illustrated by the following examples, which are provided for the purpose of demonstration rather than limitation. Those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.

[0004] 5. EXAMPLES5.1 Example 1Mucin production in the human goblet-like cell line LS 174T ECACC catalogue Bo.:87060401 / ATCC catalogue No.: CCL 188) was quantified in response to riboprine (N6-isopentenyladenosine; ChemScene, CS-W011925, CAS n°: 7724-76-7).LS174T cells were incubated for 24 hours at 150,000 cells / well in a 96 well plate in 200µL ofculture medium (MEM supplemented with glutamax (Gibco), NEAA (Gibco), sodium pyruvate(Gibco), 10% FBS (Gibco), and penicillin-streptomycin (ThermoFisher)). Subsequently, theculture medium was removed and the cells washed with PBS. The cultures were thenincubated at 37°C for a further 24h in 200µL of assay buffer (culture medium containing 1%serum) containing riboprine at different concentrations in 0.1% DMSO. Basal conditions wereestablished in negative control cultures incubated in assay buffer and 0.1% DMSO alone.Maximum production was established in positive control cultures containing 30 µM TNFα.The cells were lysed and Muc2 intracellular content evaluated by ELISA using a commercial kitaccording to the manufacturer's protocol (ABCAM, KIT: ab282871). Final absorbance wasmeasured on a multimode reader (Bioteck synergy neo signal exc 485 nm; em 535 nm). Data were normalized to percentage of activity, determined using basal and maximum mucin production from the control cultures according to the formula: (x-basal) / (max-basal)*100.FIGURE 2 shows that the intracellular production of Muc2 increased in a dose-dependentfashion, in both experiments, reaching the highest concentration of Muc2 between 10-5and 10-5.5M riboprine.5.2 Example 2Example 1 was repeated using 1 and 10 µM riboprine, with the exception that 10 µM forskolin(Sigma-Aldrich, F6886) used in the positive control cultures.Riboprine induced a significant increase in Muc2 production at both 1 µM and 10 µM ascompared to the CTL group (p<0.05; FIGURE 3).5.3 Example 3Quantification of metabolic activity as an indicator of cell viability on riboprine exposure wasassessed using the same conditions / protocol as Example 1.One hour before the end of the 24 hour riboprine treatment period (1, 10, 100, 1000 µM),11µL / well of 10X PrestoBlue HS Cell Viability Reagent (ThermoFisher) were added to 100µL ofconditioned media, and the plate was incubated 37°C for the remaining hour. At the end ofthe treatment period, media was collected in a black flat bottom black plate (Corning Costar)for fluorescence measurement at 590 nm using a Varioskan Lux Multimode Reader(ThermoFisher). FIGURE 4 shows that the cell viability was not modified at 1 or 10 µM riboprine, but wassignificantly reduced at 100 and 1000 µM riboprine relative to control cultures.5.4 Example 4The effect of riboprine on gut barrier function was assessed in an in vivo model of intestinalepithelial integrity. Specifically, intestinal permeability in response to riboprine was evaluatedin the nematode Caenorhabditis elegans (C elegans) under two conditions, (1) during aging;and (2) during aging with previous exposure to microbial lipopolysaccharide.5.4.1 Aging modelThe C. elegans wild-type N2 strain was maintained as described in Membrez et al., Nat Metab6 (2024), 433-447. For heat inactivation (HI) of E. coli OP50, bacteria were incubated at 65 ℃for 30 min and stored at 4 ℃ until use.To evaluate the gut barrier function (intestinal epithelial / barrier integrity), FITC-dextranpassage to C. elegans bodies was determined according to a protocol adapted from Kim et al.,Phytomedicine 103(2022), 154209. Briefly, L4 C. elegans were fed HI E. coli OP50supplemented with or without 1 mM riboprine (ChemScene, CS-W011925, CAS n°: 7724-76-7) for 8 days and thereafter transferred to new (NGM) plates containing HI E. coli OP50 andFITC-dextran (10kDa, 20µg / mL) for 14–15h. Subsequently, the worms were washed with M9- buffer and left for 2h on NGM plates without food to remove the excess FITC-dextran. Theworms were then washed and fixed in 4% paraformaldehyde for 2 minutes followed by afurther wash in M9 medium. The worms were then transferred to a 96-well plate (Corning,black plates with clear flat bottom) at approximately 50 worms / well, and fluorescencemicroscope images obtained using an Cytation 7 system (Agilent Biotek) with EGFP and a bright-field filter set.A significant reduction in the passage of FITC-dextran was identified in the riboprine treatedgroup (p<0.0001; FIGURE 5).5.4.2 Aging model, challenge with LPSTo assess gut barrier function in response to riboprine when challenged withlipopolysaccharide (LPS), L4 C. elegans were treated for 14-15 h on salmonella LPS (Sigma-Aldrich, #L6511) containing plates (100µg / mL). The worms were then placed on new platesand the protocol described above in section 5.4.1 was followed, but for supplement with 0.5or 1 mM riboprine.At day 8 of age, a significant reduction in the passage of FITC-Dextran was identified in wormstreated with either 0.5 mM or 1 mM riboprine (p<0.05; FIGURE 6).5.5 Example 5Comparative analysis of the efficacy in promoting Muc-2 production between riboprine andadenosine, a closely related molecule.The same protocol as defined in “Example 1” was followed, including the 2 positive controlmolecules used in these experiments (TNF-α and Forskolin), a negative control containingonly culture medium containing 1% serum (0% DMSO), a negative control with the culturemedium containing 1% serum plus the vehicle (0.1% DMSO) and the 2 batches of eachcompound solubilized in the vehicle (0.1% DMSO), both tested at a range of concentration,as indicated below. Results are expressed as fold-change, respect to the vehicle group (0.1%DMSO).- Riboprine tested at 3 concentrations: 1; 3; 10 µM:Batch 1: riboprine provided by the supplier Carbosynth (ref: ND08001-MFCD00005741)Batch 2: riboprine provided by supplier Fluorochem (ref: FLUH99C88CB8-F239110)- Adenosine tested at 4 concentrations: 0.1; 1; 10; 100 µM:Batch 1: adenosine provided by Sigma-Aldrich, ref. A9251 (batch number : 102383695-WXBD3428V).Batch 2: adenosine provided by Sigma-Aldrich, ref. A9251 (batch number: 102788099-WXBF2652V).FIGURE 7 shows that riboprine significantly increased (between 1.4-1.5 times) the intracellularMuc-2 protein concentration at 10µM, in the 2 batches tested. Adenosine did not increase theconcentration of Muc-2 at any concentration tested. These results prove the higher efficacyof riboprine as compared to adenosine in producing mucus in this in vitro model.

Claims

CLAIMS1. Riboprine for use in the(a) maintenance;(b) improvement; or(c) dietary managementof gut barrier function.

2. The riboprine for the use according to claim 1, wherein said use is the dietarymanagement of gut barrier function in a subject in need of maintenance, or improvement of gut barrier function.

3. A method for the(a) maintenance;(b) improvement; or(c) dietary managementof the gut barrier function in a subject in need thereof, comprising administering a therapeutically effective amount of riboprine.

4. The riboprine for the use according to claim 1 or 2, or the method according to claim 3,wherein said riboprine is formulated as an oral composition, a dietary supplement, afood product, a functional beverage product, a medical food, a food for specified health uses, a food for special medical purposes (FSMP) or a food for special dietary use (FSDU).

5. The riboprine for the use according to any one of claims 1, 2 and 4, or the methodaccording to any one of claims 3 to 4, wherein said improvement of gut barrier function is the improvement of barrier structure, barrier protection, tight junction structure, intestinal epithelial integrity, or the quantity of mucin produced by the intestinal epithelia.

6. The riboprine for the use according to any one of claims 1, 2 and 4 to 5, or the methodaccording to any one of claims 3 to 5, wherein said improvement of gut barrier function, includes the reduction of barrier dysfunction, intestinal ulcers, intestinal wounds, or passage of luminal contents into systemic circulation.

7. The riboprine for the use according to any one of claims 1, 2 and 4 to 6, or the methodaccording to any one of claims 3 to 6, wherein the improvement of gut barrier functiona) reduces passage of luminal contents into systemic circulation, wherein the luminalcontents comprise or consist of lipopolysaccharide (LPS), a pathogen, an allergen, and / or a test compound; and / or b) alters the level of LPS binding protein (LBP) in a biological sample.

8. The riboprine for the use according to claim 7, or the method according to claim 7,wherein said reduction or alteration is relative to a control that is a) to be determined in a subject prior to the exposure or administration of riboprine;or b) a level as previously determined in one or more of a group of similarly situatedsubjects prior to exposure or administration of riboprine.

9. The riboprine for the use according to any one of claims 1, 2 and 4 to 8, or the methodaccording to any one of claims 3 to 8, wherein the improvement of gut barrier function is the reduction of local gut inflammation or systemic inflammation in a subject.

10. The riboprine for the use according to claim 9, or the method according to claim 9,wherein said subject is characterized as having systemic inflammation by having a level of one or more inflammatory cytokines above a predetermined threshold.

11. The riboprine for the use according to any one of claims 1, 2 and 4 to 10, or the methodaccording to any one of claims 3 to 10, wherein the improvement of gut barrier function is for the treatment of obesity, metabolic syndrome, insulin-deficiency or insulin- resistance related disorders, diabetes mellitus, glucose intolerance, abnormal lipid metabolism, hyperglycaemia, barrier function diseases (including inflammatory bowel disease, Crohn's disease and ulcerative colitis), irritable bowel syndrome, gut contractility disorder, hypercholesterolemia, atherogenic dyslipidemia, leaky gut, malnutrition, chronic inflammation, cardiovascular disease, functional dyspepsia, gastrointestinal infection, food allergy, ageing, menopause, recovery from antibiotic treatment, recovery from surgery, a neurodegenerative disorder, and autoimmune disease or kidney disease.

12. The riboprine for the use according to any one of claims 1, 2 and 4 to 11, wherein saidsubject to be treated is a mammal.

13. The method according to any one of claims 3 to 11, wherein said subject is a mammal.

14. The riboprine for the use according to any one of claims 1, 2 and 4 to 12, or the methodaccording to any one of claims 3 to 11, and 13, wherein the riboprine administered orused at a concentration of at least 5µM, preferably at least 8 µM, more preferably atleast 10 µM or 10 µM to 10 µM-500 µM or 10 µM to 10 µM-100 µM.

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