Galacto-oligosaccharide for use in treating neuronal diseases

Abstract

The invention relates to prebiotics, and their use in treating, preventing or ameliorating psychiatric disorders, improving neurotransmission, improving emotional well-being and / or improving sleep. The invention also relates to a method of treating, preventing or ameliorating psychiatric disorders, improving neurotransmission, improving emotional well-being and / or improving sleep, by administering a prebiotic to a subject.

Description

[0001] GALACTO-OLIGOSACCHARIDE FOR USE IN TREATING NEURONAL DISEASES

[0002] The present invention relates to prebiotics, and their use in treating, preventing or ameliorating psychiatric disorders, improving neurotransmission, improving emotional well-being and / or improving sleep. The invention also relates to a method of treating, preventing or ameliorating psychiatric disorders, improving neurotransmission, improving emotional well-being and / or improving sleep, by administering a prebiotic to a subject.

[0003] Many children and young people struggle with establishing effective emotional responses and this difficulty has been suggested to contribute to the rise in mental health problems during this developmental period. These early difficulties also increase the likelihood of lifelong mental health problems. Several factors increase vulnerability in this developmental period, such as ongoing maturational changes in both the cognitive mechanisms supporting emotion regulation abilities but also the underlying brain networks. In the recent years, we have come to understand the important role of the gut microbiome in influencing brain function and behaviour, particularly in childhood and adolescence. The gut and the brain are intimately connected via the gut-brain axis, which involves bidirectional communication via neural, endocrine and immune pathways. For example, gut microbial composition — which itself alters throughout the lifespan and in response to factors such as stress and lifestyle choices including diet — has been shown to regulate gene expression and the release of metabolites in the brain. There is also evidence that a significant reduction in microbial diversity, or an increased number of pathogenic microbes, affects brain-behaviour relationships, and may lead to psychological abnormalities that underlie mental illness.

[0004] One way of ameliorating gut dysbiosis and fortifying the microbiome-gut-brain axis is through dietary interventions which has been the focus of intense research in animal models. Drastic changes in diet can alter microbial diversity in a matter of days, and research also suggests that modifying microbial ecology via the intake of so-called 'psychobiotics' could help reduce stress responses and symptoms of anxiety and depression. The term psychobiotics refers to live cultures of beneficial gut bacteria (probiotics) or substrates which enhance the growth of indigenous 'good' intestinal bacteria (prebiotics), which when ingested in sufficient amounts improve brain function via the regulation of gene expression in the brain. Prebiotics are nutritional compounds ('dietary fibres') in cereals, fruits and vegetables, but are also available as individual supplements. Effective emotion regulation abilities are a key factor in building resilience and in supporting mental health, both at the preventive and intervention stage in preclinical and clinical populations. Difficulties with emotion regulation abilities contribute to a number of mental health problems, such as anxiety, but also other, anxiety-related disorders, such as obsessive-compulsive disorder (OCD), social anxiety disorder, specific phobias and generalised anxiety disorder and mood disorders with symptoms including high blood pressure, irritability, difficulty concentrating, rumination, fear, restlessness, low mood, headaches, stomach aches, fatigue, nausea, changes in eating habits, and sleep disorders. Sleep not only represents an important predictor of wellbeing and mental health, but it has also been shown that sleep affects the composition and functionality of the gut microbiome. Further, young people frequently report that sleep is disrupted at school or university, particularly during exam periods, which not only affects wellbeing but also academic performance.

[0005] About one in four children and young people are affected by a mental health problem, with higher incidence rates in females. These early difficulties lead to problems with friendships and school performance, and if unmanaged, reliably predict lifelong, persistent mental health problems. Current treatment approaches include lifestyle changes, counselling, and medications. Counselling is typically with a type of cognitive behavioural therapy. Medications, such as antidepressants, benzodiazepines, or beta blockers, may improve symptoms, however, the use of antidepressants may be accompanied with side effects, which may stop patients from taking their medication. Especially for less severe anxiety disorder levels, there is a desire not to use medicines in view of the side effects or in view of a general desire not to take medicines. Likewise, access to counselling comes at a premium in most countries, as mental health provisions, especially for children and young people are chronically oversubscribed and underfunded. There is, therefore, a need for products or methods that reduce anxiety-related disorders in a subject, preferably products that are not considered a medicine and / or that are easy to combine with a standard diet.

[0006] Gamma-Aminobutyric acid, also referred to as y-aminobutyric acid or GABA, and glutamate, are two neurotransmitters (also referred to as metabolites or neurochemicals) of the brain. GABA is the chief inhibitory neurotransmitter in the developmentally mature mammalian central nervous system. Its principal role is reducing neuronal excitability throughout the nervous system. In humans, GABA is also directly responsible for the regulation of muscle tone. GABA is found naturally in varieties of green, black, and oolong tea. Other foods contain GABA or may boost its production in the body, including whole grains, fava beans, soy, lentils and other beans, nuts including walnuts, almonds and sunflower seeds, fish, including shrimp and halibut, citrus, tomatoes, berries, spinach, broccoli, potatoes, and cocoa.

[0007] GABA is also available as a supplement. GABA supplements are often used to treat high blood pressure, depression, low mood (i.e. a person has a low mood if they are thinking negatively about themself and others, or is withdrawing from activities or social interaction, sleep difficulties, as well as eating problems), emotion regulation, anxiety, and sleep disorders, as well as to stimulate the body's natural growth hormone, often by athletes. However, there is a lack of research in humans on the effects of GABA supplements. It is believed that direct GABA supplementation is ineffective as GABA cannot cross the blood-brain barrier.

[0008] Glutamate is the most abundant excitatory neurotransmitter / neurochemical in the brain, and it ensures effective signalling. Research has shown that in adults, concentrations of glutamate and GABA have been associated with facets of anxiety including arousal in post-traumatic stress disorder, neuroticism, social anxiety, and generalised anxiety. Moreover, research in children and young people has shown variations in the balance of glutamate and GABA, also known as excitation / inhibition (E / I) ratios, are required for effective cognitive processing and learning, and neuroplasticity during typical development, and to moderate neural responses in anxious states. Moreover, GABAergic activity within key regions in the brain that control cognitive and emotional behaviour, such as the prefrontal cortex (PFC) is critical in balancing amygdala activity and supporting plasticity. In addition, recent research has shown that lower levels of GABA are associated with lower levels of anxiety. Thus, E / I ratios in key emotion regulation regions of the brain, such as the PFC may be adaptive in regulating amygdala response and contribute to effective emotion behaviour.

[0009] There is, therefore, a need for the development of a method that can influence both the production and regulation of the availability of the body's own GABA and glutamate. In particular, there is a need to provide a food product that helps to ameliorate functionality of these neurotransmitters / neurochemicals in the brain to improve emotional wellbeing at both the preclinical and clinical level and treat mental health disorders.

[0010] Accordingly, in a first aspect of the invention, there is provided Galactooligosaccharide (GOS), or an analogue or derivative thereof, for use in (i) treating, preventing or ameliorating a psychiatric disorder, (ii) improving neurotransmission, (iii) improving emotional well-being in a subject, or (iv) improving sleep, wherein the GOS causes alteration of the concentration of glutamate and / or gamma amino butyric acid in the subject's brain.

[0011] In a second aspect of the invention, there is provided a method of altering the concentration of glutamate and / or gamma amino butyric acid in a subject's brain to (i) treat, prevent or ameliorate a psychiatric disorder, (ii) improve neurotransmission, (iii) improve emotional well-being in a subject, or (iv) improve sleep, the method comprising administering, to a subject in need of such treatment, a therapeutically active amount of Galacto-oligosaccharide (GOS), or an analogue or derivative thereof.

[0012] In one embodiment, the invention provides Galacto-oligosaccharide (GOS), or an analogue or derivative thereof, and at least one probiotic, for use in (i) treating, preventing or ameliorating a psychiatric disorder, (ii) improving neurotransmission, (iii) improving emotional well-being in a subject, or (iv) improving sleep, wherein the GOS causes alteration of the concentration of glutamate and / or gamma amino butyric acid in the subject's brain.

[0013] In one embodiment, therefore, the invention provides GOS, or an analogue or derivative thereof, for use in (i) treating, preventing or ameliorating a psychiatric disorder, (ii) improving neurotransmission, (iii) improving emotional well-being in a subject, or (iv) improving sleep, wherein the GOS causes alteration of the concentration of glutamate and / or gamma amino butyric acid in the subject's brain, further comprising administering at least one probiotic, optionally wherein the at least one probiotic comprises a bacterium or yeast.

[0014] It will be appreciated that a prebiotic and a probiotic which together confer one or more health benefits but do not require co-dependent function may be referred to as a synbiotic. In one embodiment, therefore, the GOS, or an analogue or derivative thereof, and at least one probiotic, may comprise a synbiotic.

[0015] In another embodiment, the invention provides a method of altering the concentration of glutamate and / or gamma amino butyric acid in a subject's brain to (i) treat, prevent or ameliorate a psychiatric disorder, (ii) improve neurotransmission, (iii) improve emotional well-being in a subject, or (iv) improve sleep, the method comprising administering, to a subject in need of such treatment, a therapeutically active amount of Galacto-oligosaccharide (GOS), or an analogue or derivative thereof, and at least one probiotic.

[0016] The at least one probiotic may comprise a bacterium or yeast.

[0017] The bacterium may comprise a bacterial species belonging to the genera Lactobacillus, Bifidobacterium, and / or Streptococcus.

[0018] The bacterial species belonging to the genera Lactobacillus may be selected from a list of bacterial species consisting of: L. acetotolerans, L. acidophilus, L. aivi, L. amylolyticus, L. amylovorus, L. apis, L. backi, L. bombicola, L. casei, L. colini, L. crispatus, L. delbrueckii, L. equicursoris, L. fermentum, L. fornicalis, L. gallinarum, L. gasseri, L. gigeriorum, L. ginsenosidimutans, L. hamster, L. helsingborgensis, L. helveticus, L.hominis, L. iners, L. intestinalis, L. jensenii, L. jinshani, L. johnsonii, L. kalixensis, L. kefiranofaciens, L. kimbladii, L. kitasatonis, L. kullabergensis, L.melliventris, L. mulieris, L. nasalidis, L. panisapium, L. paracasei, L. paragasseri, L. pasteurii, L. plantarum, L. porci, L. psittaci, L. raoultii, L. reuteri, L. rhamnosus, L. rodentium, L. rogosae, L. salivarius, L. taiwanensis, L. thermophilus, L. timonensis, L. ultunensis, and L. xujianguonis.

[0019] Typically, however, the bacterial species belonging to the genera Lactobacillus is selected from a list of bacterial species consisting of: L. acidophilus, L. casei, L. crispatus, L. delbrueckii, L. fermentum, L. gasseri, L. helveticus, L. johnsonii, L. paracasei, L. plantarum, L. reuteri, L. rhamnosus, and L. salivarius.

[0020] The bacterial species belonging to the genera Bifidobacterium may be selected from a list of bacterial species consisting of: B. actinocoloniiforme, B. adolescentis, B. aemilianum, B. aerophilum, B. aesculapii, B. amazonense, B. angulatum, B. animalis, B. anseris, B. apousia, B. apri, B. aquikefiri, B. asteroids, B. avesanii, B. biavatii, B. bifidum, B. bohemicum, B. bombi, B. bourn, B. breve, B. callimiconis, B. callitrichidarum, B. callitrichos, B. canis, B. castoris, B. catenulatum, B. catulorum, B. cebidarum, B. choerinum, B.choladohabitans, B. choloepi, B. colobi, B. commune, B. criceti, B. crudilactis, B. cuniculi, B. dentium, B. dolichotidis, B. eriksonii, B. erythrocebi , B. eulemuris, B. faecale, B. felsineum, B. gallicum, B. gallinarum, B. globosum, B. goeldii, B. hapali, B. indicum, B. infantis, B. italicum, B. jacchi, B. lactis, B. lemurum, B. leontopitheci, B. longum, B. magnum, B. margollesii, B. merycicum, B. miconis, B. miconisargentati, B. minimum, B. mongoliense, B. moraviense, B. moukalabense, B. myosotis, B. oedipodis, B. olomucense, B. panos, B. parmae, B. platyrrhinorum, B. pluvialisilvae, B. polysaccharolyticum, B. pongonis, B. porcinum, B. primatium, B. pseudocatenulatum, B. pseudoIongum, B. psychraerophilum, B. pullorum, B. ramosum, B. reuteri, B. rousetti, B. ruminale, B. ruminantium, B. saguini, B. saguinibicoloris, B. saimiriisciurei, B. samirii, B. santillanense, B. scaligerum, B. scardovii, B. simiarum, B. simiiventris, B. stellenboschense, B. subtile, B. thermacidophilum, B. thermophilum, B. tibiigranuli, B. tissieri, B. tsurumiense, B. urinalis, B. vansinderenii, B. vespertilionis, and B. xylocopae.

[0021] Typically, however, the bacterial species belonging to the genera Bifidobacterium is selected from a list of bacterial species consisting of: B. adolescentis, B. animalis, B. bifidum, B. breve, B. longum, B. lactis, and B. infantis.

[0022] The bacterial species belonging to the genera Streptococcus may be selected from a list of bacterial species consisting of: S. acidominimus, S. agalactiae (Group B Streptococcus), S. alactolyticus, S. anginosus, S. australis, S. caballi, S. cameli, S. canis, S. caprae, S. castoreus, S. constellatus, S. criceti, S. cristatus, S. cuniculi, S. danieliae, S. dentasini, S. dentiloxodontae, S. dentirousetti, S. devriesei, S. didelphis, S. downei, S. dysgalactiae, S. entericus, S. equi, S. equinus, S. faecalis (Group D Strepcoccus), S. ferus, S. gallinaceus, S. gallolyticus, S. gordonii, S. halichoeri, S. halotolerans, S. henryi, S. himalayensis, S. hongkongensis, S. hyointestinalis, S. hyovaginalis, S. ictal urid, S. infantarius, S. infantis, S. iniae, S. intermedius, S. lactarius, S. loxodontisalivarius, S. lutetiensis, S. macacae, S. marimammalium, S. marmotae, S. massiliensis, S. merionis, S. minor, S. mitis, S. moroccensis, S. mutans, S. oralis, S. oricebi, S. oriloxodontae, S. orisasini, S. orisratti, S. orisuis, S. ovis, S. panodentis, S. pantholopis, S. parasanguinis, S. parasuis, S. parauberis, S. peroris, S. pharynges, S. phocae, S. pluranimalium, S. plurextorum, S. pneumoniae, S. porci, S. porcinus, S. porcorum, S. pseudopneumoniae, S. pseudoporcinus, S. pyogenes (Group A Streptococcus), S. ratti, S. rifensis, S. rubneri, S. rupicaprae, S. salivarius, S. saliviloxodontae, S. sanguinis, S. sinensis, S. sobrinus, S. suis, S. tangierensis, S. thermophilus, S. thoraltensis, S tigurinus, S. troglodytae, S. troglodytidis, S. uberis, S. urinalis, S. ursoris, S. vestibularis, and S. zooepidemicus.

[0023] Typically, however, the bacterial species belonging to the genera Streptococcus is selected from a list of bacterial species consisting of: S. thermophilus, and S. salivarius.

[0024] As described in the Examples, the inventors surprisingly discovered that the administration of GOS resulted in an alteration of the brain-based metabolite (or neurochemical) concentrations of glutamate and gamma amino butyric acid ratios. Advantageously, the inventors discovered that this change in neurotransmitter / neurochemical concentration resulted in surprisingly positive responses to several indices of emotional wellbeing, including anxiety and depression, and also had a beneficial effect on sleep.

[0025] In one embodiment, the Galacto-oligosaccharide (GOS), or an analogue or derivative thereof, is for use in treating, preventing or ameliorating a psychiatric disorder.

[0026] It will be appreciated that a psychiatric disorder may be characterised by a clinically significant disturbance in an individual's cognition, emotional regulation, or behaviour, including sleep.

[0027] Psychiatric disorders or mental health conditions presenting as generalised anxiety disorder (GAD) or differential diagnosis may include social phobia, situational anxiety, adjustment disorder, depression, panic disorder, obsessive-compulsive disorder, or post-traumatic stress disorder, where symptoms include excessive worry about everyday events that is out of proportion with the inherent risk (NICE, 2020). Symptoms include poor concentration, restlessness, nervousness, easy fatigue, irritability, muscle tension, disordered eating, or sleep disturbance. For GAD, symptoms must be present for at least 6 months and cause distress or impairment across social and / or occupational functioning. In one embodiment, therefore, the psychiatric disorder is selected from the group of conditions consisting of: anxiety, mood disorders, obsessive-compulsive disorder (OCD), phobias, post-traumatic stress disorder, eating disorders, neuroticism, social phobia, situational anxiety, adjustment disorder, depression, panic disorder, obsessive-compulsive disorder, and post-traumatic stress disorder.

[0028] Preferably, the psychiatric disorder is selected from the group of conditions consisting of: anxiety, mood disorders, obsessive-compulsive disorder (OCD), phobias, post-traumatic stress disorder, eating disorders, and neuroticism.

[0029] The psychiatric disorder may be associated with and / or characterised by symptoms including excessive worry about everyday events that is out of proportion with the inherent risk, poor concentration, restlessness, nervousness, easy fatigue, irritability, muscle tension, disordered eating, and sleep disturbance. Symptoms may cause distress or impairment across social and / or occupational functioning.

[0030] The anxiety may be social anxiety or generalised anxiety. The generalised anxiety may be associated with symptoms including high blood pressure, depression, low mood, emotion regulation, sleep disorders, irritability, difficulty concentrating, rumination, fear, restlessness, headaches, stomach aches, fatigue, nausea, changes in eating habits, disordered eating, and sleep disorders.

[0031] The mood disorder may be depression.

[0032] In another embodiment, the Galacto-oligosaccharide (GOS), or an analogue or derivative thereof, is for use in improving neurotransmission.

[0033] Preferably, improving neurotransmission comprises modulating cortical excitability via the abundance of excitatory and inhibitory neurotransmitters and / or altered receptor site function. More preferably, improving neurotransmission comprises altering the balance of glutamate and GABA, by increasing the ratio of glutamate to gamma-aminobutyric acid (GABA). Preferably, increasing the ratio of glutamate to gamma-aminobutyric acid (GABA) comprises reducing the levels of gamma- aminobutyric acid (GABA). In another embodiment, increasing the ratio of glutamate to gamma-aminobutyric acid (GABA) comprises increasing the levels of glutamate. Improving neurotransmission may be assessed by the use of magnetic resonance imaging (MRI) spectroscopy to measure metabolite (e.g., GABA and / or glutamate) levels in the brain.

[0034] Improving neurotransmission may comprise improving homeostatic regulation of inhibitory processes, optionally in the brain. Improving homeostatic regulation of inhibitory processes may be assessed by the use of magnetic resonance imaging (MRI) spectroscopy to measure metabolite (e.g., GABA and / or glutamate) levels in the brain.

[0035] It will be appreciated that improving homeostatic regulation of inhibitory processes leads to improved efficiency in neural circuits. It will also be appreciated that the term "inhibitory processes" can mean neural processes which involve at least one inhibitory neurotransmitter, such as GABA.

[0036] Conditions for which improving neurotransmission may be appropriate may be selected from the list of conditions including: generalised anxiety disorder (GAD), social phobia, situational anxiety, adjustment disorder, depression, panic disorder, obsessive-compulsive disorder, and post-traumatic stress disorder, including subclinical presentations of excessive worry.

[0037] It will be appreciated that the above-listed conditions are impacted by improved neurotransmission.

[0038] It will be appreciated that a neurotransmitter (i.e. GABA and glutamate) may also be referred to as a neurochemical or a metabolite. Metabolites refer to GABA and glutamate anywhere in the body, and these metabolites may be intracellular metabolites or extracellular metabolites. Neurotransmitters are brain-specific and are a type of intracellular metabolite.

[0039] In another preferred embodiment, the Galacto-oligosaccharide (GOS), or an analogue or derivative thereof, is for use in improving emotional well-being in a subject.

[0040] Preferably, improving emotional well-being in a subject comprises reducing depression symptoms, improving sleep, reducing social worry, and / or reducing anxiety. Conditions for which improving emotional well-being may be appropriate may be selected from the list of conditions including: generalised anxiety disorder (GAD), social phobia, situational anxiety, adjustment disorder, depression, panic disorder, obsessive-compulsive disorder, and post-traumatic stress disorder, including subclinical presentations of excessive worry.

[0041] It will be appreciated that the above-listed conditions are impacted by improved emotional well-being.

[0042] In another preferred embodiment, the Galacto-oligosaccharide (GOS), or an analogue or derivative thereof, is for use in improving sleep.

[0043] Preferably, improving sleep comprises improving the quantity and / or quality of sleep. Preferably, improved sleep is measured using subject report on validated questionnaires.

[0044] Conditions for which improving sleep may be appropriate may be selected from the list of conditions including : generalised anxiety disorder (GAD), social phobia, situational anxiety, adjustment disorder, depression, panic disorder, obsessive- compulsive disorder, and post-traumatic stress disorder, including subclinical presentations of excessive worry.

[0045] It will be appreciated that the above-listed conditions are impacted by improved sleep.

[0046] The Galacto-oligosaccharide (GOS), or an analogue or derivative thereof, causes an alteration of the concentration of glutamate and / or gamma amino butyric acid in the subject's brain.

[0047] In one embodiment, the Galacto-oligosaccharide (GOS), or an analogue or derivative thereof, causes an alteration of the concentration of glutamate in the subject's brain. In another embodiment, the Galacto-oligosaccharide (GOS), or an analogue or derivative thereof, causes an alteration of the concentration of gamma amino butyric acid in the subject's brain. Most preferably, the Galactooligosaccharide (GOS), or an analogue or derivative thereof, causes an alteration of the concentration of glutamate and gamma amino butyric acid in the subject's brain.

[0048] Preferably, an alteration of the concentration of glutamate and / or gamma amino butyric acid in the subject's brain, comprises an increase in the ratio of glutamate to gamma amino butyric acid in the subject's brain. Preferably, this increase in the ratio of glutamate to gamma amino butyric acid is driven by a reduction in the concentration of gamma amino butyric acid. In another embodiment, this increase in the ratio of glutamate to gamma amino butyric acid is driven by an increase in the concentration of glutamate.

[0049] Preferably, the concentration of glutamate and / or gamma amino butyric acid in the subject's brain is measured using magnetic resonance spectroscopy CH-MRS). Alternatively, in another embodiment, the concentration of glutamate and / or gamma amino butyric acid in the subject's brain is measured using a PET scan.

[0050] GOS are soluble non-digestible carbohydrates that are not digested by human digestive enzymes but are fermented by the microbiota in the intestine. GOS is an ingredient rich in galacto-oligosaccharides that promote the growth of beneficial bacteria in the intestinal tract.

[0051] Preferably, the GOS is manufactured using lactose and g-galactosidase derived from the enzyme Papiliotrema terrestris.

[0052] Preferably, the GOS is administered daily to the subject.

[0053] The method according to the invention may comprise the use of a positive control and / or a negative control against which the alteration in concentration of glutamate and / or gamma amino butyric acid in a subject's brain may be compared. For example, a negative control sample is a sample taken from a subject who does not suffer from a psychiatric disorder. A positive control sample is a sample taken from a subject who does have a psychiatric disorder.

[0054] Accordingly, in one embodiment, the method further comprises comparing the concentration of glutamate and / or gamma amino butyric acid in a subject's brain with the concentration of glutamate and / or gamma amino butyric acid of a positive and / or negative control. It will be appreciated that the GOS, or analogue or derivative thereof according to the invention may be used in a medicament, which may be used as a monotherapy (i.e. use of the GOS, or analogue or derivative thereof alone), for (i) treating, preventing or ameliorating a psychiatric disorder, (ii) improving neurotransmission, (iii) improving emotional well-being in a subject, and / or (iv) improving sleep. Alternatively, the GOS, or analogue or derivative thereof according to the invention may be used as an adjunct to, or in combination with, known therapies for (i) treating, preventing or ameliorating a psychiatric disorder, (ii) improving neurotransmission, (iii) improving emotional well-being in a subject, and / or (iv) improving sleep. For example, the subject may be additionally treated with antidepressants, talking therapies including cognitive behavioural therapy, applied relaxation therapy, exposure therapies or lifestyle changes including physical activity and dietary modifications, and sleep therapy.

[0055] The GOS, or analogue or derivative thereof according to the invention may be combined in compositions having a number of different forms depending, in particular, on the manner in which the composition is to be used. Thus, for example, the composition may be in the form of a powder, tablet, capsule, liquid, ointment, cream, gel, hydrogel, aerosol, spray, micellar solution, transdermal patch, liposome suspension or any other suitable form that may be administered to a person or animal in need of treatment. It will be appreciated that the vehicle of medicaments according to the invention should be one which is well-tolerated by the subject to whom it is given. Most preferably, however, the GOS, or analogue or derivative thereof is in the form of a powder or a liquid.

[0056] Medicaments comprising the GOS, or analogue or derivative thereof according to the invention may be used in a number of ways. For instance, oral administration may be required, in which case the GOS, or analogue or derivative thereof may be contained within a composition that may, for example, be ingested orally in the form of a tablet, capsule or liquid. Preferably, therefore, the GOS, or analogue or derivative thereof of the invention is administered orally.

[0057] It will be appreciated that the amount of the GOS, or analogue or derivative thereof that is required is determined by its biological activity and bioavailability, which in turn depends on the mode of administration, the physiochemical properties of the GOS, or analogue or derivative thereof and whether it is being used as a monotherapy or in a combined therapy. The frequency of administration will also be influenced by the half-life of the GOS, or analogue or derivative thereof within or on the subject being treated. Optimal dosages to be administered may be determined by those skilled in the art, and will vary with the particular GOS, or analogue or derivative thereof in use, the strength of the pharmaceutical composition, and the mode of administration. Additional factors depending on the particular subject being treated will result in a need to adjust dosages, including subject age, weight, gender, diet, and time of administration.

[0058] Optimal dosages may be determined depending on the severity of the condition to be treated. The GOS, or analogue or derivative thereof may be administered once or twice a day. Other subjects may require less frequent administration of the GOS, or analogue or derivative thereof, such as once or twice a week. Alternatively, the GOS, or analogue or derivative thereof may be administered even less frequently when being used as a prophylactic treatment. For example, weekly or monthly administration of the GOS, or analogue or derivative thereof may be required.

[0059] Generally, a daily dose of between O.OOlpg / kg of body weight and lOmg / kg of body weight, or between O.Olptg / kg of body weight and Img / kg of body weight, of the GOS, or analogue or derivative thereof according to the invention may be used for treating, preventing or ameliorating the particular condition.

[0060] The GOS, or analogue or derivative thereof may be administered before, during or after onset of symptoms associated with the particular condition to be treated.

[0061] Daily doses may be given as a single administration (e.g. a single daily application). Alternatively, the GOS, or analogue or derivative thereof may require administration twice or more times during a day. As an example, the GOS, or analogue or derivative thereof may be administered as two (or more) daily doses of between 0.07 jig and 700 mg (i.e. assuming a body weight of 70 kg). A patient receiving treatment may take a first dose upon waking and then a second dose in the evening (if on a two-dose regime) or at 3- or 4-hourly intervals thereafter.

[0062] Known procedures, such as those conventionally employed by the pharmaceutical industry (e.g. in vivo experimentation, clinical trials, etc.), may be used to form specific formulations of the GOS, or analogue or derivative thereof according to the invention and precise therapeutic regimes (such as daily doses of the agents and the frequency of administration). The inventors believes that they are the first to suggest the alteration of the concentration of glutamate and / or gamma amino butyric acid ratios in a subject's brain, based on the use of the GOS or analogue or derivative thereof of the invention.

[0063] Hence, in a third aspect of the invention, there is provided a pharmaceutical composition comprising a therapeutically active amount of Galacto-oligosaccharide (GOS), or an analogue or derivative thereof, and a pharmaceutically acceptable vehicle, for use in (i) treating, preventing or ameliorating a psychiatric disorder, (ii) improving neurotransmission, (iii) improving emotional well-being in a subject, or (iv) improving sleep, wherein the GOS causes alteration of the concentration of glutamate and / or gamma amino butyric acid in the subject's brain.

[0064] The composition may further comprise one or more probiotic.

[0065] In one embodiment, therefore, the invention provides a pharmaceutical composition comprising a therapeutically active amount of Galacto-oligosaccharide (GOS), or an analogue or derivative thereof, at least one probiotic, and a pharmaceutically acceptable vehicle, for use in (i) treating, preventing or ameliorating a psychiatric disorder, (ii) improving neurotransmission, (iii) improving emotional well-being in a subject, or (iv) improving sleep, wherein the GOS causes alteration of the concentration of glutamate and / or gamma amino butyric acid in the subject's brain.

[0066] In one embodiment, therefore, the pharmaceutical composition may comprise a probiotic, optionally wherein the probiotic is a bacterium or yeast.

[0067] The invention also provides in a fourth aspect, a process for making the pharmaceutical composition for use according to the third aspect, the process comprising combining a therapeutically effective amount of the Galactooligosaccharide (GOS), or an analogue or derivative thereof, with a pharmaceutically acceptable vehicle.

[0068] In one embodiment, the invention provides a process for making the pharmaceutical composition for use according to the third aspect, the process comprising combining a therapeutically effective amount of the Galacto- oligosaccharide (GOS), or an analogue or derivative thereof, with at least one probiotic and a pharmaceutically acceptable vehicle.

[0069] Preferably, the pharmaceutical composition comprises GOS, lactose, additional sugars and / or moisture. Preferably, the additional sugars are glucose and / or galactose.

[0070] Preferably, the pharmaceutical composition comprises per gram of product: at least 0.20g of GOS, at least 0.30g of GOS, at least 0.40g of GOS, at least 0.50g of GOS, at least 0.60g of GOS, at least 0.70g of GOS, or at least 0.80g of GOS.

[0071] Most preferably, the pharmaceutical composition comprises per gram of product: 0.70g of GOS, 0.22g of lactose, 0.055g of additional sugars, and 0.024g of moisture.

[0072] The subject may be a vertebrate, mammal, or domestic animal. Most preferably, however, the subject is a human being. The subject may be a male or female.

[0073] The subject may be a child or adult. The subject may be at least 10, 20, 30 40, 50, 60, 70, 80, 90 or 100 years old. Alternatively, the subject may be less than 10, 8, 6, 4 or 2 years old.

[0074] A "therapeutically active amount" of GOS, or analogue or derivative thereof is any amount which, when administered to a subject, is the amount of active agent that is needed to treat, ameliorate, or prevent the particular condition, or produce the desired effect. The GOS, or analogue or derivative thereof may be used as an adjuvant for the prevention or treatment of a particular condition. This means that lower doses of other prophylactic or therapeutic treatments would be required.

[0075] For example, the therapeutically effective amount of GOS, or analogue or derivative thereof used may be from about 0.001 mg to about 800 mg, and preferably from about 0.01 mg to about 500 mg.

[0076] A "pharmaceutically acceptable vehicle" as referred to herein, is any known compound or combination of known compounds that are known to those skilled in the art to be useful in formulating pharmaceutical compositions. In one embodiment, the pharmaceutically acceptable vehicle may be a solid, and the composition may be in the form of a powder or tablet. A solid pharmaceutically acceptable vehicle may include one or more substances which may also act as flavouring agents, lubricants, solubilisers, suspending agents, dyes, fillers, glidants, compression aids, inert binders, sweeteners, preservatives, coatings, or tabletdisintegrating agents. The vehicle may also be an encapsulating material. In powders, the vehicle is a finely divided solid that is in admixture with the finely divided active agents according to the invention. In tablets, the active agent (i.e. the GOS or analogue or derivative thereof) may be mixed with a vehicle having the necessary compression properties in suitable proportions and compacted in the shape and size desired. Suitable solid vehicles include, for example calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatine, cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins. In another embodiment, the pharmaceutical vehicle may be a gel and the composition may be in the form of a cream or the like.

[0077] However, the pharmaceutical vehicle may be a liquid, and the pharmaceutical composition is in the form of a solution. Liquid vehicles are used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions. The active agent according to the invention (i.e. the GOS or analogue or derivative thereof) may be dissolved or suspended in a pharmaceutically acceptable liquid vehicle such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats. The liquid vehicle can contain other suitable pharmaceutical additives such as solubilisers, emulsifiers, buffers, preservatives, sweeteners, flavouring agents, suspending agents, thickening agents, colours, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid vehicles for oral and parenteral administration include water (partially containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil).

[0078] The GOS or analogue or derivative thereof and compositions of the invention may be administered orally in the form of a sterile solution or suspension containing other solutes or suspending agents (for example, enough saline or glucose to make the solution isotonic), bile salts, acacia, gelatine, sorbitan monoleate, polysorbate 80 (oleate esters of sorbitol and its anhydrides copolymerized with ethylene oxide) and the like. The GOS or analogue or derivative thereof used according to the invention can also be administered orally either in liquid or solid composition form. Compositions suitable for oral administration include solid forms, such as pills, capsules, granules, tablets, and powders, and liquid forms, such as solutions, syrups, elixirs, and suspensions. Preferably, orally administrable formulations do not dissolve in the stomach, but preferentially dissolve in the duodenum. Orally administrable formulations may be enterically-coated, for example enteric-coated tablets or capsules. Forms useful for parenteral administration include sterile solutions, emulsions, and suspensions.

[0079] All of the features described herein (including any accompanying claims, abstract and drawings), and / or all of the steps of any method or process so disclosed, may be combined with any of the above aspects in any combination, except combinations where at least some of such features and / or steps are mutually exclusive.

[0080] For a better understanding of the invention, and to show how embodiments of the same may be carried into effect, reference will now be made, by way of example, to the accompanying Figures, in which :-

[0081] Figure 1 illustrates an overview of the dietary intervention protocol. All participants were required to consume a daily dose of GOS (i.e. the prebiotic GOS group), or maltodextrin (i.e. the placebo group) over a four-week period. Participants were also asked to keep a food diary during the supplement intervention period on days 1-4 and again on days 25-28 in the post-intervention period, when no supplement intervention is administered.

[0082] Figure 2 shows the number of participants responding to the dietary intervention in the prebiotic GOS group vs the placebo group. A. Number of participants who showed a change in brain excitability levels (glutamate / GABA) in the prebiotic GOS group vs the placebo group. B. Changes in self-report measures on emotional wellbeing in the prebiotic GOS group.

[0083] Figure 3 (A) shows a general reduction in gamma-ammino butyric acid (GABA) abundance levels in the prebiotic GOS group after intervention at Time 2 assessments. This reduction in GABA is maintained at follow up at Time 3. (B) shows a specific reduction in GABA abundance levels for a group of highly anxious participants in brain regions that support emotion processing and regulation, such as the prefrontal cortex (DLPFC), and higher-level cognition regions, such as the anterior cingulate cortex (ACC). Immediately after treatment at Time 2, the prebiotic GOS group shows reduced GABA abundance levels in the dorsolateral prefrontal cortex, which supports emotional processing and regulation and reward including in conditions such as anxiety and depression. At follow up 4 weeks later, this reduction in GABA abundance levels in the prebiotic GOS group is evident in a neighbouring region, the anterior cingulate cortex, which supports emotion control. Improving effective neurotransmission in these frontal regions by reducing GABAergic activity is critical for improving emotion responses and balancing neural circuitry. (C) shows a specific increase in glutamate abundance levels following intervention for a group of highly anxious participants in the DLPFC region at Time 2 in the prebiotic GOS group, compared to the placebo group. (D) shows a specific increase in glutamate to GABA ratio following intervention for a group of highly anxious participants in the DLPFC region at Time 2 in the prebiotic GOS group, compared to the placebo group.

[0084] Examples

[0085] The inventors have surprisingly discovered that GOS is able to influence the production and regulation of neurotransmitters, to improve emotional wellbeing, and treat mental health disorders. The inventors have also set out to identify whether GOS influences the composition of the gut microbiome and functional potential of the gut microbiome in the production and regulation of metabolites, to improve emotional wellbeing and treat mental health and psychiatric disorders via mechanisms of the gut-brain axis.

[0086] Example 1 - Use of GOS to assess the production and regulation of neurotransmitters / neurochemicals

[0087] The inventors set out to identify a food product or food additive that influences both the production and regulation of GABA and glutamate neurotransmitters / neurochemicals, to improve emotional wellbeing at both the preclinical and clinical level, and treat mental health disorders.

[0088] Materials and Methods

[0089] The inventors carried out an intervention protocol which used a two-arm parallel assignment double-blind randomised controlled trial design; randomized with stratification for baseline trait anxiety levels (measured using the T-anxiety subscale of the State-Trait Anxiety Inventory measure, Spielberger, 1983). Based on initial trait anxiety scores (median split based on sample distribution), participants were stratified into a high versus low anxiety group and subsequently randomly assigned into two groups. Groups were matched for age, handedness and socio-economic status.

[0090] Group 1 received a daily dosage of Galacto-oligosaccharides (GOS, 'prebiotics') over 4 weeks (~ 7.5g powder ~ 5.5g active GOS (70%)), whereas Group 2 received a placebo (maltodextrin) over the same period. There were three testing sessions spaced 4 weeks apart; Time 1 (baseline), Time 2 (post-intervention) and Time 3 (follow-up). The total study duration was 8 weeks. At each testing time (Time 1, 2 and 3), participants in both groups underwent comprehensive behavioural and psychological testing and MRI brain scanning to establish baseline measures of cognitive functioning and psychological well-being (such as anxiety levels). Each participant was asked to collect a stool sample at home for metagenomic sequencing of the microbiome at all testing times and detailed instructions on how to do this safely and hygienically was provided, together with the sample material.

[0091] Food supplement intervention protocol

[0092] One group received a daily dosage of GOS over 4 weeks, whereas the other group received a placebo over the same period (Figure 1). Additionally, participants were asked to keep a food diary during the supplement intervention period on days 1-4 and again on days 25-28 in the post intervention period when no supplement intervention is received.

[0093] All participants were required to consume a daily dietary fibre for 28 days following time 1 testing (baseline). The intervention arm received galacto-oliogosaccharides (GOS). The GOS used in this study is manufactured using lactose and 8- galactosidase derived from the enzyme Papiliotrema terrestris. GOS are soluble non-digestible carbohydrates that are not digested by human digestive enzymes but are fermented by the microbiota in the intestine. GOS is an ingredient rich in galacto-oligosaccharides that promote the growth of beneficial bacteria in the intestinal tract. GOS (2.9 kcal / g) has the following typical composition per gram of product: GOS 0.70g, lactose 0.22g, other sugars 0.055g (glucose+galactose), moisture 0,024g. The ingredients used are safe and well tolerated. GOS is 'Generally Recognised as Safe' (GRAS) by the FDA and moreover has been approved by the EU. The placebo was maltodextrin (Tate & Lyle). Unlike GOS, maltodextrin is absorbed in the upper part of the intestine and does not reach the colon. Maltodextrin as a placebo has been used previously in other studies, in which GOS was used as the active intervention. The placebo is similar in taste and colour to the active intervention. The dietary fibre and placebo were provided in powdered form and supplied in coded sachets (7.5g) for dispensing. For the repackaging of GOS and maltodextrin powder into the individual 7.5-gram sachets, < 0.5% oil (mediumchain triglyceride) was added to each sachet. Each participant was required to consume 1 sachet daily during breakfast.

[0094] As this was a double-blind randomised controlled study, neither the participants nor the experimenter interacting with the participants was aware of the group allocation.

[0095] Assessment of neurochemical architecture

[0096] Neurochemical architecture was assessed with magnetic resonance spectroscopy CH-MRS) to quantify neurotransmitter concentrations and structural imaging was used to assess tissue composition in three predefined brain regions. Two of these regions, the dorsolateral prefrontal cortex (dIPFC) and the anterior cingulate cortex, have been shown to support emotion regulation and processing in the brain; while the third is a conceptually-unrelated region in the inferior occipital cortex (IOG).

[0097] ^-MRS in vivo spectra were acquired in the three volumes of interest (VOIs) using a 2 cm3voxel manually centred in reference to the sagittal acquisition over the region of interest. Spectra were acquired using the Spin Echo full Intensity-Acquired Localized spectroscopy sequence, (SPECIAL, Mlynarik et al., 2006). Water suppressed spectra were acquired with TR = 3200 ms, TE 8500 ms, flip angle of 90° over 192 averages. Immediately prior, water unsuppressed spectra were acquired over 16 averages in the same region. Saturation bands were manually aligned along the six outer planes of each voxel prior to acquisition to suppress undesirable signals beyond the voxel boundaries.

[0098] Results

[0099] As illustrated in Figure 2A, the inventors have demonstrated that four weeks of GOS intake are sufficient to alter cortical excitability levels, as assessed via the abundance of excitatory and inhibitory neurotransmitters / neurochemicals (glutamate / GABA) in the prebiotic GOS group in comparison to the placebo group. Moreover, as shown in Figure 2B, the inventors have demonstrated that the administration of GOS lead to improved emotional well-being in young females aged 17-25 years, as evident by the number of subjects reducing the self-report scores for depression, sleep, social worry and anxiety.

[0100] Referring to Figure 3 (A), there is shown a general reduction in gamma-ammino butyric acid (GABA) abundance levels in the prebiotic GOS group after intervention at Time 2 assessments. This reduction in GABA is maintained at follow up at Time 3. (B) shows a specific reduction in GABA abundance levels for a group of highly anxious participants in brain regions that support emotion processing and regulation, such as the prefrontal cortex (DLPFC), and higher-level cognition regions, such as the anterior cingulate cortex (ACC). Immediately after treatment at Time 2, the prebiotic GOS group shows reduced GABA abundance levels in the dorsolateral prefrontal cortex, which supports emotional learning and reward including in conditions such as anxiety and depression. At follow up 4 weeks later, this reduction in GABA abundance levels in the prebiotic GOS group is evident in a neighbouring region, the anterior cingulate cortex, which supports emotion control. Improving effective neurotransmission in these (pre)-frontal regions by reducing GABAergic activity is critical for improving emotion responses and balancing neural circuitry.

[0101] As shown in Figure 3C, the inventors have demonstrated that the administration of GOS lead to a specific increase in glutamate abundance levels in highly anxious participants, compared to placebo. Furthermore, as shown in Figure 3D, the inventors have demonstrated that the administration of GOS lead to a specific increase in glutamate to GABA ratio in highly anxious participants, compared to placebo.

[0102] Example 2 - Use of GOS to assess alterations in the gut microbiome

[0103] The inventors set out to identify a food product or food additive that influences both the composition of the gut microbiome and functional potential of the gut microbiome in the production and regulation of metabolites to improve emotional wellbeing at both the preclinical and clinical level, and treat mental health and psychiatric disorders, via mechanisms of the gut-brain axis.

[0104] Materials and Methods The inventors, Dr Nicola Johnstone and Dr Kathrin Cohen Kadosh, at the University of Surrey, will use an intervention protocol in a two-arm parallel assignment double-blind randomised controlled trial design, which will be able to assess how GOS influences the gut microbiome using shallow shotgun metagenomic analysis of stool samples to evaluate the microbial communities of stool in terms of diversity and characteristics. This involves the extraction of microbial DNA from a sample and matching this information to a library to identify the species present. Further bioinformatics analysis will compare the microbial communities present against the functional potential for metabolite production and degradation in the gut. By doing so, the inventors will be informed of how GOS affects the gut microbiome composition and functional potential of gut produced metabolites.

[0105] 126 stool samples will be obtained female participants aged 17-25 years old. Participants will be randomly assigned to one of two groups, stratified by baseline trait anxiety scores. Group 1 will receive a daily dosage of Galacto-oligosaccharides (GOS, 'prebiotics') over 4 weeks (~ 7.5g powder ~ 5.5g active GOS (70%)), whereas Group 2 will receive a placebo (maltodextrin) over the same period. There will be three testing sessions spaced 4 weeks apart, at Time 1 (baseline), Time 2 (post-intervention) and Time 3 (follow-up), where the participant will provide a stool sample using an at-home collection kit. The total study duration will be 8 weeks.

[0106] Food supplement intervention protocol

[0107] During the supplement intervention period, participants will be asked to keep a food diary on days 1-4, days 25-28, and again on days 52-56 in the post intervention period when no supplement intervention will be received. Participants will be asked to consume one supplement daily with breakfast for the first 28 days of the intervention. The supplement will be GOS, the prebiotic active intervention, or maltodextrin, the placebo. The GOS used in this study is manufactured using lactose and [3-galactosidase derived from the enzyme Papiliotrema terrestris. GOS are soluble non-digestible carbohydrates that are not digested by human digestive enzymes, but are fermented by the microbiota in the intestine. GOS is an ingredient rich in galacto-oligosaccharides that promote the growth of beneficial bacteria in the intestinal tract. GOS (2.9 kcal / g) has the following typical composition per gram of product: GOS 0.70g, lactose 0.22g, other sugars 0.055g (glucose+galactose), moisture 0,024g. The ingredients used are safe and well tolerated. GOS is 'Generally Recognised as Safe' (GRAS) by the FDA and moreover has been approved by the EU.

[0108] The placebo will be maltodextrin (Tate & Lyle). Unlike GOS, maltodextrin is absorbed in the upper part of the intestine and does not reach the colon. Maltodextrin as a placebo has been used previously in other studies, in which GOS was used as the prebiotic active intervention. The placebo is similar in taste and colour to the active intervention. The dietary fibre and placebo were provided in powdered form and will be supplied in coded sachets (7.5g) for dispensing. For the repackaging of GOS and maltodextrin powder into the individual 7.5-gram sachets, < 0.5% oil (medium-chain triglyceride) will be added to each sachet.

[0109] Assessment of gut microbiome from stool samples and predicted results Microbial communities will be identified by extracting DNA from stool samples. Following quality control of the extraction process, shotgun sequencing will be performed using Novaseq X plus, PE 150 to a depth of 20 million reads. Sequences will then be annotated using an industry standard library. Annotated sequences will be compared across time and between groups to identify microbial communities that have altered due to GOS consumption. The inventors expect there to be evident growth in species under the genus Bifidobacteria for the prebiotic GOS group compared to the placebo group following intervention. The inventors, using further analysis and library sequencing (KEGG KO matching to the gut-brain module library (https: / / raeslab.org / software / gbms.html), will examine the microbial communities' contribution to the production and degradation of the metabolites GABA and glutamate, amongst others, in the gut. Comparative analysis will be used to show how GOS treatment modulates metabolite production in the gut compared to the placebo group. To show how GOS alters microbial communities in the gut to support improved emotional wellbeing, biomarker analysis will contrast microbial community relationships to psychological phenotypes between the prebiotic GOS group and the placebo group to show that GOS has improved behavioural phenotypes including reduced indicators of anxiety, and improve neural circuitry by altering the abundance of the neurotransmitters GABA and glutamate in the brain via improvements in the health of the gut microbiome.

[0110] Conclusions

[0111] The inventors have advantageously demonstrated that the administration of GOS resulted in an alteration of the brain-based metabolite (or neurochemical) concentrations of glutamate and gamma amino butyric acid. Advantageously, the inventors discovered that this change in neurotransmitter / neurochemical concentration resulted in positive responses to several indices of emotional wellbeing, including anxiety and depression, and also had a beneficial effect on sleep. Advantageously, the administration of GOS was already effective at the pre- clinical level of depression or anxiety, and improved emotional behaviour, meaning that it is beneficial at already low levels of well-being and particularly good for the prevention and early intervention range.

Claims

Claims1. Galacto-oligosaccharide (GOS), or an analogue or derivative thereof, for use in (i) treating, preventing or ameliorating a psychiatric disorder, (ii) improving neurotransmission, (iii) improving emotional well-being in a subject, or (iv) improving sleep, wherein the GOS causes alteration of the concentration of glutamate and / or gamma amino butyric acid in the subject's brain.

2. The GOS, or analogue or derivative thereof, for use according to claim 1, wherein the psychiatric disorder is selected from the group of conditions consisting of: anxiety, mood disorders, obsessive-compulsive disorder (OCD), phobias, post- traumatic stress disorder, eating disorders, and neuroticism.

3. The GOS, or analogue or derivative thereof, for use according to claim 2, wherein the anxiety is social anxiety or generalised anxiety.

4. The GOS, or analogue or derivative thereof, for use according to claim 3, wherein the generalised anxiety is associated with symptoms including high blood pressure, depression, low mood, emotion regulation, sleep disorders, irritability, difficulty concentrating, rumination, fear, restlessness, headaches, stomach aches, fatigue, nausea, changes in eating habits, disordered eating, and sleep disorders.

5. The GOS, or analogue or derivative thereof, for use according to any preceding claim, wherein improving neurotransmission comprises modulating cortical excitability via the abundance of excitatory and inhibitory neurotransmitters and / or altered receptor site function.

6. The GOS, or analogue or derivative thereof, for use according to any preceding claim, wherein improving neurotransmission comprises increasing the ratio of glutamate to gamma-aminobutyric acid (GABA), preferably by reducing the levels of gamma-aminobutyric acid (GABA).

7. The GOS, or analogue or derivative thereof, for use according to any preceding claim, wherein improving emotional well-being in a subject comprises reducing depression symptoms, improving sleep, reducing social worry, and / or reducing anxiety.

8. The GOS, or analogue or derivative thereof, for use according to any preceding claim, wherein improving sleep comprises improving the quantity and / or quality of sleep, preferably wherein improved sleep is measured using subject report on validated questionnaires.

9. The GOS, or analogue or derivative thereof, for use according to any preceding claim, wherein the alteration of the concentration of glutamate and / or gamma amino butyric acid in the subject's brain, comprises an increase in the ratio of glutamate to gamma amino butyric acid in the subject's brain.

10. The GOS, or analogue or derivative thereof, for use according to claim 9, wherein the increase in the ratio of glutamate to gamma amino butyric acid is driven by a reduction in the concentration of gamma amino butyric acid.

11. The GOS, or analogue or derivative thereof, for use according to claim 9, wherein the increase in the ratio of glutamate to gamma amino butyric acid is driven by an increase in the concentration of glutamate.

12. The GOS, or analogue or derivative thereof, for use according to any preceding claim, wherein the concentration of glutamate and / or gamma amino butyric acid in the subject's brain is measured usingmagnetic resonance spectroscopy CH-MRS).

13. The GOS, or analogue or derivative thereof, for use according to any preceding claim, wherein the GOS is administered daily to the subject.

14. The GOS, or analogue or derivative thereof, for use according to any preceding claim, wherein the GOS is administered orally.

15. The GOS, or analogue or derivative thereof, for use according to any preceding claim, further comprising administering at least one probiotic, optionally wherein the at least one probiotic comprises a bacterium or yeast.

16. The GOS, or analogue or derivative thereof, for use according to claim 15, wherein the bacterium comprises a bacterial species belonging to the genera Lactobacillus, Bifidobacterium, and / or Streptococcus.

17. A pharmaceutical composition comprising a therapeutically active amount of Galacto-oligosaccharide (GOS), or an analogue or derivative thereof, and a pharmaceutically acceptable vehicle, for use in (i) treating, preventing or ameliorating a psychiatric disorder, (ii) improving neurotransmission, (iii) improving emotional well-being in a subject, or (iv) improving sleep, wherein the GOS causes alteration of the concentration of glutamate and / or gamma amino butyric acid in the subject's brain.

18. A process for making the pharmaceutical composition for use according to claim 17, the process comprising combining a therapeutically effective amount of the Galacto-oligosaccharide (GOS), or an analogue or derivative thereof, with a pharmaceutically acceptable vehicle.

19. The pharmaceutical composition according to claim 17, or the process according to claim 18, wherein the pharmaceutical composition comprises GOS, lactose, additional sugars and / or moisture, preferably wherein the additional sugars are glucose and / or galactose.

20. The pharmaceutical composition according to claim 17 or 19, or the process according to claim 18 or 19, wherein the pharmaceutical composition comprises per gram of product: at least 0.20g of GOS, at least 0.30g of GOS, at least 0.40g of GOS, at least 0.50g of GOS, at least 0.60g of GOS, at least 0.70g of GOS, or at least 0.80g of GOS.

21. The pharmaceutical composition according to claim 17, 19, or 20, or the process according to any one of claims 18-20, wherein the pharmaceutical composition comprises a probiotic, optionally a bacterium or yeast.

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