Nutritional composition for neurodegenerative disorders and neurotrauma

Abstract

The present invention relates to a nutritional composition for use in the treatment of neurodegenerative diseases and / or neurotrauma comprising a combination of (i) omega-3 fatty acid DHA with (ii) vitamin B2 and (iii) vitamin D3. The invention also relates to a composition comprising DHA, vitamin B2, vitamin D3, and optionally one or more of: (iv) choline or a salt and / or choline ester thereof; and (v) dietary fibers and / or dietary butyric acid.

Description

Technical Field

[0001] The present invention belongs to the field of compositions and nutritional compositions for use in the treatment of neurodegenerative diseases, preferably the treatment and / or amelioration of symptoms of neurodegenerative diseases, and their use in neurotrauma / brain trauma and / or neurological damage caused by trauma. Background Art

[0002] Neurite outgrowth refers to the process by which nerve cells (also called neurons) extend their long, thin projections called neurites. Neurites include both axons and dendrites. Axons transmit electrical signals to other neurons, while dendrites receive signals from neighboring neurons.

[0003] When neurons undergo neurite outgrowth, it enables them to establish connections and communicate with other neurons in the brain. These connections are essential for brain function and form what is known as functional connectivity. Functional connectivity refers to the pattern of communication and interaction between different brain regions. It involves the synchronized activity of multiple neurons and neural circuits. Neurite outgrowth plays a key role in forming these connections and influencing how brain regions communicate with each other.

[0004] Neurons extend their neurites toward specific target areas and seek out other neurons or brain regions to form connections, allowing neural circuits to be established and enabling information processing and transmission. The growth of neurites helps to form synapses, which are connection points between neurons, contributing to the overall functional connectivity of the brain. Complex networks of neurons are responsible for a variety of brain functions, including sensory perception, motor control, sleep, memory, and cognitive processes, by sending and receiving signals.

[0005] Neurodegenerative diseases may disrupt the brain's functional connections primarily through the accumulation of abnormal proteins, inflammation, and loss of supportive glial cells. Impaired neurite outgrowth in neurodegenerative diseases affects the ability of neurons to form new connections in the brain and to maintain functional connections, and leads to a progressive decline in brain function and characteristic symptoms associated with these diseases, such as memory loss, movement difficulties, sleep disturbances, and cognitive impairment.

[0006] Treatment of neurodegenerative diseases focuses on pharmaceuticals, physical therapy, lifestyle changes, and supportive care. Regarding lifestyle changes, a balanced diet has been shown to play a role in disease management and slow disease progression.

[0007] CN 107889992 describes a functional health drink for preventing or treating dementia, which contains omega-3 fatty acids, choline and uridine as active ingredients to reduce disease progression, and further contains vitamins and trace elements.

[0008] WO 2021 / 034942 describes a dietary supplement for improving dietary deficiencies associated with brain health or neurodegenerative diseases, which contains two polyphenolic compounds in addition to omega-3 fatty acids, water-soluble and oil-soluble vitamin components and magnesium.

[0009] CN 112890136 describes an antioxidant total nutritional powder as an adjunct therapy for treating Alzheimer's disease, which contains DHA, B vitamins, vitamin D, phospholipids and taurine as well as many other ingredients.

[0010] WO 2018 / 226089 focuses on treating impaired motor skills in mammals with Parkinson's disease and mentions the presence of omega-3 fatty acids, choline and D3, and relates to the neuroprotective effects of dietary fiber in PD patients.

[0011] Neurotrauma refers to injury or damage to the brain, spinal cord, or peripheral nerves, typically caused by a sudden traumatic event. It encompasses a wide range of injuries, including traumatic brain injury (TBI), spinal cord injury (SCI), and peripheral nerve injury.

[0012] Traumatic brain injury (TBI) occurs when the head is suddenly hit, shaken or suffers penetrating injury, causing normal brain function to be disrupted. The range of TBI can range from mild concussion to severe injuries that cause long-term or permanent neurological defects. Spinal cord injury (SCI) refers to damage to the spinal cord, which causes loss of motor and sensory function below the level of injury. Depending on the location and severity of the injury, SCI may cause varying degrees of paralysis. Peripheral nerve injury involves damage to nerves located outside the brain and spinal cord. These injuries may occur due to trauma (such as lacerations, fractures or compression) and may cause loss of sensory or motor function in the affected area.

[0013] Neurotrauma can have significant consequences and may lead to physical, cognitive, and psychological impairments. In this regard, neurotrauma may have both direct and indirect effects on neurite outgrowth, depending on the severity and type of injury.

[0014] Several ways in which neurotrauma may affect neurite outgrowth are: destruction / disconnection of neuronal structures (including axons and dendrites); axonal degeneration, which results in the retraction or loss of axonal processes; excessive or chronic inflammation may inhibit neurite outgrowth; scar tissue formation at the site of injury may produce a physical barrier that hinders the extension of neuronal processes; changes in the cell environment via the release of inflammatory molecules, excitotoxicity, and changes in neurotransmitter balance, thereby affecting neurite outgrowth by affecting the availability of growth factors and the guidance cues necessary for proper neuronal development and regeneration. However, in some cases, neuronal regeneration may occur, in which damaged or interrupted axons grow again. The degree and success of regeneration depend on multiple factors, including age, overall health, the severity of injury, the presence of inhibitory factors in the environment, and the ability of damaged neurons to grow again.

[0015] WO 2012125034 describes a composition comprising: i) one or more of: uridine and cytidine, or salts, phosphates, acyl derivatives or esters thereof; ii) a lipid fraction comprising at least one of docosahexaenoic acid (22:6; DHA), eicosapentaenoic acid (20:5; EPA), and docosapentaenoic acid (22:5; DPA), or esters thereof, wherein the lipid fraction comprises less than 2 wt% alpha-linolenic acid (ALA) based on the weight of all fatty acids; iii) choline, or a salt or ester thereof; the composition is for use in preventing or treating neurological trauma TBI, cerebral palsy and SCI.

[0016] WO 2019013615 describes a composition for producing white matter, producing myelin and / or reducing brain lesion size in a mammal suffering from or recovering from traumatic brain injury, comprising enterally administering to a subject a composition comprising a therapeutically effective amount of: (i) uridine, cytidine, or one or more of their salts, phosphates, acyl derivatives or esters; (ii) a lipid fraction comprising at least one of DHA, EPA and DPA, wherein the lipid fraction comprises less than 2% by weight of ALA, calculated on the weight of all fatty acids; (iii) choline, or a salt or ester thereof; and (iv) at least one vitamin B selected from vitamin B6, B9 and B12. US 20170127693 describes a nutritional composition comprising butyrate, DHA, phosphatidylcholine, vitamin D and B2 for pediatric use.

[0017] WO 2019013635 describes an enteral nutritional composition comprising (a) a lipid fraction, (b) a digestible carbohydrate fraction and (c) a protein fraction, wherein the lipid fraction comprises a therapeutically effective amount of (i) DHA and optionally EPA, and (ii) medium chain triglycerides, preferably at least 2 wt% C8 and C10 medium chain triglycerides based on the weight of fatty acids; and wherein the composition has a ketogenic weight ratio between 1.4:1 and 3:1, for use in the treatment of TBI.

[0018] In this regard, current dietary options involve many different nutrients that show mixed results in different combinations of nutrients. Thus, there remains a need to find ways to treat neurodegenerative diseases and neurotrauma with nutritional supplements or nutritional compositions. Summary of the invention

[0019] The inventors surprisingly found that a composition comprising a therapeutically effective amount of a combination of ω-3 fatty acid docosahexaenoic acid (DHA), vitamin B2, and vitamin D3 can effectively treat neurodegenerative diseases and neural trauma. Treating neurodegenerative diseases includes treating the symptoms of these neurodegenerative diseases, and treating neural trauma includes treating neural trauma caused by external factors.

[0020] Surprisingly, a composition has been developed that includes a limited number of ingredients that work in a synergistic manner. This composition is established to reduce the risk of counteracting mechanisms of action in neurodegenerative diseases and neural trauma, or to reduce undesirable side effects in patients. Without being bound by theory, it is believed that therapeutically effective amounts of omega-3 fatty acids DHA, vitamin B2, and vitamin D3 reduce the effects of oxidative stress and inhibit inflammation, regulate synaptic plasticity, and transport of molecules in organelles in a synergistic manner.

[0021] In the in vitro PC12 model, it was found that the composition comprising the combination of these components resulted in an increase in neurite outgrowth (as defined by the number of neurites per cell and / or neurite length) compared to the composition without ω-3 fatty acid DHA, vitamin B2 and vitamin D3. The increase in neurite outgrowth (referring to the number of neurites per cell and / or neurite length) in PC12 cells was higher than expected based on the additive effect of each individual component, thereby demonstrating a synergistic effect between the three components.

[0022] It is also observed that adding choline, particularly phosphatidylcholine (PC) to the combination of DHA, B2 and D3 further improves neurite outgrowth, which is also better than expected based on the effect of choline or PC plus the effect of DHA, B2 and D3. When butyric acid is supplemented together with DHA, B2 and D3, the same situation is also observed. In addition, it is found that compared with the effect of each individual component added together, the combination of all five above-mentioned components is used to supplement PC12 cells unexpectedly causing further improvement (i.e. increase) of neurite outgrowth, thereby showing that there is a synergistic effect between these components to increase neurite outgrowth.

[0023] In this regard, the inventors surprisingly discovered that a combination of a smaller pool of nutrients comprising the omega-3 fatty acid DHA, vitamin B2 and vitamin D3, and optionally adding choline, particularly phosphatidylcholine (PC) and / or butyrate to the combination, has a synergistic effect on neurite outgrowth, indicating an improved composition with fewer nutrients necessary to achieve this effect.

[0024] Neurite outgrowth increase refers to the neurite number and / or neurite length of each cell, preferably the neurite number of each cell and the neurite length neurite density.Particularly in the case of brain trauma, neurite outgrowth increase can have a positive effect and contribute to functional recovery in supporting brain functional connection.As observed neurite outgrowth in PC12 cell research, any improvement (i.e. increase) can cause the improvement of those brain parts affected by trauma.

[0025] Similarly, the increase in neurite outgrowth density in neurodegenerative disease situations can contribute to the loss of neuronal connections in compensation neurodegenerative disease. It can allow the surviving neuron to extend its neurite and set up new synaptic connections, thereby partially recovering functional circuits. This compensation can help alleviate the impact of neuronal loss and maintain or obtain the normal brain function of some aspects again, thereby causing improved prognosis and functional recovery. In addition, neurite outgrowth increases and can contribute to neural plasticity, which allows the surviving neuron to adapt and set up new connections to respond to the environment of changes. This adaptability can help the brain compensate for the loss of specific neuronal populations and maintain functional connections, thereby potentially slowing down disease progression and improving prognosis.

[0026] Without being bound by theory, it is believed that DHA is used together with vitamin D2 and vitamin B2 to beneficially reduce oxidative damage, thereby helping to reduce the degree of neuronal damage and supporting brain metabolism, cell survival, and providing anti-inflammatory effects, thereby supporting the recovery or recovery of neuronal damage. Choline is associated with neuroinflammation reduction, functional and structural connectivity, and has a beneficial effect on cerebral blood flow. Dietary fiber and / or dietary butyrate provide butyrate as an alternative energy source, and butyrate can show neuroprotective effects by reducing oxidative stress and inflammation in neurons. It is believed that the ingredients of the composition according to the present invention provide the best promotion of outgrowth and recovery of neurites after neuronal damage on the one hand, while supporting brain function.

[0027] Therefore, the present invention relates to a method for treating neurodegenerative diseases and / or neural trauma, the method comprising administering a composition according to the present invention to a subject. The present invention also relates to a composition for use in the treatment of neurodegenerative diseases and / or neural trauma, the composition comprising a combination of i) ω-3 fatty acid DHA and ii) vitamin B2 and iii) vitamin D3.

[0028] In one embodiment, the composition optionally further comprises one or more of the following: iv) choline and / or PC; and v) dietary fiber and / or dietary butyric acid, such as in some embodiments, dietary fiber is selected from scGOS, lcFOS and low viscosity pectin. Therefore, the present invention also relates to a composition comprising i) a combination of ω-3 fatty acid DHA, ii) vitamin B2, iii) vitamin D3, and optionally further comprising iv) choline and / or PC and / or v) dietary fiber and / or dietary butyric acid.

[0029] Preferably, the composition according to the invention further comprises one or more selected from vitamins of group A, B, C and E, phospholipids, selenium, magnesium and coenzyme Q10. In another preferred aspect, the composition according to the invention comprises a combination of: i) ω-3 fatty acid DHA, ii) vitamin B2, iii) vitamin D3, iv) choline and / or PC, and v) dietary fiber and / or dietary butyrate, and one or more additional B vitamins.

[0030] According to one embodiment, the present invention relates to a method for treating neurodegenerative diseases and / or neural trauma in a subject, the method comprising administering a composition according to the present invention to the subject. The present invention may also be described as the use of a therapeutically effective combination of i) ω-3 fatty acids DHA, ii) vitamin B2 and iii) vitamin D3 for the manufacture of a composition for treating neurodegenerative diseases and / or neural trauma. In further embodiments, the present invention may be described as the use of a therapeutically effective combination of i) ω-3 fatty acids DHA, ii) vitamin B2 and iii) vitamin D3 and one or more of iv) choline and / or PC and v) dietary fiber and / or dietary butyric acid for the manufacture of a composition for treating neurodegenerative diseases and / or neural trauma. In addition, the present invention relates to the use of a therapeutically effective combination of i) ω-3 fatty acids DHA, ii) vitamin B2 and iii) vitamin D3 and optionally further comprising iv) choline and / or PC and / or v) dietary fiber and / or dietary butyric acid for the manufacture of a composition for treating neurodegenerative diseases and / or neural trauma in a subject. In other words, the present invention relates to a composition for treating a neurodegenerative disease and / or neurotrauma in a subject, said composition comprising a combination of i) ω-3 fatty acid DHA, ii) vitamin B2, iii) vitamin D3 and optionally further comprising iv) choline and / or PC and / or v) dietary fiber and / or dietary butyrate.

[0031] In an embodiment, the present invention is particularly directed to treating or preventing symptoms associated with a neurodegenerative disease, which relates to improving the outward growth of neurites in a treated subject with the neurodegenerative disease (e.g., increasing the number of neurites and the length of neurites) compared to a subject suffering from a neurodegenerative disease and not treated with a composition according to the present invention. In another embodiment, the present invention is particularly directed to treating nerve trauma, which relates to improving the outward growth of neurites in a treated subject with nerve trauma (e.g., increasing the number of neurites and the length of neurites) compared to a subject not treated with a composition according to the present invention. In certain embodiments, the treatment of neurodegenerative disease and / or nerve trauma further relates to neuroprotection after being diagnosed as a neurodegenerative disease or nerve trauma.

[0032] In some further embodiments, the present invention is particularly directed to treating or preventing symptoms associated with neurodegenerative diseases, which involves preventing or ameliorating the functional consequences of neurodegenerative diseases.

[0033] In some embodiments, the present invention is particularly directed to treating a neurodegenerative disease selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, frontotemporal dementia, and Lewy body dementia. In some further embodiments, the present invention is particularly directed to treating or preventing symptoms associated with a neurodegenerative disease, which involves preventing or ameliorating the functional consequences of a neurodegenerative disease, such as, but not limited to:

[0034] - Cognitive decline associated with memory loss, reduced attention span, decreased executive function, and impaired ability to perform activities of daily living; and / or

[0035] -Motor symptoms related to tremor, rigidity, bradykinesia, coordination and balance;

[0036] -Behavioral and psychological changes associated with depression, anxiety, irritability, fatigue, emotional apathy, social withdrawal, and mood swings;

[0037] - Sensory disturbances associated with loss of sensation, numbness, tingling, or altered perception of touch, pain, or temperature;

[0038] - Sleep disturbances related to insomnia, excessive daytime sleepiness, sleep fragmentation, restless legs syndrome, and rapid eye movement (REM) sleep behavior disorder;

[0039] -Autonomic dysfunction associated with orthostatic hypotension, urinary problems, incontinence, constipation, sweating, and changes in temperature regulation.

[0040] In preferred embodiments, the neurodegenerative disease as defined herein is not caused by stroke or ischemic stroke.

[0041] In further embodiments, the present invention is particularly directed to treating neurotrauma selected from traumatic brain injury (TBI), spinal cord injury (SCI) and peripheral nerve injury. In some further embodiments, the present invention is particularly directed to treating neurotrauma caused by one or more external factors selected from the following:

[0042] - Occupational hazards, including automotive, sports and workplace accidents;

[0043] - explosion and blast damage;

[0044] -electric shock;

[0045] - Blunt force trauma;

[0046] - Penetrating injuries, which involve penetration of a foreign object (including a bullet or sharp object) into the brain, spinal cord, or peripheral nerves.

[0047] In an alternative embodiment, the invention is directed to treating cerebral palsy.

[0048] In preferred embodiments, administration or use of the composition is initiated after diagnosis of a neurodegenerative disease or a prodromal phase thereof and / or after neurotrauma has occurred, and administration or use of the composition continues for a period of at least 2 weeks, preferably at least 1 month, preferably at least 2 months, more preferably at least 4 months, even more preferably at least 6 months.

[0049] In a further preferred embodiment, a daily supplement of 150 to 2000 mg of DHA, 5-80 μg of vitamin D3 and 0.8 to 7.6 mg of vitamin B2 is provided with the composition according to the invention.

[0050] Figure List

[0051] The present invention will be discussed in more detail below with reference to the accompanying drawings.

[0052] Figure 1 .Shows the effects of ω-3 fatty acids DHA (6.7 μM) and eicosapentaenoic acid (EPA) (10 μM), vitamin B2 (1.25 μM), and vitamin D3 (0.25 μM) and their combination on neurite outgrowth in PC12 neuronal cells. Neurite outgrowth is expressed as a percentage relative to the control (100%).

[0053] Figure 2 .Shows the effect of a combination of the omega-3 fatty acid DHA (6.7 μM), vitamin B2 (0.5 μM) and vitamin D3 (0.25 μM) and a combination of DHA (6.7 μM), vitamin B2 (1 μM) and vitamin D3 (0.25 μM) on neurite outgrowth in PC12 neuronal cells. Neurite outgrowth is expressed as a percentage relative to the control (100%).

[0054] Figure 3 .Shows the effect of a combination of the omega-3 fatty acid DHA (3.3 μM), vitamin B2 (0.5 μM) and vitamin D3 (0.25 μM) and a combination of DHA (3.3 μM), vitamin B2 (1 μM) and vitamin D3 (0.25 μM) on neurite outgrowth in PC12 neuronal cells. Neurite outgrowth is expressed as a percentage relative to the control (100%).

[0055] Figure 4 . Shown are the effects of Choline chloride (20 μM), PC (20 μM) and their combination providing 20 μM choline at a molar ratio of 60:40 or 40:60, respectively, on neurite outgrowth in PC12 neuronal cells. Neurite outgrowth is expressed as a percentage relative to the control (100%).

[0056] Figure 5.Show the effect of choline chloride (20 μM), PC (20 μM) alone and their combination with DHA (3.3 μM), vitamin B2 (0.5 μM) and vitamin D3 (0.25 μM) on the outgrowth of neurites in PC12 neuronal cells. Also show the effect of a combination of choline chloride and phosphatidylcholine (the combination provides 20 μM choline, wherein 80 mol% of the choline is derived from choline chloride and 20 mol% is derived from PC based on total choline) together with DHA, vitamin B2 and vitamin D3. Neurite outgrowth is expressed as a percentage relative to a control (100%).

[0057] Figure 6 .Shows the effect of PC (20 μM), a combination of DHA (5 μM) and EPA (1 μM), vitamin B2 (0.5 μM) and vitamin D3 (0.25 μM), and a combination of PC with DHA, EPA, vitamin B2 and vitamin D3 on neurite outgrowth in PC12 neuronal cells. Neurite outgrowth is expressed as a percentage relative to the control (100%).

[0058] Figure 7 . Shows the effect of different concentrations of butyric acid (BA) on neurite outgrowth in PC12 neuronal cells. Neurite outgrowth is expressed as a percentage relative to the control (100%).

[0059] Figure 8 .Shows the effect of BA (200 μM), vitamin B2 (0.25 μM), DHA (2.5 μM), vitamin D3 (0.25 μM) and PC (20 μM) alone on neurite outgrowth in PC12 neuronal cells. Also shown are the effects of the combination of DHA, vitamin B2 and D3, the combination of DHA, vitamin B2 and D3 with BA or PC, and the combination of all nutrients BA, DHA, PC, vitamin B2 and D3. Neurite outgrowth is expressed as a percentage relative to the control (100%).

[0060] List of Preferred Embodiments

[0061] 1. A nutritional composition for use in the treatment of neurodegenerative diseases and / or neurotrauma and / or cerebral palsy, the nutritional composition comprising a therapeutically effective combination of:

[0062] i) omega-3 fatty acids;

[0063] ii) Vitamin B2; and

[0064] iii) Vitamin D3,

[0065] Wherein the omega-3 fatty acids comprise at least DHA.

[0066] 2. The nutritional composition for use according to embodiment 1, wherein the composition further comprises one or more selected from the following:

[0067] iv) choline or a salt thereof and / or phosphatidylcholine; and

[0068] v) dietary fiber and / or dietary butyrate.

[0069] 3. The nutritional composition according to embodiment 2, wherein at least 40 mol% of choline is provided in the form of phosphatidylcholine, preferably the molar ratio of choline or its salt to PC is in the range of 40:60 to 60:40.

[0070] 4. The nutritional composition for use according to any one of embodiments 1-3, further comprising one or more components selected from vitamins A, C and E, phospholipids, selenium, magnesium and additional B vitamins.

[0071] 5. The nutritional composition for use according to any one of the preceding embodiments, wherein the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, frontotemporal dementia, and Lewy body dementia.

[0072] 6. The nutritional composition for use according to any of the preceding embodiments, wherein the treatment of a neurodegenerative disease relates to treating and / or preventing and / or delaying symptoms associated with said neurodegenerative disease in a subject suffering from said neurodegenerative disease or wherein a prodromal stage of said neurodegenerative disease has been diagnosed in said subject, preferably wherein these symptoms relate to one or more of the following:

[0073] - Cognitive decline associated with memory loss, reduced attention span, decreased executive function, and impaired ability to perform activities of daily living; and / or

[0074] - Motor symptoms related to tremor, rigidity, bradykinesia, coordination and balance; and / or

[0075] - Behavioral and psychological changes associated with depression, anxiety, irritability, fatigue, emotional apathy, social withdrawal, and mood swings; and / or

[0076] - sensory disturbances associated with loss of sensation, numbness, tingling, or altered perception of touch, pain, or temperature; and / or

[0077] - Sleep disturbances associated with insomnia, excessive daytime sleepiness, sleep fragmentation, restless legs syndrome, and rapid eye movement (REM) sleep behavior disorder; and / or

[0078] -Autonomic dysfunction associated with orthostatic hypotension, urinary problems, incontinence, constipation, sweating, and changes in temperature regulation.

[0079] 7. The nutritional composition for use according to embodiment 1, wherein the neurological injury is selected from traumatic brain injury (TBI), spinal cord injury (SCI) and peripheral nerve injury.

[0080] 8. The nutritional composition for use according to embodiment 7, wherein the nerve trauma is caused by one or more external factors selected from the group consisting of:

[0081] - Occupational hazards, including automotive, sports and workplace accidents;

[0082] - explosion and blast damage;

[0083] -electric shock;

[0084] - Blunt force trauma;

[0085] - Penetrating injuries, which involve penetration of a foreign object (including a bullet or sharp object) into the brain, spinal cord, or peripheral nerves.

[0086] 9. A nutritional composition for use according to any one of embodiments 1 to 8, wherein the treatment of a neurodegenerative disease involves an increase in the outgrowth of neurites in a subject having the neurodegenerative disease and treated with the composition, compared to a subject having the neurodegenerative disease and not treated with the composition, and / or wherein the treatment of neural trauma involves an increase in the length of the outgrowth of neurites in a subject having the neural trauma and treated with the composition, compared to a subject having the neural trauma and not treated with the composition.

[0087] 10. The nutritional composition for use according to any one of the preceding embodiments, wherein the composition is used daily for at least 4 weeks after diagnosis of the neurodegenerative disease and / or after diagnosis or occurrence of the neurotrauma.

[0088] 11. The nutritional composition for use according to any one of the preceding embodiments, wherein the composition comprises a daily dose of:

[0089] i) 150 to 1200 mg, preferably 200 to 1100 mg, more preferably 250 to 1000 mg of DHA per day;

[0090] ii) 0.8 to 7.6 mg, preferably 1 to 7.4 mg, more preferably in the range of 1.2 to 7.2 mg of vitamin B2;

[0091] iii) 6 to 75 μg, preferably 8 to 70 μg, more preferably 10 to 65 μg of vitamin D3;

[0092] and optionally

[0093] iv) 200 to 1400 mg, preferably 300 to 1200 mg, more preferably 350 to 1100 mg of choline, based on the molar weight of choline, wherein the choline is selected from free choline, choline salts and / or choline esters, preferably at least phosphatidylcholine;

[0094] and / or

[0095] v) 2.5 to 12.5 g, preferably 3 to 12 g, more preferably 3.5 to 11.5 g of dietary fiber and / or 0.125 g to 0.65 g, preferably 0.025 g to 0.65 g, more preferably 0.043 g to 0.65 g of dietary butyrate.

[0096] 12. The nutritional composition for use according to any one of the preceding embodiments, wherein the nutritional composition is a liquid nutritional composition, preferably wherein the nutritional composition is an oral nutritional supplement or a tube feed.

[0097] 13. A liquid nutritional composition comprising a combination of:

[0098] i) DHA;

[0099] ii) Vitamin B2;

[0100] iii) Vitamin D3;

[0101] and optionally one or more of the following:

[0102] iv) choline or a salt thereof and / or phosphatidylcholine; and

[0103] v) dietary fiber and / or dietary butyrate.

[0104] 14. The liquid nutritional composition according to embodiment 13, wherein per 100 kcal the liquid nutritional composition comprises:

[0105] i) 20 to 100 mg, preferably 25 to 90 mg, more preferably 30 to 80 mg DHA;

[0106] ii) 0.4 to 0.6 mg vitamin B2;

[0107] iii) 1.3 to 4.5 μg vitamin D3;

[0108] and optionally further comprises:

[0109] iv) 100 to 1000 mg, preferably 200 to 800 mg, more preferably 300 to 500 mg choline or a salt thereof and / or phosphatidylcholine;

[0110] and / or

[0111] v) 0.75 to 2.5 g, preferably 1.0 to 2.0 g, more preferably 1.1 to 1.5 g dietary fiber and / or 0.015 to 0.25 g, preferably 0.03 to 0.25 g, more preferably 0.05 to 0.25 g dietary butyric acid.

[0112] 15. The liquid nutritional composition according to embodiment 13 or 14, wherein the composition additionally comprises 4 to 7 g protein / 100 kcal, 3 to 5.5 g lipid / 100 kcal and 8.5 to 10.5 g carbohydrate / 100 kcal. DETAILED DESCRIPTION

[0113] The present invention relates to a method for treating neurodegenerative diseases and / or neural trauma, the method comprising administering to a subject a composition comprising a combination of i) ω-3 fatty acid DHA, ii) vitamin B2 and iii) vitamin D3, optionally further comprising one or more of the following: iv) choline and / or PC and v) dietary fiber and / or dietary butyrate.

[0114] In a preferred embodiment, the dietary butyric acid is selected from butyric acid and its salts and glyceride-bound forms of butyric acid containing one, two or three butyric acid chains. In a preferred embodiment, the dietary fiber is selected from pectin, mucilage, gum, galacto-oligosaccharide, oligofructose, inulin, polyfructose, fructo-oligosaccharide, arabinogalactan, (hemi)cellulose, resistant starch, soy fiber, oligosaccharides, and mixtures thereof, more preferably scGOS, lcFOS and low viscosity pectin.

[0115] In an embodiment, the present invention relates to a composition comprising a combination of i) ω-3 fatty acid DHA, ii) vitamin B2, iii) vitamin D3, and optionally further comprising iv) choline and / or PC and / or v) dietary fiber and / or dietary butyric acid. Preferably, the composition according to the present invention further comprises one or more selected from A, B, C and E vitamins, phospholipids, selenium, magnesium and coenzyme Q10. In another preferred aspect, the composition according to the present invention comprises a combination of i) ω-3 fatty acid DHA, ii) vitamin B2, iii) vitamin D3, iv) choline and / or PC, and v) dietary fiber and / or dietary butyric acid, and one or more additional B vitamins.

[0116] Described in an alternative manner, the present invention also relates to the use of a composition comprising i) a combination of ω-3 fatty acids DHA, ii) vitamin B2, iii) vitamin D3 and optionally further comprising iv) choline and / or PC and / or v) dietary fiber and / or dietary butyrate for the manufacture of a composition for treating a neurodegenerative disease and / or a neurotrauma in a subject, preferably for treating a neurodegenerative disease selected from Alzheimer's disease, Parkinson's disease, Huntington's disease, frontotemporal dementia and Lewy body dementia and for treating a neurotrauma selected from traumatic brain injury (TBI), spinal cord injury (SCI) and peripheral nerve injury. Preferably, the composition according to the present invention further comprises one or more selected from vitamins of group A, B, C and E, phospholipids, selenium, magnesium and coenzyme Q10.

[0117] In addition, the present invention relates to a composition for use in the treatment of neurodegenerative diseases and / or neural trauma, wherein the neurodegenerative disease is preferably selected from the disease selected from Alzheimer's disease, Parkinson's disease, Huntington's disease, frontotemporal dementia and Lewy body dementia, and wherein the neural trauma is selected from traumatic brain injury (TBI), spinal cord injury (SCI) and peripheral nerve injury, the composition comprises i) ω-3 fatty acid DHA, ii) vitamin B2, iii) a combination of vitamin D3, and optionally further comprises iv) choline and / or PC and / or v) dietary fiber and / or dietary butyric acid. Preferably, the composition according to the present invention further comprises one or more selected from A, B, C and E vitamins, phospholipids, selenium, magnesium and coenzyme Q10. In a specific preferred embodiment, the composition comprises a combination of i) ω-3 fatty acid DHA, ii) vitamin B2, iii) vitamin D3, iv) choline and / or PC and v) dietary fiber and / or dietary butyric acid, and one or more additional B vitamins.

[0118] The present invention also particularly relates to treating neurodegenerative diseases, more particularly treating, reducing, delaying or preventing symptoms of neurodegenerative diseases, wherein the neurodegenerative disease is preferably selected from Alzheimer's disease, Parkinson's disease, Huntington's disease, frontotemporal dementia and Lewy body dementia. In a preferred embodiment, the treatment of a neurodegenerative disease involves or includes treating, reducing, delaying and / or preventing symptoms associated with the neurodegenerative disease in a subject suffering from the neurodegenerative disease or in the prodromal stage of the neurodegenerative disease, wherein these symptoms involve one or more of the following:

[0119] - Cognitive decline associated with memory loss, reduced attention span, decreased executive function, and impaired ability to perform activities of daily living; and / or

[0120] -Motor symptoms related to tremor, rigidity, bradykinesia, coordination and balance;

[0121] -Behavioral and psychological changes associated with depression, anxiety, irritability, fatigue, emotional apathy, social withdrawal, and mood swings;

[0122] - Sensory disturbances associated with loss of sensation, numbness, tingling, or altered perception of touch, pain, or temperature;

[0123] - Sleep disturbances related to insomnia, excessive daytime sleepiness, sleep fragmentation, restless legs syndrome, and rapid eye movement (REM) sleep behavior disorder;

[0124] -Autonomic dysfunction associated with orthostatic hypotension, urinary problems, incontinence, constipation, sweating, and changes in temperature regulation.

[0125] Treatment of neurodegenerative diseases, preferably Alzheimer's disease, Parkinson's disease, Huntington's disease, frontotemporal dementia and dementia with Lewy bodies, involves improvement in neurite outgrowth, meaning an increase in the number of neurites per cell and the length of neurites in subjects treated with a composition according to the invention compared to subjects not treated with a composition according to the invention.

[0126] In some embodiments, the treatment of neurodegenerative diseases, preferably Alzheimer's disease, Parkinson's disease, Huntington's disease, frontotemporal dementia and Lewy body dementia, further involves neuroprotection after diagnosis. Therefore, the treatment of neurodegenerative diseases involves neuronal repair or regeneration and neuronal network recovery in neurodegenerative diseases. In embodiments, the treatment of neurodegenerative diseases includes neuronal repair and / or neuronal network recovery. In embodiments, treatment involves symptomatic treatment and / or delays the progression of neurodegenerative diseases.

[0127] In addition, the present invention further particularly relates to the treatment of neurotrauma, preferably traumatic brain injury (TBI), spinal cord injury (SCI) and peripheral nerve injury. In some further embodiments, the present invention particularly relates to the treatment of neurotrauma caused by one or more external factors selected from the following:

[0128] - Occupational hazards, including automotive, sports and workplace accidents;

[0129] - explosion and blast damage;

[0130] -electric shock;

[0131] - Blunt force trauma;

[0132] - Penetrating injuries, which involve penetration of a foreign object (including a bullet or sharp object) into the brain, spinal cord, or peripheral nerves.

[0133] Treatment of neurotrauma, preferably traumatic brain injury (TBI), spinal cord injury (SCI) and peripheral nerve injury involves improvement in neurite outgrowth, meaning an increase in the number of neurites per cell and the length of neurites in subjects treated with a composition according to the invention compared to subjects not treated with a composition according to the invention.

[0134] In some embodiments, the treatment of neurotrauma, preferably traumatic brain injury (TBI), spinal cord injury (SCI) and peripheral nerve injury further involves neuroprotection after diagnosis. Therefore, the treatment of neurotrauma involves neuronal repair or regeneration and neuronal network recovery after neurotrauma occurs. In an embodiment, the treatment of neurotrauma includes neuronal repair and / or neuronal network recovery. In an embodiment, the treatment of neurotrauma includes treating the consequences of neurotrauma and / or preventing the progression of neurological damage as a consequence of neurotrauma.

[0135] The methods or uses according to the invention or the compositions for use according to the invention are further described in the following examples.

[0136] definition

[0137] Throughout this application, the following terms and abbreviations may be used. "Nutritional composition" means a substance or formulation that satisfies at least a portion of a subject's nutritional needs. Throughout this disclosure, the terms "nutrition," "nutritional formula," "enteral nutrition," and "nutritional supplement" are used as non-limiting examples of nutritional compositions. In addition, "nutritional composition" may refer to an enteral formula, oral formula, infant formula, pediatric subject formula, children's formula, growing-up milk, and / or adult formula in a liquid, powder, gel, paste, solid, concentrate, suspension, or ready-to-use form.

[0138] The term "supplement" or "nutritional supplement" refers to a nutritional product that provides an individual with nutrients that the individual may not otherwise be able to conveniently consume in sufficient quantities and can be used to supplement the individual's nutrition. It can be in the form of tablets, capsules, lozenges, or liquids. Supplements generally provide selected nutrients but do not represent a major part of the subject's overall nutritional needs. Typically, they do not exceed 0.1%, 1%, 5%, 10% of the subject's daily energy needs.

[0139] As used herein, "neuroprotection" refers to promoting neuronal repair, limiting neuronal oxidative stress, limiting cellular damage, and / or promoting neuronal network recovery following neurotrauma or during neurodegenerative disease.

[0140] "Prevention" includes reducing the risk and / or severity of neuronal damage of neurodegenerative diseases. The terms "treatment" and "relief" include both: preventive treatment or preventive treatment (preventing targeted pathological conditions or disorders and / or slowing down their development) and curative, therapeutic or disease-modifying treatment, including curing, slowing down, alleviating the symptoms of diagnosed pathological conditions or disorders and / or stopping the treatment of their progress; and treatment is faced with the risk of suffering from the disease or suspected of having suffered from the disease, and patients who are ill or have been diagnosed with a disease or medical condition. The term does not necessarily mean that the subject is treated until fully recovered. The terms "treatment" and "relief" also refer to maintaining and / or promoting health in individuals who do not suffer from the disease but may be prone to developing unhealthy conditions. The terms "treatment" and "relief" are also intended to include strengthening or otherwise enhancing one or more primary preventive or therapeutic measures. The terms "treatment" and "relief" are further intended to include dietary management of disease or illness in subjects in need or dietary management for preventing or preventing disease or illness.

[0141] As used herein, a subject is a mammal, preferably a human, more preferably a human subject older than 40 years old, preferably older than 55 years old, more preferably older than 65 years old.

[0142] As used herein, a "therapeutically effective amount" is an amount that alleviates symptoms, manages the progression of a neurodegenerative disease and / or the consequences of neurotrauma, or provides a nutritional, physiological or medical benefit to an individual. In a preferred embodiment, as used herein, a therapeutically effective amount refers to at least 1 times, preferably 1.1 times, the recommended daily intake. The recommended daily intake is defined by agencies such as EFSA or FDA.

[0143] The term "neurite" refers to the outgrowth process of a neuron. As used herein, the term neurite encompasses all such cellular processes (including both axons and dendrites) that grow outward from a neuron.

[0144] The term "neurite outgrowth" refers to the cellular process of outgrowth from a neuron, or to a cell comprising outgrowth from a neuron, and herein refers to the number of neurites per cell and the neurite length.

[0145] The terms "butyric acid" and "butyrate" (also referred to as BA) are used interchangeably and refer to a short-chain fatty acid (SCFA) with a four-carbon chain, or an anion thereof, that can be covalently bound to another compound, such as with an ester bond.

[0146] In this document and its claims, the verb "comprise" and its word form changes are used in its non-restrictive sense, meaning to include the part after the word, but not excluding the part not specifically mentioned. In addition, when used in this article, the term weight percentage (wt%) is the weight percentage based on the total weight. In addition, unless the context clearly requires the presence of one / a kind and only one / a kind of element, the possibility of referring to an element by the indefinite article "a" or "an" is not excluded that there are more than one / a kind of element. Therefore, the indefinite article "a" or "an" usually means "at least one / a kind".

[0147] Composition

[0148] The method or use according to the invention or the composition for use according to the invention relates to administering the composition according to the invention. The composition according to the invention can be used as a pharmaceutical product or preferably a nutritional product. In one embodiment, the nutritional composition according to the invention is a liquid. In one embodiment, preferably, the nutritional composition according to the invention is a liquid, ready-to-feed composition. Preferably, the composition is administered orally or as a tube feed.

[0149] In one aspect, the composition according to the present invention can be used as a pharmaceutical product, which includes one or more pharmaceutically acceptable carrier materials. Such a product can contain a daily dose defined as follows in one or more dosage units. The dosage unit can be in liquid form or solid form, wherein in the latter case, the daily dose can be provided by one or more solid dosage units, such as in one or more capsules or tablets. The pharmaceutical product (preferably for enteral application) can be a solid or liquid galenic formulation. Examples of solid galenic formulations are tablets, capsules (e.g., hard shell or soft shell gelatin capsules), pills, sachets, powders, granules, etc. containing active ingredients and conventional galenic carriers. Any conventional carrier material can be utilized. The carrier material can be an organic or inorganic inert carrier material suitable for oral administration. Suitable carriers include water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, etc. In addition, additives such as thickeners, flavoring agents, preservatives, stabilizers, emulsifiers, buffers, etc. can be added according to the recognized practice of drug compounding. While the individual active ingredients are suitably administered in a single composition, they may also be administered in separate dosage units.

[0150] In preferred aspects, compositions according to the present invention can be used as nutritional products, for example, as nutritional supplements, for example, as additives for normal diets, as fortifiers added to normal diets, or as complete nutrition. The nutritional products preferably comprise at least one component, preferably all components, selected from the group of fat, protein and carbohydrates. It should be understood that the difference between nutritional products and pharmaceutical products is that the existence of nutrients, particularly protein, fat, digestible carbohydrates and dietary fiber, that provide nutrition for the experimenter using the composition. It can further contain ingredients such as minerals, vitamins, organic acids and flavorings. Although the term "nutritional health products" is often used in the literature, it represents a nutritional product with a pharmaceutical component or pharmaceutical purpose. Therefore, nutritional compositions according to the present invention can also be used in nutritional health products.

[0151] In one embodiment, the composition comprises a lipid portion, wherein the lipid portion provides 15% to 50% of the energy of the composition. In one embodiment, the composition is a liquid composition containing 1.1 to 2.6 kcal / ml, preferably 1.2 to 2.4 kcal / ml. In one embodiment, the composition is a tube feed with a caloric density of 1.1 to 1.7 kcal / ml, preferably 1.2 to 1.6 kcal / ml. In another embodiment, the composition is in the form of an oral nutritional supplement with a caloric density of 2.2 to 2.6 kcal / ml. The energy provided by the nutrients is calculated using the following Atwater calculation coefficients: 9 kcal / g lipid, 4 kcal / g protein or digestible carbohydrates, 2 kcal / g fiber and other components in the 0 kcal product.

[0152] The amount of the lipid fraction can be determined by applying methods known in the art for measuring the fat content in food matrices (when applicable). For example, the fat content of general foods is determined by applying AOAC (R) official method 983.23, while the Roese-Gottlieb method (AOAC (R) 932.06) is more suitable for products based on dry milk powder (Lehner, R., Estoppey, A., (1954) Mitt. Lebensmitteluntersuchung Hyg. [News on food inspection and hygiene] 54: 183-185). The amount of individual lipid components can be determined by applying methods specifically designed to measure specific components or by fractionating the fat fraction separated from the extract of the chloroform-ethanol fraction as given in the 983.23 method.

[0153] Suitable sources of omega-3 fatty acids for use in the composition include, but are not limited to, fish oil, krill oil, algae oil, preferably fish oil.

[0154] Suitable sources of other lipids for use in the compositions include, but are not limited to, soybean oil, rapeseed oil (such as rapeseed oil, canola oil and canola oil), high oleic sunflower oil, coconut oil, high oleic safflower oil and olive oil. Alternative selection is the lipid obtained from the milk of non-human mammals, preferably cow's milk, goat's milk, sheep's milk, horse's milk, buffalo's milk, yak's milk, reindeer's milk, donkey's milk and camel's milk, particularly cow's milk and / or goat's milk. Milk lipids are sometimes also referred to as milk fat or butter fat.

[0155] Therefore, the nutritional composition according to the invention preferably comprises a lipid fraction, preferably a lipid fraction suitable for nutrition as known in the art. The composition comprises 4 to 12 g lipid / 100 ml, preferably 4.5 to 11 g lipid / 100 ml, more preferably 5 to 10 g / 100 ml. Based on calories, preferably, the composition according to the invention may comprise 3 to 5.5 g lipid / 100 kcal, preferably 3.5 to 5 g / 100 kcal, more preferably 3.8 to 4.5 g lipid / 100 kcal based on the total energy content of the composition. The lipid fraction comprises polyunsaturated fatty acids and optionally also monounsaturated fatty acids (MUFA) and saturated fatty acids (SFA).

[0156] The composition according to the present invention preferably comprises 4 to 17g protein / 100ml composition. The total protein present in the nutritional composition, i.e. the combination of all proteins present, can also be referred to as the "protein portion" of the nutritional composition. Therefore, the nutritional composition preferably comprises 4-17g protein portion / 100ml composition. In a preferred aspect, the nutritional composition comprises 5 to 16g protein portion / 100ml composition, more preferably 6-15g. Most preferably, the composition comprises 11 to 14.5g protein portion / 100ml composition. Based on heat, preferably, the composition according to the present invention can comprise 4 to 7g protein portion / 100kcal, preferably 4.5 to 6.5g protein portion / 100kcal, more preferably 5 to 6g protein portion / 100kcal based on the total energy content of the composition.

[0157] Suitable protein sources can be based on milk proteins (such as whey, casein, and mixtures thereof) and vegetable proteins (such as those based on soy, potato, pea, rapeseed, etc.). The nutritional composition preferably further comprises a carbohydrate portion. The composition preferably comprises 9 to 25 g carbohydrates / 100 ml, more preferably 10 to 24 g / 100 ml, even more preferably 11 to 23 g / 100 ml. Based on heat, preferably, the composition according to the present invention can comprise 8.5 to 10.5 g carbohydrates / 100 kcal, preferably 9 to 10 g / 100 kcal, more preferably 9.2 to 9.6 g carbohydrates / 100 kcal based on the total energy content of the composition.

[0158] The composition according to the invention preferably comprises 4 to 7 g protein / 100 kcal, 3 to 5.5 g lipid / 100 kcal and 8.5 to 10.5 g carbohydrate / 100 kcal.

[0159] Suitable carbohydrate sources include lactose, glucose, sucrose, fructose, galactose, maltose, starch, isomaltose and maltodextrin.

[0160] The composition of the present invention is typically an enteral composition, i.e. intended for oral administration, such as tube feedings, nutritional drinks and oral nutritional supplements. It is preferably administered in liquid form. Preferably, the composition comprises water in which the further components are dissolved or suspended.

[0161] Thus, the composition is preferably a liquid or a solid (typically a powder or tablet, preferably a powder) that can be reconstituted with a liquid, preferably water, to obtain a liquid composition. The dosage of the components defined below may be, for example, a daily dose or a concentration per 100 mL or 100 kcal.

[0162] Compositions according to the present invention are used to treat neurodegenerative diseases and / or neural trauma. Neurodegenerative diseases are preferably selected from Alzheimer's disease, Parkinson's disease, Huntington's disease, frontotemporal dementia and Lewy body dementia. Nerve trauma is preferably selected from traumatic brain injury (TBI), spinal cord injury (SCI) and peripheral nerve injury. Treatment is particularly related to the symptoms of treating neurodegenerative diseases and / or delaying the progression of neurodegenerative diseases and the consequences of treating neural trauma and / or preventing the progression of nerve damage as a consequence of neural trauma. Neurotrauma includes trauma caused by external factors, such as occupational hazards; explosion and blast injuries; electric shock; blunt force trauma and external objects penetrate into the brain, spinal cord or peripheral nerves. Treatment is related to the improvement of neurite outgrowth.

[0163] Composition as above can be used as nutrition therapy, nutritional support, medical food, food or nutritional supplement for special medical purposes. The use of composition according to the present invention typically occurs during the recovery and / or rehabilitation after diagnosing neurodegenerative diseases and / or after nerve trauma occurs, and as long as its negative effect is extended, it is possible to continue. Although active effects may have been observed during the first week of use, it is preferably continued for at least 2 weeks, preferably at least 4 weeks, preferably at least 2 months, more preferably at least 4 months, even more preferably at least 6 months. Use preferably after diagnosing neurodegenerative diseases and / or after nerve trauma occurs / diagnosis on the first day.

[0164] The composition according to the present invention can be taken in one, two or three portions (typically 125 mL per portion) of 50-250 mL / day in the form of a liquid composition, preferably an oral nutritional supplement, after being diagnosed with a neurodegenerative disease and / or during recovery and / or rehabilitation after a neural trauma occurs. The preferred daily dose is in the range of 100 to 500 mL, more preferably 125 to 375 mL, most preferably 200 to 300 mL. Preferably, the composition is administered enterally. Administration is preferably at least once a day, although alternative dosage regimens can be determined from these numbers. Alternatively, the composition can be a tube feed and is administered continuously. The preferred daily dose of the tube feed is in the range of 1000 to 3000 kcal / day, preferably 1500 kcal to 2500 kcal / day. Preferably, about 1 to 2 liters of tube feed are administered every day.

[0165] The method or use according to the invention or the composition used according to the invention relates to a composition comprising a combination of i) ω-3 fatty acid DHA and ii) vitamin B2 and iii) vitamin D3, optionally further comprising one or more of the following: iv) choline and / or PC; and v) dietary fiber and / or dietary butyric acid. In an embodiment, the composition further comprises one or more selected from A, B, C and E vitamins, phospholipids, selenium, magnesium and coenzyme Q10. In another preferred aspect, the composition according to the invention comprises a combination of i) ω-3 fatty acid DHA, ii) vitamin B2, iii) vitamin D3, iv) choline and / or PC, and v) dietary fiber and / or dietary butyric acid, and one or more additional B vitamins.

[0166] Omega-3 fatty acids

[0167] The composition of the invention according to the invention comprises ω-3 polyunsaturated fatty acids (PUFA), wherein the PUFA is an n-3 LC-PUFA (long-chain PUFA). In an embodiment, the composition comprises at least docosahexaenoic acid (22:6, ω-3; DHA). Preferably, the composition comprises two ω-3 long-chain polyunsaturated fatty acids (LC-PUFA; chain lengths of 18 and more carbon atoms), wherein one ω-3 fatty acid is DHA and the second ω-3 fatty acid is selected from eicosapentaenoic acid (20:5, ω-3; EPA) and docosapentaenoic acid (22:5, ω-3; DPA), preferably the second ω-3 fatty acid is EPA. EPA is converted into DPA (ω-3), thereby increasing the subsequent conversion of DPA to DHA in the brain. In an alternative embodiment, the composition comprises only DHA as ω-3 fatty acid, and preferably does not comprise EPA.

[0168] In an embodiment, the composition comprises ω-3 fatty acid DHA, vitamin B2 and vitamin D3, optionally further comprising EPA as ω-3 fatty acid. In a further embodiment, the composition according to the present invention may comprise a combination of DHA, vitamin B2, vitamin D3 and EPA and optionally one or more of the following: choline and / or PC; and dietary fiber and / or dietary butyric acid. In a further embodiment, the composition according to the present invention may comprise a combination of one or more of ω-3 fatty acid DHA and EPA, vitamin B2, vitamin D3, choline, and dietary fiber and dietary butyric acid.

[0169] DHA, EPA and / or DPA can be provided in any form, such as but not limited to triglycerides, diglycerides, monoglycerides, free fatty acids, or salts or esters thereof, phospholipids, lysophospholipids, glycerol ethers, lipoproteins, ceramides, glycolipids, or combinations thereof. Preferably, the composition of the present invention comprises at least DHA in the form of triglycerides.

[0170] Suitable sources of ω-3 LCPUFA and / or DHA and EPA include tuna oil, (other) fish oils, alkyl esters rich in DHA, algae oil, egg yolk, krill oil or phospholipids rich in ω-3 LCPUFA such as phosphatidylserine-DHA. Preferably, the composition or the composition used according to the invention comprises a fish oil providing one or more ω-3 LCPUFA.

[0171] Preferably, DHA is administered in an amount of 100 to 1250 mg / day, more preferably 150 to 1200 mg / day, even more preferably 200 to 1100 mg / day, most preferably 250 to 1000 mg / day.

[0172] In an embodiment, when the composition is in the form of a tube feed, the daily administration amount of DHA is preferably 200 to 1100 mg / day, more preferably 250 to 1050 mg / day, most preferably 300 to 1000 mg / day.

[0173] In another embodiment, when the composition is in the form of an oral nutritional supplement, the daily administration amount of DHA is preferably 150 to 850 mg / day, more preferably 200 to 800 mg / day, most preferably 250 to 750 mg / day.

[0174] The composition of the present invention preferably comprises 30 to 240 mg DHA / 100 ml of composition, preferably 35 to 220 mg DHA / 100 ml, more preferably 40 to 200 mg DHA / 100 ml of composition.

[0175] On a caloric basis, preferably the nutritional composition according to the invention comprises 20 to 100 mg DHA / 100 kcal, preferably 25 to 90 mg DHA / 100 kcal, more preferably 30 to 80 mg DHA / 100 kcal, based on the total energy content of the nutritional composition. The above figures are based on the molar weight of DHA.

[0176] Preferably, EPA is administered in an amount of 40 to 350 mg, more preferably 50 to 300 mg, most preferably 60 to 250 mg EPA / day. In an embodiment, when the composition is in the form of a tube feed, the daily administration amount of EPA is preferably 30 to 300 mg, more preferably 50 to 280 mg / day, most preferably 80 to 250 mg / day.

[0177] In another embodiment, when the composition is in the form of an oral nutritional supplement, the daily administration amount of EPA is preferably 40 to 220 mg, more preferably 50 to 200 mg / day, and most preferably 60 to 180 mg / day.

[0178] The composition of the present invention preferably comprises 5 to 60 mg, more preferably 7 to 55 mg, most preferably 9 to 50 mg EPA / 100 ml composition. Based on calories, preferably, the nutritional composition according to the present invention comprises 5 to 30 mg, more preferably 6 to 25 mg, most preferably 8 to 20 mg EPA / 100 kcal based on the total energy content of the nutritional composition. The above figures are based on the molar weight of EPA.

[0179] If EPA is present in the composition, the composition preferably comprises more DHA than EPA, ie the weight ratio of DHA to EPA is preferably greater than 1, more preferably from 1.5:1 to 4:1, even more preferably from 2:1 to 4:1.

[0180] In terms of daily doses, the uses and methods of the present invention preferably comprise administration, which preferably comprises 200 to 2000 mg ω-3 fatty acids (preferably DHA+EPA+DPA, most preferably DHA+EPA) / day, more preferably 230 to 1750 mg / day, even more preferably 250 to 1600 mg EPA / day.

[0181] The composition of the present invention preferably comprises 0.3wt% to 3wt% ω-3 fatty acids (more preferably DHA+EPA+DPA, most preferably DHA+EPA) based on total fatty acids, more preferably 0.5wt% to 2.5wt%, even more preferably 0.75wt% to 2.0wt% ω-3 fatty acids based on total fatty acids.

[0182] The composition of the present invention preferably comprises 0.1wt% to 3.5wt% DHA based on total fatty acids, preferably 0.3wt% to 3wt% DHA based on total fatty acids, more preferably 0.5wt% to 2.5wt% DHA based on total fatty acids. The composition of the present invention preferably comprises 0.05wt% to 0.30wt% EPA based on total fatty acids, preferably 0.1wt% to 0.25wt% based on total fatty acids, even more preferably 0.15wt% to 0.20wt% EPA.

[0183] The above ratios and amounts take into account and optimize several aspects including taste (too high n-3 LC-PUFA levels reduce taste, leading to reduced compliance), balance between DHA and its precursors to ensure optimal effectiveness while maintaining a low volume formulation.

[0184] Vitamin B2 and other B vitamins

[0185] The composition of the invention according to the invention comprises vitamin B2. In an embodiment, the composition may comprise a combination of DHA, vitamin B2, vitamin D3 and EPA and optionally one or more of the following: choline and / or PC; and dietary fiber and / or dietary butyric acid. In a further embodiment, the composition of the invention may comprise a combination of one or more of the omega-3 fatty acids DHA and EPA, vitamin B2, vitamin D3, choline, and dietary fiber and dietary butyric acid.

[0186] In some embodiments, the composition may comprise additional B vitamins, preferably the composition comprises at least two B vitamins, wherein one B vitamin is B2 and the second B vitamin is selected from the group consisting of vitamin B1 (thiamine), B3 (niacin or niacinamide), vitamin B5 (pantothenic acid), B6 ​​(pyridoxine, pyridoxal, or pyridoxamine, or pyridoxine hydrochloride), vitamin B7 (biotin), vitamin B9 (folic acid or folate), and vitamin B12 (cobalamin). Functional equivalents are encompassed within these terms. The term "vitamin B12" encompasses all cobalamin equivalents known in the art.

[0187] B vitamins are known as nutritional cofactors that act as biochemical "spark plugs" in the mitochondria and thus function to further foster and support optimal neural metabolism. In an embodiment, the composition comprises DHA, vitamin D, and vitamin B2. In a further embodiment, the composition comprises DHA, vitamin D, vitamin B2, and optionally vitamin B6 and / or vitamin B9.

[0188] Preferably, in the context of the composition according to the invention, the B vitamins comprise at least three B vitamins, wherein the first B vitamin is B2, and the second B vitamin and the third B vitamin are selected from the group consisting of vitamin B1, B3, B5, B6, B7, vitamin B12 and vitamin B9. Preferably, the composition comprises vitamins B2, B6 and B9, more preferably vitamins B2, B6, B9 and B12, even more preferably vitamins B1, vitamin B2, vitamin B6, vitamin B9 and vitamin B12. In one embodiment, the composition according to the invention may include all of vitamin B1 (thiamine), B2 (riboflavin), B6 ​​(pyridoxine, pyridoxal, or pyridoxamine, or pyridoxine hydrochloride), vitamin B9 (folic acid or folate) and vitamin B12 (cyanocobalamin). In some embodiments, the composition may comprise additional B vitamins, as used herein, additional B vitamins are vitamins B1, B3, B5 and B7 that the composition may also comprise in addition to vitamin B2 and one or more of vitamins B6 and vitamin B9.

[0189] If present in the composition, vitamin B1 is preferably present in an amount providing a daily dose in the range of 0.7 to 5 mg, preferably in the range of 0.8 to 4.9 mg, more preferably in the range of 0.9 to 4.8 mg. When the composition is in the form of a tube feed, the daily application amount of vitamin B1 is preferably 1.2 to 5.5 mg / day, more preferably 1.5 to 5 mg / day, and most preferably 1.6 to 4.8 mg / day. When the composition is in the form of an oral nutritional supplement, the daily application amount of vitamin B1 is preferably 0.7 to 2.9 mg / day, more preferably 0.8 to 2.8 mg / day, and most preferably 0.9 to 2.7 mg / day. If present, the composition preferably comprises 0.1 to 0.9 mg vitamin B1 / 100 ml, more preferably 0.15 to 0.8 mg vitamin B1 / 100 ml, and more preferably 0.2 to 0.75 mg vitamin B1 / 100 ml. Based on calories, preferably, the nutritional composition according to the invention may comprise 0.05 to 0.4 mg vitamin B1 / 100 kcal, preferably 0.1 to 0.35 mg vitamin B1 / 100 kcal, more preferably 0.15 to 0.30 vitamin B1 / 100 kcal, based on the total energy content of the composition. The above figures are based on the molar weight of thiamine.

[0190] In the composition according to the present invention, vitamin B2 is preferably present in an amount providing a daily dose in the range of 0.8 to 7.6 mg, preferably in the range of 1 to 7.4 mg, more preferably in the range of 1.2 to 7.2 mg. When the composition is in the form of a tube feed, the daily application amount of vitamin B2 is preferably 2 to 7.6 mg / day, more preferably 2.2 to 7.4 mg / day, most preferably 2.4 to 7.2 mg / day. When the composition is in the form of an oral nutritional supplement, the daily application amount of vitamin B2 is preferably 0.8 to 4 mg / day, more preferably 1 to 3.8 mg / day, most preferably 1.2 to 3.6 mg / day. The composition preferably comprises 0.1-1.4 mg vitamin B2 / 100 ml, more preferably 0.2-1.2 mg vitamin B2 / 100 ml, more preferably 0.3-1 mg vitamin B2 / 100 ml. Based on calories, preferably, the nutritional composition according to the present invention may contain 0.4 to 0.6 mg vitamin B2 / 100 kcal, preferably 0.15 to 0.5 mg vitamin B2 / 100 kcal, more preferably 0.2 to 0.4 mg vitamin B2 / 100 kcal based on the total energy content of the composition. The above figures are based on the molar weight of riboflavin.

[0191] In another preferred embodiment, if the nutritional supplement or composition provides at least 1.2 times of the recommended daily intake (RDI), preferably at least 1.3 times and preferably no more than 20 times of the RDI, preferably no more than 10 times, then vitamin B2 is preferably present in a therapeutically effective amount. In a preferred aspect, 1.2 to 5 times, preferably 1.3 to 4.5 times, more preferably 1.4 to 4 times of the recommended daily intake are provided. RDI is a common reference in the art, for example, referred to herein as a population reference intake (PRI), as summarized by the dietary reference values ​​of the EU population obtained by the European Food Safety Authority (European Food Safety Authority) determined in September 2017. In the EU, the RDI of vitamin B2 based on ESFA is 1.6 mg / day.

[0192] If present in the composition, vitamin B3 is preferably present in an amount providing a daily dose of niacin equivalents in the range of 3 to 45 mg per day, preferably in the range of 3.5 to 42 mg, more preferably in the range of 3.8 to 40 mg. When the composition is in the form of a tube feed, the daily application of vitamin B3 is preferably 11 to 42 mg / day, more preferably 12 to 40 mg / day, most preferably 12.5 to 39 mg niacin equivalents / day. When the composition is in the form of an oral nutritional supplement, the daily application of vitamin B3 is preferably 3.4 to 20 mg / day, more preferably 3.6 to 19 mg / day, most preferably 3.8 to 18 mg niacin equivalents / day. If present, the composition preferably comprises 1.2 to 6 mg niacin equivalents / 100 ml, more preferably 1.4 to 5.5 mg niacin equivalents / 100 ml, more preferably 1.6 to 5 mg niacin equivalents / 100 ml. Based on calories, preferably, the nutritional composition according to the present invention may contain 1 to 2.5 mg niacin equivalent / 100 kcal, preferably 1.1 to 2.2 mg niacin equivalent / 100 kcal, more preferably 1.2 to 2 mg niacin equivalent / 100 kcal based on the total energy content of the composition. The above figures are based on the molar weight of niacin.

[0193] If present in the composition, vitamin B5 is preferably present in an amount providing a daily dose in the range of 0.8 to 15 mg, preferably in the range of 1 to 14 mg, more preferably in the range of 1.2 to 13 mg. When the composition is in the form of a tube feed, the daily application amount of vitamin B5 is preferably 3.5 to 14 mg / day, more preferably 4 to 13 mg / day, and most preferably 4.1 to 12.6 mg / day. When the composition is in the form of an oral nutritional supplement, the daily application amount of vitamin B5 is preferably 0.8 to 7.5 mg / day, more preferably 1 to 7 mg / day, and most preferably 1.2 to 6.8 mg / day. If present, the composition preferably comprises 0.3 to 2.2 mg vitamin B5 / 100 ml, more preferably 0.4 to 2 mg vitamin B5 / 100 ml, and more preferably 0.5 to 1.8 mg vitamin B5 / 100 ml. Based on calories, preferably, the nutritional composition according to the invention may comprise 0.2 to 1 mg vitamin B5 / 100 kcal, preferably 0.3 to 0.9 mg vitamin B5 / 100 kcal, more preferably 0.4 to 0.8 mg vitamin B5 / 100 kcal, based on the total energy content of the composition. The above figures are based on the molar weight of pantothenic acid.

[0194] The active form of vitamin B6, pyridoxal 5'-phosphate (PLP), acts as a coenzyme in multienzyme reactions of amino acid, glucose and lipid metabolism, and is known to be the rate-limiting factor in the synthesis of some neurotransmitters.

[0195] If present in the composition, vitamin B6 is preferably present in an amount providing a daily dose in the range of 0.7 to 9 mg, preferably in the range of 0.8 to 8 mg, more preferably in the range of 0.9 to 7.5 mg. When the composition is in the form of a tube feed, the daily application amount of vitamin B6 is preferably 1.5 to 9 mg / day, more preferably 2 to 8 mg / day, and most preferably 2.5 to 7.5 mg / day. When the composition is in the form of an oral nutritional supplement, the daily application amount of vitamin B6 is preferably 0.7 to 3.5 mg / day, more preferably 0.8 to 3 mg / day, and most preferably 0.9 to 2.7 mg / day. If present, the composition preferably comprises 0.2 to 1 mg vitamin B6 / 100 ml, more preferably 0.25-0.8 mg vitamin B6 / 100 ml, and more preferably 0.3 to 0.7 mg vitamin B6 / 100 ml. Based on calories, preferably, the composition according to the invention may contain 0.1 to 0.5 mg vitamin B6 / 100 kcal, preferably 0.2 to 0.4 mg vitamin B6 / 100 kcal, more preferably 0.25 to 0.3 mg vitamin B6 / 100 kcal, based on the total energy content of the composition. The above figures are based on the molar weight of pyridoxine.

[0196] If present in the composition, vitamin B7 is preferably present in an amount providing a daily dose in the range of 8 to 95 μg per day, preferably in the range of 9 to 90 μg, more preferably in the range of 9.5 to 85 μg. When the composition is in the form of a tube feed, the daily dosage of vitamin B7 is preferably 24 to 95 μg / day, more preferably 26 to 90 μg / day, and most preferably 28 to 88 μg / day. When the composition is in the form of an oral nutritional supplement, the daily dosage of vitamin B7 is preferably 9.4 to 45 μg / day, more preferably 9.6 to 42 μg / day, and most preferably 9.8 to 41 μg / day. If present, the composition preferably contains 2 to 14 μg vitamin B7 / 100 ml, more preferably 3 to 12 μg vitamin B7 / 100 ml, and more preferably 3.5 to 11 μg vitamin B7 / 100 ml. Based on calories, preferably, the composition according to the invention may contain 1.5 to 6 μg vitamin B7 / 100 kcal, preferably 2 to 5.5 μg vitamin B7 / 100 kcal, more preferably 2.5 to 5 μg vitamin B7 / 100 kcal, based on the total energy content of the composition. The above figures are based on the molar weight of biotin.

[0197] Vitamin B9 or folic acid is an essential nutrient that is converted to folate by the body and is required for DNA and RNA biosynthesis, DNA repair and one-carbon metabolic reactions. Decreased folate levels are frequently reported in patients with neurodegenerative diseases (Kronenberg, G, Curr Mol Med [Contemporary Molecular Medicine], 2009).

[0198] If present in the composition, vitamin B9 is preferably present in an amount providing a daily dose in the range of 150 to 900 μg per day, preferably in the range of 175 to 800 μg, more preferably in the range of 200 to 750 μg. When the composition is in the form of a tube feed, the daily administration of vitamin B9 is preferably 200 to 800 μg / day, more preferably 225 to 775 μg / day, and most preferably 240 to 750 μg / day. When the composition is in the form of an oral nutritional supplement, the daily administration of vitamin B9 is preferably 150 to 700 μg / day, more preferably 175 to 650 μg / day, and most preferably 200 to 600 μg / day. If present, the composition preferably contains 20 to 225 μg vitamin B9 / 100 ml, more preferably 25 to 200 μg vitamin B9 / 100 ml, and more preferably 30 to 175 μg vitamin B9 / 100 ml. Based on calories, preferably, the composition according to the invention may contain 16 to 80 μg vitamin B9 / 100 kcal, preferably 18 to 75 μg vitamin B9 / 100 kcal, more preferably 20 to 70 μg vitamin B9 / 100 kcal, based on the total energy content of the composition. The above figures are based on the molar weight of folic acid.

[0199] If present in the composition, vitamin B12 is preferably present in an amount providing a daily dose in the range of 2 to 20 μg per day, preferably in the range of 2.5 to 19 μg, more preferably in the range of 3 to 18 μg. When the composition is in the form of a tube feed, the daily administration of vitamin B9 is preferably 4 to 22 μg / day, more preferably 5 to 20 μg / day, and most preferably 6 to 18 μg / day. When the composition is in the form of an oral nutritional supplement, the daily administration of vitamin B9 is preferably 2 to 12 μg / day, more preferably 2.5 to 10 μg / day, and most preferably 3 to 9 μg / day. If present, the composition preferably contains 0.5 to 3 μg vitamin B12 / 100 ml, more preferably 0.6 to 2.6 μg vitamin B12 / 100 ml, and more preferably 0.7 to 2.4 μg vitamin B12 / 100 ml. Based on calories, preferably, the composition according to the invention may contain 0.4 to 1.4 μg vitamin B12 / 100 kcal, preferably 0.5 to 1.2 μg vitamin B12 / 100 kcal, more preferably 0.6 to 1 μg vitamin B12 / 100 kcal, based on the total energy content of the composition. The above figures are based on the molar weight of cyanocobalamin.

[0200] Vitamin D3

[0201] The composition of the present invention comprises vitamin D3. In an embodiment, the composition may comprise a combination of DHA, vitamin B2, vitamin D3 and EPA and optionally one or more of the following: choline and / or PC; and dietary fiber and / or dietary butyric acid. In a further embodiment, the composition according to the present invention may comprise a combination of one or more of the omega-3 fatty acids DHA and EPA, vitamin B2, vitamin D3, choline, and dietary fiber and dietary butyric acid.

[0202] Vitamin D is a group of fat-soluble secosteroids, the two main physiologically relevant forms of which are vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol). These are collectively referred to as calciferols. Vitamin D without a subscript refers to all forms of vitamin D, D1, D2, D3 or D4, in particular D2 and D3, or any mixture thereof. Vitamin D can be provided in active (1,25(OH)2D) or inactive (vitamin D3 or D2) form. The composition according to the invention comprises vitamin D3.

[0203] When ingested, vitamin D is hydroxylated in the liver (endoplasmic reticulum) by the enzyme 25-hydroxylase produced by hepatocytes to 25-hydroxycholecalciferol (25(OH)D), also known as calcifediol. Once made, the product is stored in the hepatocytes until it is needed and can be released into the plasma where it will be bound to alpha-globulin. 25-hydroxycholecalciferol is then transported to the proximal tubules of the kidneys where it can be hydroxylated by one of two enzymes to different forms of vitamin D, one of which is active vitamin D (1,25(OH)2D) and the other is inactive vitamin D (24,25(OH)D). The enzyme 1α-hydroxylase, activated by parathyroid hormone (and additionally by low calcium or phosphate), forms the major biologically active vitamin D hormone, where C1 is hydroxylated to form 1,25-dihydroxycholecalciferol (1,25(OH)2D, also known as calcitriol). When 1α-hydroxylase is inactive, a separate enzyme hydroxylates the C24 atom to form 24R,25(OH)2D3, which inactivates the molecule and renders it devoid of any biological activity.

[0204] The composition of the present invention preferably comprises 1.5 to 10 μg vitamin D3, preferably 2 to 9 μg vitamin D3 / 100 ml, more preferably 2.5 to 8 μg vitamin D3 / 100 ml of the composition.

[0205] According to one embodiment, vitamin D3 is supplemented in an amount of 5 to 80 μg / day, preferably 6 to 75 μg / day, more preferably 8 to 70 μg / day, even more preferably 10 to 65 μg / day.

[0206] In an embodiment, the composition is in the form of a gavage and vitamin D3 is preferably provided in an amount of 14 to 80 μg / day, more preferably 16 to 75 μg / day, even more preferably 18 to 70 μg / day, most preferably 20 to 65 μg / day.

[0207] In another embodiment, when the composition is in the form of an oral nutritional supplement, vitamin D3 is preferably provided in an amount of 5 to 45 μg / day, more preferably 6 to 40 μg / day, even more preferably 8 to 35 μg / day, most preferably 10 to 30 μg / day.

[0208] Based on calories, preferably, the nutritional composition according to the invention comprises 1.3 to 4.5 μg vitamin D3 / 100 kcal, preferably 1.5 to 4 μg vitamin D3 / 100 kcal, more preferably 2 to 3.5 μg / 100 kcal, based on the total energy content of the nutritional composition. The above figures are based on the molar weight of vitamin D3.

[0209] In another preferred embodiment, if the nutritional supplement or composition provides at least 1.2 times the recommended daily intake (RDI), preferably at least 1.3 times and preferably no more than 7 times the RDI, vitamin D3 is preferably present in a therapeutically effective amount. In a preferred aspect, 1.2 to 5 times, preferably 1.3 to 4.5 times, more preferably 1.4 to 4 times the recommended daily intake is provided. RDI is a common reference in the art, for example, referred to herein as a population reference intake (PRI), such as a summary of dietary reference values ​​for EU populations obtained by the European Safety Authority as determined in September 2017. In an embodiment, the RDI of vitamin D3 is 15 μg / day.

[0210] choline

[0211] The composition of the present invention preferably further comprises choline. Choline can exist as is, or in the form of a choline salt and / or a choline ester. The choline salt is preferably selected from choline chloride, choline bitartrate, choline butyrate or choline stearate. The choline ester is preferably selected from phosphatidylcholine and lysophosphatidylcholine, preferably phosphatidylcholine. In a preferred embodiment, the composition of the present invention comprises the following two: a) choline as is or a choline salt, and b) a choline ester, preferably phosphatidylcholine.

[0212] The compositions and methods of use of the present invention preferably comprise administration of more than 70 mg of a) choline or a choline salt per day, preferably 70 to 1300 mg / day, more preferably 80 to 1200 mg / day, most preferably 100 to 1100 mg / day.

[0213] In embodiments, when the composition is in the form of a gavage, the daily administration amount of choline or a choline salt is preferably 200 to 1400 mg / day, more preferably 300 to 1200 mg / day, most preferably 350 to 1100 mg / day.

[0214] In another embodiment, when the composition is in the form of an oral nutritional supplement, the daily administration amount of choline or choline salt is preferably 70 to 500 mg / day, more preferably 80 to 400 mg / day, most preferably 100 to 300 mg / day.

[0215] The composition of the invention preferably comprises 30 to 180 mg a) choline or a choline salt per 100 ml liquid composition, preferably 35 to 170 mg choline per 100 ml, more preferably 40 to 160 mg choline per 100 ml composition, most preferably 45 to 150 mg choline per 100 ml.

[0216] On a caloric basis, preferably the nutritional composition according to the invention comprises 25 to 110 mg choline / 100 kcal, preferably 30 to 105 mg choline / 100 kcal, more preferably 33 to 100 mg / 100 kcal, based on the total energy content of the nutritional composition.

[0217] The above figures are based on choline, and the amount of choline salt or ester can be calculated taking into account the molar equivalent of choline.

[0218] Choline is necessary for the synthesis of acetylcholine, which is critical for communication between neurons in the brain and plays a role in cognitive processes such as attention, concentration, and memory formation. Choline is a component of phospholipids, which are the building blocks of cell membranes, and adequate choline intake ensures the integrity and fluidity of neuronal membranes, which is necessary for the proper functioning of neurons. Choline deficiency can lead to impaired membrane function and affect neuronal signaling.

[0219] Furthermore, choline is involved in the process of neurotransmitter release in neurons. It helps regulate the release of neurotransmitters, including acetylcholine, by maintaining the balance of acetylcholine within synaptic vesicles. Proper neurotransmitter release is essential for neuronal communication and overall brain function. In addition, choline is involved in neurogenesis, which is the process of creating new neurons in the brain. It supports the growth and development of neuronal cells. Finally, choline has been linked to memory enhancement and cognitive function. It has been suggested that choline supplementation can improve memory and attention in certain groups, especially the elderly (Liu, L, Behaviourial Neurology, 2021).

[0220] Compositions of the present invention may include choline in the form of choline esters, preferably provided in the form of phospholipids. Preferably, one or more phospholipids are present in compositions according to the present invention. The one or more phospholipids are selected from the group consisting of: phosphatidic acid (PA), phosphatidylethanolamine (PE), phosphatidylcholine (PC), phosphatidylserine (PS) and phosphoinositide (PI), preferably at least phosphatidylcholine. In a preferred embodiment, phospholipids are the source of choline ester phosphatidylcholine.

[0221] Suitable sources of phospholipids herein are soy lecithin, egg lecithin, and rapeseed and sunflower lecithin. Milk contains phospholipids in the milk fat globule membrane (MFGM), and suitable sources include milk phospholipid concentrates such as those commercially available from Lecico Ltd, whey protein concentrate from Arla Foods MFGM. Depending on the source, the phospholipids contain about 10 wt% to 40 wt% phosphatidylcholine.

[0222] If present, the composition and the use or method of using the composition preferably comprises administering a phospholipid in an amount of 0.6 to 6.6 g mg / day, preferably 0.8 to 6.4 g phospholipid / day, more preferably 0.9 to 6.2 g phospholipid / day, most preferably 1 to 6 g phospholipid / day. In one aspect, the amount of the phospholipid is about 200 mg / day. The phospholipid preferably provides at least phosphatidylcholine.

[0223] If present, the composition of the invention preferably comprises phospholipids in an amount between 150 and 900 mg / 100 ml, more preferably between 200 and 850 mg / 100 ml, most preferably between 250 and 800 mg / 100 ml. The phospholipids preferably provide at least phosphatidylcholine.

[0224] In embodiments, when the composition is in the form of a gavage, the daily administration amount of the phospholipid is preferably 1 to 7 g / day, more preferably 1.5 to 6.5 g / day, most preferably 2 to 6 g / day.

[0225] In another embodiment, when the composition is in the form of an oral nutritional supplement, the daily administration amount of the phospholipid is preferably 0.5 to 4 g / day, more preferably 0.75 to 3.5 g / day, most preferably 1 to 3 g / day.

[0226] On a caloric basis, preferably the nutritional composition according to the invention comprises 100 to 500 mg phospholipids / 100 kcal, preferably 150 to 400 mg phospholipids / 100 kcal, more preferably 200 to 350 mg phospholipids / 100 kcal, based on the total energy content of the nutritional composition.

[0227] In a specific embodiment, the nutritional composition according to the present invention comprises a) choline or a choline salt and b) phosphatidylcholine (PC). In such an embodiment, the weight ratio of phosphatidylcholine to choline is generally greater than 0.1, preferably greater than 0.26, particularly 0.30-6, more preferably 0.36-3. Most preferably, the weight ratio of phosphatidylcholine to choline is in the range of 40:60 to 60:40. In this article, the amount of choline expressed in grams will be calculated as the molar contribution of choline provided by all choline sources (including PC when orally digested and assuming 100% bioavailability) multiplied by the molecular weight of choline (104g / mol). In this article, the molecular weight of PC is 810g / mol. Thus, for example, including 400 mg of choline chloride (molecular weight 139.6 g / mol) and 200 mg of phosphatidylcholine and 200 mg of phospholipids other than PC would result in a weight ratio of PC to choline of 200 / [(104 / 139.6)x400+(104 / 810)x200]=200 / [298+25.7]=0.62.

[0228] The presence of PC is particularly preferred because the content of choline (salt) can be reduced while still providing a bioavailable source of choline. In addition, dietary choline can be metabolized to trimethylamine (TMA) in the intestine, which in turn is oxidized to trimethylamine N-oxide (TMAO) in the liver. Both TMA and TMAO are associated with an increased risk of cardiovascular disease (Zhu et al., Cell 2016; Jaworska et al. Cardiovac. Res 2019), so it is preferred to provide choline in free (salt) form and as phosphatidylcholine.

[0229] Preferably, the composition according to the invention comprises DHA, vitamin B2, vitamin D3 and choline, optionally in combination with one or more of dietary fiber and / or dietary butyric acid. In a further preferred embodiment, the composition comprises a combination of one or more of ω-3 fatty acids DHA and EPA, vitamin B2, vitamin D3, choline, and dietary fiber and / or dietary butyric acid, wherein choline is provided in the form of phosphatidylcholine for at least 20 mol%, preferably at least 30 mol%, more preferably at least 40 mol%, preferably in the molar ratio of choline (salt) to PC in the range of 40:60 to 60:40, i.e. wherein 40 mol% to 60 mol% of choline is derived from phosphatidylcholine based on the total choline in the composition. Preferably, the composition comprises a combination of one or more of ω-3 fatty acids DHA and EPA, vitamin B2, vitamin D3, choline, and dietary fiber and dietary butyric acid, wherein choline is provided in the form of phosphatidylcholine at least 40 mol%, preferably in a molar ratio of choline to PC in the range of 40:60 to 60:40, and further comprises one or more selected from A, additional B, C and E vitamins, phospholipids, selenium and magnesium. More preferably, the composition contains two or more of these additional ingredients. Additional ingredients and their corresponding amounts will be discussed later.

[0230] Dietary fiber and dietary butyrate

[0231] The composition according to the invention preferably comprises dietary fibres. In the context of the present invention, dietary fibres for use in the composition are defined as butyrate-producing dietary fibres or dietary fibre blends, preferably, they produce butyrate and propionate in a beneficial ratio.

[0232] In a preferred embodiment, the composition comprises a combination of DHA, vitamin B2, vitamin D3 and EPA, dietary fiber, and optionally one or more of choline and / or PC. In a further embodiment, the composition according to the present invention may comprise a combination of ω-3 fatty acids DHA and EPA, vitamin B2, vitamin D3, choline, and one or more dietary fibers (such as fibers selected from scGOS, lcFOS, and low-viscosity pectin), and may further comprise dietary butyric acid.

[0233] Dietary fibers that can serve as substrates for the production of fatty acids preferably produce acetate, butyrate, propionate, and caproate, more preferably propionate and butyrate in a beneficial ratio, which allows for increased butyrate production in a subject.

[0234] As used herein, the expression "beneficial butyrate to propionate ratio" means that the weight of butyrate produced by fermentation of a fiber or fiber mixture is at least equal to or greater than the amount of propionate produced by fermentation. For example, locust bean gum or yeast beta-glucan produce more propionate than butyrate when fermented, and these fibers have a butyrate to propionate ratio of less than 1 and do not enhance or increase butyrate production. In contrast, soy fiber and inulin are exemplary fibers that have a beneficial butyrate to propionate ratio when fermented.

[0235] In a preferred embodiment, the fermentation of dietary fiber beneficially results in the production of fatty acids, wherein butyrate and propionate are produced in a weight ratio of butyrate:propionate of at least 1, preferably at least 1.1. The fermentation characteristics of dietary fiber, and the accompanying butyrate to propionate ratio from a single source fiber or a fiber blend, can be evaluated using fermentation assays known in the art. An exemplary manner of evaluating fiber fermentation includes using the fiber in a fermentation model, using a pool of fecal samples from healthy adults, exposed to about 10 mg / ml of fiber for 24 hours at 37°C under anaerobic conditions.

[0236] In certain embodiments, it is preferred to use a fiber blend as dietary fiber. Exemplary fiber blends for use in the context of the present invention are blends that are fermentable and provide a beneficial C4:C3 weight ratio of at least 1, preferably at least 1.1, and even more preferably at least 1.5. An exemplary fiber blend is a fiber mixture comprising a) β-galacto-oligosaccharides, b) inulin, c) resistant starch, and / or d) soluble soy polysaccharides. The blend is fermentable and provides fatty acids, particularly at a beneficial C4:C3 weight ratio of at least 1, preferably at least 1.1, and even more preferably at least 1.5.

[0237] Additional exemplary fiber blends include a) FOS, b) inulin, c) soy fiber, d) resistant starch, e) gum arabic, and / or f) cellulose. The blends are fermentable and provide fatty acids, particularly in a beneficial C4:C3 weight ratio of at least 1, preferably at least 1.1, even more preferably at least 1.5.

[0238] Additional exemplary fiber blends include a) arabinoxylan, b) oat beta-glucan, c) pectin and / or d) resistant starch. The fiber mixture is fermentable and produces butyrate and propionate at a C4:C3 weight ratio of at least 1, preferably at least 1.1, and even more preferably at least 1.5.

[0239] A preferred fiber blend for use in the composition comprises a) scGOS, b) lcFOS and c) low viscosity pectin. The fiber blend is fermentable and produces butyric acid in particular at a beneficial C4:C3 weight ratio of at least 1, preferably at least 1.1, even more preferably at least 1.5.

[0240] ScGOS refers to short-chain GOS with a low degree of polymerization, which is typically composed of 2 to 6 galactose units. Examples of scGOS include, but are not limited to, galactobiose, lactulose, and isomaltooligosaccharides. In a preferred embodiment, scGOS comprises galacto-oligosaccharides having β-(1,4), β-(1,3) and / or β-(1,6) glycosidic bonds and terminal glucose. Trans-galacto-oligosaccharides are available, for example, under the trade name (FrieslandCampina Ingredients), Bi2muno (Clasado), Cup-oligo (Nissin Sugar) and Oligomate 55 (Yakult).

[0241] LcFOS refers to long chain FOS with a relatively high degree of polymerization, preferably consisting of a degree of polymerization higher than 8, more preferably from 10 to 100, most preferably from 20 to 50. Examples of lcFOS include, but are not limited to, inulin and oligofructose. LcFOS may refer to an oligosaccharide comprising β-linked fructose units, which are preferably linked by β-(2,1) and / or β-(2,6) glycosidic bonds. Preferably, lcFOS contains terminal β-(2,1) glycosidically linked glucose. In a further preferred embodiment, inulin is used. Inulin is a type of lcFOS in which at least 75% of the glycosidic bonds are β-(2,1) bonds. Typically, the average chain length of inulin is from 8 to 60 monosaccharide units. Suitable lcFOS for use in the composition according to the method or use of the present invention may be obtained under the trade name Other suitable sources are Raftilose (Orafti), Fibruloseh and Fibruline (Cosucra) and Frutafit and Frutalose (Sensus).

[0242] In one embodiment, the dietary fiber is a mixture of scGOS and lcFOS. Preferably, the mixture of scGOS and lcFOS is present in a weight ratio of 1 / 99 to 99 / 1, more preferably 1 / 19 to 19 / 1, more preferably 1 / 1 to 19 / 1, more preferably 2 / 1 to 15 / 1, more preferably 5 / 1 to 12 / 1, even more preferably 8 / 1 to 10 / 1, even more preferably in a ratio of about 9 / 1.

[0243] In a preferred embodiment, another dietary fiber is low viscosity pectin. Low viscosity pectin is a modified form of pectin, a naturally occurring polysaccharide found in the cell walls of fruits and vegetables. Low viscosity pectin is specially processed to have a lower molecular weight and reduced ability to form gels compared to conventional pectin. Modification of pectin to produce low viscosity pectin involves various methods, such as acid hydrolysis or enzyme treatment. These methods break down the long chains of pectin molecules into shorter chains, resulting in lower viscosity and improved dispersibility in liquid formulations.

[0244] In a further preferred embodiment, the composition comprises a mixture of dietary fibers comprising scGOS, lcFOS and low viscosity pectin, wherein the scGOS:lcFOS:low viscosity pectin is in the range of 5:1:1 to 12:1:3, more preferably in the range of 7:1:1.5 to 11:1:2.5, most preferably in the range of 8:1:1.5 to 10:1:2.5.

[0245] Preferably the daily dose comprises 2.5 to 12.5 g, more preferably 3 to 12 g, most preferably 3.5 to 11.5 g of dietary fiber.

[0246] In another preferred embodiment, the composition comprises 0.5 to 4.0 g, more preferably 1.0 to 3.5 g, most preferably 1.5 to 3.0 g dietary fiber per 100 ml of the composition.

[0247] In another preferred embodiment, the composition comprises 0.75 to 2.5 g, more preferably 1.0 to 2.0 g, most preferably 1.1 to 1.5 g dietary fiber per 100 kcal.

[0248] The inventive composition according to the invention preferably comprises dietary butyric acid. In the context of the present invention, dietary butyric acid for use in the composition is defined as butyric acid, butyrates, butyric esters, such as glyceride-bound forms of butyric acid preferably comprising one, two or three butyric acid chains.

[0249] Dietary butyric acid can be provided by any suitable source known in the art. Non-limiting sources of dietary butyric acid include animal-derived fats and derived products, such as but not limited to milk, milk fat, butter fat, butter oil, butter, buttermilk, cream whey, cream; microbial fermentation derived products, such as but not limited to yogurt and fermented buttermilk; and plant-derived seed oil products, such as pineapple and / or pineapple oil, almonds and / or almond oil, barley, oats, brown rice, bran, green beans, legumes, green leafy vegetables, apples, kiwis, oranges. In some embodiments, dietary butyric acid is synthetically produced.

[0250] In some embodiments, the composition comprises dietary butyric acid in the form of a butyrate salt, such as sodium butyrate, potassium butyrate, calcium butyrate, magnesium butyrate, choline butyrate, and combinations thereof. In certain embodiments, the dietary butyric acid comprises suitable butyric acid coated with one or more fats or lipids. Preferably, the dietary butyric acid is provided as a butyrate ester, such as in a preferred embodiment as part of a (tri)glyceride. This is advantageous because butyric acid is volatile (and malodorous) when provided in free or salt form. In the (tri)glyceride form, butyric acid will be released in and after the stomach due to the action of lipase.

[0251] In a preferred embodiment, the dietary butyric acid for use in the composition comprises a glyceride containing a butyric acid chain, preferably a triglyceride containing a butyric acid chain. In the context of the present invention, the glyceride containing a butyric acid chain comprises at least one butyric acid chain, preferably at least two or three butyric acid chains. Preferably, the dietary butyric acid comprises tributyrin (i.e., a triglyceride in which 3 butyric acid chains are attached to a glycerol backbone via ester bonds). If butyric acid is added as a triglyceride or a diglyceride, 0, 1 or 2 other side chains may be other fatty acid chains besides butyric acid, or in other words, the diglyceride or triglyceride may be a mixed glyceride in which at least one fatty acid chain is butyric acid.

[0252] Preferably, the daily dose comprises 0.125 g to 0.65 g dietary butyric acid, more preferably 0.025 g to 0.65 g, most preferably 0.043 g to 0.65 g dietary butyric acid, based on the weight of butyric acid.

[0253] In another preferred embodiment, the composition comprises 0.01 to 0.175 g dietary butyric acid / 100 ml, more preferably 0.02 to 0.175 g dietary butyric acid / 100 ml, and most preferably 0.035 to 0.175 g dietary butyric acid / 100 ml, based on the weight of butyric acid.

[0254] In another preferred embodiment, the composition comprises 0.015 to 0.25 g dietary butyric acid / 100 kcal, more preferably 0.03 to 0.25 g dietary butyric acid / 100 kcal, and most preferably 0.05 to 0.25 g dietary butyric acid / 100 kcal, based on the weight of butyric acid.

[0255] In a further preferred embodiment, the composition according to the invention comprises a mixture of dietary fiber and dietary butyric acid. Preferably, the mixture of dietary fiber and dietary butyric acid contains at least 50 wt% dietary fiber, more preferably, the weight ratio of dietary fiber to dietary butyric acid in the mixture is in the range of 80:20 to 50:50, more preferably 75:25 to 60:40.

[0256] The energy demand of neurons is high, and butyrate can be derived from dietary fiber, and dietary butyrate can serve as an alternative energy source for neurons. It can be metabolized by neurons to produce ATP (adenosine triphosphate), which is the main energy flow of cells. In addition, butyrate can show neuroprotective effects by reducing oxidative stress and inflammation in neurons. It can help protect neurons from damage caused by harmful molecules and promote their survival. Importantly, butyrate has been found to increase the production of brain-derived neurotrophic factor (BDNF) in neurons. BDNF is a protein that plays a key role in the growth, survival and synaptic plasticity of neurons, which is important for learning and memory. Finally, butyrate has anti-inflammatory properties that can help regulate inflammatory responses in neurons. Excessive inflammation in the brain may be harmful to neuronal health, and the anti-inflammatory effects of butyrate can contribute to neuroprotection.

[0257] Vitamin A

[0258] The composition of the present invention may further comprise vitamin A. Vitamin A is a fat-soluble vitamin that appears in several forms (e.g., retinol, retinal, retinoic acid, or retinyl esters). Any functional form of vitamin A known in the art is suitable for use herein, including retinol (particularly retinol esters), retinal, retinoic acid, beta-carotene, provitamin A, or any combination thereof. Preferably, the composition comprises retinol, particularly retinyl acetate and / or retinyl palmitate.

[0259] Vitamin A intake or requirements are usually expressed in the form of retinol equivalents (RE). One RE is defined as the biological activity associated with 1 μg of all-trans retinol. Thus, 1 μg of retinol equivalent is similar to 1 μg of all-trans retinol. One international unit (IU) of retinol is equivalent to 0.3 μg of retinol equivalent.

[0260] If present in the composition, vitamin A is preferably administered in an amount of 300 to 2800 μg retinol equivalents / day, more preferably 350 to 2700 μg retinol equivalents / day, even more preferably 650 to 900 μg retinol equivalents / day, most preferably 375 to 2600 μg retinol equivalents / day.

[0261] In an embodiment, the composition is in the form of a tube feed, and the daily administration amount of vitamin A is preferably 700 to 2850 μg retinol equivalent / day, more preferably 800 to 2750 μg retinol equivalent / day, most preferably 850 to 2600 μg retinol equivalent / day.

[0262] In another embodiment, the composition is in the form of an oral nutritional supplement, and the daily administration amount of vitamin A is preferably 300 to 1200 μg retinol equivalents / day, more preferably 350 to 1150 μg retinol equivalents / day, most preferably 375 to 1125 μg retinol equivalents / day.

[0263] The composition of the present invention may preferably contain vitamin A, preferably 50 to 400 μg retinol equivalent / 100 ml composition, more preferably 75 to 350 μg retinol equivalent / 100 ml, most preferably 100 to 300 μg retinol equivalent / 100 ml composition.

[0264] Based on calories, preferably, the nutritional composition according to the present invention may contain 60 to 150 μg retinol equivalent / 100 kcal, preferably 70 to 140 μg retinol equivalent / 100 kcal, more preferably 80 to 130 μg retinol equivalent / 100 kcal, based on the total energy content of the nutritional composition.

[0265] Vitamin C

[0266] Compositions of the present invention may further include vitamin C. Vitamin C is an antioxidant that can provide beneficial features in neurodegenerative diseases and after nerve trauma. Vitamin C includes its functional equivalents (including sodium ascorbate and calcium ascorbate), and can be present in an amount providing a daily dose in the range of 75 to 700 mg, preferably in the range of 85 to 600 mg, more preferably in the range of 95 to 550 mg. When said composition is a tube feeding form, the daily application amount of vitamin C is preferably 140 to 600 mg / days, more preferably 160 to 575 mg / days, most preferably 180 to 550 mg / days. When said composition is an oral nutritional supplement form, the daily application amount of vitamin C is preferably 80 to 320 mg / days, more preferably 90 to 300 mg / days, most preferably 95 to 290 mg / days. In one embodiment, if present, vitamin C is present in an amount in the range of 10 to 100 mg per 100 ml of composition, preferably in the range of 15 to 90 mg, more preferably in the range of 20 to 80 mg. Based on calories, preferably, the composition according to the invention may contain 12 to 40 mg vitamin C / 100 kcal, preferably 14 to 35 mg vitamin C / 100 kcal, more preferably 16 to 32 mg vitamin C / 100 kcal, based on the total energy content of the composition. The above figures are based on the molar weight of ascorbic acid.

[0267] Vitamin E

[0268] The composition according to the invention may comprise vitamin E. Vitamin E refers to a compound having vitamin E activity as known in the art, typically tocopherol and / or its equivalent.

[0269] If included, vitamin E can be present in the composition in an amount that provides a daily dose of α-TE in the range of 8 to 75 mg, preferably in the range of 10 to 70 mg, and more preferably in the range of 12.5 to 70 mg. When the composition is in the form of a tube feed, the daily application of vitamin E is preferably 18 to 80 mg / day, more preferably 20 to 75 mg / day, and most preferably 22 to 70 mg α-TE / day. When the composition is in the form of an oral nutritional supplement, the daily application of vitamin E is preferably 8 to 42 mg / day, more preferably 10 to 40 mg / day, and most preferably 12.5 to 37.5 mg α-TE / day. Such an amount of vitamin E prevents oxidative damage to the site of injury. In one embodiment, tocopherol and / or an equivalent are present in an amount in the range of 2 to 14 mg α-TE per 100 ml composition, preferably in the range of 2.5 to 12 mg α-TE, and more preferably in the range of 2.75 to 10 mg α-TE. Based on calories, preferably, the composition according to the present invention may contain 1 to 5.5 mg α-TE / 100 kcal, preferably 1.5 to 5 mg α-TE / 100 kcal, more preferably 2 to 4.5 mg α-TE / 100 kcal, based on the total energy content of the composition.

[0270] As used in this specification, the term "tocopherol and / or its equivalent" includes tocopherols (e.g., α-tocopherol and γ-tocopherol), tocotrienols, pharmaceutically and / or nutritionally acceptable derivatives thereof, and any combination thereof. The above figures are based on α-tocopherol equivalents (α-TE) and their molecular weights, as recognized in the art.

[0271] Vitamin K1

[0272] The composition according to the invention may optionally contain vitamin K, preferably vitamin K1, although it is preferred that the composition contains no vitamin K or contains a minimal amount of vitamin K. Vitamin K is the common name for a group of compounds containing a 2-methyl-1,4-naphthoquinone nucleus and having side chains of different lipophilicity at position 3, hereinafter also referred to as "K vitamins". Vitamin K exists naturally in the form of vitamin K1 (phytomenaquinone, phytonaphthoquinone, α-phylloquinone) and vitamin K2 (toluoquinone), which is produced by gastrointestinal bacteria in essentially two different isoforms, namely vitamin K2 (35) (C46H64O2) and vitamin K2 (30) (C41H56O2). Vitamin K3 (menaquinone) is a provitamin that can be converted into vitamin K2 by animals.

[0273] If present in the composition, vitamin K1 is preferably present in a daily dose of at most 240 μg, preferably at most 200 μg, more preferably at most 100 μg / day. The composition of the present invention preferably contains less than 40 μg vitamin K1 / 100 ml, more preferably less than 35 μg vitamin K1 / 100 ml, more preferably less than 30 μg vitamin K1 / 100 ml. Based on calories, preferably, the composition according to the present invention may contain less than 18 μg vitamin K1 / 100 kcal, preferably less than 16 μg vitamin K1 / 100 kcal, more preferably less than 15 μg vitamin K1 / 100 kcal based on the total energy content of the composition. The above figures are based on the molar weight of phylloquinone.

[0274] In a preferred embodiment, the composition comprises less than 15 μg vitamin K1 / 100 kcal.

[0275] selenium

[0276] The composition of the present invention may include selenium. The antioxidant activity of selenium may advantageously prevent and / or inhibit damage to brain regions.

[0277] If present in the composition, selenium is preferably present in an amount providing a daily dose in the range of 30 to 275 μg per day, preferably in the range of 35 to 250 μg, more preferably in the range of 38 to 225 μg. When the composition is in the form of a tube feed, the daily application amount of selenium is preferably 60 to 275 μg / day, more preferably 70 to 250 μg / day, most preferably 75 to 225 μg / day. When the composition is in the form of an oral nutritional supplement, the daily application amount of selenium is preferably 25 to 140 μg / day, more preferably 30 to 130 μg / day, most preferably 35 to 120 μg / day. The composition of the present invention preferably comprises 8 to 45 μg selenium / 100 ml, more preferably 10 to 40 μg selenium / 100 ml, more preferably 11 to 35 μg selenium / 100 ml. On a caloric basis, preferably, the composition according to the invention may comprise 4 to 18 μg selenium / 100 kcal, preferably 6 to 16 μg selenium / 100 kcal, more preferably 8 to 14 μg selenium / 100 kcal, based on the total energy content of the composition.

[0278] magnesium

[0279] The composition of the present invention may contain magnesium. Magnesium plays a vital role in neurotransmission and neuromuscular conduction. It also plays a protective role against excessive excitation that may lead to neuronal cell death (excitotoxicity).

[0280] If present in the composition, magnesium is preferably present in an amount providing a daily dosage in the range of 125 to 850 mg, preferably in the range of 150 to 800 mg, more preferably in the range of 170 to 750 mg. When the composition is in the form of a tube feed, the daily dosage of magnesium is preferably 200 to 780 mg / day, more preferably 220 to 760 mg / day, most preferably 240 to 740 mg / day. When the composition is in the form of an oral nutritional supplement, the daily dosage of magnesium is preferably 150 to 600 mg / day, more preferably 160 to 550 mg / day, most preferably 170 to 525 mg / day. The composition of the present invention preferably comprises 20 to 160 mg magnesium / 100 ml, more preferably 25 to 150 mg magnesium / 100 ml, more preferably 30 to 140 mg magnesium / 100 ml. On a caloric basis, preferably, the composition according to the invention may comprise 10 to 70 mg magnesium / 100 kcal, preferably 15 to 65 mg magnesium / 100 kcal, more preferably 20 to 60 mg magnesium / 100 kcal, based on the total energy content of the composition.

[0281] The composition may contain additional minerals including, but not limited to, sodium, potassium, chloride, calcium, phosphorus, iron, zinc, copper, manganese, fluorite, molybdenum, chromium and iodine in amounts consistent with the general recommendations for the nutritional requirements of the FSMP.

[0282] Coenzyme Q10

[0283] The composition according to the invention preferably comprises a therapeutically effective amount of coenzyme Q10. In an embodiment, the composition according to the invention comprises a combination of DHA, vitamin B2 and D3 with coenzyme Q10. In a further embodiment, the composition according to the invention may comprise a combination of one or more of the omega-3 fatty acids DHA and EPA, vitamin B2, vitamin D3, choline, coenzyme Q10, and dietary fiber and dietary butyrate.

[0284] Coenzyme Q10 (also known as CoQ10, Q10, vitamin Q10, ubiquinone, and ubidecarenone) is a benzoquinone compound synthesized naturally by the human body. The "Q" and "10" in the name refer to the quinone chemical group and the 10 isoprenyl chemical subunits, respectively, that are part of the structure of the compound. As used herein, Coenzyme Q10 refers to ubiquinone (2,3-dimethoxy-5-methyl-6-decaisoprenylbenzoquinone) and / or its functional analogs, including ubiquinol.

[0285] Coenzyme Q10 is a natural, fat-soluble substance that functions primarily as an essential enzyme cofactor in the mitochondrial electron transport chain and is a key factor in oxidative phosphorylation and aerobic cellular respiration through the generation of adenosine triphosphate (ATP) (Egil Fosslien; Mitochondrial Medicine-Molecular Pathology of Defective Oxidative Phosphorylation, Annals of Clinical and Laboratory Science, 2000).

[0286] Due to the lipid solubility of CoQ10 and its ability to exist in both a fully reduced form (ubiquinol) and a fully oxidized form (ubiquinone), it has been shown to function both as an antioxidant and as an electron carrier.

[0287] CoQ10 accepts electrons derived from Complex I (NADH ubiquinone oxidoreductase) and Complex II (succinate ubiquinone reductase) and then transports them to Complex III (ubiquinol cytochrome c reductase).

[0288] Natural sources of CoQ10 and / or analogs suitable for use in the present invention include extracts or isolates of fungi, yeast or bacteria, canola oil or soybean oil.

[0289] Preferably, the composition comprises 0.0001 mg to 0.8 mg Coenzyme Q10, more preferably 0.001 to 0.6 mg Coenzyme Q10, even more preferably 0.01 to 0.4 mg Coenzyme Q10 per day.

[0290] According to one embodiment, Coenzyme Q10 is preferably provided in an amount of 0.0001 to 0.5 mg / 100 ml, more preferably 0.001 to 0.4 mg / 100 ml, even more preferably 0.001 to 0.3 mg / 100 ml.

[0291] According to a further embodiment, Coenzyme Q10 is preferably provided in an amount of 0.0001 to 0.3 mg / 100 kcal of the composition, preferably in an amount of 0.001 to 0.3 mg / 100 kcal, even more preferably 0.001 to 0.2 mg / 100 kcal.

[0292] The above figures are based on the molar weight of ubiquinone.

[0293] LA / ALA

[0294] In addition to one or more ω-3 fatty acids, the lipid fraction may also comprise lipids that are a source of the essential fatty acids alpha-linolenic acid (ALA, C-18:3) and linoleic acid (LA, C-18:2). LA and / or ALA may be provided as free fatty acids, triglycerides, diglycerides, monoglycerides, phospholipids or a mixture of one or more of the above. Preferably, the composition of the present invention contains at least one, preferably at least two, lipid sources selected from the group consisting of soybean oil, rapeseed oil (such as colza oil, canola oil and canola oil), high oleic sunflower oil, high oleic safflower oil and olive oil. The LA:ALA weight ratio is preferably in the range of 8:1 to 3:1, preferably 7:1 to 4:1, more preferably 6:1 to 5:1.

[0295] If present in the composition, the composition of the invention preferably comprises 0.2 to 3.5 g LA / 100 ml, more preferably 0.3 to 3 g LA / 100 ml, more preferably 0.4 to 2.5 g LA / 100 ml. On a caloric basis, preferably, the composition according to the invention may comprise 0.1 to 1.5 g LA / 100 kcal, preferably 0.2 to 1.1 g LA / 100 kcal, more preferably 0.25 to 1 g LA / 100 kcal, based on the total energy content of the composition.

[0296] If present in the composition, the composition of the present invention preferably comprises 0.02 to 0.2 g ALA / 100 ml, more preferably 0.05 to 0.15 g ALA / 100 ml, more preferably 0.06 to 0.1 g ALA / 100 ml. On a caloric basis, preferably, the composition according to the present invention may comprise 0.03 to 0.08 g ALA / 100 kcal, preferably 0.04 to 0.07 g ALA / 100 kcal, more preferably 0.05 to 0.065 g ALA / 100 kcal based on the total energy content of the composition.

[0297] In an embodiment, the composition according to the invention comprises per daily dose:

[0298] (i) 150 to 1200 mg, preferably 200 to 1100 mg, more preferably 250 to 1000 mg DHA; and

[0299] (ii) 0.8 to 7.6 mg, preferably 1 to 7.4 mg, more preferably in the range of 1.2 to 7.2 mg of vitamin B2; and

[0300] (iii) 6 to 75 μg, preferably 8 to 70 μg, more preferably 10 to 65 μg of vitamin D3;

[0301] and optionally

[0302] (iv) 200 to 1400 mg, preferably 300 to 1200 mg, more preferably 350 to 1100 mg of choline, based on the molar weight of choline, wherein the choline is selected from free choline, choline salts and / or choline esters, preferably at least phosphatidylcholine;

[0303] and / or

[0304] v) 2.5 to 12.5 g, preferably 3 to 12 g, more preferably 3.5 to 11.5 g of dietary fiber and / or 0.125 g to 0.65 g of dietary butyric acid, preferably 0.025 g to 0.65 g, more preferably 0.043 g to 0.65 g of dietary butyric acid.

[0305] In an embodiment, the composition according to the invention comprises per daily dose:

[0306] (i) 150 to 1200 mg, preferably 200 to 1100 mg, more preferably 250 to 1000 mg DHA; and

[0307] (ii) 0.8 to 7.6 mg, preferably 1 to 7.4 mg, more preferably in the range of 1.2 to 7.2 mg of vitamin B2; and

[0308] (iii) 6 to 75 μg, preferably 8 to 70 μg, more preferably 10 to 65 μg of vitamin D3;

[0309] (iv) 200 to 1400 mg, preferably 300 to 1200 mg, more preferably 350 to 1100 mg of choline, based on the molar weight of choline, wherein the choline is selected from free choline, choline salts and / or choline esters, preferably at least phosphatidylcholine;

[0310] and

[0311] v) 2.5 to 12.5 g, preferably 3 to 12 g, more preferably 3.5 to 11.5 g dietary fiber selected from scGOS, lcFOS and low viscosity pectin and / or 0.125 g to 0.65 g dietary butyric acid, preferably 0.025 g to 0.65 g, more preferably 0.043 g to 0.65 g dietary butyric acid.

[0312] In an embodiment, the composition according to the invention comprises per daily dose:

[0313] (i) 150 to 1200 mg, preferably 200 to 1100 mg, more preferably 250 to 1000 mg DHA, and 40 to 350 mg, preferably 50 to 300 mg, more preferably 60 to 250 mg EPA; and

[0314] (ii) 0.8 to 7.6 mg, preferably 1 to 7.4 mg, more preferably in the range of 1.2 to 7.2 mg of vitamin B2; and

[0315] (iii) 6 to 75 μg, preferably 8 to 70 μg, more preferably 10 to 65 μg of vitamin D3;

[0316] and optionally

[0317] (iv) 200 to 1400 mg, preferably 300 to 1200 mg, more preferably 350 to 1100 mg of choline, based on the molar weight of choline, wherein the choline is selected from free choline, choline salts and / or choline esters, preferably at least phosphatidylcholine;

[0318] and / or

[0319] v) 2.5 to 12.5 g, preferably 3 to 12 g, more preferably 3.5 to 11.5 g of dietary fiber and / or 0.125 g to 0.65 g of dietary butyric acid, preferably 0.025 g to 0.65 g, more preferably 0.043 g to 0.65 g of dietary butyric acid.

[0320] In an embodiment, the composition according to the invention comprises per daily dose:

[0321] (i) 150 to 1200 mg, preferably 200 to 1100 mg, more preferably 250 to 1000 mg DHA; and

[0322] (ii) 0.8 to 7.6 mg, preferably 1 to 7.4 mg, more preferably in the range of 1.2 to 7.2 mg of vitamin B2; and

[0323] (iii) 6 to 75 μg, preferably 8 to 70 μg, more preferably 10 to 65 μg of vitamin D3;

[0324] and

[0325] (iv) 200 to 1400 mg, preferably 300 to 1200 mg, more preferably 350 to 1100 mg of choline, based on the molar weight of choline, wherein the choline is selected from free choline, choline salts and / or choline esters, preferably at least phosphatidylcholine; wherein the composition preferably comprises v a ) phosphatidylcholine and v b ) choline or a salt thereof, and wherein at least 20 mol % of the choline is provided in the form of phosphatidylcholine, preferably the molar ratio of choline or a salt thereof to PC is in the range of 40:60 to 60:40

[0326] and optionally

[0327] v) 2.5 to 12.5 g, preferably 3 to 12 g, more preferably 3.5 to 11.5 g of dietary fiber and / or 0.125 g to 0.65 g of dietary butyric acid, preferably 0.025 g to 0.65 g, more preferably 0.043 g to 0.65 g of dietary butyric acid.

[0328] In an embodiment, the composition according to the invention comprises per daily dose:

[0329] (i) 150 to 1200 mg, preferably 200 to 1100 mg, more preferably 250 to 1000 mg DHA; and

[0330] (ii) 0.8 to 7.6 mg, preferably 1 to 7.4 mg, more preferably in the range of 1.2 to 7.2 mg of vitamin B2; and

[0331] (iii) 6 to 75 μg, preferably 8 to 70 μg, more preferably 10 to 65 μg of vitamin D3;

[0332] In combination with:

[0333] (iv) 200 to 1400 mg, preferably 300 to 1200 mg, more preferably 350 to 1100 mg of choline, based on the molar weight of choline, wherein the choline is selected from free choline, choline salts and / or choline esters, preferably at least phosphatidylcholine;

[0334] and optionally

[0335] v) 2.5 to 12.5 g, preferably 3 to 12 g, more preferably 3.5 to 11.5 g dietary fiber selected from scGOS, lcFOS and low viscosity pectin, preferably wherein the dietary fiber comprises a mixture of scGOS, lcFOS and low viscosity pectin and wherein the ratio of scGOS:lcFOS:low viscosity pectin is in the range of 5:1:1 to 12:1:3, more preferably in the range of 7:1:1.5 to 11:1:2.5, most preferably in the range of 8:1:1.5 to 10:1:2.5, and / or 0.125 g to 0.65 g dietary butyric acid, preferably 0.025 g to 0.65 g, more preferably 0.043 g to 0.65 g dietary butyric acid.

[0336] In an embodiment, the composition according to the present invention comprises per daily dose;

[0337] (i) 150 to 1200 mg, preferably 200 to 1100 mg, more preferably 250 to 1000 mg DHA, and

[0338] 40 to 350 mg, preferably 50 to 300 mg, more preferably 60 to 250 mg EPA; and

[0339] (ii) 0.8 to 7.6 mg, preferably 1 to 7.4 mg, more preferably in the range of 1.2 to 7.2 mg of vitamin B2; and

[0340] (iii) 6 to 75 μg, preferably 8 to 70 μg, more preferably 10 to 65 μg of vitamin D3;

[0341] In combination with:

[0342] (iv) 200 to 1400 mg, preferably 300 to 1200 mg, more preferably 350 to 1100 mg of choline, based on the molar weight of choline, wherein the choline is selected from free choline, choline salts and / or choline esters, preferably at least phosphatidylcholine; wherein the choline is selected from free choline, choline salts and / or choline esters, preferably at least phosphatidylcholine; wherein the composition preferably comprises v a ) phosphatidylcholine and v b ) choline or a salt thereof, and wherein at least 20 mol % of the choline is provided in the form of phosphatidylcholine, preferably the molar ratio of choline or a salt to PC is in the range of 40:60 to 60:40;

[0343] and

[0344] v) 2.5 to 12.5 g, preferably 3 to 12 g, more preferably 3.5 to 11.5 g dietary fiber selected from scGOS, lcFOS and low viscosity pectin, preferably wherein the dietary fiber comprises a mixture of scGOS, lcFOS and low viscosity pectin and wherein the ratio of scGOS:lcFOS:low viscosity pectin is in the range of 5:1:1 to 12:1:3, more preferably in the range of 7:1:1.5 to 11:1:2.5, most preferably in the range of 8:1:1.5 to 10:1:2.5, and / or 0.125 g to 0.65 g dietary butyric acid, preferably 0.025 g to 0.65 g, more preferably 0.043 g to 0.65 g dietary butyric acid.

[0345] In an embodiment, the composition according to the invention comprises per daily dose:

[0346] (i) 150 to 1200 mg, preferably 200 to 1100 mg, more preferably 250 to 1000 mg DHA, and 40 to 350 mg, preferably 50 to 300 mg, more preferably 60 to 250 mg EPA; and

[0347] (ii) 0.8 to 7.6 mg, preferably 1 to 7.4 mg, more preferably in the range of 1.2 to 7.2 mg of vitamin B2; and

[0348] (iii) 6 to 75 μg, preferably 8 to 70 μg, more preferably 10 to 65 μg of vitamin D3;

[0349] (vi) 0.7 to 9 mg, preferably 0.8 to 8 mg, more preferably 0.9 to 7.5 mg of vitamin B6;

[0350] (vii) 150 to 900 μg, preferably 175 to 800 μg, more preferably 200 to 750 μg of vitamin B9;

[0351] and optionally

[0352] (iv) 200 to 1400 mg, preferably 300 to 1200 mg, more preferably 350 to 1100 mg of choline, based on the molar weight of choline, wherein the choline is selected from free choline, choline salts and / or choline esters, preferably at least phosphatidylcholine;

[0353] and / or

[0354] v) 2.5 to 12.5 g, preferably 3 to 12 g, more preferably 3.5 to 11.5 g of dietary fiber and / or 0.125 g to 0.65 g of dietary butyric acid, preferably 0.025 g to 0.65 g, more preferably 0.043 g to 0.65 g of dietary butyric acid.

[0355] In an embodiment, the composition according to the invention comprises per daily dose:

[0356] (i) 150 to 1200 mg, preferably 200 to 1100 mg, more preferably 250 to 1000 mg DHA, and 40 to 350 mg, preferably 50 to 300 mg, more preferably 60 to 250 mg EPA; and

[0357] (ii) 0.8 to 7.6 mg, preferably 1 to 7.4 mg, more preferably in the range of 1.2 to 7.2 mg of vitamin B2; and

[0358] (iii) 6 to 75 μg, preferably 8 to 70 μg, more preferably 10 to 65 μg of vitamin D3;

[0359] (vi) 0.7 to 9 mg, preferably 0.8 to 8 mg, more preferably 0.9 to 7.5 mg of vitamin B6;

[0360] (vii) 150 to 900 μg, preferably 175 to 800 μg, more preferably 200 to 750 μg of vitamin B9;

[0361] and

[0362] (iv) 200 to 1400 mg, preferably 300 to 1200 mg, more preferably 350 to 1100 mg of choline, based on the molar weight of choline, wherein the choline is selected from free choline, choline salts and / or choline esters, preferably at least phosphatidylcholine;

[0363] and

[0364] v) 2.5 to 12.5 g, preferably 3 to 12 g, more preferably 3.5 to 11.5 g dietary fiber selected from scGOS, lcFOS and low viscosity pectin and / or 0.125 g to 0.65 g dietary butyric acid, preferably 0.025 g to 0.65 g, more preferably 0.043 g to 0.65 g dietary butyric acid.

[0365] In an embodiment, the composition according to the invention comprises per daily dose:

[0366] (i) 150 to 1200 mg, preferably 200 to 1100 mg, more preferably 250 to 1000 mg DHA, and

[0367] 40 to 350 mg, preferably 50 to 300 mg, more preferably 60 to 250 mg EPA; and

[0368] (ii) 0.8 to 7.6 mg, preferably 1 to 7.4 mg, more preferably in the range of 1.2 to 7.2 mg of vitamin B2; and

[0369] (iii) 6 to 75 μg, preferably 8 to 70 μg, more preferably 10 to 65 μg of vitamin D3;

[0370] (vi) 0.7 to 9 mg, preferably 0.8 to 8 mg, more preferably 0.9 to 7.5 mg of vitamin B6;

[0371] (vii) 150 to 900 μg, preferably 175 to 800 μg, more preferably 200 to 750 μg of vitamin B9;

[0372] and

[0373] (iv) 200 to 1400 mg, preferably 300 to 1200 mg, more preferably 350 to 1100 mg of choline, based on the molar weight of choline, wherein the choline is selected from free choline, choline salts and / or choline esters, preferably at least phosphatidylcholine; wherein the choline is selected from free choline, choline salts and / or choline esters, preferably at least phosphatidylcholine; wherein the composition preferably comprises v a ) phosphatidylcholine and v b ) choline or a salt thereof, and wherein at least 20 mol % of the choline is provided in the form of phosphatidylcholine, preferably the molar ratio of choline or a salt to PC is in the range of 40:60 to 60:40;

[0374] as well as

[0375] v) 2.5 to 12.5 g, preferably 3 to 12 g, more preferably 3.5 to 11.5 g dietary fiber selected from scGOS, lcFOS and low viscosity pectin, preferably wherein the dietary fiber comprises a mixture of scGOS, lcFOS and low viscosity pectin and wherein the ratio of scGOS:lcFOS:low viscosity pectin is in the range of 5:1:1 to 12:1:3, more preferably in the range of 7:1:1.5 to 11:1:2.5, most preferably in the range of 8:1:1.5 to 10:1:2.5, and / or 0.125 g to 0.65 g dietary butyric acid, preferably 0.025 g to 0.65 g, more preferably 0.043 g to 0.65 g dietary butyric acid.

[0376] In another preferred embodiment, the composition comprising at least one of (i), (ii) and (iii), (vi) and (vii) and optionally a combination of (iv) and / or (v) per daily dose as implemented above further comprises one or more of the following:

[0377] (viii) 350 to 2700 μg retinol equivalent, preferably 650 to 900 μg retinol equivalent, more preferably 375 to 2600 μg retinol equivalent of vitamin A;

[0378] (ix) 0.7 to 5 mg, preferably 0.8 to 4.9 mg, more preferably 0.9 to 4.8 mg of vitamin B1;

[0379] (x) 2 to 20 μg, preferably 2.5 to 19 μg, more preferably 3 to 18 μg of vitamin B12;

[0380] (xi) 75 to 700 mg, preferably 85 to 600 mg, more preferably 95 to 550 mg of vitamin C;

[0381] (xii) 8 to 75 mg, preferably 10 to 70 mg, more preferably 12.5 to 70 mg of α-TE;

[0382] (xiii) 30 to 275 μg, preferably 35 to 250 μg, more preferably 38 to 225 μg of selenium; and

[0383] (xiv) 125 to 850 mg, preferably 150 to 800 mg, more preferably 170 to 750 mg of magnesium

[0384] (xv) 0.0001 mg to 0.8 mg coenzyme Q10, more preferably 0.001 to 0.6 mg coenzyme Q10, even more preferably 0.01 to 0.4 mg coenzyme Q10.

[0385] In another preferred embodiment, the composition comprises, per daily dose, at least one of (i), (ii), (iii), (iv) and (v), (vi) and (vii), and one or more of the following:

[0386] (viii) 350 to 2700 μg retinol equivalent, preferably 650 to 900 μg retinol equivalent, more preferably 375 to 2600 μg retinol equivalent of vitamin A;

[0387] (ix) 0.7 to 5 mg, preferably 0.8 to 4.9 mg, more preferably 0.9 to 4.8 mg of vitamin B1;

[0388] (x) 2 to 20 μg, preferably 2.5 to 19 μg, more preferably 3 to 18 μg of vitamin B12;

[0389] (xi) 75 to 700 mg, preferably 85 to 600 mg, more preferably 95 to 550 mg of vitamin C;

[0390] (xii) 8 to 75 mg, preferably 10 to 70 mg, more preferably 12.5 to 70 mg of α-TE;

[0391] (xiii) 30 to 275 μg, preferably 35 to 250 μg, more preferably 38 to 225 μg of selenium; and

[0392] (xiv) 125 to 850 mg, preferably 150 to 800 mg, more preferably 170 to 750 mg of magnesium

[0393] (xv) 0.0001 mg to 0.8 mg coenzyme Q10, more preferably 0.001 to 0.6 mg coenzyme Q10, even more preferably 0.01 to 0.4 mg coenzyme Q10

[0394] In another preferred embodiment, the composition comprises (i), (ii) and (iii), at least one of both (vi) and (vii) and optionally (iv) and / or (v), a combination of one or more selected from (vii)-(xv), per daily dose, further comprising at least one of the following:

[0395] (xvi) 3 to 45 mg, preferably 3.5 to 42 mg, more preferably 3.8 to 40 mg of vitamin B3 (niacin equivalent);

[0396] (xvii) 0.8 to 15 mg, preferably 1 to 14 mg, more preferably 1.2 to 13 mg of vitamin B5;

[0397] (xviii) Vitamin B7 in the range of 8 to 95 μg, preferably in the range of 9 to 90 μg, more preferably in the range of 9.5 to 85 μg.

[0398] The present invention also provides a liquid nutritional composition, wherein each 100 ml of the liquid nutritional composition comprises:

[0399] (i) 30 to 240 mg, preferably 35 to 220 mg, more preferably 40 to 200 mg DHA; and

[0400] (ii) 0.1 to 1.4 mg, preferably 0.2 to 1.2 mg, more preferably 0.3 to 1 mg of vitamin B2; and

[0401] (iii) 1.5 to 10 μg, preferably 2 to 9 μg, more preferably 2.5 to 8 μg of vitamin D3;

[0402] and optionally

[0403] (iv) 35 to 170 mg, preferably 40 to 160 mg, more preferably 45 to 150 mg, of choline, wherein the choline is selected from free choline, choline salts and / or choline esters, preferably at least phosphatidylcholine;

[0404] and / or

[0405] v) 1.5 to 4.5 g, preferably 2 to 4 g, more preferably 2.5 to 3.5 g dietary fiber and / or 0.01 to 0.175 g dietary butyric acid, preferably 0.02 to 0.175 g, more preferably 0.035 to 0.175 g dietary butyric acid.

[0406] The present invention also provides a liquid nutritional composition, wherein each 100 ml of the liquid nutritional composition comprises:

[0407] (i) 30 to 240 mg, preferably 35 to 220 mg, more preferably 40 to 200 mg DHA; and

[0408] (ii) 0.1 to 1.4 mg, preferably 0.2 to 1.2 mg, more preferably 0.3 to 1 mg of vitamin B2; and

[0409] (iii) 1.5 to 10 μg, preferably 2 to 9 μg, more preferably 2.5 to 8 μg of vitamin D3;

[0410] and

[0411] (iv) 35 to 170 mg, preferably 40 to 160 mg, more preferably 45 to 150 mg, of choline, wherein the choline is selected from free choline, choline salts and / or choline esters, preferably at least phosphatidylcholine;

[0412] and

[0413] v) 0.5 to 4.0 g, preferably 1.0 to 3.5 g, more preferably 1.5 to 3.0 g dietary fiber and / or 0.01 to 0.175 g dietary butyric acid, preferably 0.02 to 0.175 g, more preferably 0.035 to 0.175 g dietary butyric acid.

[0414] The present invention also provides a liquid nutritional composition, wherein each 100 ml of the liquid nutritional composition comprises:

[0415] (i) 30 to 240 mg, preferably 35 to 220 mg, more preferably 40 to 200 mg DHA, and 5 to 60 mg, preferably 7 to 55 mg, more preferably 9 to 50 mg EPA; and

[0416] (ii) 0.1 to 1.4 mg, preferably 0.2 to 1.2 mg, more preferably 0.3 to 1 mg of vitamin B2; and

[0417] (iii) 1.5 to 10 μg, preferably 2 to 9 μg, more preferably 2.5 to 8 μg of vitamin D3;

[0418] and optionally

[0419] (iv) 35 to 170 mg, preferably 40 to 160 mg, more preferably 45 to 150 mg, of choline, wherein the choline is selected from free choline, choline salts and / or choline esters, preferably at least phosphatidylcholine;

[0420] and / or

[0421] v) 0.5 to 4.0 g, preferably 1.0 to 3.5 g, more preferably 1.5 to 3.0 g dietary fiber and / or 0.01 to 0.175 g dietary butyric acid, preferably 0.02 to 0.175 g, more preferably 0.035 to 0.175 g dietary butyric acid

[0422] The present invention also provides a liquid nutritional composition, wherein each 100 ml of the liquid nutritional composition comprises:

[0423] (i) 30 to 240 mg, preferably 35 to 220 mg, more preferably 40 to 200 mg DHA; and

[0424] (ii) 0.1 to 1.4 mg, preferably 0.2 to 1.2 mg, more preferably 0.3 to 1 mg of vitamin B2; and

[0425] (iii) 1.5 to 10 μg, preferably 2 to 9 μg, more preferably 2.5 to 8 μg of vitamin D3;

[0426] and

[0427] (iv) 35 to 170 mg, preferably 40 to 160 mg, more preferably 45 to 150 mg of choline, wherein the choline is selected from free choline, choline salts and / or choline esters, preferably at least phosphatidylcholine; and wherein the composition preferably comprises v a ) phosphatidylcholine and v b ) choline or a salt thereof, and wherein at least 20 mol % of the choline is provided in the form of phosphatidylcholine, preferably the molar ratio of choline or a salt to PC is in the range of 40:60 to 60:40;

[0428] and optionally

[0429] v) 1.5 to 4.5 g, preferably 2 to 4 g, more preferably 2.5 to 3.5 g dietary fiber and / or 0.01 to 0.175 g dietary butyric acid, preferably 0.02 to 0.175 g, more preferably 0.035 to 0.175 g dietary butyric acid.

[0430] The present invention also provides a liquid nutritional composition, wherein each 100 ml of the liquid nutritional composition comprises:

[0431] (i) 30 to 240 mg, preferably 35 to 220 mg, more preferably 40 to 200 mg DHA; and

[0432] (ii) 0.1 to 1.4 mg, preferably 0.2 to 1.2 mg, more preferably 0.3 to 1 mg of vitamin B2; and

[0433] (iii) 1.5 to 10 μg, preferably 2 to 9 μg, more preferably 2.5 to 8 μg of vitamin D3;

[0434] In combination with:

[0435] (iv) 35 to 170 mg, preferably 40 to 160 mg, more preferably 45 to 150 mg, of choline, wherein the choline is selected from free choline, choline salts and / or choline esters, preferably at least phosphatidylcholine;

[0436] and / or

[0437] v) 0.5 to 4.0 g, preferably 1.0 to 3.5 g, more preferably 1.5 to 3.0 g dietary fiber selected from scGOS, lcFOS and low viscosity pectin, preferably wherein the dietary fiber comprises a mixture of scGOS, lcFOS and low viscosity pectin and wherein the ratio of scGOS:lcFOS:low viscosity pectin is in the range of 5:1:1 to 12:1:3, more preferably in the range of 7:1:1.5 to 11:1:2.5, most preferably in the range of 8:1:1.5 to 10:1:2.5, and / or 0.01 to 0.175 g dietary butyric acid, preferably 0.02 to 0.175 g, more preferably 0.035 to 0.175 g dietary butyric acid.

[0438] The present invention also provides a liquid nutritional composition, wherein each 100 ml of the liquid nutritional composition comprises:

[0439] (i) 30 to 240 mg, preferably 35 to 220 mg, more preferably 40 to 200 mg DHA, and

[0440] 5 to 60 mg, preferably 7 to 55 mg, more preferably 9 to 50 mg EPA; and

[0441] (ii) 0.1 to 1.4 mg, preferably 0.2 to 1.2 mg, more preferably 0.3 to 1 mg of vitamin B2; and

[0442] (iii) 1.5 to 10 μg, preferably 2 to 9 μg, more preferably 2.5 to 8 μg of vitamin D3;

[0443] and

[0444] (iv) 35 to 170 mg, preferably 40 to 160 mg, more preferably 45 to 150 mg of choline, wherein the choline is selected from free choline, choline salts and / or choline esters, preferably at least phosphatidylcholine; and wherein the composition preferably comprises v a ) phosphatidylcholine and v b ) choline or a salt thereof, and wherein at least 20 mol % of the choline is provided in the form of phosphatidylcholine, preferably the molar ratio of choline or a salt to PC is in the range of 40:60 to 60:40;

[0445] and

[0446] v) 0.5 to 4.0 g, preferably 1.0 to 3.5 g, more preferably 1.5 to 3.0 g dietary fiber selected from scGOS, lcFOS and low viscosity pectin, preferably wherein the dietary fiber comprises a mixture of scGOS, lcFOS and low viscosity pectin and wherein the ratio of scGOS:lcFOS:low viscosity pectin is in the range of 5:1:1 to 12:1:3, more preferably in the range of 7:1:1.5 to 11:1:2.5, most preferably in the range of 8:1:1.5 to 10:1:2.5, and / or 0.01 to 0.175 g dietary butyric acid, preferably 0.02 to 0.175 g, more preferably 0.035 to 0.175 g dietary butyric acid

[0447] The present invention also provides a liquid nutritional composition, wherein each 100 ml of the liquid nutritional composition comprises:

[0448] (i) 30 to 240 mg, preferably 35 to 220 mg, more preferably 40 to 200 mg DHA, and

[0449] 5 to 60 mg, preferably 7 to 55 mg, more preferably 9 to 50 mg EPA; and

[0450] (ii) 0.1 to 1.4 mg, preferably 0.2 to 1.2 mg, more preferably 0.3 to 1 mg of vitamin B2; and

[0451] (iii) 1.5 to 10 μg, preferably 2 to 9 μg, more preferably 2.5 to 8 μg of vitamin D3;

[0452] and optionally

[0453] (iv) 35 to 170 mg, preferably 40 to 160 mg, more preferably 45 to 150 mg of choline, wherein the choline is selected from free choline, choline salts and / or choline esters, preferably at least phosphatidylcholine; and wherein the composition preferably comprises v a ) phosphatidylcholine and v b ) choline or a salt thereof, and wherein at least 20 mol % of the choline is provided in the form of phosphatidylcholine, preferably the molar ratio of choline or a salt to PC is in the range of 40:60 to 60:40;

[0454] and / or

[0455] v) 0.5 to 4.0 g, preferably 1.0 to 3.5 g, more preferably 1.5 to 3.0 g dietary fiber selected from scGOS, lcFOS and low viscosity pectin, preferably wherein the dietary fiber comprises a mixture of scGOS, lcFOS and low viscosity pectin and wherein the ratio of scGOS:lcFOS:low viscosity pectin is in the range of 5:1:1 to 12:1:3, more preferably in the range of 7:1:1.5 to 11:1:2.5, most preferably in the range of 8:1:1.5 to 10:1:2.5, and / or 0.01 to 0.175 g dietary butyric acid, preferably 0.02 to 0.175 g, more preferably 0.035 to 0.175 g dietary butyric acid

[0456] and at least one of (vi) and (vii);

[0457] (vi) 0.2 to 1 mg, preferably 0.25 to 0.8 mg, more preferably 0.3 to 0.7 mg of vitamin B6;

[0458] (vii) 20 to 225 μg, preferably 25 to 200 μg, more preferably 30 to 175 μg of vitamin B9.

[0459] In a further preferred embodiment, the liquid nutritional composition comprising at least one of (i) and (ii), (iii), (vi) and (vii), and optionally a combination of (iv) and / or (v) per 100 ml further comprises one or more of the following:

[0460] (viii) 50 to 400 μg, preferably 75 to 350 μg, more preferably 100 to 300 μg retinol equivalent vitamin A;

[0461] (ix) 0.1 to 0.9 mg, preferably 0.15 to 0.8 mg, more preferably 0.2 to 0.75 mg of vitamin B1;

[0462] (x) 0.5 to 3 μg, preferably 0.6 to 2.6 μg, more preferably 0.7 to 2.4 μg of vitamin B12;

[0463] (xi) 10 to 100 mg, preferably 15 to 90 mg, more preferably 20 to 80 mg of vitamin C;

[0464] (xii) 2 to 14 mg, preferably 2.5 to 12 mg, more preferably 2.75 to 10 mg of α-TE;

[0465] (xiii) 8 to 45 μg, preferably 10 to 40 μg, more preferably 11 to 35 μg of selenium;

[0466] (xiv) 20 to 160 mg, preferably 25 to 150 mg, more preferably 30 to 140 mg of magnesium; and

[0467] (xv) 0.0001 to 0.5 mg, preferably 0.001 to 0.4 mg, more preferably 0.001 to 0.3 mg of coenzyme Q10.

[0468] In another preferred embodiment, the liquid nutritional composition may further contain one or more of the following per 100 ml:

[0469] (xvi) 1.2 to 6 mg, preferably 1.4 to 5.5 mg, more preferably 1.6 to 5 mg of vitamin B3 (niacin equivalent);

[0470] (xvii) 0.3 to 2.2 mg, preferably 0.4 to 2 mg, more preferably 0.5 to 1.8 mg of vitamin B5;

[0471] (xviii) 2 to 14 mg, preferably 3 to 12 mg, more preferably 3.5 to 11 mg of vitamin B7.

[0472] The present invention further provides a liquid nutritional composition, wherein the liquid nutritional composition comprises per 100 kcal:

[0473] (i) 20 to 100 mg, preferably 25 to 90 mg, more preferably 30 to 80 mg DHA; and

[0474] (ii) 0.4 to 0.6 mg, preferably 0.15 to 0.5 mg, more preferably 0.2 to 0.4 mg of vitamin B2; and

[0475] (iii) 1.3 to 4.5 μg, preferably 1.5 to 4 μg, more preferably 2 to 3.5 μg of vitamin D3;

[0476] and optionally

[0477] (iv) 100 to 1000 mg, preferably 200 to 800 mg, more preferably 300 to 500 mg of choline, wherein the choline is selected from free choline, choline salts and / or choline esters, preferably at least phosphatidylcholine;

[0478] and / or

[0479] v) 0.75 to 2.5 g, preferably 1.0 to 2.0 g, more preferably 1.1 to 1.5 g dietary fiber and / or 0.015 to 0.25 g dietary butyric acid, preferably 0.03 to 0.25 g, more preferably 0.05 to 0.25 g dietary butyric acid.

[0480] The present invention further provides a liquid nutritional composition, wherein the liquid nutritional composition comprises per 100 kcal:

[0481] (i) 20 to 100 mg, preferably 25 to 90 mg, more preferably 30 to 80 mg DHA; and

[0482] (ii) 0.4 to 0.6 mg, preferably 0.15 to 0.5 mg, more preferably 0.2 to 0.4 mg of vitamin B2; and

[0483] (iii) 1.3 to 4.5 μg, preferably 1.5 to 4 μg, more preferably 2 to 3.5 μg of vitamin D3;

[0484] and

[0485] (iv) 100 to 1000 mg, preferably 200 to 800 mg, more preferably 300 to 500 mg of choline, wherein the choline is selected from free choline, choline salts and / or choline esters, preferably at least phosphatidylcholine;

[0486] and

[0487] v) 0.75 to 2.5 g, preferably 1.0 to 2.0 g, more preferably 1.1 to 1.5 g dietary fiber and / or 0.015 to 0.25 g dietary butyric acid, preferably 0.03 to 0.25 g, more preferably 0.05 to 0.25 g dietary butyric acid.

[0488] The present invention further provides a liquid nutritional composition, wherein the liquid nutritional composition comprises per 100 kcal:

[0489] (i) 20 to 100 mg, preferably 25 to 90 mg, more preferably 30 to 80 mg DHA, and 5 to 30 mg, preferably 6 to 25 mg, more preferably 8 to 20 mg EPA; and

[0490] (ii) 0.4 to 0.6 mg, preferably 0.15 to 0.5 mg, more preferably 0.2 to 0.4 mg of vitamin B2; and

[0491] (iii) 1.3 to 4.5 μg, preferably 1.5 to 4 μg, more preferably 2 to 3.5 μg of vitamin D3;

[0492] and optionally

[0493] (iv) 100 to 1000 mg, preferably 200 to 800 mg, more preferably 300 to 500 mg of choline, wherein the choline is selected from free choline, choline salts and / or choline esters, preferably at least phosphatidylcholine

[0494] and / or

[0495] v) 0.75 to 2.5 g, preferably 1.0 to 2.0 g, more preferably 1.1 to 1.5 g dietary fiber and / or 0.015 to 0.25 g dietary butyric acid, preferably 0.03 to 0.25 g, more preferably 0.05 to 0.25 g dietary butyric acid.

[0496] The present invention further provides a liquid nutritional composition, wherein the liquid nutritional composition comprises per 100 kcal:

[0497] (i) 20 to 100 mg, preferably 25 to 90 mg, more preferably 30 to 80 mg DHA; and

[0498] (ii) 0.4 to 0.6 mg, preferably 0.15 to 0.5 mg, more preferably 0.2 to 0.4 mg of vitamin B2; and

[0499] (iii) 1.3 to 4.5 μg, preferably 1.5 to 4 μg, more preferably 2 to 3.5 μg of vitamin D3;

[0500] and

[0501] (iv) 100 to 1000 mg, preferably 200 to 800 mg, more preferably 300 to 500 mg of choline, wherein the choline is selected from free choline, choline salts and / or choline esters, preferably at least phosphatidylcholine; and wherein the composition preferably comprises v a ) phosphatidylcholine and v b ) choline or a salt thereof, and wherein at least 20 mol % of the choline is provided in the form of phosphatidylcholine, preferably the molar ratio of choline or a salt to PC is in the range of 40:60 to 60:40;

[0502] and optionally

[0503] v) 0.75 to 2.5 g, preferably 1.0 to 2.0 g, more preferably 1.1 to 1.5 g dietary fiber and / or 0.015 to 0.25 g dietary butyric acid, preferably 0.03 to 0.25 g, more preferably 0.05 to 0.25 g dietary butyric acid.

[0504] The present invention further provides a liquid nutritional composition, wherein the liquid nutritional composition comprises per 100 kcal:

[0505] (i) 20 to 100 mg, preferably 25 to 90 mg, more preferably 30 to 80 mg DHA; and

[0506] (ii) 0.4 to 0.6 mg, preferably 0.15 to 0.5 mg, more preferably 0.2 to 0.4 mg of vitamin B2; and

[0507] (iii) 1.3 to 4.5 μg, preferably 1.5 to 4 μg, more preferably 2 to 3.5 μg of vitamin D3;

[0508] In combination with:

[0509] (iv) 100 to 1000 mg, preferably 200 to 800 mg, more preferably 300 to 500 mg of choline, wherein the choline is selected from free choline, choline salts and / or choline esters, preferably at least phosphatidylcholine;

[0510] and / or

[0511] v) 0.75 to 2.5 g, preferably 1.0 to 2.0 g, more preferably 1.1 to 1.5 g dietary fiber selected from scGOS, lcFOS and low viscosity pectin, preferably wherein the dietary fiber comprises a mixture of scGOS, lcFOS and low viscosity pectin and wherein the ratio of scGOS:lcFOS:low viscosity pectin is in the range of 5:1:1 to 12:1:3, more preferably in the range of 7:1:1.5 to 11:1:2.5, most preferably in the range of 8:1:1.5 to 10:1:2.5, and / or 0.015 to 0.25 g dietary butyric acid, preferably 0.03 to 0.25 g, more preferably 0.05 to 0.25 g dietary butyric acid.

[0512] The present invention further provides a liquid nutritional composition, wherein the liquid nutritional composition comprises per 100 kcal:

[0513] (i) 20 to 100 mg, preferably 25 to 90 mg, more preferably 30 to 80 mg DHA 5 to 30 mg, preferably 6 to 25 mg, more preferably 8 to 20 mg EPA; and

[0514] (ii) 0.4 to 0.6 mg, preferably 0.15 to 0.5 mg, more preferably 0.2 to 0.4 mg of vitamin B2; and

[0515] (iii) 1.3 to 4.5 μg, preferably 1.5 to 4 μg, more preferably 2 to 3.5 μg of vitamin D3;

[0516] In combination with:

[0517] (iv) 100 to 1000 mg, preferably 200 to 800 mg, more preferably 300 to 500 mg of choline, wherein the choline is selected from free choline, choline salts and / or choline esters, preferably at least phosphatidylcholine; and wherein the composition preferably comprises v a ) phosphatidylcholine and v b) choline or a salt thereof, and wherein at least 20 mol % of the choline is provided in the form of phosphatidylcholine, preferably the molar ratio of choline or a salt to PC is in the range of 40:60 to 60:40;

[0518] and

[0519] v) 0.75 to 2.5 g, preferably 1.0 to 2.0 g, more preferably 1.1 to 1.5 g dietary fiber selected from scGOS, lcFOS and low viscosity pectin, preferably wherein the dietary fiber comprises a mixture of scGOS, lcFOS and low viscosity pectin and wherein the ratio of scGOS:lcFOS:low viscosity pectin is in the range of 5:1:1 to 12:1:3, more preferably in the range of 7:1:1.5 to 11:1:2.5, most preferably in the range of 8:1:1.5 to 10:1:2.5, and / or 0.015 to 0.25 g dietary butyric acid, preferably 0.03 to 0.25 g, more preferably 0.05 to 0.25 g dietary butyric acid

[0520] The present invention further provides a liquid nutritional composition, wherein the liquid nutritional composition comprises per 100 kcal:

[0521] (i) 20 to 100 mg, preferably 25 to 90 mg, more preferably 30 to 80 mg DHA

[0522] 5 to 30 mg, preferably 6 to 25 mg, more preferably 8 to 20 mg EPA; and

[0523] (ii) 0.4 to 0.6 mg, preferably 0.15 to 0.5 mg, more preferably 0.2 to 0.4 mg of vitamin B2; and

[0524] (iii) 1.3 to 4.5 μg, preferably 1.5 to 4 μg, more preferably 2 to 3.5 μg of vitamin D3;

[0525] and at least one of (vi) and (vii);

[0526] (vi) 0.1 to 0.5 mg, preferably 0.2 to 0.4 mg, more preferably 0.25 to 0.3 mg of vitamin B6;

[0527] (vii) 16 to 80 μg, preferably 18 to 75 μg, more preferably 20 to 70 μg of vitamin B9;

[0528] and optionally

[0529] (iv) 100 to 1000 mg, preferably 200 to 800 mg, more preferably 300 to 500 mg of choline, wherein the choline is selected from free choline, choline salts and / or choline esters, preferably at least phosphatidylcholine; and wherein the composition preferably comprises v a ) phosphatidylcholine and v b ) choline or a salt thereof, and wherein at least 20 mol % of the choline is provided in the form of phosphatidylcholine, preferably the molar ratio of choline or a salt to PC is in the range of 40:60 to 60:40;

[0530] and / or

[0531] v) 0.75 to 2.5 g, preferably 1.0 to 2.0 g, more preferably 1.1 to 1.5 g dietary fiber selected from scGOS, lcFOS and low viscosity pectin, preferably wherein the dietary fiber comprises a mixture of scGOS, lcFOS and low viscosity pectin and wherein the ratio of scGOS:lcFOS:low viscosity pectin is in the range of 5:1:1 to 12:1:3, more preferably in the range of 7:1:1.5 to 11:1:2.5, most preferably in the range of 8:1:1.5 to 10:1:2.5, and / or 0.015 to 0.25 g dietary butyric acid, preferably 0.03 to 0.25 g, more preferably 0.05 to 0.25 g dietary butyric acid.

[0532] In another preferred embodiment, the liquid nutritional composition comprises at least one of (i), (ii) and (iii), (vi) and (vii), and optionally a combination of (iv) and / or (v), per 100 kcal, and further comprises one or more of the following:

[0533] (viii) 60 to 150 μg, preferably 70 to 140 μg, more preferably 80 to 130 μg retinol equivalent vitamin A;

[0534] (ix) 0.05 to 0.4 mg, preferably 0.1 to 0.35 mg, more preferably 0.15 to 0.30 mg of vitamin B1; (x) 0.4 to 1.4 μg, preferably 0.5 to 1.2 μg, more preferably 0.6 to 1 μg of vitamin B12;

[0535] (xi) 12 to 40 mg, preferably 14 to 35 mg, more preferably 16 to 32 mg of vitamin C;

[0536] (xii) 1 to 5.5 mg, preferably 1.5 to 5 mg, more preferably 2 to 4.5 mg of α-TE;

[0537] (xiii) 4 to 18 μg, preferably 6 to 16 μg, more preferably 8 to 14 μg of selenium; and

[0538] (xiv) 10 to 70 mg, preferably 15 to 65 mg, more preferably 20 to 60 mg of magnesium

[0539] (xv) 0.0001 to 0.3 mg, preferably 0.001 to 0.3 mg, more preferably 0.001 to 0.2 mg of coenzyme Q10.

[0540] In another preferred embodiment, the liquid nutritional composition may further contain one or more of the following per 100 kcal:

[0541] (xv) 1 to 2.5 mg, preferably 1.1 to 2.2 mg, more preferably 1.2 to 2 mg of vitamin B3 (niacin equivalent);

[0542] (xvi) 0.2 to 1 mg, preferably 0.3 to 0.9 mg, more preferably 0.4 to 0.8 mg of vitamin B5;

[0543] (xvii) 1.5 to 6 mg, preferably 2 to 5.5 mg, more preferably 2.5 to 5 mg of vitamin B7.

[0544] In a specific embodiment, a composition is provided, comprising:

[0545] (i) DHA and EPA;

[0546] (ii) Vitamin D3;

[0547] (iii) Vitamin B2;

[0548] (iv) choline, choline salts and / or choline esters, preferably at least phosphatidylcholine;

[0549] (v) dietary fiber and / or dietary butyrate;

[0550] (vi) Vitamin B6;

[0551] (vii) Vitamin B9;

[0552] And at least one or more of the following ingredients:

[0553] (viii) retinol equivalents of vitamin A;

[0554] (ix) vitamin B1;

[0555] (x) Vitamin B12;

[0556] (xi) vitamin C;

[0557] (xii) α-TE;

[0558] (xiii) selenium; and

[0559] (xiv) Magnesium

[0560] (xv) Coenzyme Q10.

[0561] Examples

[0562] For a more complete understanding of the present disclosure, reference is now made to the following examples in conjunction with the accompanying drawings.

[0563] Example 1 - Synergistic effects between DHA and EPA, B2 and D3 on neurite outgrowth in PC12 cells

[0564] PC12 neuronal cell culture

[0565] To evaluate the effects of nutritional components on axonal outgrowth and dendritic branching, which underlie functional brain connectivity, the effects of nutritional supplementation on neurite outgrowth parameters in PC12 pheochromocytoma cells were investigated. The PC12 neuronal cell model is one of the most widely used cell models for studying neuronal differentiation.

[0566] PC12 pheochromocytoma cells were grown in DMEM (Gibco) supplemented with 10% fetal bovine serum (FBS), penicillin (100 units / ml) and streptomycin (100 μg / ml) (Gibco) at 37°C in a humidified atmosphere with 95% air and 5% CO2. Cells were seeded at a density of 5000 cells / well onto 96-well plates coated with collagen (0.01 mg / ml) and supplemented 24 hours later with medium containing 20 ng / ml nerve growth factor (NGF), with or without the components defined in this and subsequent examples. Cell cultures were incubated at 37°C in 5% CO2, and the medium was changed every 2-3 days.

[0567] Nutrient Supplementation

[0568] The effect of nutrient supplementation of neuronal PC12 cultures was evaluated by comparing different concentrations of DHA (3.3 μM and 6.7 μM), EPA (10 μM), vitamin B2 (0.5 μM and 1 μM) and vitamin D3 (0.25 μM) with vehicle control (0 μM). Nutrients were supplemented individually or in combination with each other.

[0569] DHA and EPA are resuspended in absolute ethanol and diluted 5 times in fetal bovine serum. Other compounds are dissolved in DMEM. All compounds are purchased from Sigma (Zwijndrecht, the Netherlands). Cells are supplemented in 96-well plates in 6 copies. The neurite outgrowth under these conditions is compared with unsupplemented cells.

[0570] Neurite outgrowth: immunocytochemistry and imaging

[0571] After 48 hours of nutrient supplementation, calcein-AM stain (0.2 μg / ml) (Invitrogen, lot number C3100MP) was used in the culture medium of 100 μl per well to stain the cell body and neurite, and Hoechst stain (1.2 μg / ml) (Thermo Scientific, lot number 62249) was used to counterstain the nucleus, and incubated at 37 ° C for 20 min. Subsequently, FITC and DAPI images (9 images per hole, 6 holes per condition) were taken using ImageXpress micro-confocal high-content imaging system (Molecular Devices). The neurite outgrowth module in MetaXpress was used to quantify the length of neurite. Image analysis was performed using the neurite outgrowth analysis module in MetaXpress (Molecular Devices). The measured values ​​obtained from each hole include the number of nuclei and the average neurite outgrowth (μm) of each cell. Data were normalized to vehicle-treated control wells and expressed as relative percentage of the plate mean for the vehicle-treated control wells.

[0572] result

[0573] Image analysis of neurite outgrowth demonstrated that supplementation with omega-3 fatty acids DHA and EPA, vitamins B2 and D3 alone increased neurite outgrowth compared to controls in an in vitro PC12 neuronal cell model. Neurite outgrowth is expressed as a percentage relative to control (100%). Furthermore, when taken together, neurite outgrowth improved in a synergistic manner: the mean percentage of neurite outgrowth was higher than expected based on the additive effects of the individual components (calculated or expected mean neurite outgrowth was 183.1, observed mean neurite outgrowth was 186.4). These results are depicted in Figure 1 middle.

[0574] Figure 2Performed in separate 96-well plates, supplemented with DHA (6.7 μM) as the sole ω-3 fatty acid, and in which the concentration of vitamin B2 was varied between 0.5 μM and 1 μM, showed a similar trend of improved neurite outgrowth compared to controls. Figure 3 Similar effects were shown where the concentration of DHA was 3.3 μM and the concentration of vitamin B2 varied between 0.5 μM and 1 μM. Taken together, these results indicate that there is an effect on neurite outgrowth over a wide range of concentrations of DHA and vitamin B2.

[0575] It should be noted that inter-plate comparisons cannot be made, as neurite outgrowth is a relative measure compared to vehicle-supplemented controls, and therefore only intra-plate variation should be considered.

[0576] Example 2 - Choline chloride:PC ratio affects neurite outgrowth in PC12 cells

[0577] For PC12 neuronal cell cultures and measurement of neurite outgrowth by immunohistochemistry and imaging, refer to Example 1.

[0578] Nutrient Supplementation

[0579] The effect of nutrient supplementation of choline from different sources by supplementing chol-Cl or PC in neuronal culture was evaluated by comparing choline chloride (chol-Cl) and phosphatidylcholine (PC) in different molar ratios with vehicle control (0 μM). Nutrients were supplemented alone (100 mol% chol-Cl or 100 mol% PC) and with chol-Cl:PC at a molar ratio of 60:40 and 40:60. Choline was supplemented to cells with choline derived from chol-Cl, PC, or both at a total concentration of 20 μM in 96-well plates, in 6 copies, wherein the total amount of choline was 20 μM. These conditions were compared with control cells supplemented with vehicle.

[0580] result

[0581] Image analysis of neurite outgrowth showed that supplementation with 100% PC increased neurite outgrowth more than supplementation with 100 mol% chol-Cl compared to the control. In addition, chol-Cl:PC molar ratios of 60:40 to 40:60 showed similar improvements in neurite outgrowth compared to the control group and compared to supplementation with 100 mol% chol-Cl. These results are depicted in Figure 4 middle.

[0582] The results for neurite outgrowth indicated that both choline chloride and PC enhanced neurite outgrowth. Choline provided in the form of a combination of PC and chol-Cl slightly enhanced the effect on neurite outgrowth.

[0583] Example 3 - Synergistic effects between DHA (and EPA), B2 and D3 with chol-Cl and / or PC on neurite outgrowth in PC12 cells

[0584] For PC12 neuronal cell cultures and measurement of neurite outgrowth by immunohistochemistry and imaging, refer to Example 1.

[0585] Nutrient Supplementation

[0586] The effects of chol-Cl, PC, and a combination of DHA, B2, and D3 nutrient supplementation on neurite outgrowth of PC12 cells were evaluated by comparison with vehicle control. PC12 cells were supplemented with the following nutrients:

[0587] (1) 100% chol-Cl (20 μM choline),

[0588] (2) 100% PC (20 μM choline),

[0589] (3) A combination of DHA (3.3 μM), B2 (0.5 μM) and D3 (0.25 μM),

[0590] (4) A combination of 100% chol-Cl (20 μM), DHA (3.3 μM), B2 (0.5 μM) and D3 (0.25 μM),

[0591] (5) Combination of 80 mol% chol-Cl + 20 mol% PC (total 20 μM), DHA (3.3 μM), B2 (0.5 μM) and D3 (0.25 μM)

[0592] (6) A combination of 100% PC (20 μM), DHA (3.3 μM), B2 (0.5 μM) and D3 (0.25 μM).

[0593] In separate experiments, PC12 cells were supplemented with PC alone (20 μM, yielding 2.8 μM choline), a combination of DHA (5 μM) and EPA (1 μM), B2 (0.5 μM), and D3 (0.25 μM), and a combination of PC (20 μM), DHA (5 μM), and EPA (1 μM), B2 (0.5 μM), and D3 (0.25 μM).

[0594] In all relevant conditions, the amount of choline (whether derived from chol-Cl or PC) was kept constant at a concentration of 20 μM. Cells were supplemented in 96-well plates in six replicates. These conditions were compared to unsupplemented cells.

[0595] result

[0596] Likewise, image analysis of neurite outgrowth indicated that supplementation with 100% PC increased neurite outgrowth more than supplementation with 100 mol% chol-Cl compared to the control. Furthermore, the combination of DHA, B2 and D3 beneficially increased neurite outgrowth further.

[0597] Unexpectedly, the combination of 100 mol% chol-Cl with DHA, B2 and D3 increased neurite outgrowth in a synergistic manner, to an extent that exceeded the prediction based on the additive effects of chol-Cl alone and the combination of DHA, B2 and D3 (calculated or expected average neurite outgrowth of 122.9, observed average neurite outgrowth of 127.7). The same effect was observed for the combination of 100 mol% PC with DHA, B2 and D3 (calculated or expected average neurite outgrowth of 129.8, observed average neurite outgrowth of 134.3). In the case of a molar ratio of chol-Cl to PC of 20:80, the synergistic effect of the combination with DHA, B2 and D3 remained (observed average neurite outgrowth of 135.2). These results are depicted in Figure 5 middle.

[0598] also, Figure 6 The effect of PC in combination with DHA and EPA, B2 and D3 on neurite outgrowth in PC12 cells is shown. Likewise, when the effect of PC alone was compared with the combination of DHA, EPA, B2 and D3, a synergistic effect was observed (calculated or expected average neurite outgrowth of 130.7, observed average neurite outgrowth of 136.3).

[0599] These results indicate that there is improved neurite outgrowth when combined with chol-Cl or PC, and that this effect is present over a range of DHA concentrations and also in the presence of EPA as the ω-3FA.

[0600] Example 4 - BA promotes neurite outgrowth in PC12 cells in a dose-dependent proportional effect

[0601] For PC12 neuronal cell cultures and measurement of neurite outgrowth by immunohistochemistry and imaging, refer to Example 1.

[0602] Nutrient Supplementation

[0603] The nutrient supplementation effect of butyrate (BA) in neuronal cell cultures was evaluated by comparing different concentrations of BA (12.5 μM, 25 μM, 50 μM, 100 μM and 200 μM) with vehicle control (0 μM). Cells were supplemented in 96-well plates in 6 replicates. These conditions were compared with unsupplemented cells.

[0604] result

[0605] Image analysis of neurite outgrowth indicated that BA supplementation increased neurite outgrowth in a dose-dependent manner. The results are depicted in Figure 7 middle.

[0606] A dose response effect was observed, with the strongest effect on neurite outgrowth being observed at 200 μM BA concentration.

[0607] Example 5 - Synergistic effects between DHA, B2, D3, PC and BA on neurite outgrowth in PC12 cells

[0608] For PC12 neuronal cell cultures and measurement of neurite outgrowth by immunohistochemistry and imaging, refer to Example 1.

[0609] Nutrient Supplementation

[0610] The effects of nutrient supplementation with BA, B2, DHA, D3 and PC alone and in combination were evaluated in neuronal cultures by comparison with vehicle control. The concentrations of BA, B2, DHA, D3 and PC were 200 μM, 0.25 μM, 2.5 μM, 0.25 μM and 20 μM, respectively.

[0611] Several conditions were studied and PC12 cells were supplemented with:

[0612] (1) BA only

[0613] (2) B2 only

[0614] (3) DHA only

[0615] (4) D3 only

[0616] (5) PC only

[0617] (6) DHA+B2+D3

[0618] (7) BA+DHA+B2+D3

[0619] (8) PC+DHA+B2+D3

[0620] (9) BA+PC+DHA+B2+D3

[0621] Cells were supplemented in 96-well plates in six replicates and these conditions were compared to unsupplemented cells.

[0622] result

[0623] Image analysis of neurite outgrowth showed that in an in vitro PC12 neuronal cell model, supplementation with BA, DHA, and PC alone increased neurite outgrowth more than supplementation with vitamin B2 and D3 alone compared to the control. Neurite outgrowth is expressed as a percentage relative to the control (100%). The results are depicted in Figure 8 middle.

[0624] Unexpectedly, the nutrient combination supplements the effect of neurite outgrowth and produces a greater effect than the sum of the individual effects of the nutrient. The combination of DHA with B2 and D3 (condition (6)) produces a synergistic effect on neurite outgrowth (the average neurite outgrowth calculated or expected is 132.4, and the average neurite outgrowth observed is 138.3). When the nutrient of the latter condition is combined with BA, even other synergistic effects (condition (7) are observed; the average neurite outgrowth calculated or expected is 146.6, and the average neurite outgrowth observed is 149.2). When PC is supplemented together with DHA, B2 and D3, similar effects (condition (8) are observed; the average neurite outgrowth calculated or expected is 143, and the average neurite outgrowth observed is 152.8). Supplementation of PC12 cells with all five components together increased neurite outgrowth more than predicted based on the individual components, indicating a synergistic effect between BA+DHA+PC+B2+D3 (condition (9); calculated or expected mean neurite outgrowth of 157.2, observed mean neurite outgrowth of 1).

[0625] Overall, the results indicate that the combination of DHA, B2 and D3 synergistically increased neurite outgrowth, and this also held true when PC and / or BA were added to the combination.

[0626] Example 6 - Tube Feed Formulation

[0627] An exemplary enteral tube feed is formulated containing 128 kcal per 100 ml and 4.88 g protein, 4.5 g lipid and 9.3 g carbohydrate per 100 kcal. The tube feed contains ingredients according to Table 1 and is intended for administration to a patient via tube during recovery after suffering a neurotrauma or after being diagnosed with a neurodegenerative disease.

[0628] unit Nutrients Per 100kcal μg Vitamin D3 2.08 g DHA 0.03 g EPA 0.008 mg choline 36.67 mg Short chain GOS 887 mg Long chain FOS 97.5 mg Low viscosity pectin 195 mg magnesium 24.7 μg selenium 7.5 μg RE Vitamin A 85.71 mgα-TE Vitamin E 2.32 mg Thiamine 0.16 mg Riboflavin 0.24 mg Niacin (equivalent) 1.29 mg Pantothenic acid 0.42 mg Vitamin B6 0.25 μg Folic acid 24.24 μg Vitamin B12 0.60 μg Biotin 2.91 mg Vitamin C 18.17 g Phospholipids 0.20

[0629] Example 7 - Oral Nutritional Supplement

[0630] An exemplary oral nutritional supplement was formulated containing 240 kcal per 100 ml and 6 g protein, 3.89 g lipid and 9.57 g carbohydrate per 100 kcal. The nutritional supplement contained ingredients according to Table 2 and was used to be administered as a drink to a patient during recovery after suffering a neurological trauma or after being diagnosed with a neurodegenerative disease.

[0631] unit Nutrients Per 100kcal μg Vitamin D3 3.33 g DHA 0.08 g EPA 0.02 mg choline 33.33 mg Short chain GOS 937 mg Long chain FOS 104 mg Low viscosity pectin 208 mg magnesium 58.3 μg selenium 13 μg RE Vitamin A 125 mgα-TE Vitamin E 4.17 mg Thiamine 0.3 mg Riboflavin 0.4 mg Niacin (equivalent) 1.29 mg Pantothenic acid 0.42 mg Vitamin B6 0.30 μg Folic acid 66.67 μg Vitamin B12 1 μg Biotin 3.5 mg Vitamin C 31.67 g Phospholipids 0.33

Claims

1. A nutritional composition for use in the treatment of neurodegenerative diseases and / or neurotrauma and / or cerebral palsy, the nutritional composition comprising a therapeutically effective combination of: vi) omega-3 fatty acids; vii) vitamin B2; and viii) Vitamin D3, Wherein the omega-3 fatty acids comprise at least DHA.

2. The nutritional composition for use according to claim 1, wherein the composition further comprises one or more selected from the following: ix) choline or a salt thereof and / or phosphatidylcholine; and x) dietary fiber and / or dietary butyrate.

3. A nutritional composition according to claim 2, wherein at least 40 mol% of choline is provided in the form of phosphatidylcholine, preferably the molar ratio of choline or a salt thereof to PC is in the range of 40:60 to 60:

40.

4. The nutritional composition for use according to any one of claims 1 to 3, further comprising one or more components selected from vitamins A, C and E, phospholipids, selenium, magnesium and additional B vitamins.

5. Nutritional composition for use according to any one of the preceding claims, wherein the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, frontotemporal dementia and dementia with Lewy bodies.

6. The nutritional composition for use according to any of the preceding claims, wherein the treatment of a neurodegenerative disease relates to treating and / or preventing and / or delaying symptoms associated with said neurodegenerative disease in a subject suffering from said neurodegenerative disease or wherein a prodromal phase of said neurodegenerative disease has been diagnosed in said subject, preferably wherein these symptoms relate to one or more of the following: - Cognitive decline associated with memory loss, reduced attention span, decreased executive function, and impaired ability to perform activities of daily living; and / or - Motor symptoms related to tremor, rigidity, bradykinesia, coordination and balance; and / or - Behavioral and psychological changes associated with depression, anxiety, irritability, fatigue, emotional apathy, social withdrawal, and mood swings; and / or - sensory disturbances associated with loss of sensation, numbness, tingling, or altered perception of touch, pain, or temperature; and / or - Sleep disturbances associated with insomnia, excessive daytime sleepiness, sleep fragmentation, restless legs syndrome, and rapid eye movement (REM) sleep behavior disorder; and / or -Autonomic dysfunction associated with orthostatic hypotension, urinary problems, incontinence, constipation, sweating, and changes in temperature regulation.

7. The nutritional composition for use according to claim 1, wherein the neurological injury is selected from the group consisting of traumatic brain injury (TBI), spinal cord injury (SCI) and peripheral nerve injury.

8. The nutritional composition for use according to claim 7, wherein the nerve trauma is caused by one or more external factors selected from the group consisting of: - Occupational hazards, including automotive, sports and workplace accidents; - Explosion and blast damage; -electric shock; - Blunt force trauma; - Penetrating injuries involve external objects, including bullets or sharp objects, penetrating into the brain, spinal cord, or peripheral nerves.

9. A nutritional composition for use according to any one of claims 1 to 8, wherein the treatment of a neurodegenerative disease involves an increase in the outgrowth of neurites in a subject suffering from the neurodegenerative disease and treated with the composition, compared to a subject suffering from the neurodegenerative disease and not treated with the composition, and / or wherein the treatment of neural trauma involves an increase in the length of the outgrowth of neurites in a subject suffering from the neural trauma and treated with the composition, compared to a subject suffering from the neural trauma and not treated with the composition.

10. The nutritional composition for use according to any of the preceding claims, wherein the composition is used daily for at least 4 weeks after diagnosis of the neurodegenerative disease and / or after diagnosis or occurrence of the neurotrauma.

11. A nutritional composition for use according to any one of the preceding claims, wherein the composition comprises a daily dose of: vi) 150 to 1200 mg, preferably 200 to 1100 mg, more preferably 250 to 1000 mg of DHA per day; vii) 0.8 to 7.6 mg, preferably 1 to 7.4 mg, more preferably in the range of 1.2 to 7.2 mg of vitamin B2; viii) 6 to 75 μg, preferably 8 to 70 μg, more preferably 10 to 65 μg of vitamin D3; and optionally ix) 200 to 1400 mg, preferably 300 to 1200 mg, more preferably 350 to 1100 mg of choline, based on the molar weight of choline, wherein the choline is selected from free choline, choline salts and / or choline esters, preferably at least phosphatidylcholine; and / or x) 2.5 to 12.5 g, preferably 3 to 12 g, more preferably 3.5 to 11.5 g of dietary fiber and / or 0.125 g to 0.65 g, preferably 0.025 g to 0.65 g, more preferably 0.043 g to 0.65 g of dietary butyric acid.

12. The nutritional composition for use according to any one of the preceding claims, wherein the nutritional composition is a liquid nutritional composition, preferably wherein the nutritional composition is an oral nutritional supplement or a tube feed.

13. A liquid nutritional composition comprising a combination of: iv) DHA; v) Vitamin B2; vi) Vitamin D3; and optionally one or more of the following: iv) choline or a salt thereof and / or phosphatidylcholine; and v) dietary fiber and / or dietary butyrate.

14. The liquid nutritional composition according to claim 13, wherein the composition comprises per 100 kcal: vi) 20 to 100 mg, preferably 25 to 90 mg, more preferably 30 to 80 mg DHA; vii) 0.4 to 0.6 mg vitamin B2; viii) 1.3 to 4.5 μg vitamin D3; and optionally further comprises: ix) 100 to 1000 mg, preferably 200 to 800 mg, more preferably 300 to 500 mg choline or a salt thereof and / or phosphatidylcholine; and / or x) 0.75 to 2.5 g, preferably 1.0 to 2.0 g, more preferably 1.1 to 1.5 g dietary fiber and / or 0.015 to 0.25 g, preferably 0.03 to 0.25 g, more preferably 0.05 to 0.25 g dietary butyric acid.

15. Liquid nutritional composition according to claim 13 or 14, wherein the composition additionally comprises 4 to 7 g protein / 100 kcal, 3 to 5.5 g lipid / 100 kcal and 8.5 to 10.5 g carbohydrate / 100 kcal.

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